8. Palliative Therapy of Pancreatic Cancer – Pancreatic Cancer
8.1 Introduction
Since the studies by Mallinson [617], Palmer [618] and Glimelius [619], chemotherapy in the palliative setting has been shown to be superior to purely supportive therapy in terms of patient survival and quality of life. This was also confirmed in a Cochrane analysis [620].
Standard options in first-line therapy of advanced or metastatic pancreatic cancer are FOLFIRINOX and gemcitabine+nab-paclitaxel. In patients with reduced general condition, monotherapy with gemcitabine is also well established [621]. The PARP inhibitor olaparib represents the first molecularly targeted treatment option as maintenance therapy for the small subgroup of patients with BRCA-1/2 germline mutations after at least 16 weeks of platinum-based pretreatment. All patients should be offered the option of second-line therapy whenever possible.
The value of radiotherapy after prior chemotherapy, according to current knowledge, lies primarily in prolonged local tumor control. Phase III studies demonstrating a survival benefit in this constellation are not available [589].
8.2 Indication for Chemotherapy
Systemic therapies in the first and second line
In metastatic or locally advanced pancreatic cancer, palliative chemotherapy shall be offered to patients with an ECOG Performance Status of 0 to 2 to improve quality of life, clinical benefit and survival.
- Recommendation grade
- A: Starke Empfehlung für oder gegen ein Maßnahme - verwendete Ausdrucksweise = soll/soll nicht
- Level of evidence
- 5
- Consensus
- Strong consensus
- References
- [622]
Background
Chemotherapy prolonged survival in metastatic or locally advanced pancreatic cancer in a meta-analysis (HR 0.64, 95% CI 0.42-0.98) [623]. In individual studies, it also improved quality of life [619], [624], [623], [625] and led to clinical benefit, i.e., in particular, reduced analgesic use and weight loss [617], [618], [619], [624], [625].
Chemotherapy should be started immediately upon detection of metastases. Tumor size progression, symptoms or other complications should not be awaited.
Patients with locally advanced, unresectable pancreatic cancer should also be treated from the time of diagnosis, as they derive similar benefit from chemotherapy as patients with metastatic pancreatic cancer [624], [626], [627], [628], [629]. In this subgroup, regular evaluation of secondary resectability by an experienced surgeon is recommended.
In patients in poor general condition (Karnofsky index <70%, ECOG Performance Status > 2), the benefit of chemotherapy is questionable [530], [626], [627], [630], [631]. However, if the reduced Performance Status is due to advanced tumor disease, chemotherapy for symptom control may be considered in individual cases.
There are no data defining the optimal duration of tumor therapy in metastatic pancreatic cancer. Therefore, the duration of treatment is based on tolerability and treatment goals.
- Level of evidence
- 5
- Consensus
- Strong consensus
Background
Advanced and metastatic pancreatic cancer is such an aggressive disease that the continuation of systemic therapy is recommended as long as both the efficacy of the treatment can be proven and there is sufficient tolerance and motivation on the part of the patient.
In this context, reference is made to the randomized Unicancer/PRODIGE trial (FOLFIRINOX vs gemcitabine), which recommends a chemotherapy duration of 6 months in case of response. With this approach, an OS of 11.1 months has been achieved in the FOLFIRINOX arm and 6.8 months in the gemcitabine arm [596].
Various chemotherapy regimens can be used in the first-line treatment of advanced or metastatic pancreatic cancer. These include the combination regimens FOLFIRINOX, gemcitabine+nab-paclitaxel and gemcitabine+erlotinib as well as monotherapy with gemcitabine.
The choice of the optimal therapeutic regimen is primarily based on ECOG Performance Status, comorbidity and patient preference.
- Level of evidence
- 5
- Consensus
- Strong consensus
- References
- [622]
Background
The choice of the optimal therapy regime is made after a thorough analysis of several levels: it is important to clarify the therapeutic goal, which must first be defined in a multidisciplinary tumor board and subsequently agreed on with the patient. Patient preference after detailed information plays a central role. However, other important parameters guiding the decision are also the patient's comorbidity profile and psychosocial status, the symptomatology of the disease and the treatment environment.
Patients with ECOG Performance Status 0-1 benefit from combination chemotherapies. These patients should be offered combination therapies in first- and second-line therapy. In contrast, patients with an ECOG performance status ≥ 2 should rather be treated with monotherapy. In any case, patients shall have early access to supportive treatment options.
- Recommendation grade
- B: Empfehlung für oder gegen eine Maßnahme - verwendete Ausdrucksweise = sollte/sollte nicht
- Level of evidence
- 5
- Consensus
- Strong consensus
- References
- [622]
Background
The relevance of ECOG Performance Status (PS) to the choice of optimal systemic therapy for advanced or metastatic pancreatic cancer was evaluated in a meta-analysis of 5 randomized trials (1682 patients). These trials compared gemcitabine-based combination therapy with gemcitabine monotherapy. This meta-analysis showed that patients with good Performance Status (ECOG PS 0-1) benefited from treatment with gemcitabine-based combination therapy in terms of overall survival (HR 0.76; 95% CI 0.67–0.87; p<0.0001). In contrast, patients with poorer Performance Status (ECOG PS > 1) did not benefit from combination therapy (HR 1.08; 95% CI 0.90–1.29, p=0.40) [634].
The Unicancer and PRODIGE Intergroup study also confirmed a significant benefit of FOLFIRINOX combination chemotherapy compared with gemcitabine monotherapy in patients with metastatic pancreatic cancer and good Performance Status (ECOG PS 0-1) and normotensive bilirubin (≤ 1.5 ULN) [596].
For the combination of nab-paclitaxel+gemcitabine, a significant survival benefit compared to gemcitabine monotherapy was demonstrated in a global phase III study (MPACT) in patients with metastatic pancreatic cancer with good Performance Status (Karnofsky index 70-100%) and with normal bilirubin levels [635]. A subgroup analysis of the MPACT trial showed a benefit of combination therapy with gemcitabine+nab-paclitaxel compared to gemcitabine monotherapy for both a Karnofsky Performance Status of 70-80 (HR 0.61) and a score of 90-100 (HR 0.75). Safety and efficacy of this treatment in ECOG Performance Status 2 were further confirmed by a phase I/II study [598].
Patients with an ECOG Perfomance Status of 2 and higher remission pressure (symptomatic disease) may also be offered combination therapy with dose-reduced nab-paclitaxel (100mg/m² instead of 125mg/m² weekly) and gemcitabine [598] [see Evidence Table: Evidence Level 2] or a combination of gemcitabine with erlotinib as an alternative to gemcitabine monotherapy in the absence of clinically relevant comorbidity [632].
There is insufficient data to support the need to use the numerical age of patients to make a treatment decision. Rather, factors such as biological age, organ function and patient motivation are of primary importance in the assessment of treatment eligibility. In this context it can be pointed out that an age limit of ≥ 76 years had been set for the PRODIGE trial (FOLFIRINOX vs. gemcitabine) [596]. This fact indicates that the published data from the PRODIGE trial are for patients 18-75 years of age. However, the study record does not indicate that older patients should not be treated with this regimen. In contrast, the MPACT trial (gemcitabine+nab-paclitaxel vs gemcitabine) did not specify an age limit. Accordingly, patients in this trial ranged in age from 27-88 years [633].
The "APC-SAKK Toxicity Score" was developed as a predictor of adverse events during palliative gemcitabine-based therapy [636]. This score includes four variables (bilirubin, renal function, WBC and ALP) and was recommended by the authors as easily applicable clinically [636].
8.3 Monochemotherapy
When patients with advanced or metastatic pancreatic cancer receive monochemotherapy, gemcitabine is preferable to 5-FU monotherapy.
- Recommendation grade
- A: Starke Empfehlung für oder gegen ein Maßnahme - verwendete Ausdrucksweise = soll/soll nicht
- Level of evidence
- 5
- Consensus
- Strong consensus
- References
- [622]
8.3.1 Gemcitabine Monotherapy
Monotherapy with gemcitabine should be offered to patients who cannot tolerate or do not prefer combination therapy due to ECOG Performance Status 2 and/or their comorbidity profile.
- Recommendation grade
- B: Empfehlung für oder gegen eine Maßnahme - verwendete Ausdrucksweise = sollte/sollte nicht
- Level of evidence
- 5
- Consensus
- Strong consensus
Background
Extensive experience from numerous phase III studies is available for gemcitabine monotherapy [596], [621], [637], [632], [633], [638]. The 1-year survival rates for gemcitabine therapy are 18-20% [637].
Gemcitabine was approved for the treatment of advanced pancreatic cancer based on a randomized trial comparing weekly gemcitabine (1000 mg/m²) therapy with 5-fluorouracil bolus treatment [621]. Gemcitabine was shown to be superior to 5-FU bolus with respect to the newly defined parameter "clinical benefit response", which included analgesic consumption, pain intensity, body weight, and Karnofsky Performance Status (23.8% vs. 4.8%, p=0.0025) and also significantly longer survival (5.65 months vs. 4.41 months, p=0.0025). Gemcitabine is predominantly well tolerated. The most common grade III/IV adverse events include neutropenia (25.9%), leukopenia (9.7%), thrombocytopenia (9.7%), and anemia (6.5%) [621].
Gemcitabine is recommended with only a weak recommendation (recommendation level B) despite convincing proof of benefit because, for example, FOLFIRINOX or nabPaclitaxel+Gemcitabine may be more effective therapies in certain patient groups. A quality-of-life analysis in the CALGB 80303 trial (gemcitabine+bevacizumab vs. gemcitabine+placebo) failed to demonstrate that response to gemcitabine treatment was associated with improvement in quality of life. In this study, health-related quality of life (HRQOL) was evaluated using the EQ-5D [639].
Gemcitabine monotherapy should therefore be used preferentially in those patients in whom a reduced general condition (ECOG PS ≥2) or clinically relevant comorbidity prevent the use of more intensive chemotherapy. In this constellation, the combination of gemcitabine with erlotinib may also be considered [207].
Patients with ECOG performance status ≥ 3 or with poorly controlled comorbidity can receive tumor-specific therapies on a case-by-case basis if oncologic treatment is continued.
- Recommendation grade
- 0: offene Empfehlung (Option) bzgl. einer Maßnahme - verwendete Ausdrucksweise = kann
- Level of evidence
- 5
- Consensus
- Strong consensus
- References
- [207]
Background
There is insufficient evidence supporting the benefit of tumor therapy in ECOG Performance Status ≥ 3 or in the presence of unmanaged comorbidity. In individual cases, patient preference takes a central role in treatment decisions [207]. In addition, supportive therapy is the main focus. Exceptions are those patients in whom a decisive improvement in ECOG Performance Status is expected as a result of effective tumor therapy. In any case, supportive therapy and palliative care should be included in these patients at an early stage.
Gemcitabine shall be administered at conventional doses (1000mg/m² over 30 minutes).
- Recommendation grade
- A: Starke Empfehlung für oder gegen ein Maßnahme - verwendete Ausdrucksweise = soll/soll nicht
- Level of evidence
- 2
- References
- [640]
Background
Conventional dosing of gemcitabine (1000 mg/m² as a weekly 30-minute infusion x7 with a 1-week break or thereafter for 3 weeks with a 1-week break) was tested in both the pivotal study [621] and several phase III studies [207], [596], [637], [632], [633], [638], [640], [641], [642], [643].
A randomized phase III trial of gemcitabine as a "fixed dose rate" infusion, using a higher dose and infusing gemcitabine over a longer period of time (1500 mg/m² for 150 min. every 2 weeks) did not result in significantly longer survival compared to conventional therapy [640]. Accordingly, there is no indication for the administration of gemcitabine as a "fixed dose-rate" infusion. The initial gemcitabine regimen published by Burris et al. [621] (1000mg/m² over 30 minutes intravenously) is therefore considered the established standard.
8.3.2 5-FU Monotherapy
5-FU with or without folic acid shall not be used as a sole first-line therapy.
- Recommendation grade
- A: Starke Empfehlung für oder gegen ein Maßnahme - verwendete Ausdrucksweise = soll/soll nicht
- Level of evidence
- 2
- Consensus
- Strong consensus
- References
- [621]
Background
The pivotal study by Burris et al. showed clear inferiority of a 5-FU bolus regimen compared with gemcitabine monotherapy [621]. In Asian patients, noninferiority of oral fluoropyrimidine S1 compared with gemcitabine is supported [644]. A randomized phase II study supports the recommendation to administer S1 as part of a daily regimen (rather than every other day) [645].
8.4 Combination Therapies
8.4.1 5-FU-based Combination Chemotherapies
8.4.1.1 FOLFIRINOX and NALIRIFOX*
FOLFIRINOX or NALIRIFOX* shall be offered to patients with metastatic pancreatic cancer if the following criteria are met: ECOG performance status of 0-1, favorable comorbidity profile, patient preference, adequate options for supportive therapy.
* off label use
Background
A large randomized trial demonstrated a clear advantage of the FOLFIRINOX regimen compared to gemcitabine [596]. Important inclusion criteria in this study included ECOG Performance Status 0-1, bilirubin ≤ 1.5 times upper normal value and age < 76 years. In patients with metastatic pancreatic cancer, median survival was increased from 6.8 to 11.1 months (HR 0.57; p<0.001). Similarly, compared with gemcitabine, administration of the FOLFIRINOX protocol improved progression-free survival from 3.3 to 6.4 months (HR 0.47, p<0.001) and response rate from 9.4% to 31.6% (p<0.001) [625].
The clinically relevant benefit is counterbalanced by a significantly higher toxicity of the FOLFIRINOX regimen, reflected in an increase in the rate of grade III/IV neutropenia (45.7% vs. 21.0%), febrile neutropenia (5.4% vs. 1.2%), and grade III/IV diarrhea (12.7% vs. 1.8%) compared to gemcitabine. In the study, therapy was temporarily paused at grade II neutropenia or thrombocytopenia and dose was adjusted according to the study criteria ([647], Appendix online).
G-CSF was given in 42.5% of patients treated with FOLFIRINOX and in 5.3% of patients treated with gemcitabine (p<0.001). Because of the relatively low rate of febrile neutropenia (5.4%), general primary G-CSF prophylaxis was not recommended. Despite the treatment-associated adverse events, fewer patients in the FOLFIRINOX group experienced worsening quality of life (QoL) 6 months after initiation of therapy than in the gemcitabine group (31% vs. 66%; HR 0.47 p<0.001) [596]. The significant reduction in QoL worsening by FOLFIRINOX was later confirmed in a more detailed analysis [648].
The efficacy data from the phase III study of FOLFIRINOX are confirmed by several phase II studies and cohort analyses [649]. A meta-analysis of the use of FOLFIRINOX in locally advanced pancreatic cancer showed a median survival of 24.2 months in 315 evaluable patients, which was significantly longer than has been reported for gemcitabine therapy in this patient population (6-13 months) [608].
However, not every patient can be expected to receive a full-dose FOLFIRINOX regimen. Several studies and meta-analyses of modified FOLFIRINOX regimens indicate good efficacy with better tolerability [608], [650]. The tolerability of the modified FOLFIRINOX regimen and its feasibility over a median duration of 12 cycles has also been demonstrated in the adjuvant treatment of pancreatic cancer [528]. This modified FOLFIRINOX regimen is given with an irinotecan dose reduced from 180 mg/m² to 150 mg/m² and without the 5-FU bolus.
In summary, FOLFIRINOX is a highly effective treatment option that can be safely administered with careful attention to indication and with assurance of adequate supportive therapy. Treatment with FOLFIRINOX should therefore be offered primarily to patients with a good ECOG Performance Status of 0-1, favorable comorbidity profile, and a stated preference in first-line therapy [128], [207]. While there should be no categorical age restriction, it is important to note that the recommendation is based on a phase III study in which only patients younger than 76 years of age were studied [596].
In the NAPOLI-3 study, a randomized phase III study, NALIRIFOX was compared with gemcitabine/nab-paclitaxel and showed a significant survival benefit with a median overall survival of 11.1 months (95% CI 10.0-12.1) vs. 9.2 months (95% CI 8.3-10.6) with gemcitabine/nab-paclitaxel. The incidence of peripheral neuropathy was lower in the NALIRIFOX group (3.2%) than in the nab-paclitaxel group (5.8%). The most common grade 3-4 side effects of NALIRIFOX were neutropenia, hypokalemia, diarrhea and nausea [Wainberg, ZA et al. 2023].
8.4.1.2 Other 5-FU-based Combination Chemotherapies
Several phase III trials tested 5-fluorouracil-based combination chemotherapies. Neither 5-FU/mitomycin-C [651] nor 5-FU/gemcitabine/epirubicin/cisplatin (PEGFG ) [652], nor 5-FU/cisplatin [653], [654] have found their way into routine clinical practice due to poor efficacy data [655].
In addition, the FIRGEM regimen and the combination of 5-FU/leucovorin and nab-paclitaxel have most recently been studied in randomized phase II trials. Both regimens show clinically relevant efficacy data.
FIRGEM regimen
In the FIRGEM trial, FOLFIRI.3 (5-FU, leucovorin, irinotecan) alternating with gemcitabine (fixed-dose rate) was compared with gemcitabine monotherapy (fixed-dose rate) in 98 patients in a 1:1 randomization [656]. The 6-month PFS (primary endpoint) was 43.5% in the experimental arm (arm A) and 26.1% in the gemcitabine arm (arm B). Response rates were 37% vs. 10%. Both median PFS (5.0 vs. 3.4 months, HR 0.59 and median OS (11.0 vs. 8.2 months, HR 0.71) were longer in arm A compared with arm B. The most common grade III-IV adverse events included neutropenia (49% vs 24%), febrile neutropenia, (4% vs 0%) and diarrhea (12% vs 0%).
5-FU/leucovorin plus nab-paclitaxel
The AFUGEM GERCOR trial compared gemcitabine+nab-paclitaxel with 5-FU+leucovorin+nab-paclitaxel in first-line metastatic pancreatic cancer. A total of 114 patients were enrolled in the randomized trial (1:2 randomization). The 4-month PFS (primary endpoint) was 56% in the experimental arm and 54% in the gemcitabine+nab-paclitaxel arm. PFS (5.9 vs. 4.9 months) and OS was numerically longer with treatment with 5-FU+leucovorin+nab-paclitaxel compared with gemcitabine+nab-paclitaxel (11.4 vs. 9.2 months). The most common grade III-IV adverse events were neutropenia (without fever) (23% vs. 32%), fatigue (22% vs. 21%) and paraesthesia (19% vs. 11%) [657].
8.4.2 Gemcitabine-based Combination Therapies
Gemcitabine-based combination therapies can be used in patients who do not tolerate or do not prefer FOLFIRINOX or NALIRIFOX.
- Recommendation grade
- 0: offene Empfehlung (Option) bzgl. einer Maßnahme - verwendete Ausdrucksweise = kann
- Level of evidence
- 5
- Consensus
- Strong consensus
- References
- [622]
Background
The survival gain from combination therapy must be balanced with the increased side effects that occur with this treatment and the patients' existing comorbidities. Some gemcitabine-based combination therapies have also been studied in patients with an ECOG less than or equal to 2, in contrast to FOLFIRINOX and NALIRIFOX, which have been studied almost exclusively with an ECOG of 0-1 [658], [128], [Chin, V. et al. 2018], [633].
8.4.2.1 Combination of Gemcitabine and nab-Paclitaxel
The combination of gemcitabine with nab-paclitaxel shall be offered to patients when the following criteria are met: ECOG Performance Status 0-1, relatively favorable comorbidity profile, patient preference, adequate supportive therapy.
- Recommendation grade
- A: Starke Empfehlung für oder gegen ein Maßnahme - verwendete Ausdrucksweise = soll/soll nicht
- Level of evidence
- 5
- Consensus
- Strong consensus
- References
- [207]
Background
Nab-paclitaxel is an albumin-bound nanoparticle formulation of paclitaxel. The superiority of gemcitabine/nab-paclitaxel compared with gemcitabine monotherapy was confirmed in a randomized phase III trial (MPACT) [633]. Important inclusion criteria were a Karnofsky Performance Status ≥ 70 and bilirubin ≤ upper normal value. Thereby, gemcitabine + nab-paclitaxel achieved a highly significant prolongation of overall survival (8.5 vs. 6.7 months; HR 0.72, p<0.001), which was investigated as the primary study endpoint. In addition, a significant increase in response rate (independent review: 23% vs. 7%; p<0.001) and progression-free survival (5.5 months vs. 3.7 months; HR 0.69, p<0.001) was observed.
As expected, the higher efficacy of the combination was accompanied by a higher rate of adverse events compared with gemcitabine monotherapy, which particularly affected grade III/IV rates of neutropenia (38% vs. 27%), neuropathy (17% vs. 1%) and diarrhea (6% vs. 1%) [633]. Gemcitabine+nab-paclitaxel is approved for use in the first-line treatment of metastatic pancreatic cancer. The MPACT trial included patients with a Karnofsky performance status KPS ≥ 70. Accordingly, patients with an ECOG Performance Status 0-2 can be treated [128], [635].
A phase II study demonstrated the safety and efficacy of a nab-paclitaxel dose of 100 mg/m² and 125 mg/m² in combination with gemcitabine (application on days 1, 8, 15 every week) in patients with ECOG Performance Status 2 [598].
8.4.2.2 Combination of Gemcitabine with Fluoropyrimidines
The combination of gemcitabine with fluoropyrimidines such as 5-fluorouracil, capecitabine or S1 is not a standard of care in the first-line treatment of metastatic or locally advanced unresectable pancreatic cancer.
- Recommendation grade
- B: Empfehlung für oder gegen eine Maßnahme - verwendete Ausdrucksweise = sollte/sollte nicht
- Level of evidence
- 1
- Consensus
- Strong consensus
- References
- [655] [660]
Evidence tables (2)
Li, Q. et al. Efficacy and safety of gemcitabine-fluorouracil combination therapy in the management of advanced pancreatic cancer: A meta-analysis of randomized controlled trials. PLoS ONE. 9. e104346. 2014; Tu, C. et al. An Updated Meta-analysis and System Review:is Gemcitabine+Fluoropyrimidine in Combination a Better Therapy Versus Gemcitabine Alone for Advanced and Unresectable Pancreatic Cancer?. Asian Pacific journal of cancer prevention : APJCP. 16. 5681-5686. 2015Background
The combination of gemcitabine with fluoropyrimidines such as 5-FU [661], [662], capecitabine [638], [642], [663], S1 [664], [665], [666] has been tested in randomized phase III trials. In a meta-analysis of 8 randomized trials (2,126 patients), the combination of gemcitabine with a fluoropyrimidine was shown to significantly improve OS (HR 0.83, p<0.01) and tumor response rate (OR 0.51, p<0.01) compared with gemcitabine monotherapy. The 1-year OS rate was also significantly increased with combination therapy with a fluoropyrimidine (OR 0.78, p=0.01) [660]. Another meta-analysis attested that the combination of gemcitabine plus fluoropyrimidine had a moderate improvement in survival with higher toxicity [655]. The combination of gemcitabine plus S1 was not found to be superior to gemcitabine monotherapy in Asian patients in a randomized phase III trial [644].
8.4.2.3 Other Gemcitabine-based Combination Chemotherapies
The combination of gemcitabine with oxaliplatin, cisplatin, cisplatin/epirubicin/5-FU, pemetrexed, docetaxel or exatecan is not a standard of care in the first-line treatment of metastatic or locally advanced unresectable pancreatic cancer.
- Recommendation grade
- B: Empfehlung für oder gegen eine Maßnahme - verwendete Ausdrucksweise = sollte/sollte nicht
- Level of evidence
- 1
- Consensus
- Strong consensus
- References
- [659]
Background
The combination of gemcitabine with irinotecan [667], [668], oxaliplatin [669], [640], cisplatin [670], [641], cisplatin/epirubicin/5-FU [652], pemetrexed [671], exatecan [672] or docetaxel/cisplatin [673] has been tested in randomized phase III trials. None of these trials demonstrated a statistically significant survival benefit for gemcitabine-based combination chemotherapy compared with gemcitabine monotherapy.
However, there are subgroup analyses from several studies suggesting that patients with good Performance Status (Karnofsky index ≥ 90% or ECOG 0–1) can benefit from gemcitabine-based combination therapies [634], [642]. However, a significant survival benefit has only been shown in meta-analyses [637], [634], [674]. This assumption applies to the gemcitabine/oxaliplatin and gemcitabine/capecitabine combinations. The publication of a randomized Italian phase III trial of the gemcitabine/cisplatin combination, which showed no advantage of the combination over gemcitabine monotherapy in patients with good Performance Status, puts the therapeutic benefit of these gemcitabine-containing combination chemotherapies into perspective [641]. A survival benefit was also not shown in a meta-analysis [659].
However, the combination of gemcitabine with cisplatin may represent a treatment option for the subgroup of patients with BRCA-mutated pancreatic cancer, especially if contraindications to the FOLFIRINOX regimen are present (see 8.6)
8.5 Molecular Biology Targeted Therapies
8.5.1 Gemcitabine/Erlotinib
As an alternative to gemcitabine monotherapy, a combination therapy of gemcitabine and the EGF receptor tyrosine kinase inhibitor erlotinib can be used in metastatic pancreatic cancer.
- Recommendation grade
- 0: offene Empfehlung (Option) bzgl. einer Maßnahme - verwendete Ausdrucksweise = kann
- Level of evidence
- 5
- Consensus
- Strong consensus
- References
- [207]
Background
Erlotinib is an oral EGFR tyrosine kinase inhibitor approved in combination with gemcitabine for the treatment of pancreatic cancer. In the PA.3 trial, the combination of gemcitabine plus erlotinib (100 mg per day) achieved a statistically significant increase in progression-free survival (HR 0.77; p=0.004) and overall survival (HR 0.82; p=0.038) compared to gemcitabine monotherapy. Given the rather modest improvement in median survival in the intent-to-treat analysis (6.24 months vs. 5.91 months), the clinical significance of this study and subsequent erlotinib-based trials is assessed with caution [632], [675].
However, patients who develop acneiform skin exanthema on combination therapy with erlotinib show a substantial survival benefit (HR 0.74; p=0.037) [676], [677]. In the PA.3 study, 72% of the 282 patients studied developed skin exanthema. For grade ≥ II skin exanthema, median survival was 10.5 months compared with 5.8 months for grade I or 5.3 months for grade 0 (p<0.001) [632]. The adverse event profile of the gemcitabine and erlotinib combination in the trial was comparable to that of gemcitabine, except for a higher rate of grade III/IV diarrhea (6% vs. 2%) and incidence of skin rash (all grades: 72% vs. 29%) [632].
The LAP07 trial was conducted in patients with locally advanced pancreatic cancer [589]. This randomized trial compared gemcitabine with gemcitabine/erlotinib and also evaluated the efficacy of chemoradiotherapy in a second randomization.
A meta-analysis of 24 trials showed an ORR of 14.4%; 95% CI 11.6–17.7%), PFS of 2.63 to 9.6 months, and OS of 6 to 10 months [675] in 1,742 patients with locally advanced or metastatic pancreatic cancer treated with gemcitabine/erlotinib.
The combination of gemcitabine plus erlotinib may be considered, particularly when more intensive and effective combination chemotherapies cannot be used. This recommendation is supported by a subgroup analysis of the PA.3 trial [632], which documented a more significant survival benefit for ECOG 2 patients than for ECOG 0/1 patients (HR 0.61; 95% CI 0.41-0.92 in ECOG 2 vs. HR 0.87; 95% CI 0.71-1.06 in ECOG 0/1). Because patients who do not develop exanthema predominantly do not benefit from combination therapy, in the absence of exanthema the indication for continued treatment with erlotinib should be strictly defined and a potential clinical benefit evaluated early (for example, after 8 weeks). In contrast, patients with skin rash benefit from continued treatment with erlotinib and achieve comparable overall survival to rash-negative patients after switching to FOLFIRINOX [678].
In the absence of a rash up to 8 weeks after initiation of therapy, erlotinib therapy should be discontinued.
Background
A skin rash with papulo-pustular acneiform efflorescences as well as the occurrence of paronychia are typical side effects of therapy with erlotinib. These efflorescences occur in varying degrees in approximately 50-70% of patients with metastatic pancreatic cancer. Subgroup analyses of two large studies on palliative therapy of pancreatic cancer with erlotinib [676], [632], [677] show that patients without recognizable skin reaction within 8 weeks after starting erlotinib do not benefit from the additional administration of this substance.
8.5.2 Gemcitabine plus other Molecularly Targeted Agents
Other combinations of gemcitabine with so-called “targeted therapies” such as cetuximab, bevacizumab, or axitinib have no value in the therapy of pancreatic cancer and shall not be used outside of prospective, controlled studies. These combinations are not recommended.
- Recommendation grade
- A: Starke Empfehlung für oder gegen ein Maßnahme - verwendete Ausdrucksweise = soll/soll nicht
- Level of evidence
- 1
- Consensus
- Strong consensus
- References
- [679] [680] [681]
Evidence tables (3)
Ciliberto, D. et al. Role of gemcitabine-based combination therapy in the management of advanced pancreatic cancer: a meta-analysis of randomised trials. Eur J Cancer. 49. 593-603. 2013; Eltawil, K. M. et al. Meta-analysis of Phase III randomized trials of molecular targeted therapies for advanced pancreatic cancer. HPB. . . 2012; Tong, M. et al. Efficacy and safety of gemcitabine plus anti-angiogenesis therapy for advanced pancreatic cancer: A systematic review and meta-analysis of clinical randomized phase III trials. Journal of Cancer. 10. 968-978. 2019Background
Molecularly targeted agents have been tested in numerous phase III trials in the treatment of advanced and metastatic pancreatic cancer [679], [682]. By adding these compounds to predominantly gemcitabine-based chemotherapy, no significant survival benefit was observed compared to chemotherapy alone in the majority of studies. This is true, among others, also for substances such as marimasat [683], tipifarnib [684], bevacizumab [685], bevacizumab+erlotinib [676], cetuximab [643], axitinib [686], sorafenib [687], aflibercept [688], ganitumab [689], masitinib [690], ruxolitinib [691], elpamotide [692], vandetanib [693], nimotuzumab [694], dasatinib [695], galunisertib [696] kanglaite [697], or LY2495655 [698]. Meta-analyses confirm this statement [681], [682].
Maintenance therapy with sunitinib was evaluated in a small randomized phase II trial in patients who did not have disease progression after 6 months of chemotherapy [699]. Confirmation of the efficacy of this treatment in the highly selected patient group has not occurred at the phase III level.
8.6 Therapy in Molecular Subgroups
8.6.1 BRCA1/2 Mutation
8.6.1.1 Platinum-based Therapy for BRCA 1/2 Mutation
In patients with evidence of a BRCA-1/2 germline mutation, platinum-based first-line therapy should be preferred.
- Recommendation grade
- B: Empfehlung für oder gegen eine Maßnahme - verwendete Ausdrucksweise = sollte/sollte nicht
- Level of evidence
- 2
and
4 - Consensus
- Strong consensus
- References
- [700] [137]
Evidence tables (2)
O'Reilly, E. M. et al. Randomized, Multicenter, Phase II Trial of Gemcitabine and Cisplatin With or Without Veliparib in Patients With Pancreas Adenocarcinoma and a Germline BRCA/PALB2 Mutation. J Clin Oncol. 38. 1378-1388. 2020; Park, W. et al. Genomic Methods Identify Homologous Recombination Deficiency in Pancreas Adenocarcinoma and Optimize Treatment Selection. Clin Cancer Res. 26. 3239-3247. 2020Background
Preclinical and clinical data indicate that gemcitabine and cisplatin are particularly effective in the presence of a BRCA1 or 2 mutation [701]. Tumor cells harboring BRCA or PALB2 mutations exhibit impaired DNA repair (homologous recombination deficiency) and are therefore sensitive to an increased degree to treatment with DNA crosslinkers such as cisplatin or DNA repair inhibitors such as gemcitabine.
The preclinical data are confirmed by a randomized phase II study [O'Reilly, E. M. et al. 2020], which was conducted in patients with pancreatic cancer and proven BRCA 1/2 or PALB2 germline mutation. This study tested the efficacy of gemcitabine/cisplatin ± veliparib in a randomized comparison in 50 patients. The study demonstrated the high efficacy of gemcitabine/cisplatin in gBRCA/PALB2 mutated patients, but failed to show a significant benefit of the addition of the PARP inhibitor in terms of response rate (74.1% vs. 65.2%, p=0.55), progression-free survival (10.1 vs. 9.7 months, p=0.73) or overall survival (15.5 vs. 16.4 months, p=0.6). The most common grade III/IV side effects of combination chemotherapy included anemia (35%) and neutropenia (30%).
The present data indicate the high efficacy of gemcitabine/cisplatin in patients with BRCA 1/2 and PALB2 germline mutations. Given the comprehensible mechanism of action, this combination should be considered as standard therapy even in the absence of phase III data in selected patients.
In the POLO trial, patients with gBRCA1/2-mutated pancreatic cancer were treated with platinum-based therapy. In this trial, 81% (50/62) of patients in the control arm received treatment with FOLFIRINOX. Also in this study, predominantly FOLFIRINOX-based treatment was associated with a prolonged overall survival of 18.1 months. As a caveat, it should be noted that there was substantial positive selection in the POLO trial in that a duration of at least 16 weeks of first-line therapy was required for study inclusion. Subsequent treatment with olaparib was documented in only 9 patients in the control arm [701].
Currently, there is no direct comparison of the two platinum-based regimens (gemcitabine/cisplatin vs. FOLFIRINOX). Therefore, the choice of platinum-based therapy should be based on feasibility (and patient preference). Due to low case numbers (or incidence) for other DRD genes (such as PALB2), this recommendation should be limited to gBRCA (gPALB2 in the study conducted by O’Reilly: n=3) [O'Reilly, E. M. et al. 2020].
8.6.1.2 PARP Inhibitors
In patients with metastatic pancreatic cancer who are generally suitable for platinum-based therapy, the presence of a BRCA1/2 germline mutation shall be evaluated to identify platinum-sensitive patients early and to clarify the option of maintenance therapy with a PARP inhibitor.
- Recommendation grade
- A: Starke Empfehlung für oder gegen ein Maßnahme - verwendete Ausdrucksweise = soll/soll nicht
- Level of evidence
- 2
- Consensus
- Strong consensus
- References
- [701]
Background
The prevalence of BRCA1/2 germline mutation is 4-7% in unselected pancreatic cancer patients. In these patients, the risk of developing pancreatic cancer is increased 2-6-fold [702], [701]. In addition, the disease is also mostly diagnosed at a rather younger age than in the unselected population [142], [702]. Testing with regard to a BRCA1/2 mutation is performed using next-generation sequencing (NGS).
BRCA genes encode proteins involved in homologous recombination repair of DNA double-strand breaks [703]. BRCA1/2 mutant cells exhibit defective homologous recombination repair (HRD) and show increased sensitivity to poly (ADP-ribose) polymerase (PARP) inhibitors. Accordingly, the detection of a BRCA1/2 mutation has predictive significance for the clinical efficacy of PARP inhibitors [704].
8.6.1.2.1 Use of PARP Inhibitors in Maintenance Therapy
In the presence of a gBRCA1/2 mutation, agents that interfere with DNA repair mechanisms, such as PARP inhibitors, have value in the maintenance treatment of metastatic pancreatic cancer after platinum-based prior therapy.
- Level of evidence
- 2
- Consensus
- Strong consensus
- References
- [701]
Background
The POLO trial evaluated the efficacy of maintenance therapy with olaparib versus placebo in patients with metastatic pancreatic cancer who were not progressive on at least 16 weeks of platinum-containing chemotherapy and had a germline mutation in the BRCA1 or BRCA2 gene (gBRCA1/2 MT) [701]. From the total group of 3315 screened patients, 247 (7.5%) patients had gBRCA1/2 MT. Of these 247 patients, n=154 could be randomized (38% of patients were not eligible, had intermediate disease progression, or declined randomization).
The study was double-blind with a 3:2 randomization in a phase III design and compared maintenance therapy with olaparib (300 mg twice daily) versus placebo as maintenance therapy. Median progression-free survival was assessed as the primary endpoint and was significantly longer in the olaparib arm than in the placebo group (7.4 vs. 3.8 months; HR 0.53; p=0.004). Overall survival was evaluated in the interim analysis, but only an event rate of 46% was achieved. No significant difference was observed here (OS 18.6 vs. 18.1 months; HR 0.91, p=0.68). For toxicity analysis, 91 patients in the olaparib arm were compared with 60 patients in the placebo arm. Foremost among grade ≥ III adverse events were anemia (11% vs. 3%) and fatigue (5% vs. 2%). Among patients with measurable disease at baseline, the response rate (ORR, independently evaluated) was 23% for the olaparib arm and 12% for the placebo group (OR 2.30; 95% CI, 0.8-6.76). The median duration of response was 24.9 months (95% CI 14.8-nc) and 3.7 months (95% CI 2.1–nc) [701].
The POLO trial data demonstrate the good tolerability of olaparib and show that a significant prolongation of progression-free survival can be achieved in patients with pancreatic cancer and BRCA1/2 germline mutation by maintenance therapy with olaparib if the patients did not progress on the previous platinum-based treatment.
After meeting the eligibility criteria for PARP inhibitor maintenance therapy after platinum-based pretreatment, all patients with a primary diagnosis of metastatic pancreatic cancer who are eligible for platinum-based therapy should be screened for the presence of a BRCA1/2 mutation as early as possible. In contrast to ovarian cancer, BRCA1/2 mutations must be detected in the germline (gBRCA) for PARP inhibitor use in pancreatic cancer to be approvable. The decision on the selection of the appropriate first-line therapy (platinum-based vs. non-platinum-based) is still generally made depending on clinical selection criteria (such as ECOG performance status, comorbidity, organ function) and patient preference (see 8.4). However, in young primary age of manifestation (< 50 years) and positive personal or family history (regarding BRCA-associated malignancies such as ovarian/peritoneal, breast, prostate or pancreatic cancer), platinum-based first-line therapy should be preferred due to the higher incidence of germline mutations in DNA repair genes (such as BRCA1/2). In this situation, prompt human genetic diagnosis (using panel diagnostics including BRCA) is also indicated after appropriate counseling. In all other patients, after initiation of first-line platinum-based therapy, testing for the presence of a BRCA germline mutation (gBRCA) from a blood sample (EDTA blood) should be performed from the detection of a response to therapy (= platinum-sensitive), i.e. after at least 16 weeks of treatment. This is a diagnostic genetic test which, in accordance with the German Genetic Diagnostics Act (GenDG), can be ordered by a licensed physician after appropriate information patient briefing (with adequate cooling-off periodtime for consideration) and written patient consent in a laboratory accredited for gBRCA diagnostics (the corresponding billing code is GOP 11601). In the case of a positive result (gBRCA detection), the affected patients must be offered subsequent human genetic counseling. After at least 16 weeks of platinum-based therapy and documented response, patients with proven gBRCA mutation may be offered PARP inhibitor maintenance therapy (olaparib). Alternatively, in the absence of survival benefit to date from PARP inhibitor maintenance therapy, patients may be offered continuation or de-escalation of first-line therapy or a break in therapy.
If initial access to primary NGS-based molecular analysis from a tumor sample (somatic testing) is already available, molecular characterization of the tumor (panel diagnostics) should always include BRCA1/2 mutation analysis. If a BRCA mutation is detected in the tumor tissue, a presentation/discussion in a molecular tumor board should be performed to classify the BRCA mutation (and other genetic alterations) with regard to therapeutic relevance. Whenever a somatic BRCA mutation is detected from a tumor sample, retesting from blood is indicated to detect/exclude a germline mutation according to the above procedure and, if positive, further human genetic counseling is indicated.
8.6.2 KRAS G12C Mutation
8.6.2.1 KRAS G12C Inhibitor in KRAS G12C Mutation
If a KRAS-G12C mutation is present, treatment with a selective KRAS-G12C inhibitor can be carried out after all therapeutic options for pancreatic cancer have been exhausted.
- Consensus
- Strong consensus
KRAS mutations are found in around 90 % of pancreatic carcinomas. Targeted therapy of a KRAS p.G12C mutation in the tumor has recently become possible. This subgroup of KRAS-G12C mutated pancreatic carcinomas is small and accounts for only about 1-2 % of cases. The CodeBreaK 100 Phase I-II study investigated the efficacy of the irreversible KRAS G12C inhibitor sotorasib in predominantly intensively pre-treated metastatic pancreatic cancer patients (n=38) [705]. With an oral dose of 960 mg per day, an ORR of 21% (DCR 84%), a PFS of 4.0 months and an OS of 6.9 months were achieved with an acceptable safety profile. Sotorasib is currently not approved for the treatment of pancreatic cancer.
Adagrasib, another KRAS G12C inhibitor, was investigated in advanced solid tumors and showed a response rate of 33.3% in the included patients with metastatic pancreatic cancer (n=21) after a median of 2 prior therapies [706].
8.6.3 Immunotherapeutics in Palliative Therapy
8.6.3.1 Diagnostic Methods for the Determination of Microsatellite Instability
Immune checkpoint inhibitors are particularly effective when mismatch repair deficiency (dMMR) or microsatellite instability (MSI) is present. Determination of these parameters is therefore a prerequisite for treatment with immune checkpoint inhibitors in patients with pancreatic cancer.
- Level of evidence
- 5
- Consensus
- Strong consensus
- References
- [207]
Background
The incidence of mismatch repair deficiency (dMMR) in pancreatic cancer is low, at approximately 1% [707], [708]. A proportion of these dMMR cases are hereditary and thus associated with Lynch syndrome. Adequate selection of patients who benefit from treatment with checkpoint inhibitors involves detection of mismatch repair deficiency via evidence of loss of expression of at least one mismatch repair protein on immunohistochemistry (dMMR) or microsatellite instability (MSI) via fragment length analysis (molecular analysis) [709]. Immunohistochemical detection of mismatch repair protein deficiency appears to be superior to molecular diagnostics in pancreatic cancer in terms of sensitivity and specificity [708], [710] and is thus recommended as a primary screening method.
8.6.3.2 Effect of Immunotherapeutics in Palliative Therapy of Pancreatic Cancer
Immunotherapies with checkpoint inhibitors can be used after all therapeutic options have been exhausted in pancreatic cancer when DNA mismatch repair deficiency (MMRd), or when high-grade microsatellite instability (MSI-h) are present.
- Recommendation grade
- 0: offene Empfehlung (Option) bzgl. einer Maßnahme - verwendete Ausdrucksweise = kann
- Level of evidence
- 5
- Consensus
- Strong consensus
- References
- [207]
Background
Checkpoint inhibitors are tumor-diagnostically effective in the detection of high-grade microsatellite instability (MSI-H) or DNA mismatch repair deficiency (dMMR) [711]. Checkpoint inhibitors such as the anti-PD-1 receptor antibody pembrolizumab block PD-L1- and PD-L2-mediated inhibition of the immune response, thereby enhancing the anti-tumor T-cell response. In pancreatic cancer, DNA mismatch repair deficiency is rare and the incidence is only about 0.8% [712].
The efficacy of pembrolizumab in the presence of mismatch repair deficiency was confirmed in an initial analysis of 41 patients with various gastrointestinal and other tumors (but not pancreatic cancer) [713]. In a subsequent study of 86 patients, six pancreatic cancers were also included. Of these, two patients responded with complete remission [707].
In a recent single-arm phase II study, the Keynote 158 study, a total of 233 patients with dMMR/MSI-H tumors were enrolled and treated with pembrolizumab monotherapy. The cohort included 22 pancreatic cancer patients who had failed prior therapy. One patient achieved CR and 3 patients achieved PR (ORR: 18.2%). Median PFS was 2.1 months, and median OS was 4.0 months. However, for those patients who achieved a response, the duration of response was 13.4 months [714].
In 2017, the U.S. Food and Drug Administration (FDA) approved the checkpoint inhibitor pembrolizumab for the tumor-diagnostic treatment of tumors in which dMMR or MSI-H could be detected [207]. In Europe, checkpoint inhibitors are currently not approved for the treatment of pancreatic cancer. Therefore, the recommendation is rated with a recommendation grade of 0. The value of a high tumor mutational burden (TMB) has not yet been clarified.
Other immunotherapies
Various immunologic therapeutic approaches are available for the treatment of advanced pancreatic cancer, including the use of vaccination therapies. To date, none of the published studies has shown a survival benefit compared with standard therapy [715], [716], [717], [718]. Thus, other immunotherapies cannot be recommended at this time.
8.7 Follow-up Therapies in Case of Progression under First-line Therapy
8.7.1 Indication
Second-line therapy shall be offered for progression on first-line therapy with an ECOG ≤ 2.
- Recommendation grade
- A: Starke Empfehlung für oder gegen ein Maßnahme - verwendete Ausdrucksweise = soll/soll nicht
- Level of evidence
- 5
- Consensus
- Strong consensus
- References
- [207]
Background
Clinical studies show that adequate follow-up therapy in advanced pancreatic cancer can contribute to a relevant prolongation of survival. Accordingly, second-line therapy should be offered to all patients with good performance status and appropriate motivation [207], [622], [654], [687], [719], [720], [721], [722], [723], [724].
A subgroup analysis of the NAPOLI study indicates that older patients also benefit from second-line therapy [725].
8.7.2 Second-line Therapy after Gemcitabine-based First-line Therapy
Second-line therapies after failure of gemcitabine pre-therapy refer to both gemcitabine pretreatment and gemcitabine-based combination therapies. It is important to note that, at present there is no randomized trial that has evaluated the efficacy of second-line therapy exclusively after gemcitabine/nab-paclitaxel [622].
8.7.2.1 Second-line Therapy with Nanoliposomal Irinotecan plus 5-FU/FA
In cases of progression after gemcitabine-based pretreatment, second-line therapy with nanoliposomal irinotecan/5-FU (NAPOLI regimen) should be offered if the following criteria are met: Karnofsky performance status ≥ 70%, relatively favorable comorbidity profile, patient preference.
- Recommendation grade
- B: Empfehlung für oder gegen eine Maßnahme - verwendete Ausdrucksweise = sollte/sollte nicht
- Level of evidence
- 5
- Consensus
- Strong consensus
- References
- [207]
Background
The NAPOLI trial was conducted in gemcitabine-pretreated patients (Karnofsky performance status ≥ 70%) [724]. This randomized phase III trial compared the combination of nanoliposomal irinotecan (nal-Iri) plus 5-fluorouracl/folinic acid (FU/FA) (NAPOLI regimen) with nal-Iri or FU/FA therapy alone. Overall survival was examined as the primary endpoint. Compared to FU/FA treatment alone, the NAPOLI regimen was superior in terms of overall survival (6.2 months vs. 4.2 months; HR 0.75; p=0.039) [724], [726] as well as progression-free survival (3.1 vs. 1.6 months; HR 0.56; p=0.0001) [719]. In a „per-protocol“ analysis of patients who had received ≥ 80% of planned therapy within 6 weeks, the significant survival benefit of the NAPOLI regimen compared with 5-FU/LV was confirmed (8.9 vs 5.1 months; HR 0.57, p=0.011) [727].
Grade III/IV adverse events occurred most frequently with the NAPOLI regimen and were specifically neutropenia (27%), diarrhea (13%), vomiting (11%), and fatigue (14%). Apart from a worsening of fatigue, quality of life parameters (health related quality of life, HRQL) remained comparable between FU/FA/nal-Iri and FU/FA treatment [728].
8.7.2.2 Second-line Therapy with Oxaliplatin and 5-FU
In case of progression after gemcitabine-based pretreatment, second-line therapy with 5-FU and oxaliplatin (OFF regimen) can be offered if the following criteria are met: ECOG ≤ 2, peripheral polyneuropathy CTCAE grade ≤ 2, relatively favorable comorbidity profile, patient preference.
- Recommendation grade
- 0: offene Empfehlung (Option) bzgl. einer Maßnahme - verwendete Ausdrucksweise = kann
- Level of evidence
- 5
- Consensus
- Strong consensus
- References
- [207]
Background
The recommendation for second-line therapy with 5-FU plus oxaliplatin is given a weak recommendation grade because of conflicting data from randomized phase III trials. After prior therapy with gemcitabine-based regimens, treatment with 5-FU/oxaliplatin can be considered, particularly if the availability of 5-FU/nanoliposomal irinotecan is not available or if the administration of 5-FU/nanoliposomal irinotecan cannot be considered for toxicity reasons [207].
After prior therapy with gemcitabine/nab-paclitaxel, it must be ensured that there is no severe peripheral polyneuropathy (CTCAE > grade 2) before 5-FU/oxaliplatin is used, as overlap toxicity may occur, particularly with this sequence of therapy.
The CONKO 003 trial investigated the efficacy of the combination of 5-FU plus oxaliplatin in second-line therapy of gemcitabine-pretreated pancreatic cancer. In this study, the OFF regimen (5-FU, folinic acid, oxaliplatin) was characterized by lower dose density and thus better tolerability compared with the FOLFOX6 regimen. The CONKO 003 trial showed in a randomized comparison in 160 patients (Karnofsky performance status ≥ 70%) that the OFF regimen was superior to treatment with 5-FU plus folinic acid alone in terms of time to tumor progression (2.9 vs. 2.0 months; HR 0.68, p=0.019) and overall survival (5.9 vs. 3.3 months HR 0.66; p=0.010) [721], [722].
In contrast, the PANCREOX trial reached a different conclusion [723]: this randomized phase III trial evaluated 108 gemcitabine-pretreated patients (ECOG 0-2) treated with either mFOLFOX6 or 5-FU/leucovorin (5-FU/LV) infusion. More patients discontinued their study participation due to adverse events in the mFOLFOX6 arm than in the 5-FU/LV arm (20% vs 2%), whereas the use of "post-progression" therapy was significantly higher in the 5-FU/LV arm (25% vs 7%; p=0.015). The addition of oxaliplatin correspondingly did not improve progression-free survival (primary endpoint of the study) (3.1 vs 2.9 months; p=0.99). Overall survival was even shorter in the mFOLFOX6 arm (6.1 vs. 9.9 months; p=0.02). Further analysis supports the potential benefit of oxaliplatin-based second-line therapy [729].
8.7.2.3 Other Options for Second-line Therapy after Gemcitabine Pre-therapy
A randomized phase II trial compared the MEK inhibitor selutinib with capecitabine after failure of gemcitabine-based prior therapy [730]. In 70 patients, there was no significant difference in terms of overall survival (primary endpoint) (OS 5.4 vs. 5.0 months; HR 1.03; p=0.92) [731].
SWOG S1115 was conducted as a randomized phase II trial in pancreatic cancer patients who had failed prior gemcitabine-based chemotherapy. In a 1:1 randomization, patients (n=120) received either second-line therapy with the combination of selumetinib (MEK inhibitor) and MK-2206 (AKT inhibitor) or mFOLFOX. Combined inhibition of MEK and PI3K/AKT did not induce prolonged survival compared to chemotherapy with mFOLFOX (3.9 vs 6.7 months; HR 1.37; p=0.15). However, the study showed survival for mFOLFOX equivalent to that of the CONKO-003 trial [722], [732].
A randomized phase III trial conducted in Asian patients (n=603) showed comparable efficacy of TAS-118 (S1 plus leucovorin) and S1 in terms of overall survival (7.6 vs. 7.9 months; HR 0.98) after failure of gemcitabine pre-therapy [733]. The randomized phase III Janus 1 and Janus 2 trials were stopped after an interim analysis after it became clear that the combination of capecitabine and ruxolitinib was not superior to capecitabine plus placebo in pretreated patients [734].
In addition, further phase II studies, predominantly single-arm, indicate the efficacy of second-line therapy, e.g. with 5-FU, capecitabine, possibly also in combination with docetaxel or irinotecan.
8.7.3 Second-line Therapy after FOLFIRINOX
Gemcitabine-based chemotherapy can be considered as second-line therapy if tumor progression occurs after first-line therapy with FOLFIRINOX.
- Recommendation grade
- B: Empfehlung für oder gegen eine Maßnahme - verwendete Ausdrucksweise = sollte/sollte nicht
- Level of evidence
- 2
- Consensus
- Strong consensus
- References
- [596]
Background
Currently, there are no randomized trials that have evaluated second-line therapy after FOLFIRINOX [622]. In the UNICANCER /PRODIGE trial, 47% of patients were treated with second-line therapy. The most commonly used regimens after failure of FOLFIRINOX therapy were gemcitabine (82.5%) and gemcitabine-based combinations (12.5%).
In patients with good ECOG Performance Status 0-1, low comorbidity, and given patient preference, combination chemotherapy with gemcitabine/nab-paclitaxel may be considered after failure of FOLFIRINOX [207].
8.7.4 Second-line Therapy for Reduced ECOG Performance Status
Monotherapy with gemcitabine or 5-fluorouracil can be offered in the second-line setting when an ECOG Performance Status of ≥ 2 or comorbidity prohibits the use of combination chemotherapy.
- Recommendation grade
- 0: offene Empfehlung (Option) bzgl. einer Maßnahme - verwendete Ausdrucksweise = kann
- Level of evidence
- 5
- Consensus
- Consent
- References
- [207]
Background
There are no data from prospective studies demonstrating the benefit of second-line therapy in patients with reduced ECOG Performance Status or significant comorbidity. In any case, supportive care should be involved in these patients, as well as palliative care at an early stage.
8.7.5 Treatment in Later (> 2) Lines of Therapy
There are no data to support the benefit of third-line therapy or later lines of therapy. For the application of later lines of therapy (> 2), the consideration of the relationship between benefit and side effects is therefore clearly more in the foreground.
- Level of evidence
- 5
- Consensus
- Strong consensus
- References
- [207]
8.8 The Role of Radiotherapy
Radiotherapy (evidence level 3) or radiochemotherapy (evidence level 2) can be offered to patients up to ECOG 2 with locally advanced nonmetastatic pancreatic cancer who have not experienced disease progression during chemotherapy, to improve local control.
8.8.1 Indication for Radiotherapy
The efficacy of radiochemotherapy was compared with adequate-dose gemcitabine therapy in three randomized trials. The results were not consistent.
In the ECCOG 4201 trial, longer survival was achieved with radiochemotherapy (11.1 months vs. 9.2 months, p=0.017). Despite increased grade IV adverse events, primarily gastrointestinal (38% vs. 6%), due in part to the high dose of gemcitabine (600mg/m²) during radiochemotherapy, patients did not describe any decline in quality of life over the subsequent 9 months in the longer course. The original enrollment target was not met with only 74 patients included [736].
In the FFCD/SFRO trial, radiochemotherapy was inferior to chemotherapy in terms of both survival (median 8.6 vs. 13 months) and locoregional tumor control. There was an increased incidence of acute gastrointestinal adverse events (65% vs. 40%) and chronic hematologic toxicities (78% vs. 40%) in the radiochemotherapy arm. These were caused by the irradiation dose of 60 Gy, which was high for 3-D planned irradiation techniques, and the large irradiation volume with coverage of all elective lymph node stations, as well as by the additive administration of the non-established combination of cisplatin (2 x 5 x 20 mg/m²) and 5-FU (6 x 5 x 300 mg/m²) in comparably high doses. Ultimately, only 42% of patients received at least 75% of planned chemotherapy and radiotherapy [737].
In the most comprehensive study, the LAP07 study, which compared the effect of capecitabine-containing radiochemotherapy ( 2 x 800mg/m² daily; 54 Gy, excluding elective lymph nodes) in 269 patients after initial chemotherapy with 4 cycles of gemcitabine +/- administration of erlotinib in the second randomization phase with the continuation of the initiated system therapy, the patients with radiochemotherapy benefited from a longer progression-free survival (PFS: 9.9 vs. 8.4 months, p= 0.06) and a longer therapy-free interval compared to continued chemotherapy ± TKI, (therapy-free time: 6.1 months vs. 3.7 months, p =0.02) as well as better local control (32% vs. 46% local recurrence). The likelihood of higher-grade hematologic adverse events tended to be lower after RCT 10.4% vs. 3.9%. In contrast, only the rate of nausea was moderately increased from 0% to 5.9%. Survival (HR: 1.03, p=0.83) was comparable. With equal survival, benefits regarding secondary endpoints were achieved by radiochemotherapy. The increased acute side effects are manageable and do not lead to increased chronic toxicities. This should be discussed with the patient.
No results of randomized trials are yet available for the benefit of radiochemotherapy or radiotherapy after polychemotherapy.
8.8.2 Radiotherapy Concepts
The radiooncological radiation regimen should consist of normofractionated simultaneous radiochemotherapy (single dose of 1.8-2.0 Gy, total dose of approximately 50 Gy).
- Recommendation grade
- B: Empfehlung für oder gegen eine Maßnahme - verwendete Ausdrucksweise = sollte/sollte nicht
- Level of evidence
- 1
- Consensus
- Strong consensus
- References
- [738]
Hypofractionated intensity-modulated radiotherapies can be performed as part of sequential radiochemotherapies. With consistent use of stereotactic and image-navigating techniques, single doses of more than 3 Gy can be used with strict adherence to intestinal tolerance doses, preferably in the context of prospective studies.
- Recommendation grade
- 0: offene Empfehlung (Option) bzgl. einer Maßnahme - verwendete Ausdrucksweise = kann
- Level of evidence
- 3
- Consensus
- Strong consensus
- References
- [735]
Normofractionated radiation protocols in a dose corridor of 45-56 Gy have been used in most radiochemotherapy efficacy trials and are considered feasible. Compared with chemotherapy alone, these protocols, either 5FU- or gemcitabine-containing, resulted in grade III/IV side effects with equal frequency, but with a toxicity profile less characterized by hematologic than by gastrointestinal side effects and well managed. No increased treatment-related mortalities resulted (meta-analysis of 5 studies [738]).
However, even in pancreatic cancer, higher radiation doses can achieve better tumor control according to retrospective analyses [739], [740], [741]. This seems to be especially true for the use of radiotherapy or radiochemotherapy after initial chemotherapy [740]. For different radiotherapeutic fractionation concepts that administered a biologically equivalent dose of more than 70 Gy, a longer locoregional recurrence-free period (10.2 vs. 6.2 months, p=0.05) and a longer median survival (17.8 vs. 15.0 months p=0.03) were achieved than for concepts with lower total doses. Higher radiation doses require special quality assurance in the context of SBRT (Stereotactic Body Radiation Therapy) and strict tolerance guidelines for surrounding normal tissues. A prospective multicenter phase II study using moderate hypofractionation, quality-assured techniques of SBRT, and a biological equivalent dose of > 100 Gy (5 x 6.6 Gy), achieved local control of 78% at 12 months with short-term grade III/IV toxicity of 2% and long-term grade II-IV toxicity of 11% [735]. A large-scale analysis of the U.S. National Cancer Database including of 14,331 patients confirmed the benefit of SBRT in combination with chemotherapy (4-month improvement in median survival) [742]. Therefore, the ASCO and ASTRO Guidelines consider such an approach in the treatment of locally advanced pancreatic cancer as possible in the integrative treatment concept of chemotherapy with radiation [743], [744]. However, randomized trials and further phase II studies including SBRT are still lacking.
Either gemcitabine or capecitabine can be used as combination partners. The choice should be made according to the acceptable toxicity profile.
Within the SCALOP study, simultaneous administration of gemcitabine 300mg/m² weekly was compared to capecitabine 830mg/m² BID concurrent with radiation. Hematologic adverse events were lower (0% vs. 18%), as were nonhematologic adverse events (11.1% vs. 26.3%), and median OS moderately was 3.0 months longer (17.6 vs. 14.6 months; HR 0.68) with capecitabine than with gemcitabine [746]. However, compared with 5-FU-containing concurrent radiochemotherapy, parallel administration of gemcitabine resulted in higher survival rates at 12 months in 3 smaller-scale randomized trials (19 to 62 patients per trial), which were combined with a retrospective case collection in a meta-analysis. The dose and target volume concepts of radiotherapy varied enormously among the 3 trials, and chemotherapy was not optimally dosed in the majority of trials. For this reason, comparative conclusions regarding the optimal choice of chemotherapy are not possible. The choice should be based on the toxicity profile and prior therapies [745].
Palliative radiotherapy should be carried out only for symptomatic metastases or metastases with impending symptoms (especially skeletal and cerebral metastases). The goal is symptom control or prevention of metastasis-related complications.
- Consensus
- Strong consensus
Evidence tables
Von Hoff, D. D. et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. New England Journal of Medicine. 369. 1691-1703. 2013
| Von Hoff, D. D. et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. New England Journal of Medicine. 369. 1691-1703. 2013 | |||
|---|---|---|---|
| Population | Intervention - Comparison | Outcomes/Results | |
| Evidence level: 2 Study type: RCT, multizentrisch (151 Zentren), international (11 Länder) Number of Patient: n=861 randomisiert n=431 nab-Paclitaxel + Gemcitabin n=430 Gemcitabin Patienten in der Analyse n=421 nab-Paclitaxel + Gemcitabin n=402 Gemcitabin Recruitung Phase: 05/2009-04/2012 Inclusion Criteria: 1. Alter ≥18 Jahre 2. ≥70 Karnofsky-Performancestatus 3. metastatische Erkrankung (Diagnose: innerhalb von 6 Wochen vor Randomisierung) 4. adequate hämatologische, renale und hepatische Funktion 5. keine vorherige Chemotherapie auf Grund von metastatischer Erkrankung 6. Adjuvante Therapie mit Fluoruracil + Gemcitabin möglich (mind. 6 Monate vor Randomisierung) Exclusion Criteria: 1. adjuvante Chemotherapie 2. Islet cell Neoplasien 3. lokal fortgeschrittene Erkrankung |
Intervention: Nab-Paclitaxel + Gemcitabin (nab-Pac+Gem) Nab-Paclitaxel 125 mg/m2 intravenös Gemcitabin 1000 mg/m2 intravenös an den Tagen 1, 8, 15, 29, 36, 43 Comparison: Gemcitabin (Gem) 1000 mg/m2 intravenös 7 von 8 Wochen (1. Zyklus) Weitere Zyklen: Tage 1, 8, 15 alle 4 Wochen |
Primary: Gesamtüberleben Secondary: Progressionsfreies Überleben Ansprechrate Toxizitäten Results: Gesamtüberleben Nab-Pac+Gem vs. Gem Statistisch signifikant länger bei Nab-Pac+Gem Nab-Pac+Gem: 8,5 Monate (95% CI 7,89-9,53) Gem: 6,7 Monate (95% CI 6,01-7,23) HR: 0,72 (95% CI 0,62-0,83) p<0,001 Progressionsfreies Überleben Nab-Pac+Gem vs. Gem Statistisch signifikant länger bei Nab-Pac+Gem Nab-Pac+Gem: 5,5 Monate (95% CI 4,5-5,9) Gem: 3,7 Monate (95% CI 3,6-4,0) HR: 0,69 (95% CI 0,58-0,82) p<0,001 Ansprechrate Nab-Pac+Gem vs. Gem Statistisch signifikant höher bei Nab-Pac+Gem Nab-Pac+Gem: 23% (95% CI 19-27) Gem: 7% (95% CI 5-10) p<0,001 Toxizitäten (Grad ≥ 3) Neutropenie Nab-Pac+Gem: 153 (38%) Gem: 103 (27%) Leukopenie Nab-Pac+Gem: 124 (31%) Gem: 63 (16%) Thrombozytopenie Nab-Pac+Gem: 52 (13%) Gem: 36 (9%) Anämie Nab-Pac+Gem: 53 (13%) Gem: 48 (12%) Periphere Neuropathie Nab-Pac+Gem: 70 (17%) Gem: 3 (1%) Fatigue Nab-Pac+Gem: 70 (17%) Gem: 27 (7%) Diarrhö Nab-Pac+Gem: 24 (6%) Gem: 3 (1%) Author's Conclusion: In conclusion, nab-paclitaxel combined with gemcitabine is superior to gemcitabine alone but causes more myelosuppression and peripheral neuropathy; however, these side effects appear to be reversible. |
|
| Methodical Notes | |||
| Funding Sources: Supported by Celgene COI: Disclosure forms provided by the authors are available with the full text of this article at NEJM.org. Randomization: In this international, multicenter, open-label, randomized, phase 3 study, we randomly assigned eligible patients, in a 1:1 Blinding: keine Verblindung (open-label) Dropout Rate/ITT-Analysis: nicht angegeben Notes: |
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Li, Q. et al. Efficacy and safety of gemcitabine-fluorouracil combination therapy in the management of advanced pancreatic cancer: A meta-analysis of randomized controlled trials. PLoS ONE. 9. e104346. 2014
| Li, Q. et al. Efficacy and safety of gemcitabine-fluorouracil combination therapy in the management of advanced pancreatic cancer: A meta-analysis of randomized controlled trials. PLoS ONE. 9. e104346. 2014 | ||||
|---|---|---|---|---|
| Evidence level/Study Types | P - I - C | Outcomes/Results | Literature References | |
| Evidence level: 1 Study type: Systematisches Review + Metaanalyse Databases: PubMed, EMBASE, Central Registry of Controlled Trials of the Cochrane Library Search period: bis 31/01/2014 (keine Angabe zum Suchzeitraum) Inclusion Criteria: 1. Prospektive, randomisierte, gut durchgeführte Studien, gematcht bei Alter, Geschlecht, Tumorstadium und Performance Status 2. untersuchte Patienten mit histologisch oder zytologisch bestätigtem lokal fortgeschrittenem oder metastasiertem PDAC 3. Gemcitabin Monotherapie als Kontrolle und Gemcitabin + 5-FU, Capecitabin oder S-1 als Intervention 4. Gesamtüberleben als primärer Endpunkt und 1-Jahres-Überleben, Ansprechraten und Nebenwirkungen als weitere Endpunkte 5. explizite Überlebensinformationen und Follow-up >95% 6. Studie mit längstem Follow-up bei überlappenden Patientenpopulationen Exclusion Criteria: 1. Studien mit Patienten mit schweren Komorbiditäten oder Sekundärtumoren 2. adjuvante Chemotherapie innerhalb von 6 Monaten oder begleitende Therapien, wie Radiotherapie, die sich systematisch zwischen den Studienarmen unterscheiden |
Population: Patienten mit lokal fortgeschrittenem oder metastasiertem PDAC Intervention: Gemcitabin + 5-FU (Gem+5-FU) Gemcitabin + Capecitabin (Gem+Cap) Gemcitabin + S-1 (Gem+S-1) Comparison: Gemicitabin Monotherapie (Gem) |
Primary: Gesamtüberleben 1-Jahres-Überleben Ansprechen Toxizität Secondary: Results: n=8 Studien n=2126 Gesamtpopulation n=1067 Gemcitabin Mono n=205 Gemcitabin + 5-FU n=468 Gemcitabin + Capecitabin n=386 Gemcitabin + S-1 Gesamtüberleben Gem+5-FU/Cap/S-1 vs. Gem (8 Studien) Statistisch signifikant höher bei Gem+5-FU/Cap/S-1 HR 0,83 (95% CI: 0,76-0.91) p<0.01 Gem+5-FU vs. Gem (2 Studien) Statistisch signifikant höher bei Gem+5-FU HR 0,81 (95% CI: 0,68-0,96) p=0.02 Gem+Cap vs. Gem (3 Studien) Statistisch signifikant höher bei Gem+Cap HR 0,87 (95% CI: 0,76-0.99) p=0.03 Gem+S-1 vs. Gem (3 Studien) Statistisch signifikant höher bei Gem+S-1 HR 0,80 (95% CI: 0,67-0,95) p=0.01 Subgruppenanalyse Phase III Studien Gem+5-FU/Cap/S-1 vs. Gem (4 Studien) Statistisch signifikant höher bei Gem+5-FU/Cap/S-1 HR 0,86 (95% CI: 0,78-0.94) p<0.01 1-Jahres-Überleben Gem+5-FU/Cap/S-1 vs. Gem (7 Studien) Statistisch signifikant höher bei Gem+5-FU/Cap/S-1 OR 0,78 (95% CI: 0,64-0,95) p=0.01 Gem+5-FU vs. Gem (1 Studie) Nicht angegeben Gem+Cap vs. Gem (3 Studien) Kein statistisch signifikanter Unterschied OR 0,95 (95% CI: 0,71-1,27) p=0,72 Gem+S-1 vs. Gem (3 Studien) Statistisch signifikant höher bei Gem+S-1 OR 0,47 (95% CI: 0,23-0,96) p=0.04 Subgruppenanalyse Phase III Studien Gem+5-FU/Cap/S-1 vs. Gem (3 Studien) Kein statistisch signifikanter Unterschied OR 0,86 (95% CI: 0,68-1,08) p=0,19 Ansprechen Objektive Ansprechrate Gem+5-FU/Cap/S-1 vs. Gem (8 Studien) Statistisch signifikant höher bei Gem+5-FU/Cap/S-1 OR 0,51 (95% CI: 0,39-0,65) p<0.01 Gem+5-FU vs. Gem (2 Studien) Kein statistisch signifikanter Unterschied OR 0,76 (95% CI: 0,36-1,63) p=0,49 Gem+Cap vs. Gem (3 Studien) Statistisch signifikant höher bei Gem+Cap OR 0,66 (95% CI: 0,45-0,96) p=0.03 Gem+S-1 vs. Gem (3 Studien) Statistisch signifikant höher bei Gem+S-1 OR 0,35 (95% CI: 0,23-0,52) p<0.01 Subgruppenanalyse Phase III Studien Gem+5-FU/Cap/S-1 vs. Gem (4 Studien) Statistisch signifikant höher bei Gem+5-FU/Cap/S-1 OR 1,91 (95% CI: 1,43-2,54) p<0.01 Toxizität Grad 3-4 Neutropenie Gem+5-FU/Cap/S-1 vs. Gem (8 Studien) Statistisch signifikant höher bei Gem+5-FU/Cap/S-1 OR 1,90 (95% CI: 1,54-2,34) p<0.01 Grad 3-4 Thrombozytopenie Gem+5-FU/Cap/S-1 vs. Gem (8 Studien) Statistisch signifikant höher bei Gem+5-FU/Cap/S-1 OR 1,62 (95% CI: 1,20-2,18) p<0.01 Grad 3-4 Diarrhoe Gem+5-FU/Cap/S-1 vs. Gem (8 Studien) Statistisch signifikant höher bei Gem+5-FU/Cap/S-1 OR 2,04 (95% CI: 1,28-3,26) p<0.01 Grad 3-4 Anämie Gem+5-FU/Cap/S-1 vs. Gem (8 Studien) Kein statistisch signifikanter Unterschied OR 1,11 (95% CI: 0,82-1,50) p=0,51 Grad 3-4 Übelkeit Gem+5-FU/Cap/S-1 vs. Gem (8 Studien) Kein statistisch signifikanter Unterschied OR 1,37 (95% CI: 0,91-2,06) p=0,13 Grad 3-4 Erbrechen Gem+5-FU/Cap/S-1 vs. (8 Studien) Kein statistisch signifikanter Unterschied OR 1,18 (95% CI: 0,76-1,83) p=0,45 Author's Conclusion: This study revealed a significant improvement in OS and a significant increase in ORR when GEM combined with 5-FU/CAP/S-1 or 5-FU or CAP or S-1 were compared to GEM alone in LA/MPC patients. There was a significant increase in the oneyear survival rate when GEM combined with 5-FU/CAP/S-1 or S-1 was compared to GEM alone. Grade 3–4 neutropenia, thrombocytopenia and diarrhea were significantly increased in GEM combined with 5-FU/CAP/S-1 group. The combination of GEM and fluorouracil drugs may be considered as a valuable and acceptable alternative treatment for medically fit patients with LA/MPC. |
21. Berlin JD, Catalano P, Thomas JP, Kugler JW, Haller DG, et al. (2002) Phase III study of gemcitabine in combination with fluorouracil versus gemcitabine alone in patients with advanced pancreatic carcinoma: Eastern Cooperative Oncology Group Trial E2297. J Clin Oncol 20: 3270–3275. 22. Scheithauer W, Schull B, Ulrich-Pur H, Schmid K, Raderer M, et al. (2003) Biweekly high-dose gemcitabine alone or in combination with capecitabine in patients with metastatic pancreatic adenocarcinoma: a randomized phase II trial. Ann Oncol 14: 97–104. 23. Di Costanzo F, Carlini P, Doni L, Massidda B, Mattioli R, et al. (2005) Gemcitabine with or without continuous infusion 5-FU in advanced pancreatic cancer: a randomised phase II trial of the Italian oncology group for clinical research (GOIRC). Br J Cancer 93: 185–189. 24. Herrmann R, Bodoky G, Ruhstaller T, Glimelius B, Bajetta E, et al. (2007) Gemcitabine plus capecitabine compared with gemcitabine alone in advanced pancreatic cancer: a randomized, multicenter, phase III trial of the Swiss Group for Clinical Cancer Research and the Central European Cooperative Oncology Group. J Clin Oncol 25: 2212–2217. 25. Cunningham D, Chau I, Stocken DD, Valle JW, Smith D, et al. (2009) Phase III randomized comparison of gemcitabine versus gemcitabine plus capecitabine in patients with advanced pancreatic cancer. J Clin Oncol 27: 5513–5518. 26. Nakai Y, Isayama H, Sasaki T, Sasahira N, Tsujino T, et al. (2012) A multicentre randomised phase II trial of gemcitabine alone vs gemcitabine and S-1 combination therapy in advanced pancreatic cancer: GEMSAP study. Br J Cancer 106: 1934–1939. 27. Ozaka M, Matsumura Y, Ishii H, Omuro Y, Itoi T, et al. (2012) Randomized phase II study of gemcitabine and S-1 combination versus gemcitabine alone in the treatment of unresectable advanced pancreatic cancer (Japan Clinical Cancer Research Organization PC-01 study). Cancer Chemother Pharmacol 69: 1197–1204. 28. Ueno H, Ioka T, Ikeda M, Ohkawa S, Yanagimoto H, et al. (2013) Randomized phase III study of gemcitabine plus S-1, S-1 alone, or gemcitabine alone in patients with locally advanced and metastatic pancreatic cancer in Japan and Taiwan: GEST study. J Clin Oncol 31: 1640–1648. |
|
| Methodical Notes | ||||
| Funding Sources: This work was supported by grants from Beijing Municipal Health System High-level Health Person Foundation Project (No. 2011-3-007 to Bangwei Cao), National Nature Science Foundation of China (No. 81272615; No. 81301912) and Capital Medical University Sciences-clinical Research Cooperation Foundation (No. 12JL33). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. COI: The authors have declared that no competing interests exist. Study Quality: Bewertungsinstrument: RevMan Version 5.1, Risk of Bias Ergebnis: 3 Studien hohes Risiko für Performance und Detection Bias (Open-label-Design) 6 Studien unklares Risiko für andere Bias aufgrund fehlender Details in der Beschreibung Heterogeneity: Cochrane Q-test, I2 Ergebnis: Gemcitabin Mono vs. Gemcitabin Kombinationstherapien: keine signifikante Heterogenität Publication Bias: Bewertungsinstrument: Funnel plot, Egger’s Test Ergebnis: nicht angegeben Notes: Gesamtqualität: keine methodischen Mängel PICO Frage klar formuliert: ja Ausreichende Suchstrategie: unklar Ein- und Ausschlusskriterien klar definiert: ja Qualitätsbewertung der eingeschlossenen Studien erfolgt: ja Metaanalyse erfolgt: ja Prüfung der Heterogenität: ja |
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Tu, C. et al. An Updated Meta-analysis and System Review:is Gemcitabine+Fluoropyrimidine in Combination a Better Therapy Versus Gemcitabine Alone for Advanced and Unresectable Pancreatic Cancer?. Asian Pacific journal of cancer prevention : APJCP. 16. 5681-5686. 2015
| Tu, C. et al. An Updated Meta-analysis and System Review:is Gemcitabine+Fluoropyrimidine in Combination a Better Therapy Versus Gemcitabine Alone for Advanced and Unresectable Pancreatic Cancer?. Asian Pacific journal of cancer prevention : APJCP. 16. 5681-5686. 2015 | ||||
|---|---|---|---|---|
| Evidence level/Study Types | P - I - C | Outcomes/Results | Literature References | |
| Evidence level: 1 Study type: Systematisches Review + Metaanalyse Databases: Central, Pubmed, Embase, Web Of Science Search period: bis 11/2014 (keine Angabe zum Suchzeitraum) Inclusion Criteria: 1. RCTs 2. Abstracts oder nicht publizierte Daten bei ausreichenden Informationen zu Studiendesign, Patientencharakteristika, Interventionen und Outcomes und Bestätigung der Informationen durch den Erstautor Exclusion Criteria: 1. quasi-randomisierte Studien 2. cross-over Studien |
Population: Patienten mit fortgeschrittenem Pankreaskarzinom Intervention: Gemcitabin + Fluoropyrimidine (Gem+F) Subgruppenanalyse Gem+5-FU Gem+Capecitabin (Cap) Gem+S1 Comparison: Gemcitabin Monotherapie (Gem) |
Primary: Gesamtüberleben Secondary: Progressionsfreies Überleben Results: n=12 Studien (RCTs) n=3038 Patienten Gesamtüberleben Gem+F vs. Gem (12 Studien) Statistisch signifikant höher bei Gem+F HR 0.88 (95%CI: 0.81-0.95) p=0.001 Subgruppenanalysen Gem vs. Gem+5-FU (3 Studien) Kein statistisch signifikanter Unterschied HR 0.93 (95%CI: 0.77-1.12) p=0.451 Gem+Cap vs. Gem (5 Studien) Statistisch signifikant höher bei Gem+Cap HR 0.89 (95%CI: 0.80-0.99) p=0.038 Gem+S1 vs. Gem (4 Studien) Statistisch signifikant höher bei Gem+S1 HR 0.83 (95%CI: 0.72-0.96) p=0.011 Progressionsfreies Überleben Gem+F vs. Gem (8 Studien) Statistisch signifikant höher bei Gem+F HR 0.74 (95%CI, 0.63-0.86) p<0.001 Subgruppenanalysen Gem+Cap vs. Gem (4 Studien) Kein statistisch signifikanter Unterschied HR 0.85 (95%CI: 0.67-1. 08 p<0.076 Gem+S-1 vs. Gem (4 Studien) Statistisch signifikant höher bei Gem+S-1 HR 0.64 (95%CI: 0.56-0.74) p<0.001 Author's Conclusion: Gemcitabine combination therapy provides a modest improvement of survival, but is associated with more toxicity compared with gemcitabine monotherapy. |
Berlin JD, Catalano P, Thomas JP, et al (2002). Phase III study of gemcitabine in combination with fluorouracil versus gemcitabine alone in patients with advanced pancreatic carcinoma: eastern cooperative oncology group trial E2297. J Clin Oncol, 20, 3270-5. Bernhard J, Dietrich D, Scheithauer W, et al (2008). Clinical benefit and quality of life in patients with advanced pancreatic cancer receiving gemcitabine plus capecitabine versus gemcitabine alone: a randomized multicenter phase III clinical trial--SAKK 44/00-CECOG/PAN. 1. 3. 001. J Clin Oncol, 26, 3695-701. Cunningham D, Chau I, Stocken DD, et al (2009). Phase III randomized comparison of gemcitabine versus gemcitabine plus capecitabine in patients with advanced pancreatic cancer. J Clin Oncol, 27, 5513-8. Herrmann R, Bodoky G, Ruhstaller T, et al (2007). Gemcitabine plus capecitabine compared with gemcitabine alone in advanced pancreatic cancer: a randomized, multicenter, phase III trial of the swiss group for clinical cancer research and the central european cooperative oncology group. J Clin Oncol, 25, 2212-7. Nakai Y, Isayama H, Sasaki T, et al (2012). A multicentre randomised phase II trial of gemcitabine alone vs gemcitabine and S-1 combination therapy in advanced pancreatic cancer: GEMSAP study. Br J Cancer, 106, 1934-9. Ozaka M, Matsumura Y, Ishii H, et al (2012). Randomized phase II study of gemcitabine and S-1 combination versus gemcitabine alone in the treatment of unresectable advanced pancreatic cancer (Japan clinical cancer research organization PC-01 study). Cancer Chemother Pharmacol, 69, 1197-204. Scheithauer W, Schull B, Ulrich-Pur H, et al (2003). Biweekly high-dose gemcitabine alone or in combination with capecitabine in patients with metastatic pancreatic adenocarcinoma: a randomized phase II trial. Ann Oncol, 14, 97-104. Sudo K, Ishihara T, Hirata N, et al (2014). Randomized controlled study of gemcitabine plus S-1 combination chemotherapy versus gemcitabine for unresectable pancreatic cancer. Cancer Chemother Pharmacol, 73, 389-96. Ueno H, Ioka T, Ikeda M, et al (2013). Randomized phase III study of gemcitabine plus S-1, S-1 alone, or gemcitabine alone in patients with locally advanced and metastatic pancreatic cancer in Japan and Taiwan: GEST study. J Clin Oncol, 31, 1640-8. Riess H, Helm A, Niedergethmann M, et al (2005). A randomised, prospective, multicenter, phase III trial of gemcitabine, 5-fluorouracil (5-FU), folinic acid vs. gemcitabine alone in patientswithadvanced pancreatic cancer. J Clin Oncol, 23 Di Costanzo F, Carlini P, Doni L, et al (2005). Gemcitabine with or without continuous infusion 5-FU in advanced pancreatic cancer: a randomised phase II trial of the Italian oncology group for clinical research (GOIRC). Br J Cancer, 93, 185-9. |
|
| Methodical Notes | ||||
| Funding Sources: nicht angegeben COI: nicht angegeben Study Quality: Each article included in the composition of the funnel plot did not find significant bias. Bewertungsinstrument nicht angegeben Heterogeneity: Q-Test, I² Gesamtüberleben Gem+F vs. Gem I2=0.0%, p=0.466 Gem vs. Gem+ 5-FU ; I2=40.8%, p=0.185 Gem+Cap vs. Gem; I2=0.0%, p=0.469 Gem+S1 vs. Gem I2=0.0%, p=0.466 Progressionsfreies Überleben Gem+F vs. Gem I2=54. 5%, p=0.032 Gem vs. Gem+Cap I2=0.0%, p=0.921 Gem vs. Gem + S-1 I2=65.4%, p=0.034 Publication Bias: Egger Test, Funnel plot Ergebnis: kein Publikationsbias der Studien für Gesamtüberleben (t=0.74, p=0.474) und progressionsfreies Überleben (t=0.35, p=0.738) Notes: Gesamtqualität: ausreichend PICO Frage klar formuliert: ja Ausreichende Suchstrategie: ja Ein- und Ausschlusskriterien klar definiert: ja Qualitätsbewertung der eingeschlossenen Studien erfolgt: unklar Metaanalyse erfolgt: ja Prüfung der Heterogenität: ja |
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Chin, V. et al. Chemotherapy and radiotherapy for advanced pancreatic cancer. Cochrane Database of Systematic Reviews. 2018. CD011044. 2018
| Chin, V. et al. Chemotherapy and radiotherapy for advanced pancreatic cancer. Cochrane Database of Systematic Reviews. 2018. CD011044. 2018 | ||||
|---|---|---|---|---|
| Evidence level/Study Types | P - I - C | Outcomes/Results | Literature References | |
| Evidence level: 1 Study type: Systematisches Review + Metaanalyse Databases: Cochrane Central Register of Controlled Trials, Medline, Embase, Cancerlit Search period: Cochrane: 14.06.2017 Medline: 1946 bis 14.06.2017 Embase: 1980 bis 14.06.2017 Cancerlit: 1999 bis 2002 Inclusion Criteria: 1. RCTs (publiziert u. nicht-publiziert) 2. Vergleich Intervention vs. Placebo / andere Intervention / BSC 3. histologisch oder zytologisch gesichertes PDAC 4. fortgeschritten, nicht-resektabel oder rezidiviert 5. Intervention: Chemotherapie (ChT), Radiotherapie (RT), Radiochemotherapie (RChT) vs. Placebo / keine Therapie / BSC oder andere ChT und/oder RT Exclusion Criteria: |
Population: Patienten mit fortgeschrittenem, nicht-resektablem oder rezidiviertem PDAC Intervention: Chemotherapie (ChT) Gemcitabin-Kombination (Gem-K) Fluoropyrimidin-Kombination (Fluoro-K) Comparison: Gemcitabin (Gem) Fluoropyrimidin (Fluoro) Best supportive care (BSC) (BSC: in advanced disease is defined as anything other than chemotherapy. It may include symptom control by radiotherapy (not to the primary site), palliative surgery, biliary stent insertion, analgesia, blood transfusion, and psychological or social support) |
Primary: Gesamtüberleben Secondary: Progressionsfreies Überleben Lebensqualität Ansprechen Toxizitäten Results: Systematisches Review n=60 Studien (RCTs) Metaanalyse n=42 Studien (RCTs) Chemotherapie n=42 Studien (RCTs) n=9.463 Patienten Radiotherapie keine Studien identifiziert Gesamtüberleben ChT vs. BSC (4 Studien) Kein statistisch signifikanter Unterschied HR 1,08 (CI 95% 0,88-1,33) p nicht angegeben Median: ChT: 3,0-8,6 Monate BSC: 2,5-7,0 Monate ChT vs. Gem (8 Studien) Gepoolt in Subgruppen 5-FU vs. Gem (1 Studie) Statistisch signifikant länger bei Gem HR 1,69 (95% CI 1,25-2,27) p<0,001 Differenz im medianen Überleben 1,3 Monate länger bei Gem als bei 5-FU FOLFIRINOX vs. Gem (2 Studien) Statistisch signifikant länger bei FOLFIRINOX HR 0,51 (95% CI 0,43-0,60) p<0,001 FOLFIRINOX: 4,3 Monate Gem: 3,4 Monate CO-101 vs. Gem (1 Sudie) Kein statistisch signifikanter Unterschied HR 1,07 (95% CI 0,86-1,34) p=0,68 CO-101: 5,2 Monate Gem: 6,0 Monate ZD9331 vs. Gem (1 Studie) Kein statistisch signifikanter Unterschied HR 0,86 (95% CI 0,42-1,76) p=0,68 ZD9331: 5,0 Monate Gem: 3,6 Monate Fixed dose rate Gem (FDR-Gem) vs. Gem (2 Studien) Statistisch signifikant länger bei FDR-Gem HR 0,79 (95% CI 0,66-0,94) p=0,009 FDR-Gem: 6,2-8,0 Monate Gem: 4,9-5,0 Monate Exatecan (DX-8951f) vs. Gem (1 Studie) Kein statistisch signifikanter Unterschied HR 1,27 (95% CI 0,96-1,68) p=0,093 Exatecan: 5 Monate Gem: 6,6 Monate Gem-K vs. Gem Gepoolt in Untergruppen Gem + Platin vs. Gem (6 Studien) Kein statistisch signifikanter Unterschied HR 0,94 (95% CI 0,81-1,08) p=0,38 Gem+Platin: 5,6-9,0 Monate Gem: 4,6-9,1 Monate Gem + Fluoropyrimidin (oral/i.v.) vs. Gem (10 Studien) Statistisch signifikant länger bei G + Fluoropyrimidin HR 0,88 (95% CI 0,81-0,95) p=0,001 Gem + Fluoropyrimidin 6,7-13,7 Monate Gem 5,4-8,8 Monate Gem + Topoisomerasehemmer vs. Gem (3 Studien) Kein statistisch signifikanter Unterschied HR 1,01 (95% CI 0,87-1,16) p=0,92 Gem+Topo: 6,2-6,4 Monate Gem: 6,5-6,7 Monate Gem + Taxan vs. Gem (1 Studie) Statistisch signifikant länger bei Gem+Taxan HR 0,72 (95% CI 0,62-0,84) p<0,001 Gem+Taxan: 8,5 Monate Gem: 6,7 Monate Gem + andere ChT vs. Gem (2 Studien) Statistisch signifikant länger bei Gem+andere ChT HR 0,55 (95% CI 0,39-0,79) p=0,001 Gem+andere ChT: 11,9 Monate Gem: 7,1 Monate Gem + andere Agenzien vs. Gem (4 Studien) Kein statistisch signifikanter Unterschied HR 0,79 (95% CI 0,56-1,10) p=0,16 Gem+Agens: 5,2-10,4 Monate Gem: 5,2-9,7 Monate Fluoro-K vs. Fluoro (4 Studien) Kein statistisch signifikanter Unterschied HR 0,84 (95% CI 0,61-1,15) p=0,27 Fluoro-K: 3,7-6,5 Monate Fluoro: 3,4-5,25 Monate Progressionsfreies Überleben ChT vs. BSC nicht angegeben ChT vs. Gem 5-FU vs. Gem (1 Studie) Statistisch signifikant länger bei Gem HR 1,47 (95% CI 1,12-1,92) p=0,005 FOLFIRINOX vs. Gem (2 Studien) Statistisch signifikant länger bei FOLFIRINOX HR 0,46 (95% CI 0,38-0,57) p<0,001 CO-101 vs. G nicht angegeben ZD9331 vs. Gem (1 Studie) Kein statistisch signifikanter Unterschied HR 0,78 (95% CI 0,46-1,32) p=0,36 Fixed dose rate Gem (FDR-Gem) vs. Gem (1 Studie) Kein statistisch signifikanter Unterschied HR 0,88 (95% CI 0,77-1,01) p=0,06 Exatecan (DX-8951f) vs. Gem (1 Studie) nicht angegeben Gem-K vs. Gem Gem + Platin vs. Gem (4 Studien) Statistisch signifikant länger bei Gem+Platin HR 0,80 (95% CI 0,68-0,95) p=0,01 Gem + Fluoropyrimidin (oral/i.v.) vs. Gem (8 Studien) Statistisch signifikant länger bei Gem+Fluoropyrimidin HR 0,79 (95% CI 0,72-0,87) p<0,001 Gem + Topoisomerasehemmer vs. Gem (2 Studien) Kein statistisch signifikanter Unterschied HR 0,91 (95% CI 0,78-1,07) p=0,26 Gem + Taxan vs. Gem (1 Studie) Statistisch signifikant länger bei Gem + Taxan HR 0,69 (95% CI 0,58-0,82) p<0,001 Gem + andere ChT vs. Gem (2 Studien) Statistisch signifikant länger bei Gem+andere ChT HR 0,43 (95% CI 0,30-0,62) p<0,001 Gem + andere Agenzien vs. Gem (1 Studie) Kein statistisch signifikanter Unterschied HR 1,05 (95% CI 0,68-1,62) p=0,83 Fluoro-K vs. Fluoro (2 Studien) Kein statistisch signifikanter Unterschied HR 0,52 (95% CI 0,19-1,38) p=0,19 Lebensqualität ChT vs. BSC n=1 Studie Kein statistisch signifikanter Unterschied im Karnofsky performance Status n=1 Studie Statistische signifikant höher bei ChT n=1 Studie Statistisch signifikant höher bei BSC im ersten Monat (p=0,028), im 5. Monat (p=0,010) und im 6. Monat (p=0,0003); Kein statistisch signifikanter Unterschied in den Monaten 3 und 4 ChT vs. G 5-FU vs. G n=1 Studie n=126 Patienten Statistisch signifikant besser bei G p-Wert nicht angegeben FOLFIRINOX vs. Gem (2 Studien) Statistisch signifikant längere Zeit bis zur Verschlechterung bei FOLFIRINOX HR 0,46 (95% CI 0,35-0,61) p<0,001 CO-101 vs. G nicht angegeben ZD9331 vs. G nicht angegeben Fixed dose rate G (FDR-gem) vs. G nicht angegeben Exatecan (DX-8951f) vs. Gem (1 Studie) Schmerzen Statistisch signifikant besser bei Gem p=0,049 Karnofsky-Performance-Status Statistisch signifikant besser bei Gem p=0,011 Gewichtsverlust Statistisch signifikant besser bei Gem p=0,020 Allgemeine Lebensqualität Kein statistisch signifikanter Unterschied p nicht angegeben Gem-K vs. Gem Gem + Platin vs. Gem (4 Studien) Nicht gepoolt 3 Studien: Kein statistisch signifikanter Unterschied p=0,07; 2 p-Werte nicht angegeben 1 Studie Statistisch signifikant besser bei Gem p<0,001 Gem + Fluoropyrimidin (oral/i.v.) vs. Gem (5 Studien) 2 Studien Kein statistisch signifikanter Unterschied p-Wert nicht angegeben 2 Studien Statistisch signifikant besser bei Gem+Fluoropyrimidin p<0,02; p<0,001 1 Studie Statistisch signifikant besser bzgl. Schmerzen bei Gem+Fluoropyrimidin p-Wert nicht angegeben Gem + Topoisomerasehemmer vs. Gem (1 Studie) Kein statistisch signifikanter Unterschied p-Wert nicht angegeben Gem + Taxan vs. Gem (1 Studie) nicht angegeben Gem + andere ChT vs. Gem (2 Studien) 1 Studie Statistisch signifikant besser bei Gem+andere ChT p-Wert nicht angegeben 1 Studie Stichprobe zu klein für statistische Auswertung Gem + andere Agenzien vs. Gem (2 Studien) 1 Studie Kein statistisch signifikanter Unterschied 1 Studie Statistisch signifikant besser bei Gem+Agens bzgl. Schmerzen, Performance Status, Gewichtszunahme p-Wert nicht angegeben Fluoro-K vs. Fluoro (1 Studie) Statistisch signifikant besser nach 24 Wochen bei Fluoro-K (p=0,035) und weniger Schmerzen (p=0,048) bei Fluoro-K sowie weniger Dyspnoe nach 12 Wochen (p=0,033) Fluoro-K Ansprechen Ansprechraten ChT vs. BSC nicht angegeben ChT vs. Gem 5-FU vs. Gem (1 Studie) Kein statistisch signifikanter Unterschied RR 0,14 (95% CI 0,01-2,71) p=0,19 FOLFIRINOX vs. Gem (2 Studien) Statistisch signifikant höher bei FOLFIRINOX RR 3,38 (95% CI 2,01-5,65) p<0,001 CO-101 vs. Gem (1 Sudie) Kein statistisch signifikanter Unterschied RR 0,67 (95% CI 0,43-1,04) p=0,08 ZD9331 vs. Gem (1 Studie) Kein statistisch signifikanter Unterschied RR 0,42 (95% CI 0,04-4,33) p=0,46 Fixed dose rate Gem (FDR-Gem) vs. Gem (2 Studien) Kein statistisch signifikanter Unterschied RR 1,59 (95% CI 0,91-2,79) p=0,10 Exatecan (DX-8951f) vs. Gem (1 Studie) Statistisch signifikant höher bei Gem RR 0,10 (95% CI 0,01-0,78) p=0,03 Gem-K vs. Gem Gem + Platin vs. Gem (6 Studien) Statistisch signifikant höher bei Gem+Platin RR 1,48 (95% CI 1,11-1,98) p=0,007 Gem + Fluoropyrimidin (oral/i.v.) vs. Gem (9 Studien) Statistisch signifikant höher bei Gem+Fluoropyrimidin RR 1,78 (95% CI 1,29-2,47) p<0,001 Gem + Topoisomerasehemmer vs. Gem (3 Studien) Kein statistisch signifikanter Unterschied RR 1,50 (95% CI 0,92-2,46) p=0,11 Gem + Taxan vs. Gem (1 Studie) Statistisch signifikant höher bei Gem+Taxan RR 3.29 (95% CI 2,24-4,84) p<0,001 Gem + andere ChT vs. Gem (1 Studie) Kein statistisch signifikanter Unterschied RR 1,94 (95% CI 0,83-4,56) p=0,13 Gem + andere Agenzien vs. Gem (3 Studien) Statistisch signifikant höher bei Gem+andere Agenzien RR 3,66 (95% CI 1,04-12,82) p=0,04 Fluoro-K vs. Fluoro (4 Studien) Kein statistisch signifikanter Unterschied RR 1,18 (95% CI 0,52-2,68) p=0,10 Toxizitäten (Grad 3-4) ChT vs. BSC nicht angegeben ChT vs. Gem 5-FU vs. Gem (1 Studie) Neutropenie Statistisch signifikant mehr bei Gem p=0,006 Anämie Kein statistisch signifikanter Unterschied p=0,08 Thrombozytopenien Kein statistisch signifikanter Unterschied p=0,09 Übelkeit Kein statistisch signifikanter Unterschied p=0,13 Diarrhoen Kein statistisch signifikanter Unterschied p=0,34 FOLFIRINOX vs. Gem (2 Studien) Neutropenie Statistisch signifikant mehr Neutropenien bei FOLFIRINOX p<0,001 Anämie Kein statistisch signifikanter Unterschied p=0,52 Thrombozytopenien Kein statistisch signifikanter Unterschied p=0,05 CO-101 vs. Gem (1 Sudie) Kein statistisch signifikanter Unterschied p-Wert nicht angegeben ZD9331 vs. G n=1 Studien n=55 Patienten Kein statistisch signifikanter Unterschied p-Wert nicht angegeben Fixed dose rate Gem (FDR-Gem) vs. Gem (2 Studien) Anämie Statistisch signifikant mehr bei FDR-GEM p=0,003 Neutropenien Statistisch signifikant mehr bei FDR-GEM p<0,001 Thrombozytopenien Statistisch signifikant mehr bei FDR-GEM p<0,001 Übelkeit Kein statistisch signifikanter Unterschied p=0,09 Diarrhoen Kein statistisch signifikanter Unterschied 0,12 Exatecan (DX-8951f) vs. Gem (1 Studie) Anämie Kein statistisch signifikanter Unterschied p=1,00 Neutropenie Kein statistisch signifikanter Unterschied p=1,00 Thrombozytopenie Kein statistisch signifikanter Unterschied p=0,43 Übelkeit Kein statistisch signifikanter Unterschied p=0,36 Gem-K vs. Gem Gem + Platin vs. Gem (6 Studien) Übelkeit Statistisch signifikant mehr bei Gem+Platin p=0,001 Anämien Kein statistisch signifikanter Unterschied p=0,17 Neutropenien Kein statistisch signifikanter Unterschied p=0,14 Thrombozytopenien Kein statistisch signifikanter Unterschied p=0,05 Diarrhoen Kein statistisch signifikanter Unterschied p=0,38 Gem + Fluoropyrimidin (oral/i.v.) vs. Gem (8 Studien) Neutropenien Statistisch signifikant mehr bei Gem+Fluoropyrimidin p<0,001 Diarrhoen Statistisch signifikant mehr bei Gem+Fluoropyrimidin p=0,002 Anämien Kein statistisch signifikanter Unterschied p=0,47 Thrombozytopenien Kein statistisch signifikanter Unterschied p=0,05 Übelkeit Kein statistisch signifikanter Unterschied p=0,22 Gem + Topoisomerasehemmer vs. Gem (3 Studien) Neutropenien Statistisch signifikant mehr bei Gem+Topo p=0,03 Anämien Kein statistisch signifikanter Unterschied p=0,68 Thrombozytopenien Kein statistisch signifikanter Unterschied p=0,06 Übelkeit Kein statistisch signifikanter Unterschied p=0,09 Diarrhoen Kein statistisch signifikanter Unterschied p=0,12 Gem + Taxan vs. Gem (1 Studie) Neutropenien Statistisch signifikant mehr bei Gem+Taxan p<0,001 Neuropathien Statistisch signifikant mehr bei Gem+Taxan p<0,001 Fatigue Statistisch signifikant mehr bei Gem+Taxan p<0,001 Thrombozytopenien Kein statistisch signifikanter Unterschied p=0,11 Gesamttoxizitäten Kein statistisch signifikanter Unterschied p=0,76 (p=0,11) Gem + andere ChT vs. Gem (1 Studie) Anämien Kein statistisch signifikanter Unterschied p=0,32 Thrombozytopenien Kein statistisch signifikanter Unterschied p=0,11 Neutropenien Kein statistisch signifikanter Unterschied p=0,24 Übelkeit Kein statistisch signifikanter Unterschied p=0,10 Gem + andere Agenzien vs. Gem (3 Studien) Anämien Statistisch signifikant mehr bei Gem+Agens p<0,001 Neutropenien Kein statistisch signifikanter Unterschied p=0,10 Thrombozytopenien Kein statistisch signifikanter Unterschied p=0,56 Übelkeit Kein statistisch signifikanter Unterschied p=0,64 Fluoro-K vs. Fluoro (2 Studien) Anämien Kein statistisch signifikanter Unterschied p=0,16 Neutropenie Kein statistisch signifikanter Unterschied p=0,10 Thrombozytopenien Kein statistisch signifikanter Unterschied p=0,65 Übelkeit Kein statistisch signifikanter Unterschied p=0,93 Diarrhoen Kein statistisch signifikanter Unterschied p=0,89 Fatigue Kein statistisch signifikanter Unterschied p=0,68 Author's Conclusion: Combination chemotherapy has recently overtaken the long-standing gemcitabine as the standard of care. FOLFIRINOX and gemcitabine plus nab-paclitaxel are highly efficacious, but our analysis shows that other combination regimens also offer a benefit. Selection of the most appropriate chemotherapy for individual patients still remains difficult, with clinicopathological stratification remaining elusive. Biomarker development is essential to help rationalise treatment selection for patients. |
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Gemcitabine, oxaliplatin, and capecitabine (GEMOXEL) compared with gemcitabine alone in metastatic pancreatic cancer: a randomized phase II study. Cancer Chemotherapy and Pharmacology 2015;75(4):683. 42. Poplin E, Feng Y, Berlin J, Rothenberg MLH, Mitchell H, et al. Phase III, randomized study of gemcitabine and oxaliplatin versus gemcitabine (fixed-dose rate infusion) compared with gemcitabine (30-minute infusion) in patients with pancreatic carcinoma E6201: a trial of the Eastern Cooperative Oncology Group. Journal of Clinical Oncology 2009;27(23):3778–85. 43. Poplin E, Wasan H, Rolfe L, Raponi M, Ikdahl T, Bondarenko I, et al. Randomized, multicenter, phase II study of CO-101 versus Gemcitabine in patients with metastatic pancreatic ductal adenocarcinoma: including a prospective evaluation of the role of hENT1 in gemcitabine or CO-101 sensitivity. Journal of Clinical Oncology 2013;31 (35):4453–61. 44. Reni M, Cordio S, Milandri C, Passoni P, Bonetto E, Oliani C, et al. Gemcitabine versus cisplatin, epirubicin, fluorouracil, and gemcitabine in advanced pancreatic cancer: a randomised controlled multicentre phase III trial. Lancet Oncology 2005;6(6):369–76. 45. Reni M, Cereda S, Rognone A, Belli C, GhidiniM, Longoni S, et al. A randomized phase II trial of two different 4-drug combinations in advanced pancreatic adenocarcinoma: cisplatin, capecitabine, gemcitabine plus either epirubicin or docetaxel (PEXG or PDXG regimen). Cancer Chemotherapy and Pharmacology 2012;69(1):115–23. 46. Riess H, Helm A, Niedergethmann M, Schmidt-Wolf I, Moik M, Hammer K, et al. A randomised, prospective, multicenter, phase III trial of gemcitabine, 5-fluorouracil (5-FU), folinic acid vs. gemcitabine alone in patients with advanced pancreatic cancer. Journal of Clinical Oncology 2005;23(16 Suppl):LBA4009. 47. Rocha Lima CM, Green MR, Rotche R, Miller WH Jr, Jeffrey GM, Cisar LA. Irinotecan plus gemcitabine results in no survival advantage compared with gemcitabine monotherapy in patients with locally advanced or metastatic pancreatic cancer despite increased tumor response rate. Journal of Clinical Oncology 2004;22(18):3776–83. 48. Scheithauer W, Schull B, Ulrich-Pur H, Schmid K, Raderer M, Haider, et al. Biweekly high-dose gemcitabine alone or in combination with capecitabine in patients with metastatic pancreatic adenocarcinoma: a randomized phase II trial. Annals of Oncology 19/12/2002;14(1):97–104. 49. Singhal MK, Kapoor A, Bagri PK, Narayan S, Singh D, Nirban RK, et al. A phase III trial comparing of FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. Annals of Oncology 2014;25:iv210. 50. Smith D, Gallagher N. A phase II/III study comparing intravenous ZD9331 with gemcitabine in patients with pancreatic cancer. European Journal of Cancer 2003;39(10): 1377–83. 51. Stathopoulos GP, Syrigos K, Aravantinos G, Polyzos A, Papakotoulas P, Fountzilas G, et al. A multicenter phase III trial comparing irinotecan-gemcitabine (IG) with gemcitabine (G) monotherapy as first-line treatment in patients with locally advanced or metastatic pancreatic cancer. British Journal of Cancer 2006;95(5):587–92. 52. Takada T, Nimura Y, Katoh H, Nagakawa T, Nakayama T, Matsushiro T, et al. Prospective randomized trial of 5-fluorouracil, doxorubicin, and mitomycin C for nonresectable pancreatic and biliary carcinoma: multicenter randomized trial. Hepato-gastroenterology 1998;45(24): 2020–6. 53. Tempero M, Plunkett W, Ruiz Van Haperen V, Hainsworth J, Hochster H, Lenzi R, et al. Randomized phase II comparison of dose-intense gemcitabine: thirty-minute infusion and fixed dose rate infusion in patients with pancreatic adenocarcinoma. Journal of Clinical Oncology 2003;21(18):3402–8. 54. Topham C, Glees J, Rawson NS,Woods EM, Coombes RC. Randomised trial of epirubicin alone versus 5-fluorouracil, epirubicin and mitomycin C in locally advanced and metastatic carcinoma of the pancreas. British Journal of Cancer 1991;64(1):179–81. 55. Ueno H, Ioka T, IkedaM, Ohkawa S, Yanagimoto H, Boku N, et al. Randomized phase III study of gemcitabine plus S-1, S-1 alone, or gemcitabine alone in patients with locally advanced and metastatic pancreatic cancer in Japan and Taiwan: GEST study. Journal of Clinical Oncology 2013;31 (13):1640–8. 56. Ueno M, Kobayashi S, Ohkawa S, Kameda R, Andou T, Sugimori K, et al. Randomized phase II study of gemcitabine monotherapy versus gemcitabine with an EPAenriched oral supplement in advanced pancreatic cancer. Journal of Clinical Oncology 2013;31:e15109. 57. Viret F, Ychou M, Lepille D, Mineur L, Navarro F, Topart D, et al. Gemcitabine in combination with cisplatin (GP) versus gemcitabine (G) alone in the treatment of locally advanced or metastatic pancreatic cancer: final results of a multicenter randomized phase II study. Journal of Clinical Oncology 2004;22(14 Suppl):4118. 58. Von Hoff DD, Ervin TJ, Arena FP, Chiorean G, Infante JR, Moore MJ, et al. Randomized phase III study of weekly nab-paclitaxel plus gemcitabine versus gemcitabine alone in patients with metastatic adenocarcinoma of the pancreas (MPACT). Journal of Clinical Oncology 2013;31(4 Suppl): LBA148. 59. Wang X, Ni Q, Jin M, Li Z, Wu Y, Zhao Y, et al. Gemcitabine or gemcitabine plus cisplatin for in 42 patients with locally advanced or metastatic pancreatic cancer. Chinese Journal of Oncology 2002;24(4):404–7. 60. Xinopoulos D, Dimitroulopoulos D, Karanikas I, Fotopoulou A, Oikonomou N, Korkolis D, et al. Gemcitabine as palliative treatment in patients with unresectable pancreatic cancer previously treated with placement of a covered metal stent. A randomized controlled trial. JBUON 2008;13(3):341–7. |
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| Methodical Notes | ||||
| Funding Sources: Internal sources: The Garvan Institute of Medical Research, Australia, PhD stipend top up for Venessa Chin. External sources: The Royal Australasian College of Physicians, Australia. PhD stipend for Venessa Chin National Health and Medical Research Council, Australia. PhD stipend for Venessa Chin Pancare Australia, Australia. PhD stipend for Venessa Chin Sydney Catalyst, Australia. PhD stipend for Venessa Chin COI: VC: Venessa Chin received scholarship funding from the Research and Education Foundation of the Royal Australasian College of Physicians, Pancare Australia, Sydney Catalyst, National Health and Medical Research Council, and the Garvan Institute of Medical Research for work related to this review. AN: none known. KS: Katrin Sjoquist received programme grant funding from the National Health and Medical Research Council for work related to this review. She has received consultancy fees, fees for expert testimony and travel support for work unrelated to this review. CO: none known. LC: Lorraine Chantrill is employed (part-time) by NSWHealth as a staff specialist in medical oncology and enrolled full-time in PhD studies supported by the Australian Federal Government. She has been paid as an advisory board member in relation to chemotherapy for pancreas cancer and has been paid for formulating educational materials and presentations. She has received grants for the practice of clinical trials in pancreas and other cancers. AB: Andew Biankin received grant funding fromthe Cancer Institute NSWfor work related to this review. He also received consultancy fees from Celegene and Clovis Oncology for work unrelated to this review. His institution received consultancy fees from Roche for work unrelated to this review. RS: Rob Scholten’s institution has received grant funding from the Belgian Health Care Knowledge Centre for work related to this review. His institution has also received funding from the WHO and World Federation of Haemophilia for travel and consultancy unrelated to this review. DY: Advisory Board Member, Specialised Therapeutics. Study Quality: Bewertungsinstrumente: Risk of Bias Tool, GRADE für Gesamtüberleben Ergebnisse Risk of Bias: siehe Abbildungen 2 und 3 Ergebnisse GRADE: ChT vs. BSC: Moderate; ChT vs. G: 5-FU vs. G: Moderate; FOLFIRINOX vs. G: Moderate; FDR-gem vs. G: High; CO-101 vs. G: Moderate; ZD9331 vs. G: Moderate; Exatecan (DX-8951f) vs. G: Moderate GK vs. G: G + Platin vs. G: Low; G + Fluoropyrimidin (oral/i.v.) vs. G: High; G + Topoisomerasehemmer vs. G: High; G + Taxan vs. G: High G + ChT vs. G: Low; G + andere Agenzien vs. G: Low FK vs. F: Low Heterogeneity: ChT vs. BSC: OS: Tau2 = 0.0; Chi2 = 1.55, df = 3 (P = 0.67); I2 =0.0% (keine Heterogenität) ChT vs. G: 5-FU vs. G: OS/PFS/Ansprechrate/Anämie/Neutropenie/Thrombozytopenie/Übelkeit/Diarrhoe: nicht anwendbar FOLFIRINOX vs. G: OS: Tau2 = 0.00; Chi2 = 1.41, df = 1 (P = 0.24); I2 =29% (); PFS: Heterogeneity: Tau2 = 0.0; Chi2 = 0.07, df = 1 (P = 0.79); I2 =0.0% (keine Heterogenität); Ansprechrate/Anämie/Neutropenie/Thrombozytopenie: nicht anwendbar FDR-gem vs. G: OS: Tau2 = 0.0; Chi2 = 0.66, df = 1 (P = 0.42); I2 =0.0% (keine Heterogenität); PFS: nicht angegeben; Ansprechrate: Tau2 = 0.0; Chi2 = 0.77, df = 1 (P = 0.38); I2 =0.0% (keine Heterogenität); Anämie: Tau2 = 0.0; Chi2 = 0.93, df = 1 (P = 0.33); I2 =0.0% (keine Heterogenität); Neutropenie: Tau2 = 0.0; Chi2 = 0.00, df = 1 (P = 0.99); I2 =0.0% (keine Heterogenität); Thrombozytopenie: Tau2 = 0.0; Chi2 = 0.40, df = 1 (P = 0.53); I2 =0.0% (keine Heterogenität); Übelkeit: Tau2 = 0.0; Chi2 = 0.01, df = 1 (P = 0.92); I2 =0.0% (keine Heterogenität); Diarrhoe: Tau2 = 0.0; Chi2 = 0.16, df = 1 (P = 0.69); I2 =0.0% (keine Heterogenität) CO-101 vs. G: OS/Ansprechrate/Anämie/Neutropenie/Thrombozytopenie: nicht anwendbar ZD9331 vs. G: OS/PFS/Ansprechrate/Anämie/Neutropenie/Thrombozytopenie/Übelkeit/Diarrhoe: nicht anwendbar Exatecan (DX-8951f) vs. G: OS/Ansprechrate/Anämie/Neutropenie/Thrombozytopenie/Übelkeit: nicht anwendbar GK vs. G: G + Platin vs. G: OS: Tau2 = 0.00; Chi2 = 5.90, df = 5 (P = 0.32); I2 =15% (geringe Heterogenität); PFS: Tau2 = 0.01; Chi2 = 5.56, df = 3 (P = 0.14); I2 =46% (moderate Heterogenität); Ansprechrate: Tau2 = 0.0; Chi2 = 2.90, df = 6 (P = 0.82); I2 =0.0% (keine Heterogenität); Anämie: Tau2 = 0.14; Chi2 = 8.99, df = 6 (P = 0.17); I2 =33% (moderate Heterogenität); Neutropenie: Tau2 = 0.11; Chi2 = 10.94, df = 5 (P = 0.05); I2 =54% (erhebliche Het.); Thrombozytopenie: Tau2 = 0.39; Chi2 = 12.28, df = 5 (P = 0.03); I2 =59% (erhebliche Het.); Übelkeit: Tau2 = 0.0; Chi2 = 2.93, df = 5 (P = 0.71); I2 =0.0% (keine Het.); Diarrhoe: Tau2 = 0.34; Chi2 = 7.04, df = 5 (P = 0.22); I2 =29% (geringe Het.) G + Fluoropyrimidin (oral/i.v.) vs. G: OS: Tau2 = 0.0; Chi2 = 8.53, df = 9 (P = 0.48); I2 =0.0% (keine Heterogenität); PFS: Tau2 = 0.01; Chi2 = 10.56, df = 7 (P = 0.16); I2 =34% (moderate Heterogenität); Ansprechrate: Tau2 = 0.11; Chi2 = 16.58, df = 8 (P = 0.03); I2 =52% (erhebliche Heterogenität); Anämie: Tau2 = 0.0; Chi2 = 3.28, df = 7 (P = 0.86); I2 =0.0% (keine Heterogenität); Neutropenie: Tau2 = 0.0; Chi2 = 4.87, df = 8 (P = 0.77); I2 =0.0% (keine Het.); Thrombozytopenie: Tau2 = 0.09; Chi2 = 11.59, df = 8 (P = 0.17); I2 =31% (moderatie Het.); Übelkeit: Tau2 = 0.0; Chi2 = 4.22, df = 6 (P = 0.65); I2 =0.0% (keine Het.); Diarrhoe: Tau2 = 0.0; Chi2 = 5.27, df = 7 (P = 0.63); I2 =0.0% (keine Het.) G + Topoisomerasehemmer vs. G: OS: Tau2 = 0.0; Chi2 = 0.07, df = 2 (P = 0.96); I2 =0.0% (keine Heterogenität); PFS: Tau2 = 0.0; Chi2 = 0.07, df = 1 (P = 0.79); I2 =0.0% (keine Heterogenität); Ansprechrate: Tau2 = 0.0; Chi2 = 0.07, df = 2 (P = 0.96); I2 =0.0% (keine Heterogenität); Anämie: Tau2 = 0.0; Chi2 = 0.92, df = 2 (P = 0.63); I2 =0.0% (keine Het.); Neutropenie: Tau2 = 0.07; Chi2 = 4.75, df = 2 (P = 0.09); I2 =58% (erhebliche Het.); Thrombozytopenie: Tau2 = 0.30; Chi2 = 4.86, df = 2 (P = 0.09); I2 =59% (erhebliche Het.); Übelkeit: Tau2 = 0.0; Chi2 = 0.74, df = 2 (P = 0.69); I2 =0.0% (keine Het.); Diarrhoe: Tau2 = 1.05; Chi2 = 4.56, df = 2 (P = 0.10); I2 =56% (erhebliche Het.) G + Taxan vs. G: OS/PFS/Ansprechrate/Anämie/Neutropenie/Thrombozytopenie/Neuropathie/Fatigue: nicht anwendbar G + ChT vs. G: OS: Tau2 = 0.02; Chi2 = 1.31, df = 1 (P = 0.25); I2 =24% (geringe Heterogenität); PFS: Tau2 = 0.01; Chi2 = 1.21, df = 1 (P = 0.27); I2 =17% (geringe Heterogenität); Ansprechrate/Anämie/Neutropenie/Thrombozytopenie/Übelkeit: nicht anwendbar G + andere Agenzien vs. G: OS: Tau2 = 0.07; Chi2 = 7.87, df = 3 (P = 0.05); I2 =62% (erhebliche Heterogenität); PFS: nicht angegeben; Ansprechrate: Tau2 = 0.68; Chi2 = 4.24, df = 2 (P = 0.12); I2 =53% (erhebliche Heterogenität); Anämie: Tau2 = 0.0; Chi2 = 1.91, df = 2 (P = 0.39); I2 =0.0% (keine Het.); Neutropenie: Tau2 = 0.37; Chi2 = 6.69, df = 2 (P = 0.04); I2 =70% (erhebliche Het.); Thrombozytopenie: Tau2 = 0.62; Chi2 = 5.14, df = 2 (P = 0.08); I2 =61% (erhebliche Het.); Übelkeit: Tau2 = 0.15; Chi2 = 3.41, df = 3 (P = 0.33); I2 =12% (geringe Het.) FK vs. F: OS: Tau2 = 0.07; Chi2 = 8.83, df = 3 (P = 0.03); I2 =66% (erhebliche Heterogenität); PFS: Tau2 = 0.45; Chi2 = 8.78, df = 1 (P = 0.003); I2 =89% (beträchtliche Het.); Ansprechrate: Tau2 = 0.33; Chi2 = 6.19, df = 3 (P = 0.10); I2 =52% (erhebliche Het.); Anämie: Tau2 = 1.28; Chi2 = 2.02, df = 1 (P = 0.16); I2 =50% (erhebliche Het.); Neutropenie: Tau2 = 0.0; Chi2 = 0.05, df = 1 (P = 0.82); I2 =0.0% (keine Het.); Thrombozytopenie: Tau2 = 0.0; Chi2 = 0.82, df = 1 (P = 0.37); I2 =0.0% (keine Het.); Fatigue: nicht anwendbar; Übelkeit: Tau2 = 0.0; Chi2 = 0.47, df = 1 (P = 0.49); I2 =0.0% (keine Het.); Diarrhoe: Tau2 = 0.0; Chi2 = 0.26, df = 1 (P = 0.61); I2 =0.0% (keine Het.) Publication Bias: funnel plots Notes: Gesamtqualität: keine methodischen Mängel PICO Frage klar formuliert: ja Ausreichende Suchstrategie: ja Ein- und Ausschlusskriterien klar definiert: ja Qualitätsbewertung der eingeschlossenen Studien erfolgt: ja Metaanalyse erfolgt: ja Prüfung der Heterogenität: ja |
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Heinemann, V. et al. Gemcitabine plus erlotinib followed by capecitabine versus capecitabine plus erlotinib followed by gemcitabine in advanced pancreatic cancer: Final results of a randomised phase 3 trial of the 'arbeitsgemeinschaft internistische onkologie' (AIO-PK0104). Gut. 62. 751-759. 2013
| Heinemann, V. et al. Gemcitabine plus erlotinib followed by capecitabine versus capecitabine plus erlotinib followed by gemcitabine in advanced pancreatic cancer: Final results of a randomised phase 3 trial of the 'arbeitsgemeinschaft internistische onkologie' (AIO-PK0104). Gut. 62. 751-759. 2013 | |||
|---|---|---|---|
| Population | Intervention - Comparison | Outcomes/Results | |
| Evidence level: 2 Study type: RCT, multizentrisch (46 Zentren), Deutschland Number of Patient: n=281 randomisiert n=274 letztlich eingeschlossen n=143 Gem+E/Cap n=131 Cap+E/Gem Recruitung Phase: 05/2006-12/2008 Inclusion Criteria: 1. Alter 18-75 Jahre 2. fortgeschrittenes exokrines Pankreaskarzinom (Stadium III-IV) 3. keine vorhergehende Chemo- oder Radiotherapie 4. ausreichende Organfunktion 5. Karnofsky Performance Status ≥60 Exclusion Criteria: |
Intervention: Erstlinie: Capecitabin + Erlotinib Zweitinie: Gemcitabin (Cap+E/Gem) Capecitabin: 1000 mg/m2 oral 2 x täglich über 2 Wochen dann 1 Woche Pause Erlotinib: 150 mg täglich (oral) Gemcitabin: 1000 mg/m2 intravenös (wöchentlich) 7 Wochen 1 Woche Pause dann 3 Wochen 1 Woche Pause Comparison: Erstlinie: Gemcitabin + Erlotinib Zweitlinie: Capecitabin (Gem+E/Cap) Gemcitabin: 1000 mg/m2 intravenös (wöchentlich) 7 Wochen 1 Woche Pause dann 3 Wochen 1 Woche Pause Erlotinib: 150 mg täglich (oral) Capecitabin: 1000 mg/m2 oral 2 x täglich über 2 Wochen dann 1 Woche Pause |
Primary: Time-to-treatment-failure nach Erst- und Zweitlinie (TTF2) Secondary: Time-to-treatment-failure nach Erstlinie (TTF1) Objektives Ansprechen Gesamtüberleben Toxizitäten Results: TTF2 Gem+E/Cap vs Cap+E/Gem Kein statistisch signifikanter Unterschied Gem+E/Cap: 4,2 Monate Cap+E/Gem: 4,2 Monate HR: 1,00 (95% CI 0,78-1,28) p=1,0 TTF1 Gem+E/Cap vs Cap+E/Gem Statistisch Signifikant länger bei Gem+E/Cap Gem+E/Cap: 3,2 Monate Cap+E/Gem: 2,2 Monate HR: 0,69 (95% CI 0,54-0,89) p=0,0034 Gesamtüberleben Gem+E/Cap vs Cap+E/Gem kein statistisch signifikanter Unterschied Gem+E/Cap: 6,2 Monate Cap+E/Gem: 6,9 Monate HR: 1,02 (95% CI: 0,79-1,31) p=0,90 Author's Conclusion: In conclusion, AIO-PK0104 is the first phase 3 clinical trial in advanced PC that investigated a prospectively predefined sequential 1st- and 2nd-line treatment strategy including an anti-EGFR targeted biological agent; both treatment arms were tolerated well and clinical efficacy was comparable for TTF2 and OS. A sequential trial design is feasible within a multicentre context, and future clinical studies should also focus on 2nd-line therapy in patients with advanced PC. Furthermore, the KRAS proto-oncogene may also serve as a biomarker in patients with advanced PC treated with anti-EGFR agents; whether this correlation is prognostic or predictive remains to be defined. |
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| Methodical Notes | |||
| Funding Sources: This work was supported by Hoffmann-La Roche, Germany. COI: VH: Roche (consultant, honoraria for scientific presentations, research funding). UV-K: none. DW: none. EK: none. AM: none. CW: none. SK: none. GK: none. TCG: none. LFvW: none. MRC: Roche (honoraria for scientific presentations, research funding, travel grants). MG: none. TFG: none. SH-B: none. OR: none. GB: none. TH: none. YDK: none. AJ: none. SN: none. SB: Roche (honoraria for scientific presentations, research funding, travel grants). Randomization: For this prospective, multicentre, two-arm, AIO phase 3 trial, patients were stratified according to stage (locally advanced vs metastatic disease) and centre; randomisation was performed centrally by fax in a 1:1 ratio. Blinding: keine Verblindung Dropout Rate/ITT-Analysis: intention-to-treat population n=274 Notes: |
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Ciliberto, D. et al. Role of gemcitabine-based combination therapy in the management of advanced pancreatic cancer: a meta-analysis of randomised trials. Eur J Cancer. 49. 593-603. 2013
| Ciliberto, D. et al. Role of gemcitabine-based combination therapy in the management of advanced pancreatic cancer: a meta-analysis of randomised trials. Eur J Cancer. 49. 593-603. 2013 | ||||
|---|---|---|---|---|
| Evidence level/Study Types | P - I - C | Outcomes/Results | Literature References | |
| Evidence level: 1 Study type: Systematisches Review + Metaanalyse Databases: PubMed, Embase, Cochrane (CENTRAL), meeting abstract databases (ASCO, ESMO) Search period: 01/1997-01/2012 Inclusion Criteria: 1. lokal fortgeschrittenes oder metastasiertes Pankreaskarzinom 2. Beschreibung demographischer Patientendaten (Alter, Geschlecht, Performance) 3. keine ernsten Komorbiditäten 4. ohne onkologische Zweiterkrankung (Ausnahme Zervixkarzinom, weißer Hautkrebs) 5. Kontrollarm: Gem-Monotherapie 6. Interventionsarm: Gem-basierte Kombinationstherapie 7. adäquate Beschreibung des Stagings 8. adäquate Beschreibung der Follow-up Bedingungen Exclusion Criteria: 1. kein Erstlinien-Setting 2. nicht-komparative Studien 3. nicht-prospektive Studien 4. nicht-vergleichbare Endpunkte 5. andere Sprachen außer Englisch 6. andere Administration der Chemo-therapeutika als systemisch oder oral (z.B. intraarteriell oder intraperitoneale Infusion) |
Population: lokal fortgeschrittenes oder metastasiertes Pankreaskarzinom Intervention: Gemcitabin-Kombinationstherapie (Gem-K) Comparison: Gemcitabin Monotherapie (Gem) |
Primary: Gesamtüberleben Secondary: Ansprechen Krankheitskontrollrate Toxizitäten Results: n=34 Studien (RCTs) n=10.660 Patienten Gesamtüberleben (OS) Gem-K vs. Gem (26 Studien) statistisch signifikant höher bei Gem-K HR 0,93 (95%CI: 0,89-0,97) p=0,001 Subgruppenanalyse Gem+Fluoropyrimidine vs. Gem (9 Studien) statistisch signifikant höher bei Gem+Fluoropyrimidine HR 0,91 (95%CI: 0,84-0,99) p nicht angegeben Gem+Platin vs. Gem (6 Studien) kein statistisch signifikanter Unterschied HR 0,91 (95%CI: 0,82-1,01) p nicht angegeben Gem+Andere vs. Gem (2 Studien) kein statistisch signifikanter Unterschied HR 0,87 (95%CI: 0,63-1,22) p nicht angegeben Gem+Biotherapie vs. Gem (7 Studien) kein statistisch signifikanter Unterschied HR 0,94 (95%CI: 0,84-0,99) p nicht angegeben Gem+Irinotecan vs. Gem (2 Studien) kein statistisch signifikanter Unterschied HR 1,01 (95%CI: 0,84-0,99) p nicht angegeben Gem+ORAL Fluoropyrimidine vs. Gem (6 Studien) statistisch signifikant höher bei Gem+ORAL Fluoropyrimidines HR 0,86 (95%CI: 0,77-0,96) p nicht angegeben Gem+IV Fluoropyrimidine vs. Gem (3 Studien) kein statistisch signifikanter Unterschied HR 0,97 (95%CI: 0,82-1,16) p nicht angegeben Gem+Cisplatin vs. Gem (4 Studien) kein statistisch signifikanter Unterschied HR 0,96 (95%CI: 0,83-1,12) p nicht angegeben Gem+Oxaliplatin vs. Gem (2 Studien) statistisch signifikant höher bei Gem+Oxaliplatin HR 0,86 (95%CI: 0,75-1,00) p nicht angegeben Ansprechen Ansprechrate Gem-K vs. Gem (32 Studien) statistisch signifikant höher für Gem-K OR: 0,60 (95%CI: 0,47-0,76) p< 0,001 Subgruppenanalysen Gem+Fluoropyrimidine vs. Gem (9 Studien) kein statistisch signifikanter Unterschied OR 0,62 (95%CI: 0,33-1,14) p nicht angegeben Gem+Andere vs. Gem (3 Studien) statistisch signifikant höher bei Gem+Andere OR 0,33 (95%CI: 0,13-0,84) p nicht angegeben Gem+Platin vs. Gem (8 Studien) statistisch signifikant höher bei Gem+Platin OR 0,61 (95%CI: 0,44-0,84) p nicht angegeben Gem+Biotherapie vs. Gem (10 Studien) kein statistisch signifikanter Unterschied OR 0,84 (95%CI: 0,61-1,16) p nicht angegeben Gem+Irinotecan vs. Gem (2 Studien) kein statistisch signifikanter Unterschied OR 1,01 (95%CI: 0,14-1,11) p nicht angegeben Krankheitskontrollrate Gem-K vs. Gem (32 Studien) statistisch signifikant höher für Gem-K OR: 0,79 (95%CI: 0,66-0,93) p=0,006 Toxizitäten (Grad 3-4) Diarrhoe Gem-K vs. Gem (32 Studien) statistisch signifikant höher bei Gem-K Relatives Risiko 0,53 (95%CI: 0,36-0,79) p=0,002 Übelkeit Gem-K vs. Gem (32 Studien) statistisch signifikant höher beir Gem-K relatives Risiko 0,74 (95%CI: 0,56-0,96) p=0,026 Neutropenie Gem-K vs. Gem (32 Studien) statistisch signifikant höher für Gem-K relatives Risiko 0,71 (95%CI: 0,59-0,85) p<0,001 Thrombozytopenie Gem-K vs. Gem (32 Studien) statistisch signifikant höher für Gem-K relatives Risiko 0,57 (95%CI: 0,43-0,75) p<0,001 Anorexie Gem-K vs. Gem (32 Studien) kein statistisch signifikanter Unterschied relatives Risiko 0,80 (95%CI: 0,51-1,26) p=0,333 Fatigue Gem-K vs. Gem (32 Studien) kein statistisch signifikanter Unterschied relatives Risiko 0,90 (95%CI: 0,72-1,14) p=0,396 Erbrechen kein statistisch signifikanter Unterschied relatives Risiko 0,89 (95%CI: 0,65-1,23) p=0,481 Anämie Gem-K vs. Gem (32 Studien) kein statistisch signifikanter Unterschied relatives Risiko 0,92 (95%CI: 0,75-1,13) p=0,448 Author's Conclusion: It appears obvious that the purpose of our meta-analysis is not to modify the clinical practice, but to rise questions in order to challenge the current believes and/or to design prospective trials. We think that our results provide support to the general view that patients with APC should be considered not only for gemcitabine alone but also for intensive combination treatment, since such an approach provides benefit in terms of OS, RR and DCR at the price of increased toxicity. New approaches based on consolidated preclinical findings, on a more rational use of currently available drugs and on the selection of patients in the era of targeted therapy are eagerly awaited on this specific topic. |
Scheithauer W, Schull B, Ulrich-Pur H, et al. Biweekly high-dose gemcitabine alone or in combination with capecitabine in patients with metastatic pancreatic adenocarcinoma: a randomized phase II trial. Ann Oncol 2003;14(1):97–104. Berlin JD, Catalano P, Thomas JP, Kugler JW, Haller DG, Benson AB. 3rd. Phase III study of gemcitabine in combination with fluorouracil versus gemcitabine alone in patients with advanced pancreatic carcinoma: Eastern Cooperative Oncology Group Trial E2297. J Clin Oncol 2002;20(15):3270–5. Herrmann R, Bodoky G, Ruhstaller T, et al. Gemcitabine plus capecitabine compared with gemcitabine alone in advanced pancreatic cancer: a randomized, multicenter, phase III trial of the Swiss Group for Clinical Cancer Research and the Central European Cooperative Oncology Group. J Clin Oncol 2007;25(16):2212–7. Cunningham D, Chau I, Stocken DD, et al. Phase III randomized comparison of gemcitabine versus gemcitabine plus capecitabine in patients with advanced pancreatic cancer. J Clin Oncol 2009;27(33):5513–8. Nakai Y, Isayama H, Sasaki T, et al. A multicenter randomized controlled trial of gemcitabine (G) alone versus gemcitabine and S-1 combination therapy (GS) in patients with unresectable advanced pancreatic cancer (PC): GEMSAP study. J Clin Oncol 2010;28(Suppl. 15):4037, 2010 ASCO Annual Meeting Proceedings (Post-Meeting Edition). Riess H, Helm A, Niedergethmann M, et al. A randomised, prospective, multicenter, phase III trial of gemcitabine, 5-fluorouracil (5-FU), folinic acid vs. gemcitabine alone in patients with advanced pancreatic cancer. J Clin Oncol 2005;23 (Suppl. 16):LBA4009, 2005 ASCO Annual Meeting Proceedings. Di Costanzo F, Carlini P, Doni L, et al. Gemcitabine with or without continuous infusion 5-FU in advanced pancreatic cancer: a randomised phase II trial of the Italian oncology group for clinical research (GOIRC). Br J Cancer 2005;93(2):185–9. Ohkawa S. Randomized controlled trial of gemcitabine in combination with UFT versus gemcitabine alone in patients with advanced pancreatic cancer. J Clin Oncol 2004;22(Suppl. 14):4131, 2004 ASCO Annual Meeting Proceedings (Post-Meeting Edition). Ioka T, Ikeda M, Ohkawa S, et al. Randomized phase III study of gemcitabine plus S-1 (GS) versus S-1 versus gemcitabine (GEM) in unresectable advanced pancreatic cancer (PC) in Japan and Taiwan: GEST study. J Clin Oncol 2011;29(Suppl. 15):4007, 2011 ASCO Annual Meeting Proceedings (Post-Meeting Edition). Omuro Y, Ikari T, Ishii H, et al. A randomized phase II study of gemcitabine plus S-1 versus gemcitabine alone in patients with unresectable pancreatic cancer. J Clin Oncol 2011;29(Suppl. 15): 4029, 2011 ASCO Annual Meeting Proceedings (Post-Meeting Edition). Oettle H, Richards D, Ramanathan RK, et al. A phase III trial of pemetrexed plus gemcitabine versus gemcitabine in patients with unresectable or metastatic pancreatic cancer. Ann Oncol 2005;16(10):1639–45. Abou-Alfa GK, Letourneau R, Harker G, et al. Randomized phase III study of exatecan and gemcitabine compared with gemcitabine alone in untreated advanced pancreatic cancer. J Clin Oncol 2006;24(27):4441–7. Reni M, Cordio S, Milandri C, et al. Gemcitabine versus cisplatin, epirubicin, fluorouracil, and gemcitabine in advanced pancreatic cancer: a randomised controlled multicentre phase III trial. Lancet Oncol 2005;6(6):369–76. Colucci G, Giuliani F, Gebbia V, et al. Gemcitabine alone or with cisplatin for the treatment of patients with locally advanced and/or metastatic pancreatic carcinoma: a prospective, randomized phase III study of the Gruppo Oncologia dell’Italia Meridionale. Cancer 2002;94(4):902–10. Louvet C, Labianca R, Hammel P, et al. Gemcitabine in combination with oxaliplatin compared with gemcitabine alone in locally advanced or metastatic pancreatic cancer: results of a GERCOR and GISCAD phase III trial. J Clin Oncol 2005;23(15): 3509–16. Heinemann V, Quietzsch D, Gieseler F, et al. Randomized phase III trial of gemcitabine plus cisplatin compared with gemcitabine alone in advanced pancreatic cancer. J Clin Oncol 2006;24(24): 3946–52. Poplin E, Feng Y, Berlin J, et al. Phase III, randomized study of gemcitabine and oxaliplatin versus gemcitabine (fixed-dose rate infusion) compared with gemcitabine (30-minute infusion) in patients with pancreatic carcinoma E6201: a trial of the Eastern Cooperative Oncology Group. J Clin Oncol 2009;27(23):3778–85. Colucci G, Labianca R, Di Costanzo F, et al. Randomized phase III trial of gemcitabine plus cisplatin compared with single-agent gemcitabine as first-line treatment of patients with advanced pancreatic cancer: the GIP-1 study. J Clin Oncol 2010;28(10):1645–51. Wang X, Ni Q, Jin M, et al. Gemcitabine or gemcitabine plus cisplatin for in 42 patients with locally advanced or metastatic pancreatic cancer. Zhonghua Zhong Liu Za Zhi [Chin J Oncol] 2002;24(4):404–7. Viret F, Ychou M, Lepille D, et al. Gemcitabine in combination with cisplatin (GP) versus gemcitabine (G) alone in the treatment of locally advanced or metastatic pancreatic cancer: final results of a multicenter randomized phase II study. J Clin Oncol 2004;22(Suppl. 14):4118, 2004 ASCO Annual Meeting Proceedings (Post-Meeting Edition). Li CP, Chao Y. A prospective randomized trial of gemcitabine alone or gemcitabine + cisplatin in the treatment of metastatic pancreatic cancer. J Clin Oncol 2004;22(Suppl. 14):4144, 2004 ASCO Annual Meeting Proceedings (Post-Meeting Edition). Viret F, Ychou M, Lepille D, et al. Gemcitabine in combination with cisplatin (GP) versus gemcitabine (G) alone in the treatment of locally advanced or metastatic pancreatic cancer: final results of a multicenter randomized phase II study. J Clin Oncol 2004;22(Suppl. 14):4118, 2004 ASCO Annual Meeting Proceedings (Post-Meeting Edition). Van Cutsem E, van de Velde H, Karasek P, et al. Phase III trial of gemcitabine plus tipifarnib compared with gemcitabine plus placebo in advanced pancreatic cancer. J Clin Oncol 2004;22(8): 1430–8. Moore MJ, Goldstein D, Hamm J, et al. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 2007;25(15):1960–6. Kindler HL, Niedzwiecki D, Hollis D, et al. Gemcitabine plus bevacizumab compared with gemcitabine plus placebo in patients with advanced pancreatic cancer: phase III trial of the Cancer and Leukemia Group B (CALGB 80303). J Clin Oncol 2010;28(22): 3617–22. Philip PA, Benedetti J, Corless CL, et al. Phase III study comparing gemcitabine plus cetuximab versus gemcitabine in patients with advanced pancreatic adenocarcinoma: Southwest Oncology Group-directed intergroup trial S0205. J Clin Oncol 2010;28(22):3605–10. Kindler HL, Ioka T, Richel DJ, et al. Axitinib plus gemcitabine versus placebo plus gemcitabine in patients with advanced pancreatic adenocarcinoma: a double-blind randomised phase 3 study. Lancet Oncol 2011;12(3):256–62. Spano JP, Chodkiewicz C, Maurel J, et al. Efficacy of gemcitabine plus axitinib compared with gemcitabine alone in patients with advanced pancreatic cancer: an open-label randomised phase II study. Lancet 2008;371(9630):2101–8. Bramhall SR, Schulz J, Nemunaitis J, Brown PD, Baillet M, Buckels JA. A double-blind placebo-controlled, randomised study comparing gemcitabine and marimastat with gemcitabine and placebo as first line therapy in patients with advanced pancreatic cancer. Br J Cancer 2002;87(2):161–7. Richards DA, Kuefler PR, Becerra C, et al. Gemcitabine plus enzastaurin or single-agent gemcitabine in locally advanced or metastatic pancreatic cancer: results of a phase II, randomized, noncomparative study. Invest New Drugs 2011;29(1):144–53 Friess H, Langrehr JM, Oettle H, et al. A randomized multi-center phase II trial of the angiogenesis inhibitor Cilengitide (EMD 121974) and gemcitabine compared with gemcitabine alone in advanced unresectable pancreatic cancer. BMC Cancer 2006;6: 285. Wolpin BM, O’Reilly EM, Ko Y, Blaszkowsky LS, Rarick MU. Rocha Lima CM, et al. Global, multicenter, open-label, randomized phase II trial comparing gemcitabine (G) with. G plus AGS-1C4D4 (A) in patients (pts) with metastatic pancreatic cancer (mPC). J Clin Oncol 2011;29(Suppl. 15):4031, 2011 ASCO Annual Meeting Proceedings (Post-Meeting Edition). Meng Z, Liu L, Shen Y, et al. A randomized phase II study of gemcitabine (G) plus the cardiac glycoside huachansu (H) in the treatment of patients with locally advanced (LAPC) or metastatic pancreatic cancer (MPC). J Clin Oncol 2011;29(Suppl. 15):4127, 2011 ASCO Annual Meeting Proceedings (Post-Meeting Edition). Rocha Lima CM, Green MR, Rotche R, et al. Irinotecan plus gemcitabine results in no survival advantage compared with gemcitabine monotherapy in patients with locally advanced or metastatic pancreatic cancer despite increased tumor response rate. J Clin Oncol 2004;22(18):3776–83. Stathopoulos GP, Syrigos K, Aravantinos G, et al. A multicenter phase III trial comparing irinotecan-gemcitabine (IG) with gemcitabine (G) monotherapy as first-line treatment in patients with locally advanced or metastatic pancreatic cancer. Br J Cancer 2006;95(5):587–92. |
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| Methodical Notes | ||||
| Funding Sources: No funding source had role in the design, collection, analysis, interpretation, or writing of the study. COI: None declared Study Quality: Bewertungsinstrument: Cochrane Reviewers’ Handbook, Kriterien: Randomisierungsmethode, Verfahren der Gruppenzuteilung, Verblindungsmethode und Follow-up Ergebnis: Score A (geringes Biasrisiko): 24 Studien; Score B (intermediäres Biasrisiko): 5 Studien; Score C (hohes Biasrisiko): 5 Studien Heterogeneity: Bewertung: Cochranes Q-test, I2-Statistik: Ergebnis: Vergleich Überleben zwischen Patienten behandelt mit verschiedenen Gem-K Regimen vs. Gem Monotherapie Gem+Fluoropyrimidines vs. Gem (9 Studien), I2: 0,0%, p=0,455 Gem+Platin vs. Gem (6 Studien), I2: 0,0%, p=0,985 Gem+andere vs. Gem (2 Studien), I2: 49,2%, p=0,160 Gem+Biotherapie vs. Gem (7 Studien), I2: 0,0%, p=0,534 Gem+Irinotecan vs. Gem (2 Studien), I2: 0,0%, p=0,840 Zusammenhang zwischen oraler und intravenöser Gabe von Fluoropyrimidinen und zwischen Cisplatin und Oxaliplatin Gem+ ORAL Fluoropyrimidines vs. Gem (6 Studien), I2:0,0%, p=0,786 Gem+Cisplatin vs. Gem (4 Studien), I2:0,0%, p=0,909 Gem+Fluoropyrimidines vs. Gem (3 Studien), I2:38,6%, p=0,196 Gem+Oxaliplatin vs. Gem (2 Studien), I2:0,0%, p=0,760 Zusammenhang Ansprechrate (RR) Gem-Kombinationstherapie vs. Gem-Monotherapie Gem+Fluoropyrimidines vs. Gem (9 Studien), I2:71,8%, p=0,000 Gem+Andere vs. Gem (3 Studien), I2:64,6%, p=0,059 Gem+Platin vs. Gem (8 Studien), I2:0,0%, p=0,483 Gem+Biotherapie vs. Gem (10 Studien), I2:0,0%, p=0,512 Gem+Irinotecan vs. Gem (2 Studien), I2:53,4%, p=0,143 Publication Bias: Bewertung: Beggs-Test mit Funnel-Plot: Ergebnis: keine Evidenz für Publikations-Bias Notes: Gesamtqualität: ausreichend PICO Frage klar formuliert: ja Ausreichende Suchstrategie: unklar Ein- und Ausschlusskriterien klar definiert: ja Qualitätsbewertung der eingeschlossenen Studien erfolgt: ja Metaanalyse erfolgt: ja Prüfung der Heterogenität: ja |
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Eltawil, K. M. et al. Meta-analysis of Phase III randomized trials of molecular targeted therapies for advanced pancreatic cancer. HPB. . . 2012
| Eltawil, K. M. et al. Meta-analysis of Phase III randomized trials of molecular targeted therapies for advanced pancreatic cancer. HPB. . . 2012 | ||||
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| Evidence level/Study Types | P - I - C | Outcomes/Results | Literature References | |
| Evidence level: 1 Study type: Systematisches Review + Metaanalyse Databases: PubMed, Excerpta Medical Database, Scopus, Web of Science, the Cochrane Central Register of Controlled Trials, the hepatobiliary group in the Cochrane Library, EMBASE, CINAHL Search period: bis 11/2011 (keine Angabe zum Suchzeitraum) Inclusion Criteria: 1. unresektable Pankreaskarzinome 2. Phase III RCTs 3. Palliative Chemotherapie plus zielgerichtete Molekular-therapeutika (MTAs) 4. in Studien zugelassene MTAs Exclusion Criteria: 1. unresektable Pankreaskarzinome 2. Phase III RCTs 3. Palliative Chemotherapie plus zielgerichtete Molekular-therapeutika (MTAs) 4. in Studien zugelassene MTAs |
Population: Patienten mit nicht resektablem Pankreaskarzinom Intervention: Gemcitabin plus zielgerichtete Molekular-therapeutika (Bevacizumab, Cetuximab, Erlotinib, Marimastat, Axitinib, Pemtrexed, Tipifarnib) (Gem+MTAs) Comparison: Gemcitabin (Monotherapie oder in Kombination mit Placebo) (Gem) |
Primary: Gesamtüberleben Secondary: Progressionsfreies Überleben Ansprechen Toxizitäten Results: n=7 Studien n=3973 Patienten n=1981 Gem+MTAs n=1992 Gem Gesamtüberleben Gem+MTAs vs. Gem (7 Studien) kein statistisch signifikanter Unterschied HR 0,94 (95%CI: 0,87-1,01) p=0,09 Progressionsfreies Überleben Gem+MTAs vs. Gem (7 Studien) statistisch signifikant höher in Gem+MTAs HR 0,86 (95%CI: 0,79-0,93) p=0,000 Ansprechen Objektive Ansprechrate Gem+MTAs vs. Gem (7 Studien) statistisch signifikant höher in Gem+MTAs OR 1,35 (95%CI: 1,05-1,74) p=0,01 Toxizitäten Grad 3-4 Gem+MTAs vs. Gem (7 Studien) statistisch signifikant höher in Gem+MTAs OR 1,79 (95%CI: 1,50-2,13) p=0,00 Grad 5 (behandlungsspezifische Mortalität) Gem+MTAs vs. Gem (6 Studien) statistisch signifikant höher für Gem+MTAs OR 2,19 (95%CI: 1,19-4,0) p=0,01 Author's Conclusion: This is the first meta-analysis on the results of MTAs in the treatment of unresectable PC. For reasons that are still not very well understood, PC appears to be very resistant, not only to well known cytotoxic agents, but also to the MTAs currently available. The findings of this study do not support the use of available MTAs in combination with gemcitabine for the palliation of patients affected by advanced PC. Although the enthusiasm for MTAs in PC has declined because of their modest effects and high costs, further RCTs combining MTAs with FOLFIRNOX should be encouraged. In further trials, cost-effective analyses should also be included among the outcomes of interest as the costs of adding MTAs to other cytotoxic agents will remain a significant constraint on the wide use of these agents in the treatment of patients with PC. |
Kindler HL, Niedzwiecki D, Hollis D, Sutherland S, Schrag D, Hurwitz H et al. (2010) Gemcitabine plus bevacizumab compared with gemcitabine plus placebo in patients with advanced pancreatic cancer: phase III trial of the Cancer and Leukemia Group B (CALGB 80303). J Clin Oncol 28:3617–3622. Philip PA, Benedetti J, Corless CL, Wong R, O'Reilly EM, Flynn PJ et al. (2010) Phase III study comparing gemcitabine plus cetuximab versus gemcitabine in patients with advanced pancreatic adenocarcinoma: Southwest Oncology Group – directed intergroup trial S0205. J Clin Oncol 28:3605–3610. Moore MJ, Goldstein D, Hamm J, Figer A, Hecht JR, Gallinger S et al. (2007) Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 25:1960–1966. Bramhall SR, Schulz J, Nemunaitis J, Brown PD, Baillet M, Buckels JA. (2002) A double-blind placebo-controlled, randomized study comparing gemcitabine and marimastat with gemcitabine and placebo as first line therapy in patients with advanced pancreatic cancer. Br J Cancer 87:161–167. van Cutsem E, van de Velde H, Karasek P, Oettle H, Vervenne WL, Szawlowski A et al. (2004) Phase III trial of gemcitabine plus tipifarnib compared with gemcitabine plus placebo in advanced pancreatic cancer. J Clin Oncol 22:1430–1438. Kindler HL, Ioka T, Richel DJ, Bennouna J, Létourneau R, Okusaka T et al. (2011) Axitinib plus gemcitabine versus placebo plus gemcitabine in patients with advanced pancreatic adenocarcinoma: a double-blind randomized phase 3 study. Lancet Oncol 12:256–262. Oettle H, Richards D, Ramanathan RK, van Laethem JL, Peeters M, Fuchs M et al. (2005) A phase III trial of pemetrexed plus gemcitabine versus gemcitabine in patients with unresectable or metastatic pancreatic cancer. Ann Oncol 16:1639–1645. |
|
| Methodical Notes | ||||
| Funding Sources: nicht angegeben COI: None declared. Study Quality: Bewertungsinstrument: Cochrane Collaboration risk assessment tool Ergebnis: Design und Intervention der eingeschlossenen RCTs als homogen eingestuft Heterogeneity: nicht angegeben Publication Bias: Bewertung: Funnel-Plot-Analyse Ergebnis: Risiko für Publikation Bias als gering eingestuft, symmetrische Verteilung im Verhältnis zwischen Behandlungseffekt und Studiengröße Notes: Gesamtqualität: ausreichend PICO Frage klar formuliert: ja Ausreichende Suchstrategie: unklar Ein- und Ausschlusskriterien klar definiert: ja Qualitätsbewertung der eingeschlossenen Studien erfolgt: ja Metaanalyse erfolgt: ja Prüfung der Heterogenität: nein |
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Tong, M. et al. Efficacy and safety of gemcitabine plus anti-angiogenesis therapy for advanced pancreatic cancer: A systematic review and meta-analysis of clinical randomized phase III trials. Journal of Cancer. 10. 968-978. 2019
| Tong, M. et al. Efficacy and safety of gemcitabine plus anti-angiogenesis therapy for advanced pancreatic cancer: A systematic review and meta-analysis of clinical randomized phase III trials. Journal of Cancer. 10. 968-978. 2019 | ||||
|---|---|---|---|---|
| Evidence level/Study Types | P - I - C | Outcomes/Results | Literature References | |
| Evidence level: 1 Study type: Systematisches Review + Metaanalyse Databases: PubMed, Embase, Cochrane Central Register of Controlled Trials Search period: 01/2000 – 08/2018 Inclusion Criteria: 1. lokal fortgeschrittenes oder metastasiertes Pankreaskarzinom 2. Gemcitabin plus Anti-Angiogenese versus Gemcitabin Monotherapie 3. Erstlinie 4. RCTs Phase III Exclusion Criteria: 1. lokal fortgeschrittenes oder metastasiertes Pankreaskarzinom 2. Gemcitabin plus Anti-Angiogenese versus Gemcitabin Monotherapie 3. Erstlinie 4. RCTs Phase III |
Population: Patienten mit lokal fortgeschrittenem oder metastasiertem Pankreaskarzinom Intervention: Gemcitabin plus Anti-Angiogenese (GemAntiang) (Sorafenib, Axitinib, Elpamotid, Aflibercept, Bevacizumab, Erlotinib, Cetuximab, Marimastat) Comparison: Gemcitabin Monotherapie (Gem) |
Primary: Gesamtüberleben Progressionsfreies Überleben Krankheitskontrolle Ansprechen Secondary: Toxizitäten Results: n=8 Studien n=3586 Gesamtüberleben GemAntiang vs. Gem (8 Studien) Kein statistisch signifikanter Unterschied HR 0.96 (95%CI: 0.88-1.05) p=0.38 Progressionsfreies Überleben GemAntiang vs. Gem (8 Studien) Kein statistisch signifikanter Unterschied HR 0.92 (95%CI: 0.86-1.00) p=0.04 Krankheitskontrolle GemAntiang vs. Gem (7 Studien) Kein statistisch signifikanter Unterschied OR 0.99 (95%CI: 0.77-1.28) p=0.96 Ansprechen Objektive Ansprechrate GemAntiang vs. Gem (5 Studien) Kein statistisch signifikanter Unterschied OR 1.26 (95%CI: 0.90-1.77) p=0.18 Toxizitäten (Grad 3-4) Anämie GemAntiang vs. Gem (6 Studien) Kein statistisch signifikanter Unterschied OR 0.71 (95%CI: 0.30-1.70) p=0.44 Neutropenie GemAntiang vs. Gem (6 Studien) Kein statistisch signifikanter Unterschied OR 1.00 (95%CI: 0.59-1.68) p=1.00 Thrombozytopenie GemAntiang vs. Gem (6 Studien) Kein statistisch signifikanter Unterschied OR 1.43 (95%CI: 0.83-2.47) p=0.20 Hypertonie GemAntiang vs. Gem (6 Studien) statistisch signifikant häufiger bei GemAntiang OR 4.11 (95%CI: 1.95-8.64) p=0.0002 Author's Conclusion: In conclusion, despite the fact that the results of this meta-analysis do not change clinical guidelines, they may suggest the eventual designs of future trials. Thus, further research should focus on multi-target agents or applications of combinations of two or three anti-angiogenesis drugs, traditional cytotoxic drugs, and even immunomodulatory drugs in the treatment of pancreatic cancer. |
Moore MJ, Goldstein D, Hamm J, Figer A, Hecht JR, Gallinger S, et al. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. Journal of clinical oncology: official journal of the American Society of Clinical Oncology. 2007;25(15):1960-6. Goncalves A, Gilabert M, Francois E, Dahan L, Perrier H, Lamy R, et al. BAYPAN study: a double-blind phase III randomized trial comparing gemcitabine plus sorafenib and gemcitabine plus placebo in patients with advanced pancreatic cancer. Annals of oncology: official journal of the European Society for Medical Oncology. 012;23(11):2799-805. Kindler HL, Ioka T, Richel DJ, Bennouna J, Letourneau R, Okusaka T, et al. Axitinib plus gemcitabine versus placebo plus gemcitabine in patients with advanced pancreatic adenocarcinoma: a double-blind randomised phase 3 study. The Lancet Oncology. 2011;12(3):256-62. Yamaue H, Tsunoda T, Tani M, Miyazawa M, Yamao K, Mizuno N, et al. Randomized phase II/III clinical trial of elpamotide for patients with advanced pancreatic cancer: PEGASUS-PC Study. Cancer science. 2015;106(7):883-90. Rougier P, Riess H, Manges R, Karasek P, Humblet Y, Barone C, et al. Randomised, placebo-controlled, double-blind, parallel-group phase III study evaluating aflibercept in patients receiving first-line treatment with gemcitabine for metastatic pancreatic cancer. European journal of cancer (Oxford, England: 1990). 2013;49(12):2633-42. Kindler HL, Niedzwiecki D, Hollis D, Sutherland S, Schrag D, Hurwitz H, et al. Gemcitabine plus bevacizumab compared with gemcitabine plus placebo in patients with advanced pancreatic cancer: phase III trial of the Cancer and Leukemia Group B (CALGB 80303). Journal of clinical oncology: official journal of the American Society of Clinical Oncology. 2010;28(22):3617-22. Philip PA, Benedetti J, Corless CL, Wong R, O'Reilly EM, Flynn PJ, et al. Phase III study comparing gemcitabine plus cetuximab versus gemcitabine in patients with advanced pancreatic adenocarcinoma: Southwest Oncology Group-directed intergroup trial S0205. Journal of clinical oncology: official journal of the American Society of Clinical Oncology. 2010;28(22):3605-10. Bramhall SR, Schulz J, Nemunaitis J, Brown PD, Baillet M, Buckels JA. A double-blind placebo-controlled, randomised study comparing gemcitabine and marimastat with gemcitabine and placebo as first line therapy in patients with advanced pancreatic cancer. British journal of cancer. 2002;87(2):161-7. |
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| Methodical Notes | ||||
| Funding Sources: The National Natural Science Foundation of China (81573003) and the Medical Science and Technology Project of Zhejiang Province (2015KYB217). COI: The authors have declared that no competing interest exists. Study Quality: Bewertungsintrument: Review Manager software (version 5.3, Cochrane Collaboration, Copenhagen, Denmark) Risk of Bias Ergebnis: 1 Studie unklares Biasrisiko aufgrund der fehlenden Verblindung Heterogeneity: Gesamtüberleben (Chi2 =7,90, df=7 (p=0,34) I2 = 11%) Progressionsfreies Überleben (Chi2 =6,27, df=7 (p=0,51) I2=0%) Krankheitskontrolle (Chi2 =14,61, df=6 (p=0,02) I2 = 59%) Ansprechen (Chi2 =4,51, df=4 (p=0,34) I2=11%) Anämie (Chi2 =9,69, df=4 (p=0,05) I2=59%) Neutropenie (Chi2 =10,45, df=5 (p=0,06) I2 = 52%) Thrombozytopenie (Chi2 =5,99, df=4 (p=0,20) I2 =33%) Bluthochdruck (Chi2 =2,55, df=2 (p=0,28) I2 = 21%) Publication Bias: Bewertung: Egger’s Test, Funnel Plot Ergebnis: Gesamtüberleben – kein Publikationsbias: Funnel plot symmetrisch Egger’s Test p=0,250; Beggs Test p=0,454 progressionsfreies Überleben – kein Publikationsbias: Egger‘s Test p=0,386; Beggs Test p=0,283 Funnel plot symmetrisch Notes: Gesamtqualität: ausreichend PICO Frage klar formuliert: ja Ausreichende Suchstrategie: unklar Ein- und Ausschlusskriterien klar definiert: ja Qualitätsbewertung der eingeschlossenen Studien erfolgt: ja Metaanalyse erfolgt: ja Prüfung der Heterogenität: ja |
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O'Reilly, E. M. et al. Randomized, Multicenter, Phase II Trial of Gemcitabine and Cisplatin With or Without Veliparib in Patients With Pancreas Adenocarcinoma and a Germline BRCA/PALB2 Mutation. J Clin Oncol. 38. 1378-1388. 2020
| O'Reilly, E. M. et al. Randomized, Multicenter, Phase II Trial of Gemcitabine and Cisplatin With or Without Veliparib in Patients With Pancreas Adenocarcinoma and a Germline BRCA/PALB2 Mutation. J Clin Oncol. 38. 1378-1388. 2020 | |||
|---|---|---|---|
| Population | Intervention - Comparison | Outcomes/Results | |
| Evidence level: 2 Study type: RCT, multizentrisch (6 Zentren), international (USA, Israel, Kanada) Number of Patient: n=50 Gesamtpopulation n=27 Arm A n=23 Arm B Recruitung Phase: 01/2014 - 11/2018 Inclusion Criteria: 1. PDAC, lokal fortgeschritten oder metastasiert 2. gBRCA/PALB2+ 3. unbehandelt 4. Adjuvante Therapie mit Gemcitabin bzw. Fluoropyrimidintherapie (mit und ohne Radiotherapie) mindestens 6 Monate vor Rezidiv abgeschlossen 5. Messbare Erkrankung RECIST 1.1 6. Keine vorrangegangen Platin-basierte oder PARPI Therapie 7. Alter ≥18 Jahre 8. ECOG 0-1 9. Lebenserwartung >3 Monate 10. Normale Organ- + Knochenmarkfunktion Exclusion Criteria: 1. Aktive Metastasen im ZNS 2. Kontraindikationen für Cisplatin 3. Krampfanfälle 4. Allergie auf Wirkstoffe z.B. Velaparib 5. Schwangerschaft 6. Aktive Herzkreislauferkrankung 7. Schwere psychiatrische Erkrankungen |
Intervention: Cisplatin + Gemcitabin + Veliparib (Arm A) Zyklusdauer: 21 Tage Cisplatin: 25 mg/m2 Gemcitabin: 600 mg/m2 beides über Infusion (30 min), Tag 3 + 10 Veliparib: 2 mal 80mg/Tag an Tag 1-12 (oral) Comparison: Cisplatin + Gemcitabin (Arm B) Zyklusdauer: 21 Tage Cisplatin: 25 mg/m2 Gemcitabin: 600 mg/m2 beides über Infusion (30 min), Tag 3 + 10 |
Primary: Ansprechrate Secondary: progressionsfreies Überleben Gesamtüberleben Kontrolle der Erkrankung Toxizitäten Results: Ansprechrate Arm A vs. Arm B kein statistisch signifikanter Unterschied Arm A: n=20 (74,1%) Arm B: n=15 (65,2%) p=0,55 progressionsfreies Überleben Arm A vs. Arm B kein statistisch signifikanter Unterschied Arm A: 10,1 Monate (95% CI: 6,7-11,5) Arm B: 9,7 Monate (95% CI: 4,2-13,6) p=0,73 Gesamtüberleben Arm A vs. Arm B kein statistisch signifikanter Unterschied Arm A: 15,5 Monate (95% CI 12,2-24,3) Arm B: 16,4 Monate (95% CI 11,7-23,4) p=0,6 Krankheitskontrolle (Rate) Arm A vs. Arm B Arm A statistisch signifikant höher als Arm B Arm A: n=27 (100%) Arm B: n=18 (78,3%) p=0,02 Toxizitäten Arm A vs. Arm B Hämatologische Toxizität (Grad 3-4) Arm A: 81% Arm B: 73% Anämie Arm A: 52% (Grad 3-4) Arm B: 35% (Grad 3) keine Grad 4 Thrombozytopenie Arm A: 55% (Grad 3-4) Arm B: 9% (Grad 3) keine Grad 4 Nicht-Hämatologische Toxizität Arm A: 39% Arm B: 35% Author's Conclusion: In conclusion, cisplatin and gemcitabine is an active regimen in advanced gBRCA/PALB2+ PDAC. The addition of veliparib to cisplatin and gemcitabine was not superior to cisplatin and gemcitabine, and the triplet combination was notable for increased hematologic toxicity relative to the doublet. The data reported herein establish cisplatin and gemcitabine as a standard-of-care regimen in gBRCA/ PALB2+ PDAC. Further insights into biomarkers of response and resistance will be forthcoming. |
|
| Methodical Notes | |||
| Funding Sources: Supported by the Lustgarten Foundation, the David M. Rubenstein Center for Pancreatic Cancer Research, the Reiss Family Foundation, the National Institutes of Health, National Cancer Institute (NCI) Cancer Therapeutics Evaluation Program, and NCI Grants No. P30 CA008748 and R25CA020449. COI: Disclosures provided by the authors and data availability statement (if applicable) are available with this article at DOI https://doi.org/10.1200/JCO.19.02931. Randomization: Patients were randomly assigned to arm A or arm B, and a Simon’s two-stage minimax design was used in arm A and arm B separately. Blinding: keine Verblindung (open-label) Dropout Rate/ITT-Analysis: A modified intention-to-treat principle was applied for all randomly assigned and treated patients. The cutoff for data analysis was July 31, 2019. Notes: Gesamtqualität: ausreichend Studiendesign: RCT PICO Frage: ja Randomisiert: unklar Gruppen vergleichbar: ja Gruppen gleich behandelt (abgesehen von untersuchter Intervention): ja Patienten nachverfolgbar (Loss of Follow-Up dokumentiert etc.): ja objektive Messung: ja Verblindung: nein |
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Park, W. et al. Genomic Methods Identify Homologous Recombination Deficiency in Pancreas Adenocarcinoma and Optimize Treatment Selection. Clin Cancer Res. 26. 3239-3247. 2020
| Park, W. et al. Genomic Methods Identify Homologous Recombination Deficiency in Pancreas Adenocarcinoma and Optimize Treatment Selection. Clin Cancer Res. 26. 3239-3247. 2020 | |||
|---|---|---|---|
| Population | Intervention | Outcomes/Results | |
| Evidence level: 3 Study type: prospektive Kohortenstudie, unizentrisch, USA Number of Patient: n=262 gesamt n=50 HRD Recruitung Phase: 10/2013-07/2019 Inclusion Criteria: 1. lokal fortgeschrittenes Pankreaskarzinom 2. metastasiertes Pankreaskarzinom Exclusion Criteria: 1. kein Gentest (Germline Testing) |
Intervention: Homologous recombination deficiency (HRD) Comparison: keine HRD |
Primary: Gesamtüberleben Progressionsfreies Überleben Secondary: Results: Follow-Up: Median 21,9 Monate (1,4-57) Gesamtüberleben Gesamtkohorte 15,5 Monate (95% CI 14,6-19,0 Monate) HRD vs keine HRD HRD statistisch signifikant geringeres Mortalitätsrisiko HR: 0,50 (95% CI 0,33-0,75 Monate) p<0,01 unabhängig von der Erstlinientherapie (Platin-basiert/ nicht Platin-basiert) Progressionsfreies Überleben Gesamtkohorte 7,1 Monate (95% CI: 6,1–8,1 Monate) Progression abhängig von Erstlinientherapie! HRD vs keine HRD Platin-basierte Erstlinie HRD statistisch signifkant geringeres Risiko für Progression HR: 0,44 (95% CI 0,28-0,66) p<0,01 HRD vs keine HRD nicht Platin-basierte Erstlinie Kein statistisch signifikanter Unterschied HR: 1,42 (95% CI 0,80-2,50) p=0,23 Author's Conclusion: HRD status defined as germline or somatic pathogenic HR-gene alterations, are associated with superior survival outcome to first-line platinum in advanced PDAC. Biallelic mutation of HR-genes showed the best association with this genomic characteristic independent of germline versus somatic origin. Determining the HRD status is ideally needed at the time of diagnosis to optimize survival and refine treatment selection in advanced PDAC. Short term goals are to make this clinically realizable. |
|
| Methodical Notes | |||
| Funding Sources: This research received MSK Cancer Center Support Grant (P30 CA008748), NIH-K12 (K12 CA184746), Parker Institute for Cancer Immunotherapy MSKCC Pilot Grant Award, and funding from David M. Rubenstein Center for Pancreatic Cancer Research. Bonnie Reiss Family Foundation. Breast Cancer Research Foundation, Sarah Jenkins Fund. COI: Wungki Park: Research funding to MSK: Merck, Astellas, Gossamerbio; Honoraria: Ipsen Anna Varghese: Research funding to MSK: Illumina, Grail; Consultancy to Genentech. Kenneth Yu: Research funding to MSK: BMS, Halozyme, Ipsen. Honoraria: Ipsen, QED. Danny K. Khalil: Intellectual property interests related to CD40 and in situ vaccination James Harding: Research and consulting fees from BMS. Consulting fees from Eisai, Exilexis, Imvax, and Elly Lilly Ghassan K. Abou-Alfa: Research funding to MSK: Genentech, Roche, BMS, Halozyme, Celgene, MabVax Therapeutics, ActaBiologica, AstraZeneca, Silenseed, Polaris. Consulting/Advisory: Cytomx, BioLineRx, Targovax, Celgene, Bayer, Polaris, Sobi, Merck Mark E. Robson: Research Funding to MSK: Abbvie, AstraZeneca, Invitae, Medivation, Merck, Myriad, Pfizer, Tesaro; Uncompensated consultancy to AstraZeneca, Daiichi-Sankyo, Epic Sciences, McKesson, Merck, Pfizer. Travel, Accommodation: AstraZeneca, Merck, Other transfer of value: AstraZeneca (editorial services), Pfizer (editorial services), NIH/NCI Cancer Center Support Grant P30 CA008748, Breast Cancer Research Foundation. Liying Zhang: Honoraria from Future Technology Research LLC, Roche Diagnostics Asia Pacific, BGI, and Illumina; Family member has a leadership position and ownership interest of Shanghai Genome Center. Michael F. Berger: Research funding to MSK: Illumina, Grail; Consultancy to Genentech. Timothy Chan: Research Funding to MSK: AstraZeneca, Bristol-Myers Squibb, Illumina, Pfizer, An2H; Leadership: Cancer Genetics, Illumina, Bristol-Myers Squibb; Stock or other ownership: Gritstone Oncology; Patents, Royalties, Other Intellectual Property: neoantigen discovery and genomic biomarkers for immunotherapy response Jorge S. Reis-Filho: Consultancy to Goldman Sachs and REPARE Therapeutics; Advisory board: Volition RX and Paige.AI, Ventana Medical Systems, Roche Tissue Diagnostics, Roche, Genentech, Novartis, InVicro. Christine A. Iacobuzio-Donahue: Research funding to MSK: BMS Nadeem Riaz: Research funding to MSK: AstraZeneca, Pfizer, BMS; Consultancy and Honoraria from Illumina, Mirati Therapeutics; Eileen M. O’Reilly: Research funding to MSK: Genentech, Roche, BMS, Halozyme, Celgene, MabVax Therapeutics, ActaBiologica, AstraZeneca, Silenseed, Polaris. Consulting/Advisory: Cytomx, BioLineRx, Targovax, Celgene, Bayer, Polaris, Sobi, Merck Randomization: keine Randomisierung Blinding: keine Verblindung Dropout Rate/ITT-Analysis: nicht angegeben Notes: |
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Golan, Talia et al. Maintenance Olaparib for Germline BRCA-Mutated Metastatic Pancreatic Cancer. The New England Journal of Medicine. . . 2019
| Golan, Talia et al. Maintenance Olaparib for Germline BRCA-Mutated Metastatic Pancreatic Cancer. The New England Journal of Medicine. . . 2019 | |||
|---|---|---|---|
| Population | Intervention - Comparison | Outcomes/Results | |
| Evidence level: 2 Study type: RCT, Phase III, multizentrisch (119 Kliniken), international (12 Länder) (POLO-Studie) Number of Patient: n=154 Gesamtpopulation n=92 Olaparib n=62 Placebo Anzahl der Patienten im Analyseset n=90 Olaparib n=61 Placebo Recruitung Phase: 01/2015 – 01/2019 Inclusion Criteria: 1. Alter ≥18 Jahre 2. Histologisch und zytologisch bestätigtes PDAC 3. metastasiert 4. BRCA1 oder BRCA2 Mutation 5. Mindestens 16 Wochen first-line Platin-basierte Chemo 6. Keine Progression der Erkrankung 7. Nebenwirkungen der vorangegangenen Chemotherapie auf Grad 1 geheilt (Ausnahmen, Nebenwirkungen mit möglichen höheren Graden: Alopezie, periphere Neuropathie, Anämie) 8. Normale Organfunktion 9. Akzeptable Knochenmarkfunktion Exclusion Criteria: |
Intervention: Olaparib Olaparib: oral, 300 mg 2x/Tag Beginn 4-8 Wochen nach Verabreichung der letzten Dosis der first-line Chemotherapie Comparison: Placebo |
Primary: Progressionsfreies Überleben Secondary: Gesamtüberleben Progressionsfreies Überleben zwei (bis zur zweiten Progression) Ansprechen Toxizitäten Lebensqualität Results: Follow up nicht angegeben Progressionsfreies Überleben Olaparib vs. Placebo statistisch signifikant länger bei Olaparib Olaparib: 7,4 Monate Placebo: 3,8 Monate HR 0,53 (95% CI 0,35-0,82) p=0,004 Gesamtüberleben Olaparib vs. Placebo kein statistisch signifikanter Unterschied Olaparib: 18,9 Monate Placebo: 18,1 Monate HR 0,91 (95% CI 0,56-1,46) p=0,68 Progressionsfreies Überleben zwei (bis zur zweiten Progression) Olaparib vs. Placebo kein statistisch signifikanter Unterschied Olaparib: 13,2 Monate Placebo: 9,2 Monate HR 0,76 (95% CI 0,46-1,23) p nicht angegeben Ansprechen Objektive Ansprechrate Olaparib vs. Placebo kein statistisch signifikanter Unterschied Olaparib: 23% Placebo: 12% OR 2,30 (95% CI 0,89-6,76) p nicht angegeben Toxizitäten (Grad ≥3) Olaparib vs. Placebo keine Angaben zur statistischen Signifikanz Olaparib: 24% Placebo: 15% Lebensqualität EORTC QLQ-C30 (bei Therapiebeginn, danach alle 4 Wochen, 30 Tage nach Abschluss der Therapie; Scores von 0-100, höhere Scores = höhere Lebensqualität) Olaparib vs. Placebo keine signifikante Veränderung der Lebensqualität (signifikante Veränderung ± 10 Punkte im Score) Adjustierte Veränderung vom Ausgangswert (±SE) Olaparib -1,20 ± 1,42 (95% CI -4,01 bis 1,62) Placebo: 1,27±1,95 (95% CI -2,58 bis 5,12) Author's Conclusion: In conclusion, the POLO trial showed that maintenance olaparib provided a significant progression-free survival benefit to patients with a germline BRCA mutation and metastatic pancreatic cancer that had not progressed during platinum-based chemotherapy. |
|
| Methodical Notes | |||
| Funding Sources: Supported by AstraZeneca (as part of an alliance between AstraZeneca and Merck Sharp & Dohme, a subsidiary of Merck) and by a grant (P30-17 CA008748) from the National Institutes of Health National Cancer Institute Cancer Center. AstraZeneca was responsible for overseeing the collection, analysis, and interpretation of the data. Olaparib is being codeveloped by AstraZeneca and Merck Sharp & Dohme (MSD, a subsidiary of Merck), and MSD provided input regarding the interpretation of the data. The manuscript was written with medical writing assistance funded by AstraZeneca and MSD, with critical review and input by the authors. COI: Disclosure forms provided by the authors are available with the full text of this article at NEJM.org. Randomization: With the use of a central interactive voice or Web response system that incorporated a block randomization scheme, patients were randomly assigned, in a 3:2 ratio, to receive maintenance olaparib tablets (300 mg twice daily) or matching placebo. No stratification factors were used Blinding: doppelt verblindet, assessed by blinded independent central review Dropout Rate/ITT-Analysis: Data on efficacy were analyzed in the intention-to-treat population (all patients who underwent randomization). Data on safety were summarized in the safety population (patients who received ≥1 dose of a trial agent), and data on health-related quality of life were analyzed in all patients with a form on baseline health-related quality of life that could be evaluated. Crossover to Olaparib was not permitted during this trial. Notes: Gesamtqualität: ausreichend Studiendesign: RCT PICO Frage: ja Randomisiert: unklar Gruppen vergleichbar: unklar Gruppen gleich behandelt (abgesehen von untersuchter Intervention): ja Patienten nachverfolgbar (Loss of Follow-Up dokumentiert etc.): ja objektive Messung: ja Verblindung: ja |
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Hammel, Pascal et al. Effect of Chemoradiotherapy vs Chemotherapy on Survival in Patients With Locally Advanced Pancreatic Cancer Controlled After 4 Months of Gemcitabine With or Without Erlotinib: The LAP07 Randomized Clinical Trial. JAMA - Journal of the American Medical Association. 315. 1844-1853. 2016
| Hammel, Pascal et al. Effect of Chemoradiotherapy vs Chemotherapy on Survival in Patients With Locally Advanced Pancreatic Cancer Controlled After 4 Months of Gemcitabine With or Without Erlotinib: The LAP07 Randomized Clinical Trial. JAMA - Journal of the American Medical Association. 315. 1844-1853. 2016 | |||
|---|---|---|---|
| Population | Intervention - Comparison | Outcomes/Results | |
| Evidence level: 2 Study type: RCT, Phase III, multizentrisch (80 Zentren), Frankreich, Australien, Neuseeland, Belgien, Schweden Number of Patient: 1. Randomisierung n=442 Gesamtpopulation n=223 (Gem) n=219 (GemErlo) 2. Randomisierung n=269 Gesamtpopulation n=136 (Cth) n=133 (RCth) Recruitung Phase: 02/2008-12/2011 Inclusion Criteria: 1. Histologisch oder zytologisch bestätigtes Pankreaskarzinom 2. lokal fortgeschritten 3. Stadium III 4. Alter ≥18 Jahre 5. Messbare oder evaluierbare Erkrankung nach RECIST 1.0 6. Adäquate hämatologische, hepatische und Nierenfunktion 7. Keine vorangegangene Chemotherapie oder Strahlentherapie Exclusion Criteria: |
Intervention: Schritt 1: Gemcitabin + Erlotinib (GemErlo) Gemcitabin: 1000 mg/m2 1x/Woche für 3 Wochen in einem 4-Wochen-Zyklus, als 30-minütige intravenöse Infusion, für 4 Zyklen. Erlotinib: 100 mg 1x/tägl. Schritt 2: Radiochemotherapie (RCth) Strahlentherapie: 54 Gy in 30 täglichen Fraktionen über 6 Wochen. Capecitabin 800 mg/m2 2x/tägl. an den Tagen der Strahlentherapie Comparison: Schritt 1: Gemcitabin Monotherapie (Gem) Gemcitabin 1000 mg / m² 1x/Woche für 3 Wochen in einem 4-Wochen-Zyklus, als 30-minütige intravenöse Infusion, für 4 Zyklen. Schritt 2: Chemotherapie (Cth) Gemcitabin +/- Erlotinib Gemcitabin: 1000 mg / m² 1x/Woche für 3 Wochen als 30-minütige intravenöse Infusion, für 4 Zyklen. Erlotinib: 100 mg 1x/tägl. Erhaltungsphase: Erlotinib 150 mg 1x/tägl. |
Primary: Gesamtüberleben Secondary: Progressionsfreies Überleben Toxizität Results: Follow-up Median 36,7 Monate (95% CI 27,6-43,8) Gesamtüberleben (Median) Gem vs. GemErlo (1. Randomisierung) Kein statistisch signifikanter Unterschied Gem: 13,6 Monate (95% CI 12,3-15,3) GemErlo: 11,9 Monate (95% CI 10,4-13,5) HR 1,19 (95% CI 0,07-1,45) p=0,09 RCth vs. Cth (2. Randomisierung) Kein statistisch signifikanter Unterschied RCth: 15,2 Monate (95% CI 13,9-17,3) Cth: 16,5 Monate (95% CI 14,5-18,5) HR 1,03 (95% CI0,79-1,34) p=0,83 Subgruppenanalyse Patienten ohne 2. Randomisierung 7,7 Monate (95% CI 6,6-8,7Monate) Patienten mit 2. Randomisierung und GemErlo in erster Randomisierung Gem vs. Erlo Erhaltungstherapie Statistisch signifikant höher bei Gem Gem: 17,1 Monate (95% CI 15,3-19,0) ErloErhaltung: 14,5 Monate (95% CI 13,2-16,1) HR 1,32 (95% CI 1,01-1,72) p=0,04 Progressionsfreies Überleben Gem vs. GemErlo (1. Randomisierung) Kein statistisch signifikanter Unterschied HR 1,12 (95% CI 0,92-1,36) p=0,26 RCth vs. Cth (2. Randomisierung) Kein statistisch signifikanter Unterschied RCth: 9,9 Monate (95% CI 8,8-10,4) Cth: 8,4 Monate (95% CI 7,8-9,4) HR 0,78 (95% CI 0,61-1,01) p=0,06 Toxizität (Grad 3/4) Gem vs. GemErlo (1. Randomisierung) Statistisch signifikant häufiger bei GemErlo Anämie p=0,05 Febrile Neutropenie p=0,03 Diarrhöe p=0,006 Akneiformer Ausschlag p=0,007 Cth vs. RCth (2. Randomisierung) Statistisch signifikant häufiger bei RCth Übelkeit p=0,008 Author's Conclusion: In this open label, randomized trial among patients with locally advanced pancreatic cancer with disease controlled after 4 months of induction chemotherapy, there was no significant difference in overall survival with chemoradiotherapy compared with chemotherapy alone, and there was no significant difference in overall survival with gemcitabine compared with gemcitabine plus erlotinib used as maintenance therapy. |
|
| Methodical Notes | |||
| Funding Sources: This trial was supported by Roche and French National Institute of Cancer (INCa). Neither Roche nor the French National Institute of Cancer had a role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. COI: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Hammel reports receiving consulting fees from Celgene. Dr Huguet reports receiving personal fees and nonfinancial support from Merck Serono and Celgene. Dr Goldstein reports receiving grant support from Celgene and Pfizer. Dr Bouché reports remuneration for serving as a Roche board member and for developing educational presentations for Lilly. Dr André reports receiving personal fees from Roche, Celgene, Sanofi, Merck Serono, and Amgen. Dr Chibaudel reports receiving personal fees from Roche and Sanofi. Dr Bonnetain reports receiving personal fees from Novartis, Merck Serono, Integragen, Nestle, Eisai, and Invectys. Dr Louvet reports receiving honoraria from Celgene, Roche, and Sanofi. No other disclosures were reported. Randomization: 1:1 Minimierungsverfahren, stratifiziert nach Zentrum und Performance Status (0-1 vs. 2) Randomisierung erfolgte in 2 Schritten: 1. Induktionschemotherapie Gemcitabin mit/ohne Erlotinib für 4 Zyklen 2. Chemotherapie oder Radiochemotherapie für 2 weitere Monate. (Für Patienten mit Tumorkontrolle, Performance Status von 2 oder besser und abgeschlossener Induktionschemotherapie. Patienten mit geringen Nebenwirkungen erhielten eine Erhaltungstherapie.) Blinding: nicht verblindet (open-label) Dropout Rate/ITT-Analysis: Efficacy and safety assessments were conducted in the intent-to-treat (ITT) population. Notes: Gesamtqualität: ausreichend Studiendesign: RCT PICO Frage: ja Randomisiert: ja Gruppen vergleichbar: unklar Gruppen gleich behandelt (abgesehen von untersuchter Intervention): ja Patienten nachverfolgbar (Loss of Follow-Up dokumentiert etc.): ja objektive Messung: ja Verblindung: nein |
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Ambe, C. et al. A Meta-analysis of Randomized Clinical Trials of Chemoradiation Therapy in Locally Advanced Pancreatic Cancer. J Gastrointest Cancer. 46. 284-90. 2015
| Ambe, C. et al. A Meta-analysis of Randomized Clinical Trials of Chemoradiation Therapy in Locally Advanced Pancreatic Cancer. J Gastrointest Cancer. 46. 284-90. 2015 | ||||
|---|---|---|---|---|
| Evidence level/Study Types | P - I - C | Outcomes/Results | Literature References | |
| Evidence level: 1 Study type: systematisches Review + Metaanalyse Databases: PUBMED, MEDLINE, OLD MEDLINE, ISI Web of Science, Cancer Lit, EMBASE, Conference Proceedings, trial registries Search period: 1980-2013 Inclusion Criteria: 1. lokal fortgeschrittenes exokrines Pankreaskarzinom 2. prospektive randomisierte kontrollierte Studien 3. Chemotherapie, Radiochemotherapie Exclusion Criteria: 1. nicht randomisierte Studien 2. metastasierte Erkrankung 3. bereits operierte Patienten 4. Daten zum Pankreaskarzinom nicht extra berichtet 5. keine Daten zum Gesamtüberleben 6. alleinige Bestrahlung |
Population: Patienten mit lokal fortgeschrittenem Pankreaskarzinom Intervention: Radiochemotherapie Comparison: Chemotherapie |
Primary: Gesamtüberleben Secondary: Results: Gesamtüberleben Radiochemotherapie vs. Chemotherapie Kein statistisch signifikanter Unterschied HR 0,913 (95% CI 0,598-1,400) p=0,675 Author's Conclusion: The addition of radiation therapy to CT in the treatment of LAPC is associated with a non-significant trend toward survival advantage. Larger randomized controlled trials using modern CT regimens and radiation techniques are needed to further clarify the role of radiation in this setting. |
8. Chauffert B,Mornex F, Bonnetain F, Rougier P,Mariette C, Bouche O, et al. Phase III trial comparing intensive induction chemoradiotherapy (60 Gy, infusional 5-FU and intermittent cisplatin) followed by maintenance gemcitabine with gemcitabine alone for locally advanced unresectable pancreatic cancer. Definitive results of the 2000–01 FFCD/SFRO study. Ann Oncol. 2008;19:1592–9. doi:10.1093/annonc/mdn281. 12. Gastrointestinal Tumor Study Group. Treatment of locally unresectable carcinoma of the pancreas: comparison of combined-modality therapy (chemotherapy plus radiotherapy) to chemotherapy alone. J Natl Cancer Inst. 1988;80:751–5. 13. Hazel JJ, Thirlwell MP, Huggins M, Maksymiuk A, MacFarlane JK. Multi-drug chemotherapy with and without radiation for carcinoma of the stomach and pancreas: a prospective randomized trial. J Can Assoc Radiol. 1981;32:164–5. 16. Klaassen DJ,MacIntyre JM, Catton GE, Engstrom PF,Moertel CG. Treatment of locally unresectable cancer of the stomach and pancreas: a randomized comparison of 5-fluorouracil alone with radiation plus concurrent and maintenance 5-fluorouracil–an Eastern Cooperative Oncology Group study. J Clin Oncol. 1985;3:373–8. 18. Loehrer Sr PJ, Feng Y, Cardenes H, Wagner L, Brell JM, Cella D, et al. Gemcitabine alone versus gemcitabine plus radiotherapy in patients with locally advanced pancreatic cancer: an Eastern Cooperative Oncology Group trial. J Clin Oncol. 2011;29:4105–12. doi:10.1200/JCO.2011.34.8904. 19. Pascal Hammel FH, Jean-Luc Van Laethem, David Goldstein, Bengt Glimelius, Pascal Artru, Ivan Borbath, Oliver Bouche,Jenny Shannon, Thierry Andre, Laurent Mineur, Benoist Chibaudel, Franck Bonnetain and Christophe Louvet (2013) Comparison of chemoradiotherapy (CRT) and chemotherapy in patients with locally advanced pancreatic cancer (LAPC) controlled after 4months of gemcitabine with or without erlotinib: final results of the international phase III LAP 07 study. J Clin Oncol 31 |
|
| Methodical Notes | ||||
| Funding Sources: None COI: None Study Quality: nicht angegeben Heterogeneity: Random-effects model was used for meta-analyses, as there was significant heterogeneity between the studies (I2, p value=0.001) Publication Bias: Funnel plot did not suggest any evidence of publication bias (Fig. 3). Notes: |
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Hurt, C. N. et al. Long-term results and recurrence patterns from SCALOP: a phase II randomised trial of gemcitabine- or capecitabine-based chemoradiation for locally advanced pancreatic cancer. Br J Cancer. 116. 1264-1270. 2017
| Hurt, C. N. et al. Long-term results and recurrence patterns from SCALOP: a phase II randomised trial of gemcitabine- or capecitabine-based chemoradiation for locally advanced pancreatic cancer. Br J Cancer. 116. 1264-1270. 2017 | |||
|---|---|---|---|
| Population | Intervention - Comparison | Outcomes/Results | |
| Evidence level: 2 Study type: RCT (Phase II), multizentrisch (28 Zentren), UK Number of Patient: n=74 (randomisiert) n=36 CAP+RT n=38 GEM+RT Recruitung Phase: 12/2009-10/2011 Inclusion Criteria: 1. Alter >18 Jahre 2. Lokal fortgeschrittenes Pankreaskarzinom 3. Nicht metastasiert 4. nicht resektabel oder Patienten nicht operabel 5. Tumordurchmesser ≤ 7 cm 6. WHO Performancestatus 0-2 7. ausreichende hämatologische, renale und hepatische Funktion Exclusion Criteria: 1. Lymphome 2. Neuroendokrine Tumore des Pankreas |
Intervention: Capecitabin + Bestrahlung Comparison: Gemcitabin + Bestrahlung |
Primary: Gesamtüberleben 9-Monats-Progressionsfreies Überleben Secondary: Results: Follow-Up: 12,2 Monate (IQR 7,5-41,9) Gesamtüberleben CAP+RT vs GEM+RT Kein statistisch signifikanter Unterschied CAP+RT: 17,6 Monate (95% CI 14,6-22,7) GEM+RT: 14,6 Monate (95% CI 11,1-16,0) HR: 0,68 (95% CI 0,38-1,21) p=0,185 9-Monats-Progress vs. kein 9-Monats-Progress 9-Monats-Progress: 11,3 Monate (95% CI: 9,5-14,1) Kein 9-Monats-Progress: 20,7 Monate (95% CI: 17,6-24,6) HR: 5,2 (95% CI 1,5-5,6) p<0,001 9-Monats-Progressionsfreies Überleben CAP+RT vs GEM+RT Kein statistisch signifikanter Unterschied CAP+RT: 12,0 Monate (95% CI 10,0-15,2) GEM+RT: 10,4 Monate (95% CI 8,8-1,27) HR: 0,60 (95% CI 0,32-1,14) p=0,120 Author's Conclusion: In summary, this mature analysis shows that radiosensitisation with low-dose gemcitabine remains an inferior regimen, both in terms of efficacy and toxicity, and cannot be recommended in future CRT trials. However, only the per-protocol analysis was significant perhaps reflecting the small size of the study. CA19.9 levels o46 IU ml_1 after induction chemotherapy may define a group of patients more likely to benefit from consolidation CRT— however, this requires further validation. Futhermore, 9-month PFS is well correlated with OS and could therefore a useful end point in future phase II pancreatic CRT trials. Future trials need to optimise both systemic and local components of treatment. |
|
| Methodical Notes | |||
| Funding Sources: This work was supported by Cancer Research UK (grant number CRUK 07/040) and ISRCTN: 96169987, and Cancer Research UK core funding at Wales Cancer Trials Unit. COI: The authors declare no conflict of interest. Randomization: randomised (1:1 minimisation with a random element (80:20) stratified by recruiting hospital) Blinding: keine Verblindung Dropout Rate/ITT-Analysis: Intention-to-treat-Analyse Notes: |
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