10. Radiotherapy – Cervical Carcinoma
Major changes in the chapter on radiotherapy
The recommendations for primary radiochemotherapy — consisting of the elements external radiotherapy, simultaneous cisplatin-containing chemotherapy, and brachytherapy — were confirmed after review. The level of recommendation for the use of intensity-modulated radiotherapy techniques and MRI-supported planning of brachytherapy in the context of primary radiochemotherapy for cervical carcinoma has been raised, as there are now new data for a clinical benefit with these techniques.
D. Vordermark, S. Marnitz, K. Lössl, A. Sturdza, C. D. Alt
10.1 Radio(chemo)therapy
S. Marnitz
This section presents first the techniques and then the indications for them.
10.1.1 Radiotherapy techniques (percutaneous radiotherapy)
Intensity-modulated techniques should be used to achieve optimal sparing of the surrounding tissue during primary radiochemotherapy for cervical carcinoma.
- Recommendation grade
- B: Empfehlung für oder gegen eine Maßnahme - verwendete Ausdrucksweise = sollte/sollte nicht
- Level of evidence
- 1+
- Consensus
- Strong consensus
- References
- [364]
Change note
New intensity modulated techniques should be used for optimal sparing of the surrounding tissue in the therapy of cervical carcinoma.The use of modern techniques in radio-oncology, particularly intensity-modulated radiotherapy (IMRT) and related methods such as spiral tomotherapy and volumetric arc techniques, help protect at-risk organs such as the bladder, rectum, small intestine, ovaries, etc., and make it possible both to reduce treatment-related acute and delayed reactions and also to safely administer selective dose escalation or simultaneous integrated boost (SIB) plans. Which of these techniques should be used here is unclear from the available literature [365], [366], [367], [368]; comparisons between different techniques depend on many planning variables [369], [370], [371], [372]. A large randomized trial reported a very favorable toxicity profile and treatment adherence when predominantly modern IMRT techniques were used [373]. Although the data on toxicity reduction using IMRT are mainly based on studies of definitive radiochemotherapy studies [364], it can be assumed that reducing the dosage in at-risk organs also has a favorable effect on the side effect profile in the postoperative situation.
Fractionation is conventional, with single doses of 1.8–2.0 Gy and five fractions per week. In the area of the pelvic and para-aortic lymphatic drainage routes, standard treatment consists of administering individual doses of 1.8 or 2 Gy in a total dosage of 45–50.4 Gy or 50 Gy. The size of lymph-node metastases correlates with the prognosis [374]. For macroscopically enlarged lymph nodes, a local dosage increase (boost) can be considered if surgical staging was not possible. There is a clear dose–outcome relationship. The rate of in-field recurrences was significantly lower for pelvic and para-aortic lymph-node metastases < 10 mm than for lymph-node sizes > 10 mm [375]. In individual cases, this justifies the administration of what are called sequential or simultaneous boosts in regions with a higher risk of recurrence.
When there is an indication for para-aortic irradiation of para-aortic lymph-node metastases that have been confirmed histologically or on imaging morphology, it should be carried out at the same time as pelvic irradiation. Prophylactic para-aortic irradiation is not justified. It increases therapy-related toxicity without any evidence of prognostic improvement [376], [377], [378]. Patients with histologically confirmed para-aortic metastases should be treated using an extended-field plan and simultaneous chemotherapy with curative intent [379], [380], [381], [382], [383].
The target volumes include the internal, external, interiliac and common iliac lymph-node regions and also the presacral group up to the S2/S3 vertebrae (RTOG consensus guideline) [384]. In the primary situation, the uterus, cervix, parametria, and — depending on the depth of involvement of the vagina — also tumor-infiltrated areas are included in the target volume, along with a safety margin [384]. With small tumors, simultaneous treatment of the entire uterus is currently under discussion. However, there are as yet no prospective data to justify a departure from the previous usual practice of simultaneous treatment of the entire uterus. There is currently controversy over what constitutes an adequate safety margin for organ movement and positional inaccuracy, as well as patient movement, and no general recommendation can currently be given [384]. RTOG recommendations are available for defining the target volume in postoperative percutaneous radiotherapy [384], [355]. The selection of the safety margin (known as the planning target volume, PTV) depends on the mobility of the individual structures (mobile uterus versus less mobile lymph-node areas) as well as the technique and frequency of so-called on-board imaging. For daily IGRT and structures with little mobility, PTVs can usually be reduced to 5–8 mm. For mobile structures, it is advisable to consider using an internal target volume (ITV). Against this background, regular checks of reproducible bladder and bowel filling should be carried out during treatment — e.g., using cone-beam CT. With regard to optimal local control, it is recommended to keep the total duration of percutaneous therapy and brachytherapy as short as possible and to avoid treatment interruptions. Older recommendations assume a loss of local control if therapy is prolonged for > 56 days [372]. More recent data from the era of combined radiochemotherapy only note a deterioration in the outcome beyond the eleventh week of treatment [385]. Occasionally unavoidable delays in therapy can be compensated for by a dosage increase [386].
10.1.2 Brachytherapy technique in primary combined radio(chemo)therapy
Brachytherapy should be a component of the curative treatment approach in primary treatment for cervical carcinoma that includes radio(chemo)therapy.
- Recommendation grade
- B: Empfehlung für oder gegen eine Maßnahme - verwendete Ausdrucksweise = sollte/sollte nicht
- Level of evidence
- 4
- Consensus
- Strong consensus
- References
- [101]
MRI-planned brachytherapy should be used in primary radiochemotherapy for cervical carcinoma, to reduce the rate and severity of gastrointestinal and urogenital toxicities.
- Consensus
- Strong consensus
Change note
MRI-planned brachytherapy can help to spare organs at risk and to better adapt the dose distribution to the tumor.Brachytherapy in the area of the macroscopic tumor is an obligatory component of radiochemotherapy in primary therapy for cervical carcinoma [387]. Brachytherapy should preferably be administered in the form of image-guided adaptive brachytherapy (IGABT). This is based on performing an MRI of the pelvic region before initiating radiochemotherapy and at least one MRI at the start of afterloading. Recommendations have been published for the technical performance of the MRIs, which should be conducted consistently [388]. Repetitively performed MRI examinations allow adaptive radiation planning. In this process, a 40–50 Gy equivalent dose (EQD2, alpha/beta 10 Gy) is administered in three to five fractions after MRI-guided planning in the high dose rate (HDR) or pulse dose rate (PDR) procedures. The EQD2 in the tumor area from percutaneous irradiation and brachytherapy should reach at least 85 Gy [386]. The target volumes include the residual tumor after or during ongoing percutaneous radiotherapy as the gross tumor volume (GTV), the entire cervix including the presumed microscopic involvement, in what is termed a high-risk clinical target volume (HR-CTV). The GTV is part of the HRCTV. An intermediate-risk clinical target volume (IR-CTV) is defined as the initial extent before the start of percutaneous therapy. Graded dosage recommendations are defined in the GEC-ESTRO recommendations and ICRU Report 89 [389], [390]. Dose prescription in 4D brachytherapy corresponds to target volumes and dose–effect curves [7][8][10]. The total treatment duration including teletherapy and brachytherapy should not exceed 45–50 calendar days [6], as each additional day reduces the overall survival after 5 years by 1% [2].
10.1.3 Simultaneous chemotherapy technique
Three systematic reviews have shown that primary combined radio(chemo)therapy offers a highly significant advantage in the overall survival and progression-free survival in comparison with radiotherapy alone [391], [392], [393] (see also section 10.1.4). Another meta-analysis of three randomized studies also showed, in the adjuvant setting in early cervical carcinoma, that additional platinum-containing chemotherapy along with radiotherapy consistently reduced the risk of death in all of the studies and significantly increased the progression-free interval, as well as achieving an increase in local control [394] (see also section 10.1.5, Adjuvant radio(chemo)therapy).
Simultaneous chemotherapy during irradiation is administered with cisplatin monotherapy. At least five doses of 40 mg/m² body surface area (BSA) on days 1, 8, 15, 22, and 29 of the radiotherapy are usually administered. An alternative dosage scheme with the identical dose density is administration of 20 mg/m² BSA on days 1–5 in the first and fifth weeks of radiotherapy [395]. In the rare case of contraindications against cisplatin, the use of carboplatin, for example, is an option. Combination therapies do not show any significant difference between the treatments, although with an increase in the range of side effects.
In the case of poor renal function due to hydronephrosis, decongestion using appropriate measures is indicated before the start of therapy.
10.1.4 Indication for primary radiotherapy or radio(chemo)therapy
In patients with cervical carcinoma in whom there is an indication for primary radiotherapy from stage IB2 onwards, the radiotherapy shall be combined with cisplatin-based chemotherapy.
This recommendation is based on the recommendation given in the 2008 SIGN guideline, which also recommends platinum-based radiochemotherapy when primary radio(chemo)therapy is indicated and the patient is in a sufficiently good state of health [101].
Since the publication of the prospective randomized studies on radiotherapy versus radio(chemo)therapy in patients with cervical carcinoma, simultaneous radio(chemo)therapy has replaced the use of radiotherapy alone [398] [399] [400] [401] [402]. A total of 44,926 patients from 1987 to 2006 were included in the studies. Various chemotherapy regimens were used (cisplatin alone in three studies, cisplatin in combination in eight studies, and other agents [5-fluorouracil, mitomycin C, etc.] in three other studies). Three systematic reviews [396] [397] [403] confirmed the significant improvement in overall survival, progression-free survival, and local control achieved with radio(chemo)therapy in comparison with radiotherapy alone. According to a Cochrane analysis in 2005 (with 24 RCTs included, n = 4921), the HR of 0.69 pooled over all the studies (95% CI, 0.61 to 0.77; P < 0.00001) corresponds to a 31% reduction in the risk of death, or an absolute survival improvement of 10% (95% CI, 7 to 13%), from 60% to 70% [396]. Combined platinum-based radio(chemo)therapy, with an absolute survival improvement of 13% [396] is better in this respect (although not significantly) than non–platinum-based treatment [396] [403]. The main side effects of simultaneous chemotherapy are an increase in the acute hematological and gastrointestinal toxicity, with low urogenital toxicity [396] [397]: risk for grade I/II hematological toxicity (OR 4.57; 95% CI, 3.08 to 6.79; P < 0.00001) and grade III/IV hematological toxicity (OR 8.97; 95% CI, 6.11 to 13.15; P < 0.00001); risk for grade I/II leukopenia (OR 2.40; 95% CI, 1.91 to 3.00; P < 0.00001) and grade III/IV leukopenia (OR 6.32; 95% CI, 4.39 to 9.07; P < 0.00001); risk for grade III/IV gastrointestinal toxicity (OR 2.77; 95% CI, 1.90 to 4.02; P < 0.00001) and grade I/II neurological toxicity (OR 6.04; 95% CI, 2.35 to 15.55; P = 0.0002) [391].
As more than 70% of the above studies included patients in FIGO stages ≥ II and III, combined radio(chemo)therapy for tumors (≥ FIGO stage IIB) is the therapeutic standard. In patients in stage IIA without risk factors, primary surgery or primary radio(chemo)therapy are options. A randomized study from the period in which radiotherapy alone was used showed equivalent oncological results for radical HE and for radiotherapy in FIGO stages IB–IIA, although with different side effect profiles. In the period of combined radio(chemo)therapy, a prospective and randomized comparison of radical HE with lymphadenectomy and combined radio(chemo)therapy with or without a para-aortic field has not been published for any of the FIGO stages [404]. For patients with FIGO stage III, radio(chemo)therapy is regarded as the standard therapy (see section 8.6.2.4). For patients in FIGO stage IVA, an individual decision should be taken after interdisciplinary consultation with the patient (see section 8.6.2.5). Radiotherapy in stage IVA is associated with a high risk of fistula development [405].
If indicated, radio(chemo)therapy should be carried out in the primary situation and also in the adjuvant situation (see recommendation 10.4).
For patients with locally advanced cervical carcinoma, neoadjuvant chemotherapy followed by radical hysterectomy does not improve oncological outcomes in comparison with primary radiochemotherapy. Two randomized studies have not only shown negative results, but have also reported a serious increase in hematologic toxicity to the disadvantage of neoadjuvant chemotherapy [406], [407]. The dose density of the chemotherapy administered is a matter of debate in this context, and is regarded as problematic in the studies mentioned. The use of neoadjuvant chemotherapy can therefore not be recommended as an oncologically safe alternative to primary combined radiochemotherapy outside clinical trials [408], [409]. The advantage of neoadjuvant chemotherapy over simultaneous radiochemotherapy has not been established, and it is therefore not recommended. Early results from a randomized trial including only 80 patients show comparable response rates in both arms (radiochemotherapy plus/minus neoadjuvant chemotherapy), but the oncological end points are still awaited [410].
10.1.5 Adjuvant radio(chemo)therapy
Adjuvant radiochemotherapy is used in patients who have risk factors after histopathological processing of the radical operation. The indications for this defined by the guideline group are presented in recommendation 10.5. The background to these indications is discussed in more detail below. The prescribed dose is independent of the indication concerned. The standard dose for adjuvant treatment corresponds to the elective dosage in primary radiotherapy of 45–50 Gy (ED 1.8) (NCCN etc.). The irradiation volume (PTV) is also similar to the volume of the lymphatic drainage routes and of the primary tumor bed, of the upper vaginal dome described above. As described above, the complete lymphatic drainage area (obturator lymph nodes and internal, external, and common iliac lymph nodes, as well as the para-aortic region if affected) should also be treated in the adjuvant situation, as recommended by the 2008 RTOG guidelines on contouring for intensity-modulated radiation volumes [384]. Since there may be altered lymphatic drainage pathways after surgery, reduced treatment volumes as specified by the earlier irradiation boundaries of the former four-field box or “shortened four-field box” (up to the level of the promontory), may lead to marginal recurrences and should be avoided [378]. In order to keep long-term toxicities low, the use of more recent radiation techniques to protect at-risk organs (see above) is also required here, as in primary radiochemotherapy.
Following the GOG-92 and GOG-109 studies on the adjuvant situation in cervical carcinoma, there is an international consensus exists that the indication should be assessed in accordance with the “Sedlis” criteria [412]. In these, the risk factors are divided into “high-risk” and “intermediate-risk” categories. The “high-risk” factors include lymph-node metastases, parametrial infiltration, and positive surgical margins. One high-risk factor is sufficient to establish an indication for postoperative radiochemotherapy. Although in the 1990s the indication for radiotherapy if there was only one affected lymph node was a matter of debate, following the GOG-109 study and its follow-up publications, the locoregional and overall survival benefit has also been confirmed in this situation [413]. It has been shown that the prognosis depends on the number of affected lymph nodes, and in particular on the use of simultaneous chemotherapy in case of multiple lymph-node metastases. The situation with micrometastases is still less clear. Only a few retrospective data are available on the topic. However, since the prerequisite for micrometastasis is lymphovascular invasion, micrometastasis should also be regarded as representing a clear indication for adjuvant radiotherapy [276] as an “intermediate-risk” indication (see below).
For the “intermediate-risk” factors, which include lymphovascular invasion, deep cervical stromal invasion (see Chapter 7), and tumor size, a combination of at least two risk factors should be present in order to establish an indication for adjuvant radiochemotherapy. The 12-year follow-up data from the GOG-92 trial (FIGO IB, after surgery and lymphadenectomy, without lymph-node metastases but with “intermediate” risk factors) are continuing to show improved progression-free survival after adjuvant therapy in high-risk patients in comparison with surgery alone. With regard to overall survival, there is a clear trend towards a better outcome with additional radiotherapy. This is confirmed by a meta-analysis from China published in 2016. Although the study reported a benefit in terms of overall survival only for the “high-risk” patients as a result of the additional chemotherapy , this was not observed for the intermediate factors [414]. If necessary, additional factors can be taken into account here, such as young age, vascular invasion, grading, or the presence of an adenocarcinoma. More information may be provided here by the results of GOG-0263, which are expected at the end of 2020 (a randomized trial in postoperative cervical carcinoma patients in FIGO stages I–IIA, with intermediate risk factors, radiochemotherapy versus radiotherapy alone).
In rarer histologies such as adenocarcinoma or adenosquamous carcinoma, which account for approximately 5–20 % of all cervical carcinoma histologies, the focus is primarily on systemic metastases, which is why the use of radiotherapy is justified here and, if necessary, additional adjuvant chemotherapy can be considered.
An even rarer finding (approx. 2% of all histologies) is neuroendocrine cervical carcinoma, which has a very poor prognosis, according to the literature. It is one of the small cell tumors and should be treated analogously to these, primarily with intensified radiochemotherapy or even trimodal therapy [415], [416].
Independently of discussions on the need for adjuvant radiotherapy after surgery for cervical carcinoma, there are few randomized data available on either the postoperative situation or the treatment choice between surgery and definitive radiochemotherapy. The only randomized trial on the issue of surgery versus radiotherapy, dating from 1997 [417], discussed above in section 10.1.4, published its 20-year follow-up data in 2017 [417]. The patients were properly randomized between surgery and radiotherapy in then FIGO stages IB2 and IIA1, but the overall survival was found to be the same. However, approximately 50% of the patients who underwent surgery also received adjuvant radiotherapy. A significantly increased rate of late toxicities was observed in this group of patients who received surgery and radiotherapy.
Trimodal therapy (surgery + radio(chemo)therapy) thus doubles the rate of severe long-term toxicities without improving the oncological results, and it should be reduced to a minimum by using appropriate patient selection measures (see section 8.1.1.2) to assign them either to surgery alone OR to primary radio(chemo)therapy.
10.1.6 Adjuvant (secondary) hysterectomy after complete radio(chemo)therapy
When combined simultaneous radio(chemo)therapy has been carried out correctly, secondary (“adjuvant”) hysterectomy does not provide any survival benefit for patients [418], [419], [420]. TRetrospective data are available here suggesting a potential benefit for patients with confirmed residual tumor [421] and for a subgroup of patients with adenocarcinoma [422]. Surgery may increase the risk of complications. For salvage hysterectomy, simple hysterectomy rather than a radical procedure is therefore recommended [423]. The benefits of the procedure and its risks should therefore be discussed with the patient in a nuanced way. The presence of residual tumor is a surrogate parameter for a greater probability of progression. The majority of patients who undergo secondary hysterectomy develop distant metastases during the later course [424], [425], [426], [427] (see section 9.4).
10.1.7 Adjuvant chemotherapy after completed radio(chemo)therapy
Due to the high rate of distant metastases in patients with advanced tumors (≥ FIGO stage IIB), several studies included adjuvant (“consolidation”) chemotherapy after the completion of radio(chemo)therapy in their treatment protocols [430] [431]. Another recent randomized study (n = 515) [429] administered adjuvant chemotherapy with cisplatin 50 mg/m² d1 and gemcitabine 1000 mg/m² d1, d8 q21d in the test group. The 3-year progression-free survival and also to a slight extent the overall survival were significantly improved in comparison with the control group without adjuvant chemotherapy, but at the cost of doubling the grade III/IV treatment-related acute side effects (PFS 3 years: 74.4% vs 65.0%, P = 0,029; PFS overall: log-rank, P = 0.0227; HR: 0.68, 95% CI, 0.49 to 0.95; OS, log-rank P = 0.0224; HR: 0.68, 95% CI, 0.49 to 0.95; time to progression: log-rank P = 0.0012; HR: 0.54, 95% CI, 0.37 to 0.79; grade III/IV toxicity: 86.5% vs. 46.3%, P = 0.001, including two deaths potentially causally connected with the toxicity) [429]. A Cochrane review in 2010 in which the effects of adjuvant radio(chemo)therapy vs. radiotherapy in cervical carcinoma were investigated showed a potential additional benefit for the 5-year overall survival (HR 0.46; 95% CI, 0.32 to 0.66; P = 0.000021, absolute improvement of 19% in 5 years) as a result of consolidating chemotherapy after adjuvant radio(chemo)therapy, although with a high risk of distortion due to the study by Duenaz-Gonzales [395]. Another randomized study comparing four arms investigated radiotherapy alone with and without adjuvant chemotherapy and simultaneous radiochemotherapy with and without adjuvant chemotherapy. It failed to demonstrate any oncologic benefit for either radiotherapy alone or radiochemotherapy with the addition of adjuvant chemotherapy [432]. On the basis of the currently published literature, no recommendation can therefore be made for additional chemotherapy outside of the framework of research studies. It is possible that the adjuvant use of immunotherapies may change the state of the data for this specific clinical situation.
10.1.8 Neoadjuvant radio(chemo)therapy
Neoadjuvant radio(chemo)therapy should not be administered outside of research studies..
- Consensus
- Strong consensus
Therapeutic approaches for neoadjuvant radio(chemo)therapy include various groups of patients with widely varying tumor stages, treatment approaches, radiotherapy techniques and dosages, and with different forms of chemotherapy. Although promising response rates have been observed, none of the studies has shown any clear advantage with regard to the overall or disease-free survival in comparison with standard radio(chemo)therapy or primary radical surgery [433] [434] [435] [436] [437]. Two meta-analyses published in 2012 and 2013 reflect the unclear state of the data [322] [323] ((see section 11.1). A wide range of different surgical approaches make comparability even more difficult. Due to the approximately 10% rate of severe postoperative complications, with no proven benefit, this treatment approach should therefore not be used outside of clinical research studies [433] [434] [435] [436] [437] (see section 11.1).
10.1.9 Ovary preservation and fertility
Young patients should be offered ovariopexy and high-conformal radiotherapy techniques to preserve ovarian hormone function.
- Consensus
- Strong consensus
Together with modern techniques, ovariopexy in young premenopausal patients before the start of radio(chemo)therapy can achieve a marked reduction in the dosage to the ovaries [438], [439]. The prerequisite for this is adequate ovariopexy well above the pelvic irradiation field [440] (see section 8.6). The risks and benefits must be discussed with the patient. The presence of adenocarcinomas, poorly differentiated tumors, and evidence of lymphovascular invasion should be regarded as risk factors [441]. The risk of ovarian metastases is 1% for squamous cell carcinoma and 6% for adenocarcinoma [442].
On questions of hormone replacement therapy after squamous cell carcinoma or adenocarcinoma and after bilateral adnexectomy, or after radiotherapy with loss of ovarian function, reference may be made to the guideline currently in preparation on “Hormonal Therapy (HT) in the Perimenopause and Postmenopause” (AWMF register no. 015/062).
10.1.10 Adjuvant brachytherapy
In contrast to endometrial carcinoma, no research results were available to the guideline group on the use of vaginal brachytherapy for purposes of vaginal stump prophylaxis in cervical carcinoma. On the basis of individualized treatment approaches, consideration may be given to brachytherapy of the vaginal stump after hysterectomy with R1 or narrow R0 resection in the area of the vaginal stump, large tumors, initial vaginal involvement, or marked lymphovascular invasion in combination with teletherapy [443].
10.1.11 Intraoperative radiotherapy
Intraoperative radiotherapy (IORT) is a procedure for local dosage-boosting in high-risk areas defined during surgical resection — e.g., areas with expected or confirmed residual tumor and clinically or histologically confirmed involvement of lymph nodes. It is typically used with high single doses of 10–20 Gy with electrons, low-energy photons (100–250 kV), or as brachytherapy using moulages adapted to the tumor bed. In case series and nonrandomized studies, IORT has been incorporated both into approaches for recurrence treatment and also into the primary treatment [444] [445] [446] [447] [448]. A positive effect has been demonstrated in individual cases, although these are also influenced by additional risk factors. This is a procedure that does not currently have any place outside of research studies.
10.1.12 Anemia during radio(chemo)therapy
D. Vordermark
During radiotherapy or radio(chemo)therapy for cervical carcinoma, the patient’s hemoglobin values should be monitored and corrected via transfusion at values below 10 g/dL (6.2 mmol/L).
- Recommendation grade
- B: Empfehlung für oder gegen eine Maßnahme - verwendete Ausdrucksweise = sollte/sollte nicht
- Level of evidence
- 2++
- Consensus
- Strong consensus
- References
- [101]
Change note
During radiotherapy or radio(chemo)therapy for cervical carcinoma, hemoglobin levels should be monitored and corrected if below 12 g/dL (7.452 mmol/L).Anemia before or during primary radio(chemo)therapy in patients with cervical carcinoma is associated with clinical factors (tumor size, stage) and is an independent prognostic factor for overall survival [449], [450]. In clinical series of patients in whom systematic transfusion was not carried out, low hemoglobin (Hb) values during the course of treatment were associated with unfavorable survival [450]. In a pooled analysis of 494 patients in two studies by the Gynecologic Oncology Group (GOG) on radio(chemo)therapy, the Hb value in particular, adjusted to the tumor stage during therapy (“mean weekly lowest value”), was prognostic [449].
The positive effects of transfusion on survival after radiotherapy for cervical carcinoma that were reported in an older randomized study have been questioned in more recent publications on the basis of methodological errors [451]. In a more recent analysis of 2454 patients from the treatment period 1980–2011, the development of a hemoglobin nadir of < 10 ng/mL during therapy was prognostic for disease-free survival in the multivariate analysis in both the overall group and the group of patients treated with concurrent radiochemotherapy [452]. The authors recommend transfusion in patients with pretherapeutic levels
In four randomized trials, the use of erythropoiesis-stimulating factors to prevent or treat anemia during radio(chemo)therapy in patients with cervical carcinoma did not yield any positive results. Increased rates of thromboembolic events were seen without any improvement in tumor control, overall survival, or recurrence-free survival [453], [454], [455], [456].
10.1.13 Hyperthermia in cervical carcinoma
Locoregional hyperthermia can be used in combination with percutaneous radiotherapy to treat locoregional recurrence or primary cervical carcinoma ≥ FIGO stage IIB.
- Recommendation grade
- 0: offene Empfehlung (Option) bzgl. einer Maßnahme - verwendete Ausdrucksweise = kann
- Level of evidence
- 1-
- Consensus
- Strong consensus
- References
- [457]
No advantage in relation to overall survival or disease-free survival has so far been confirmed in randomized trials, with the addition of locoregional hyperthermia to primary radiochemotherapy for cervical carcinoma.
- Level of evidence
- 1-
- Consensus
- Strong consensus
- References
- [458]
Change note
Locoregional hyperthermia can be used in the therapy of locoregional recurrence or primary cervical carcinoma ≥ FIGO stage IIB in combination with percutaneous radiotherapy.Locoregional hyperthermia shall be administered in a quality-assured and standardized fashion, preferably in the framework of scientific studies.
- Consensus
- Strong consensus
The purpose of hyperthermia in malignant diseases to use the treatment’s own independent cytotoxic effects along with the supportive influence of the temperature increase on simultaneously administered radiotherapy or chemotherapy (radiosensitizing, chemosensitizing) [459]. Local/locoregional hyperthermia is distinguished from whole-body hyperthermia. Since the studies published to date on the use of hyperthermia in cervical carcinoma only refer to the local/regional use of hyperthermia, with one exception [460], the following statements apply exclusively to the local/regional hyperthermia treatment of cervical carcinoma. The practical implementation of local/regional deep hyperthermia must follow the relevant guidelines [461].
A Cochrane meta-analysis published in 2012 compared various studies on primary therapy (radiotherapy +/– hyperthermia) in patients with locally advanced cervical carcinoma (tumor stage FIGO IIB–IVA, 74% of which were FIGO IIIB) [457]. Although some of the individual studies presented contradictory data, the meta-analysis showed a statistically significant improvement in response rates, a reduction in the local recurrence rate, and an improvement in overall survival by combining radiotherapy with hyperthermia, with no differences in the treatment-related side effects in the two groups [457]. Since radiochemotherapy is now regarded as the standard treatment in primary therapy for locally advanced cervical cancer, it was important to determine whether the combination of hyperthermia plus radiochemotherapy would also lead to an improvement in treatment success. Harima et al. (2016) showed in a small, randomized, multicenter study including 101 patients (FIGO stage IB–IVA) that neither the disease-free survival nor the overall survival were significantly improved by the combination of radiochemotherapy with hyperthermia [458] [462].
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