17. Local recurrence – Cervical Carcinoma

Version 2.2 · March 2022 · AWMF 032/033OL
Leitlinienprogramm Onkologie · Deutsche Krebsgesellschaft · Deutsche Krebshilfe · AWMF

Major changes in the chapter on local recurrence

The chapter on local recurrence has been substantially changed. The recommendations have remained the same. A section on “Immunotherapy for recurrent/metastatic cervical carcinoma” has been added. The topic of hyperthermia has been moved to chapter 10, Radiotherapy. New literature references have been added to the background texts in the other sections.

E. Wight, K. Loessl, M.C. Koch, M.W. Beckmann

17.1 Epidemiology of local recurrences and metastases

In just under 50% of cases, cervical carcinoma is limited to the cervix at the time of first diagnosis. Regional lymph-node metastases (pelvic) are present in around one-third of cases, and the disease is primarily metastatic (to the para-aortic lymph nodes or with organ metastases) in 12% of cases [655]. Progression of the tumor following primary therapy for invasive cervical carcinoma may be localized, on the one hand, and persistent tumor or recurrence in the lesser pelvis after complete remission of the primary tumor can be assumed. On the other hand, pelvic lymphogenic metastases may occur (if there was no primary lymph-node extirpation or only incomplete extirpation; = locoregional recurrence), and/or para-aortic lymphogenic metastases, or there may be organ metastases. With local recurrence in the pelvis, a distinction is made between central recurrence and pelvic wall recurrence.

The recurrence rate for cervical carcinoma across all tumor stages and all forms of treatment is between 22% and 31% [656]. [657]. Risk factors for local/locoregional recurrence were found to be FIGO stage (tumor diameter, parametrial tumor invasion, metastatic involvement of pelvic lymph nodes), younger age ([Marth, C. et al. 2018], [658], [659], [93], [660]. Perez et al. in 1991 reported local recurrence rates after primary therapy with radiotherapy and after a follow-up period of at least 3 years in 1211 patients of 10% in stage Ib, 19% in stage IIa, 23% in stage IIb, 41% in stage III, and 75% in stage IVa [660]. Analysis of the recurrence rates relative to histological subtype showed that 20.6% of the recurrences were in squamous cell carcinoma, 28.6% in adenosquamous carcinoma, 33.6% in adenocarcinoma, and 42.8% in undifferentiated carcinoma [657], [659].

In 526 patients with cervical carcinoma (all stages), tumor recurred in 20% of cases within 6 months to 12 years after therapy, with 58% of the recurrences arising within the first year and 76–82% within the first 2 years after primary therapy (surgery or radiotherapy) [656], [658]. Only 6% of patients with recurrences survived for 3 years or more [656].

Risk factors for distant metastases were assessed by Fagundes et al. (1992) in the same patient population that had been available to Perez et al. (1991). In a retrospective analysis, after radiotherapy alone for invasive cervical carcinoma, distant metastases occurred in 3% after stage Ia, 16% after stage Ib, 31% after stage IIa, 26% after stage IIb, 39% after stage III, and 75% after stage IVa over the course of 10 years, depending on the primary tumor stage [661]. In addition to the FIGO stage (ingrowth of the cervical carcinoma into the uterine cavity was of particular importance), an elevated level of the SCC antigen tumor marker before the start of treatment was associated with an increased probability of metastasis during the course of the disease [658]. Initial manifestations of distant metastases involved the para-aortic, supraclavicular, and inguinal lymph nodes in 11%, 7%, and 3%, respectively. Organ metastases occurred in the lung in 21%, liver in 4%, abdominal cavity in 7%, gastrointestinal tract in 4%, and bone (mainly in the spine) in 7% [661]. Distant metastases occurred in 77% of cases within 3 years and in 88% within 5 years after completion of radiotherapy [661]. In a retrospective survey of 177 patients (FIGO stages IB–II) after radical hysterectomy and pelvic lymphadenectomy, Wang et al. (1999) found that the prognosis was unfavorable if recurrences arose, with a 5-year survival of 10.1% [662]. Lymph-node involvement during primary therapy and the presence of adenocarcinoma or adenosquamous carcinoma were found to be unfavorable prognostic factors. Hong et al. (2004) confirmed the poor prognosis for patients with local recurrence and distant metastasis (with 10% and 11% 5-year survival rates, respectively), but were able to identify subgroups of patients who had a significantly better prognosis and even a chance of cure. These were patients with central local recurrence after radiotherapy of squamous cell carcinoma of the uterine cervix that could be surgically extirpated (5-year survival: 29%). The extent of the local recurrence was of considerable importance for the prognosis: the 5-year survival if the local recurrence was confined to the cervix was 22%; if the tumor had spread to the parametria, uterus, and/or vagina it was 9%; and if the pelvic wall was reached, it was 4%. Subgroup analysis of patients with distant metastases showed a 5-year survival rate of 27% with metastases to the para-aortic lymph nodes, whereas patients with supraclavicular lymph-node metastases or with organ metastases had died by that time point. The authors concluded that in the presence of para-aortic lymph-node metastases, curative treatment options (radiotherapy, radiochemotherapy) were still available, whereas if the metastases were beyond that point, a palliative situation was present [658]. If the time interval between the completion of primary treatment (radiochemotherapy) for gynecological carcinomas (two-thirds of which were cervical carcinomas) and recurrence treatment by exenteration was less than 2 years, the study by McLean et al. (2001) showed a significantly shorter survival period (8 vs. 33 months) than if the recurrences arose later (> 2 years)[663]. Nicotine abuse also had a significant impact on survival [663]. The treatment approach should be decided on an individual basis for each patient with local recurrence, in the setting of an interdisciplinary tumor conference.

Tumor follow-up appointments after primary therapy for cervical carcinoma should be closely scheduled (every 3 months) during the first 3 years, since three-quarters of all recurrences arise within the first 2 years [664]. After that 6-monthly check-ups are indicated for a further 2 years before moving on to annual check-ups 5 years after the primary treatment.

The symptomatic triad of weight loss, leg edema, and pelvic pain, especially if accompanied by an aqueous and bloody vaginal discharge, is highly suspicious for the presence of local recurrence and should prompt appropriate diagnostic measures. The development of ureteral obstruction during tumor follow-up is rarely a sequela of postradiogenic fibrosis, and is usually due to tumor recurrence. A repeated positive HPV test (in the cytological smear) during follow-up after radiotherapy for cervical carcinoma is associated with an increased risk of local recurrence [665].

17.2 Diagnosis of local recurrence

17.1 · Consensus-based Recommendation · checked 2021

If a local recurrence develops, the appropriate imaging diagnostic procedures shall be carried out to exclude distant metastases and for treatment planning.

Consensus: Strong consensus

If there is a suspicion of recurrent tumor or tumor persistence in the lesser pelvis following primary treatment for cervical carcinoma, histological confirmation must be obtained and the extent and location of any metastases that are present must be clarified (see recommendations 17.5 and 18.2) — since, depending on the FIGO stage of the primary tumor, the probability of distant metastases is increased by a factor of 4–17 in case of local recurrence [666].

Depending on the location, the diagnosis can be made using vaginal ultrasound, CT, or MRI [92], [667]. The data on PET-CT in the recurrent situation are unclear [668].

17.3 Treatment for local recurrence

17.2 · Consensus-based Recommendation · checked 2021

With local recurrences, treatment decisions should be based on the following points:

Patient’s general condition (comorbidities)
Location and extent of the local recurrence
Presence of distant metastases
Extent of metastasis development
Type of primary therapy/prior therapies
Patient’s request

Consensus: Strong consensus

The generally unfavorable prognosis for patients in the recurrent situation, in which individually adjusted treatment modalities are often used, makes it difficult to set up research studies, and this is reflected in the small numbers of randomized controlled studies available. The present section is again a consensus-based section that is not based on systematic research and evaluation of research studies.

Treatment decisions on recurrent tumors should be based on the location and extent of the local recurrence, the presence of distant metastases, the extent of any metastases, and the type of primary therapy that has been administered, as well as the patient’s general condition (comorbidities) and her wishes. In addition, risk factors (e.g., age under 45, HPV persistence after primary therapy, HIV status) should also be taken into consideration [658], [665], [669]. The treatment approach should be established on an individual basis in the setting of an interdisciplinary tumor conference. Treatment should take place in a specialized (tumor) center. Table 18 provides an introductory overview of the possible treatment options in various situations.

Table 14: Treatment options in recurrent cervical carcinoma (modified 2021)

Prio treament		local recurrence/locoregional recurrence
		Central	Lateral
Cervicectomy		Radical HE Exenteration R(CH)T[/RT] ± BT	R(CH)T ± BT [poss. LEER]
Radical HE		R(CH)T[/RT] ± BT Exenteration	R(CH)T(/RT) ± BT [LEER]
Radical HE + RT/R(CH)T		Exenteration± IORT	CT ± bevacizumab [LEER ± IORT]
RT/R(CH)T		Exenteration± IORT [radical HE± IORT]	CT ± bevacizumab [LEER ± IORT]
Legend: BT, brachytherapy; CT, chemotherapy; HE, hysterectomy; IORT, intraoperative radiotherapy; LEER, laterally extended endopelvic resection; RT, radiotherapy; R(CH)T, radio(chemo)therapy; […], experimental.
EC	Consensus (92.3% [12/13])

17.3.1 Treatment for a central tumor recurrence after primary surgical treatment

17.3 · Consensus-based Statement · checked 2021

In case of a central recurrence in a patient who has not previously undergone radiotherapy, exenteration or radiochemotherapy are possible.

Consensus: Strong consensus

17.4 · Consensus-based Recommendation · checked 2021

Due to its lower morbidity, radiochemotherapy should be carried out in patients with no previous radiotherapy who develop a recurrence.

Consensus: Strong consensus

Some 30–45% of all cervical carcinoma recurrences after radical hysterectomy develop at the vaginal stump, located centrally in the lesser pelvis [646]. The treatment of choice is radiotherapy [198] by analogy with studies on the primary treatment of cervical carcinoma [377], [380], [381], [670], with response rates of up to 74% [671], with both monochemotherapies and combined chemotherapy schemes being used in addition to percutaneous radiochemotherapy ± brachytherapy. There are no randomized controlled studies comparing radio(chemo)therapy with radiotherapy alone in this situation [672]. Retrospective studies argue in favor of a therapeutic advantage for combination treatment with regard to tumor regression, progression-free survival, and overall survival [672], [671]. In comparison with exenteration, radiotherapy is associated with lower morbidity, and for this reason it is usually the preferred treatment option. The success of treatment depends on the one hand on the size of the recurrence. Ito et al. (1997) reported a 10-year overall survival rate of 72% with nonpalpable tumors, 48% with a tumor diameter 3 cm [673]. On the other hand, the success of treatment is also influenced by the location of the recurrence. Jain et al. (2007) described a 5-year overall survival rate of 55% when the vaginal stump alone was affected. With pelvic lymph-node involvement, the 5-year overall survival fell to 12.5% [674]. If the recurrent tumor reached the pelvic wall, the 5-year overall survival in a study by Ijaz et al. (1998) declined from 69% to 18% [472]. In the group of patients included, it was also found that the histology of the recurrence had a significant influence on the 5-year survival: 51% with squamous cell carcinoma, 14% with adenocarcinoma [675]. In a retrospective study, new radiotherapy techniques (intensity-modulated radiotherapy, IMRT; three-dimensional radiotherapy) held out the promise of better 5-year survival (35% vs. 21%) in comparison with conventional radiotherapy in the treatment of locoregional tumor recurrences, and a meta-analysis [676] reported fewer side effects (gastrointestinal, urogenital) due to the ability to focus on the target volumes, together with reduced radiation injury to the surrounding area. Prospective data on patient-relevant end points (progression-free survival and overall survival) are at present still awaited. A corresponding study (“The re-irradiation of recurrent cervical cancer by IMRT,” NTC03170570) is recruiting patients.

17.5 · Consensus-based Recommendation · checked 2021

Exenteration must only be carried out in cases of recurrence if resection with healthy margins appears possible and there are no distant metastases.

Consensus: Strong consensus

Exenteration is the method of second choice with central tumor recurrences after radical hysterectomy. In view of the morbidity associated with exenteration, this procedure should be carried out with curative intent. Exceptions to this rule may be present with existing or immediately imminent fistula formation (e.g., with tumor involvement of the bladder or bowel), in which case exenteration can also be carried out with palliative intent (see section 17.3.7, Palliative treatment for local recurrence when surgery with healthy margins is not possible). The scope of the exenteration must be based on the extent of the recurrent tumor, as tumor-free resection margins must be achieved. An R1 resection is associated with a marked deterioration in the prognosis. Berek et al. (2005) reported an overall survival rate after 5 years of 61% when local recurrences were excised with healthy margins; when there was tumor involvement of the resection margins, none of the patients was still alive after 3 years [677]. A distinction is made between anterior, posterior, and total exenteration, as well as supralevatory and infralevatory exenteration and exenteration with vulvectomy [678]. If it is feared even in advance of a planned exenteration operation that tumor removal with healthy margins may not be possible, then the indication for this burdensome procedure must be questioned [679]. If the recurrence is in a central or purely vaginal location, a radical colpectomy procedure with or without the creation of a neovagina (e.g., sigmoid) is an option [680]. Pretherapeutic (neoadjuvant) chemotherapy [681], intraoperative radiotherapy [421], or extension of the operation in the form of laterally extended endopelvic resection (LEER) may be considered if the recurrent tumor is growing towards the pelvic wall [682].

17.3.2 Treatment for a central recurrence after primary or adjuvant radiotherapy or radio(chemo)therapy

The frequency of recurrent or persistent tumors after primary radiotherapy or radio(chemo)therapy for squamous cell carcinoma of the uterine cervix is reported to be 32% [683]. Forty-three percent of the recurrences are in the lesser pelvis and the remaining 57% are either in the para-aortic and supraclavicular lymph nodes or are distant metastases, located mainly in the lung, bone, or liver. Risk factors reported for local recurrence include young age ([Arbyn, M. et al. 2012].

The treatment of choice with a central tumor recurrence after primary or adjuvant radiotherapy or radio(chemo)therapy is exenteration. According to the review by Peiretti et al. (2012), including nearly 3000 women treated from the years 1957 to 2010, the 5-year overall survival rate is 33.8% [672]. Higher rates of cure, with a 56–61% 5-year overall survival rate, are possible in a selected group (age under 70, no histological evidence of resection margin involvement, no involvement of the pelvic wall or rectum) [677], [684]. In view of the high level of morbidity associated with exenteration surgery after prior radiotherapy or radio(chemo)therapy — with an overall complication rate of 44% (mainly with early complications consisting of wound infection and late complications involving fistulas) — the selection process must be restrictive [677], [684]. Distant metastases should be excluded before the operation. The time interval between primary therapy and the diagnosis of recurrence correlates significantly with survival after exenteration. Marnitz et al. (2006), for example, reported a 5-year overall survival rate of only 17% when the recurrence developed within the first 2 years after the first diagnosis; if the interval was 2–5 years or more than 5 years, the 5-year survival rates increased to 28% and 83%, respectively [685]. Para-aortic and possibly also pelvic lymphogenic metastases (the details in the literature are controversial here) [686], [687] aggravate the prognosis after exenteration. Exenteration is not useful if — despite preoperative negative diagnosis — the intraoperative situation shows peritoneal tumor seeding, para-aortic lymph nodes affected by metastases, or tumor involvement of the pelvic wall (described as occurring in around one-third of cases by Estape et al. 1999) [688]. Possible alternative treatment measures in this situation include LEER or IORT [198], [682], although both of these options must be regarded as experimental.

A small tumor recurrence limited to the uterine cervix or persistent tumor after primary radiotherapy/radiochemotherapy can be treated with an extended hysterectomy instead of exenteration [689]. However, the postoperative complication rate was high, at 42% (mainly vesicovaginal and rectovaginal fistulas, ureteral injuries, postoperative bladder dysfunction). The 5-year overall survival rate in this group was 72%.

17.3.3 Treatment for pelvic wall recurrence after primary surgical therapy

Radiotherapy or radiochemotherapy can be administered with curative intent not only with central recurrences, but also with pelvic wall recurrences. However, the success rate of the treatment is lower (5-year overall survival with central recurrences 55–69%, with pelvic wall recurrences 13–28% [674], [675], [690]). The relevant factors (time interval between primary therapy and recurrence, tumor size, etc.) also have to be established in advance of salvage radiotherapy/radiochemotherapy in order to estimate the prognosis, and organ metastases in particular have to be excluded. Initial studies have been published on optimizing radiotherapy/radiochemotherapy in the recurrent setting by using alternative radiotherapy techniques (IORT, 3D radiotherapy, intensity-modulated whole-pelvis radiotherapy, stereotactic body RT, imaging-guided interstitial brachytherapy, 3D conformal brachytherapy, interstitial brachytherapy), also affecting combinations with systemic therapies and/or with locoregional hyperthermia [691], [671], [129], [692], [693]. There is a notable rate of late complications in 15% of cases, in the form of rectovaginal fistulas, strictures (rectum, ureter) and chronic pain [425], [694]. One treatment alternative with pelvic wall recurrences involves laterally extended endopelvic resection (LEER), possibly after neoadjuvant chemotherapy and in combination with IORT. The indication for IORT is justified by the assumption that in the case of narrow or involved resection margins, local control might be improved by IORT. However, practical experience with these methods is very limited. Prospective randomized studies are lacking so far [681], [682], [695], [696].

17.3.4 Treatment for pelvic wall recurrence after primary radiotherapy or adjuvant radiotherapy/radiochemotherapy

17.6 · Consensus-based Recommendation · checked 2021

Repeat radiotherapy at a curative dosage must not be administered in the previously irradiated volume.

Consensus: Strong consensus

In a review article, Jurado et al. (2010) reported, on radical surgery (exenteration) in patients with pelvic wall recurrences after primary RT, that resection with healthy margins (R0) was possible in 29% of cases. In contrast, R0 resection for central recurrences was successful in 65% of patients [679]. Tumor-specific survival was significantly associated with tumor-free resection margins and local tumor control and was 14.9% for patients with pelvic wall recurrences and 27% for those with central recurrences, after a median observation period of 115 months. The treatment-related morbidity associated with radical pelvic wall surgery was extremely high, at 73% [679]. Publications by Höckel et al. (2003, 2008, 2012) presented LEER, a treatment approach aiming at attempted cure in patients with pelvic wall recurrences after radio/radiochemotherapy for a selected population [682], [697], [698]. The following criteria for performing LEER were defined: curative goal/prolongation of life; realistic prospect of local tumor control (tumor-free resection margins, no involvement of the sciatic foramen, no peritoneal tumor seeding); no distant metastases detectable; size of the recurrent tumor less than 5 cm; no multifocality in the recurrence; time interval between primary therapy and recurrence diagnosis more than 5 months; no pelvic, para-aortic, or inguinal lymph-node metastases; age under 70; no significant comorbidity). The approach included surgery of embryonic developmental structures with complete resection of lateral tissue structures (muscle, vessels, nerves) as far as the pelvic bone. In a nonrandomized, single-center study, It a 5-year overall survival rate of 61% was achieved, although the recurrent tumor was attached to the pelvic wall in three-quarters of the patients, sometimes with development of a hydronephrosis [697]. LEER is a very complex surgical procedure, with a 70% rate of severe complications (wound dehiscence, anastomotic insufficiency, necrosis of the advancement flap, abscess formation, thromboembolism) [699]. Concomitant use of IORT is limited due to prior primary therapy. Chemotherapy is significantly less effective with recurrences arising within the radiation field [454].

17.3.5 Treatment for secondary para-aortic lymph-node metastases

The incidence of isolated para-aortic lymph-node recurrences after primary therapy (surgery or radio(chemo)therapy) for cervical carcinoma is reported to be 2–12% [656], [658], [661]. The prognosis is regarded as very unfavorable, as other distant metastases are frequently present at the same time. With para-aortic lymph-node recurrences, the time interval between the primary treatment and the development of the recurrence has prognostic significance. The data presented by Chou et al. (2001) show that a 5-year overall survival rate of 51% can be achieved when radiochemotherapy is administered (unless the recurrence is located in the original irradiation field for primary radiotherapy/radiochemotherapy) [700]. Singh et al. (2005) found that if the para-aortic lymph-node metastases are clinically symptomatic (leg edema, sciatic pain, hydronephrosis) after radiochemotherapy (none of the patients received the full dosage), the prognosis is poor (all seven patients died within 1.5 years); whereas asymptomatic patients had good chances of cure following complete salvage radiochemotherapy (45–50 Gy, cisplatin 40 mg/m2, q7d; 5-year overall survival 100%, again in seven patients) [701]. A retrospective study including 50 patients with isolated lymph-node recurrences reported an overall 3-year survival rate of 47% and an overall 5-year survival of 36.2% for the whole group [702]. The 3-year overall survival was strongly dependent on the treatment administered: after radiochemotherapy, 85.7%; after surgery, 66.7%; after chemotherapy, 48.8%; after radiotherapy, 41.3%; after best supportive care, 0%. Prognostically significant factors for treatment failure were found to be the age of the patients (> 57), a raised value for the tumor marker SCC-Ag at the time of recurrence diagnosis, and more than three lymph-node metastases being found. Although the conclusions of these studies regarding treatment success are concordant, reservations are appropriate in view of the small numbers of cases.

17.3.6 Systemic therapy in local/locoregional recurrences and distant metastases

Patients with locoregional tumor recurrences and/or metastases should have their cases discussed at an interdisciplinary tumor board and treated by a specialized team before systemic therapy is started. Systemic therapy may be with curative intent (neoadjuvant, adjuvant) or palliative. Maintaining or promoting the patient’s quality of life is of central importance when establishing the indication for palliative systemic therapy. Organ metastases are usually only suitable for palliative chemotherapy, with low response rates. In rare individual cases, mainly isolated pulmonary or hepatic metastases, metastasis surgery or radiofrequency ablation are also available as options.

Systemic treatment for metastatic cervical carcinoma is discussed in section 18.3.5, “Drug treatment in the metastatic situation.”

17.3.7 Palliative treatment for local recurrence when surgery with healthy margins is not possible

17.7 · Consensus-based Recommendation · checked 2021

A surgical intervention can be carried out with palliative intent for a local recurrence, to relieve tumor-specific symptoms.

Consensus: Strong consensus

When there are simultaneous distant metastases or when the local recurrence has extended to the pelvic bones or abdominal cavity, the situation is a palliative one. Exenteration surgery is only indicated in exceptional cases, as the extent of the procedure, the associated morbidity, and the long recovery period of 3–6 months are only justified if the patient can also expect a longer survival period and/or an improved quality of life after the operation. This is usually only the case with an R0 resection. However, exenteration may be justified in specific situations. These include tumor-related or treatment-related symptoms that are severely impairing the patient’s quality of life (fistula formation, radiation-related hemorrhagic cystitis/proctitis, painful conditions) [703], or an effort to achieve local control of the tumor process despite systemic disease. Various studies have reported 5-year survival rates of 17–19% after palliative exenteration surgery [704], [705].

17.8 · Consensus-based Recommendation · checked 2021

A radiotherapeutic intervention can be carried out with palliative intent for a local recurrence that is not operable with healthy margins, to relieve tumor-specific symptoms.

Consensus: Strong consensus

Pain and vaginal bleeding are typical indications for palliative radiotherapy of recurrent cervical carcinoma. The treatment scheme and dosage must be based on the patient’s individual condition. Tumor-related bleeding can be well treated with hemostyptic radiation [706], but embolization is preferable if there is acutely life-threatening bleeding. Bone metastases occur in 1–4% of cases in patients with cervical carcinoma, and are most often (36%) located in the lumbar spine. Evidence of bone metastases is associated with a poor prognosis (median overall survival 23 months) [707], [708]. Bone metastases must be differentiated from radio-osteonecroses in the radiation field. As a result of pain symptoms, or if there is a risk of fracture, the metastases often require therapy, and for this reason palliative radiotherapy may be indicated, taking into account the possible radiation fields from the primary treatment. In addition, systemic bisphosphonates or anti-RANKL antibody (denosumab) are available in accordance with the indications for other tumors [708]. In the case of brain metastases, in addition to steroid therapy to reduce peritumoral edema, whole-brain radiotherapy is occasionally used in combination with stereotactic radiosurgery (gamma knife) [709].

The palliative treatment options with recurrent tumor or metastatic disease must be discussed on an interdisciplinary basis and individually with the patient, taking into account her preferences, and implemented in a symptom-oriented way. Embolization, decompression procedures for intestinal obstruction (stenting, colostomy, PEG tube), pain treatment, and in general psycho-oncological care, may be administered in addition to chemotherapy and radiotherapy in this situation.

17.3.8 Value of hyperthermia in cervical carcinoma

This section discusses the current state of the data for women with recurrent or metastatic cervical carcinoma. Hyperthermia in the primary situation is dealt with in Chapter 10, Radiotherapy. The results for the use of radiochemotherapy in combination with local/regional hyperthermia in recurrent or metastatic cervical carcinoma have been summarized in a review by Burchardt et al. (2018) [702]. The effect of hyperthermia treatment for recurrent tumor or after metastasis was evaluated differently in two papers by the same research group. In a more recent retrospective study including 38 patients [708] with local recurrence of cervical carcinoma after primary radiotherapy, the combination of chemotherapy with hyperthermia significantly increased the response rate in comparison with chemotherapy alone (72% vs. 40%).
The study results on the value of hyperthermia in the treatment of cervical carcinoma can be summed up as follows:

The value of combining hyperthermia with radiotherapy, chemotherapy, or radiochemotherapy in recurrent or metastatic cervical carcinoma is unclear. Further clinical studies are needed in order to answer this question.

17.3.9 Immunotherapy for recurrent/metastatic cervical carcinoma

Various options for immunotherapy in cervical carcinoma are currently being evaluated [710]. The evidence available to date is based entirely on small studies and case reports.

Therapeutic vaccines

Prophylactic vaccines against HPV infection induce antiviral antibodies using the L1 antigen of the viral capsid. The vaccines used for treatment have a cytotoxic effect on tumor cells via activation and proliferation of T cells, mediated by the tumor antigens E6 and E7 that are expressed. A therapeutic vaccine using live but attenuated bacteria as the vector (Listeria monocytogenes) achieved a response rate of 11% (response duration 9.5 months) in patients with relapsed or progressive cervical carcinoma, with no improvement in the effect when combined with cisplatin. Typical side effects of therapeutic vaccines are flu-like symptoms with chills, fever, vomiting, and fatigue [710].

Checkpoint inhibitors

Checkpoint inhibitors block inhibitory receptors of the immune system and can therefore lead to the activation of cytotoxic cells, increasing their antitumor effect. Increased expression of PD-L1 (programmed death ligand-1) on tumor-infiltrating lymphocytes (TIL) may indicate that blocking PD-1/PD-L1 might be a treatment option in cervical carcinoma. In phase I and II trials, pembrolizumab — the antibody targeted against PD-1 — was associated with a 17% response rate in patients with inoperable or metastatic cervical cancer after unsuccessful prior systemic therapy. The treatment-related toxicity was high, in 70–75% of the patients, particularly since severe adverse events occurred in 39% of them (fever, edema, rash, musculoskeletal pain, anemia, colitis, Guillain–Barré syndrome) [711]. On the basis of these data, pembrolizumab was approved by the U.S. Food and Drug Administration (FDA) in June 2018 for the treatment of recurrent and metastatic cervical cancer (see section 18.3.5.2).

Adoptive cell transfer

Adoptive cell transfer involves autologous return transfer of tumor-infiltrating T cells (TIL) directed against tumor antigens (E6, E7) in patients with cervical carcinoma after the cells have been amplified in vitro (with or without genetic modification). A report including nine patients with metastatic cervical carcinoma, previously treated with chemoradiotherapy, described a response rate of 3/9, with two patients showing persistent remission 22 and 15 months, respectively, after the treatment [712].

With the exception of pembrolizumab, the approaches described above are experimental studies. Market approval is currently pending.

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