Recurrent cervical cancer treatment

1. What every clinician should know

Are you sure your patient has disease? What should you expect to find?

While the incidence of cervical cancer has dramatically dropped in developed countries due to widespread cervical cytology screening, it remains the second most common cause of cancer mortality in women globally. In the United States, approximately 12,000 women will be diagnosed with invasive cervical cancer and over 4000 women will die of the disease, which is overrepresented in minority women and those in underserved areas. Women who are diagnosed with early stage disease had a 5-year survival rate of over 90% with radical surgery or combination chemotherapy and radiation.

However, prognosis is dramatically poorer for those diagnosed with advanced stage disease. Overall, approximately one third of women diagnosed with cervical cancer will develop persistent or recurrent disease. Median overall survival after recurrence has been diagnosed in 10-12 months. Recurrence is associated with lymph node status, tumor size, and deep stromal invasion, therefore women with stage I disease have less than a 20% change of recurrence while patients with stage disease have a 75% risk of recurrence.

2. Diagnosis and differential diagnosis

Approximately 80% of recurrences will manifest within 2 years of initial diagnosis, therefore it is important that women who have been diagnosed and treated for cervical cancer undergo regular surveillance with physical and pelvic exam and Pap smear for at least five years after diagnosis. The most common sites of recurrence are the vaginal cuff, pelvis, para-aortic lymph nodes, lungs, and supraclavicular lymph nodes. Correspondingly, symptoms of recurrence are vaginal bleeding, lower extremity edema and pain, weight loss, respiratory symptoms, and enlarging supraclavicular lymph nodes.

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The triad of hydroureteronephrosis, lower extremity edema and sciatic pain is pathognomonic for pelvic sidewall involvement. True salvage therapy is potentially curable if the recurrence is isolated in the central pelvis; therefore it is important to obtain imaging to rule out distant disease. The most commonly employed imaging modality is positron-emission tomography (PET) scanning, although CT and MRI may also be used. If distant or widely metastatic disease is noted, treatment is limited to palliative chemotherapy.

3. Management

What therapies should you initiate immediately i.e. emergently?

Emergent therapy is generally not necessary unless the patient has significant vaginal bleeding. Palliative radiation may be used to control hemorrhage, but in the absence of hemodynamic instability therapy should be instituted only after recurrence has been confirmed and options have been discussed thoroughly with the patient.

What should the initial definitive therapy for the cancer be?

Initial definitive therapy of cervical cancer is reviewed in another chapter (please see ” Diagnosis and treatment of cervical cancer” and ” Treatment with primary chemoradiation” chapters) and will not be covered here. Management of recurrent cervical cancer is dependent on several factors: history of previous treatment, location of recurrence, size of tumor, disease-free interval, and the patient’s health status.

Surgical resection of recurrence is uncommonly employed as a treatment modality. In general, only patients who have been primarily treated with chemotherapy and radiation, and whose tumor is limited to the central pelvis, are candidates for surgical therapy. The classic procedure is a total pelvic exenteration, which involves removal of the mass and adjacent pelvic structures including the uterus, bladder, rectum, and vagina, although depending on the patient and location of the mass, this may be modified. The goal of the procedure is complete removal of the mass and establishment of negative margins, with the intent of cure.

Contraindications include metastatic/sidewall disease and hydronephrosis, therefore patients must be evaluated thoroughly prior to undertaking the procedure. Even so, up to 50% of planned exenterations are aborted intraoperatively due to findings consistent with inoperable disease. The morbidity of the procedure is high, with complications reported in up to 60% of patients, but if negative margins are achieved the 5-year survival rate is reported to be as high as 70%. Patients need to be extensively counseled regarding the impact on quality of life after exenteration, as many will lose bladder and bowel function, and sexual function can be severely compromised. This is a true life changing procedure.

Radiation therapy is another option for recurrent cervical cancer. As expected, patients who develop a recurrence after primary surgical intervention have a better response to secondary radiotherapy. This is likely due to the physiologic effects of first-line radiation on tissue including hypoxia and field effect, which may limit the dose that can be used in subsequent regimens. Most trials involving radiation are limited to primary therapy in patients with advanced disease. However, several small studies have examined the use of radiation in the recurrent setting, with and without chemotherapy, and have had encouraging results – up to a 66% complete response rate was found.

It should be noted that these patients all had recurrences limited to the pelvis, and it is unclear what was the primary treatment and the duration of the interval between initial disease and recurrence. Specifically examining patients who underwent repeat radiotherapy, complete response rates of up to 69% have been observed in small studies, with manageable toxicities. However, no randomized trials comparing radiation versus other modalities in recurrent cervical cancer have been conducted, therefore the above mentioned reports, mostly case series, are prone to biases inherent in all prospective and retrospective cohort studies. If radiation (or re-irradiation) is to be considered, patients must be carefully selected.

Most women with recurrent cervical cancer will not be candidates for either surgery or radiation therapy. Chemotherapy has long been employed for the management of recurrent disease as a palliative modality. The first GOG trial evaluating cisplatin in advanced or recurrent disease was published in 1981, showing an overall response rate of 38%. Multiple other agents have appeared to have activity in phase II trials. However, when these drugs, either in alone or in combination, have been subjected to phase III inquiry, none have proven superior to cisplatin, and little advancement has been made in overall survival. In recognition of the difficulty in treating patients with recurrent cervical cancer, the GOG alone has conducted trials involving more than 60 agents since the mid-1970s, with multiple groups looking at other drugs and combinations.

GOG 110 was a phase III multi-center trial that compared cisplatin, cisplatin with ifosfamide, and cisplatin with dibromodulcitol. While patients who received the cisplatin/ifosfamide doublet had a statistically significant increase in overall response as well as a longer progression-free interval, no overall survival benefit was noted. These gains also came with significant hematologic, renal, CNS, and peripheral neuropathic toxicity. Given the promise of combination treatment GOG 149 enrolled 303 patients into two arms: cisplatin/ifosfamide or cisplatin/ifosfamide/bleomycin. No difference between response rate, progression-free survival, or overall survival was seen with the addition of bleomycin. Since no agent alone or in combination to that point improved survival more than cisplatin, it was concluded that single-agent cisplatin should be the standard agent for future trials. GOG 169, published in 2004, examined cisplatin alone versus in combination with paclitaxel.

While no improvement in overall survival was seen, patients who received the combination had improved progression free survival, response rate, and sustained quality of life. GOG 179 compared cisplatin and cisplatin/topotecan (a third arm, consisting of methotrexate, vinblastine, doxorubicin, and cisplatin was closed early due to excessive treatment-related toxicities and deaths). Patients who received cisplatin and topotecan had a 23% improvement in overall survival compared to those who received cisplatin alone. This was the first trial to suggest that a combination regimen was superior to cisplatin alone.

However, the absolute improvement was only 2.9 months, at the cost of significant hematologic toxicity. Building on the results of GOG 169 and 179, GOG 204 compared the combinations of cisplatin/paclitaxel, cisplatin/vinorelbine, cisplatin/gemcitabine, and cisplatin/topotecan. This trial was closed early when an interim analysis demonstrated no difference between the groups in terms of overall survival, progression-free survival, response rate, or quality of life. SCOTCERV, a trial conducted in Scotland, compared docetaxel/gemcitabine in patients with recurrent cervical cancer who had received prior cisplatin therapy, either as a chemotherapeutic agent or as a radiosensitizer.

The investigators did not observe a survival advantage. They also noted that response rate and overall survival with this regimen was poorer than in GOG 204, with the caveat that the populations were slightly different in regards to prior treatment and prognostic factors.

As traditional chemotherapeutics have been largely disappointing in the recurrent setting, attention has been turned to biologic agents. Bevacizumab, a humanized monoclonal antibody against vascular endothelial growth factor (VEGF), has been studied in numerous solid tumors with varying results. GOG 227C, a phase II trial examining the efficacy of bevacizumab in recurrent cervical cancer, demonstrated a median progression-free and overall survival of 3.4 and 7.3 months, respectively. This led to the activation of GOG 240, a phase III trial comparing cisplatin/paclitaxel with and without bevacizumab versus topotecan/paclitaxel with and without bevacizumab. This trial closed to accrual in January 2012 and is currently in follow-up. Other biologics, such as cetuximab (a chimeric monoclonal antibody against the epidermal growth factor receptor) have proved disappointing with little or no activity; therefore the results of GOG 240 are eagerly awaited.

4. Complications

What complications could arise as a consequence of the condition? Are there strategies to lower the risk of complications?

Complications arising from recurrent cervical are generally those relating to past and current treatment. Recurrent tumor can cause pain, and if the mass compresses pelvic structures, can cause lower extremity edema and nerve pain.

What complications could arise as a consequence of the management – chemo, radiation and surgical?

There are numerous complications that may arise from treatment of recurrent cervical cancer. Women who undergo pelvic exenteration are at high risk for infection, urinary and gastrointestinal fistulae, venous thromboembolic events, wound complications, and sexual dysfunction. Not surprisingly, quality of life is related to extent of surgery and risk of recurrence, with women who undergo more extensive procedures reporting a worse quality of life.

Radiation treatment, especially pelvic radiation, has significant side effects- both short and long term. Radiation can cause scarring of tissue, making future surgery difficult. It also causes tissue hypoxia, which impairs healing. Bowel and ureteral strictures are not uncommon after abdominal radiation, and some degree of vaginal stenosis is often seen after brachytherapy. The iliac crests contain a large amount of bone marrow; therefore hematopoietic reserve is compromised after pelvic radiation and can significantly limit the dose of chemotherapy used after radiotherapy.

The most common complication of chemotherapy is hematologic toxicity. Significant neutropenia is often noted, and the degree of suppression is usually related to type of drug and previous therapy. The most common complications arising from administration of cisplatin include nephrotoxicity, nausea/vomiting, and ototoxicity. Paclitaxel’s most significant toxicity is peripheral neuropathy. Topotecan and gemcitabine, especially in combination with other agents, causes significant myelosuppression with subsequent risk of neutropenic fever and sepsis.

C. What other therapies are helpful for reducing complications?

As radiation toxicity is directly related to exposure and dose, care should be taken to shield structures in the area that do not require irradiation. Advances in imaging and radiation oncology have allowed specific tailoring of fields to minimize unnecessary toxicity.

Modern pharmaceuticals have significantly mitigated many chemotherapy side effects. Anti-emetics such as 5-HT3 antagonists are given prior to chemotherapy induction and have drastically reduced the incidence of chemotherapy-related nausea and vomiting, which was substantial and dose-limiting in the past.

While myelosuppression is still observed, colony-stimulating factors such as synthetic erythropoietin and filgrastim are used to treat anemia and mitigate neutropenia, respectively. Caution must be used when using these medications, however, since recent reports suggest increased risk of mortality and tumor progression in patients given epoetin alfa.

Cisplatin’s nephrotoxicity can generally be avoided with sufficient hydration, although dose modification is necessary with renal impairment. Currently there is no effective treatment for cisplatin-induced ototoxicity. Peripheral neuropathy can be symptomatically treated with gabapentin, but unfortunately sensory loss is often permanent.

5. Prognosis and outcome

What would you tell patient and family about the prognosis?

The prognosis for recurrent cervical cancer is poor. Overall, median survival after diagnosis of recurrence is 10-12 months. According to a review of GOG trials, factors that influence survival include performance status, race, interval between diagnosis and recurrence, and prior chemotherapy treatment. Location of recurrence also seems to be a prognostic factor; those with masses in a previously irradiated field have worse survival.

An important factor when considering prognosis is platinum-free interval. Several retrospective and prospective trials have shown an association between platinum-free intervals of 6 or more months and improved survival. However, as effective chemotherapeutic options in this clinical setting are very limited, most patients will receive platinum-based treatment until they progress while on chemotherapy.

The goal of treatment in most cases of recurrent cervical cancer is palliation. This must always be kept in mind, as the toxicities and complications of many of these treatments are significant. Quality of life must always be a consideration. Recognizing this, the GOG has included quality of life as an endpoint in every recurrent cervical cancer trial since GOG 169. As the authors of that study pointed out, “Because median survival in this patient population is poor, it is imperative that palliative [therapy] does not severely compromise short term QOL.”

Patients with cervical cancer should be managed by a gynecologic oncologist. Treatment is often managed by an interdisciplinary team including radiation oncologists and palliative care specialists.

6. What is the evidence for specific management and treatment recommendations?

Shingleton, HM, Soong, SJ, Gelder, MS, Hatch, KD, Baker, VV, Austin , JM. “Clinical and histopathologic factors predicting recurrence and survival after pelvic exenteration for cancer of the cervix”. Obstet Gynecol. vol. 73. 1989. pp. 1027-34. (Large single institution experience of pelvic exenteration for cervical cancer; describes factors relating to successful outcomes.)

Berek, JS, Howe, C, Lagasse, LD, Hacker, NF. “Pelvic exenteration for recurrent gynecologic malignancy: survival and morbidity analysis of the 45-year experience at UCLA”. Gynecol Oncol. vol. 99. 2005. pp. 153-9. (Single institution experience of pelvic exenteration for any gynecologic malignancy.)

Ijaz, T, Eifel, PJ, Burke, T, Oswald, MJ. “Radiation therapy of pelvic recurrence after radical hysterectomy for cervical carcinoma”. Gynecol Oncol. vol. 70. 1998. pp. 241-6. (Survival characteristics of patients who receive radiation therapy after radical surgery for cervical cancer.)

Randall, ME, Evans, L, Greven, KM, McCunniff, AJ, Doline, RM. “Interstitial reirradiation for recurrent gynecologic malignancies: results and analysis of prognostic factors”. Gynecol Oncol. vol. 48. 1993. pp. 23-31. (Case series of patients undergoing reirradiation for recurrent gynecologic malignancy.)

Moore, DH, Blessing, JA, McQuellon, RP. “Phase III study of cisplatin with or without paclitaxel in stage IVB, recurrent, or persistent squamous cell carcinoma of the cervix: a gynecologic oncology group study”. J Clin Oncol. vol. 22. 2004. pp. 3113-9. (Gynecologic Oncology Group [GOG] 169 – found that cisplatin/paclitaxel is superior to single-agent cisplatin in regards to quality of life parameters.)

Long, HJ, Bundy, BN, Grendys, EC. “Randomized phase III trial of cisplatin with or without topotecan in carcinoma of the uterine cervix: a Gynecologic Oncology Group Study”. J Clin Oncol. vol. 23. 2005. pp. 4626-33. (GOG 179 – found that while combination with may improve overall survival, toxicity may outweigh small benefit.)

Monk, BJ, Sill, MW, McMeekin, DS. “Phase III trial of four cisplatin-containing doublet combinations in stage IVB, recurrent, or persistent cervical carcinoma: a Gynecologic Oncology Group study”. J Clin Oncol. vol. 27. 2009. pp. 4649-55. (GOG 204 – platinum agents are the most important aspect of chemotherapy for advanced/recurrent cervical cancer.)

Moore, DH, Tian, C, Monk, BJ, Long, HJ, Omura, GA, Bloss, JD. “Prognostic factors for response to cisplatin-based chemotherapy in advanced cervical carcinoma: a Gynecologic Oncology Group Study”. Gynecol Oncol. vol. 116. 2010. pp. 44-9. (GOG 149 – Performance status, race, disease interval, and prior therapy are correlated with prognosis.)