Cervical Cancer

Surgical Management of Recurrent or Metastatic Disease

Recurrent advanced disease

Pelvic exenteration. For patients whose disease fails to respond to primary radiation therapy or for those with early invasive cervical carcinoma whose disease recurs after surgery or radiation therapy, pelvic exenteration offers the possibility of cure. Patients should be considered for pelvic exenteration only if they have locoregional disease that can be completely removed by this radical surgical procedure. In most cases, patients will require surgical removal of the bladder, uterus, cervix, vagina, and rectum.

Of all patients who are considered candidates for pelvic exenteration, only about half will be found to have resectable disease at the time of exploratory laparotomy. For patients who successfully undergo pelvic exenteration, 5-year survival rates range from 25% to 50%.

When the patient has central recurrence of squamous cell or adenocarcinoma of the cervix, the initial evaluation includes a complete physical examination, as well as a CT, MRI, or PET/CT scan.

Evidence of extrapelvic disease is a contraindication to pelvic exenteration. If no evidence of disease beyond the pelvis is found, the patient can be prepared for pelvic exenteration.

• Preparation for exenteration—includes complete bowel preparation, a visit with the stomal therapy nurse, and counseling regarding the radical nature of the surgery and the anticipated changes in body image after the operation. In most cases, we counsel the patient that vaginal reconstruction should be performed at the time of pelvic exenteration, both for maintenance of body image and improved healing.

• Surgical procedure—During surgery, a careful exploration is carried out to confirm that there is no evidence of unresectable disease beyond the pelvis. Explorative laparoscopy before pelvic exenteration has been used in this regard to localize the tumor and evaluate the presence of adjacent organ involvement. The pelvic sidewall spaces are opened and resectability is determined. If there is no evidence of adjacent organ involvement, an en bloc resection is usually performed; in some cases, especially when the recurrent tumor involves the lower vagina, a two-team approach can expedite the procedure. The actual exenterative portion of the procedure may take several hours and is usually accompanied by significant blood loss. In cases where surgical margin status may be questionable, the use of intraoperative radiation therapy is considered.

• Reconstruction—Following the exenterative procedure, the reconstructive portion of the procedure begins. We currently recommend a continent urinary diversion to nearly all patients. Although this step may add approximately 30 to 60 minutes to the surgical procedure, the improvement in quality of life is significant.

In patients who have undergone a supralevator pelvic exenteration, we frequently attempt a stapled reanastomosis of the colon. Unless there is excessive tension on the anastomosis or other problems, a diverting colostomy is not routinely indicated. About one-third of these patients suffer anastomotic breakdown in the postoperative period. At that time, a diverting colostomy can be performed. Unfortunately, Hatch et al (Gynecol Oncol 1990) found no benefit to the earlier use of colostomy.

Lung metastasis

For the rare patient who presents with a single isolated lung metastasis after treatment of invasive cervical carcinoma, pulmonary resection may offer the possibility of long-term disease-free survival or even cure in select cases. For patients who have multiple lung metastases or unresectable pelvic disease, surgery offers little or no hope and produces significant morbidity and mortality.

Therapy for Recurrent or Metastatic Disease

Local recurrence after radical hysterectomy

Local recurrence confined to the pelvis following radical hysterectomy for cervical cancer can be treated with radiotherapy with curative intent. An experience with 5-FU–based chemotherapy and concurrent pelvic EBRT resulted in a 58% complete response rate and a 45% no-evidence-of-disease rate at a median follow-up of 57 months. The total pelvic EBRT dose was 5,280 cGy plus a boost to sites of recurrence with twice-daily 160-cGy fractions during the 5-FU infusion. Therefore, radiotherapy, with or without chemotherapy, can provide durable local tumor control, with better results attainable for small, central recurrences, for which brachytherapy is possible.

Local recurrence after definitive radiation therapy

Local recurrence confined to the pelvis following definitive radiation therapy rarely can be cured with exenteration. In a series of patients treated with definitive radiotherapy, 21% of recurrences (80 of 376) were isolated to the pelvis. Only 29% of these localized pelvic recurrences (23 of 80) were explored for curative exenteration, and for the 43% of patients (10 of 23) deemed operable, the 5-year survival rate was 16%. Para-aortic lymph node recurrences are also observed in some of these patients, and some are successfully treated with aggressive irradiation and chemotherapy. Of 758 patients, 42 (6%) had isolated and nonisolated para-aortic lymph node failures. The 5-year survival in the above group was 28%. Careful follow-up, early detection, and aggressive treatment of para-aortic lymph node recurrences may increase the probability of salvage for some of these patients.

Palliation of metastatic disease

Palliative radiation therapy to sites of metastatic cervical cancer is effective. The most common sites of metastasis are distant lymph nodes, bone, and lungs. Reirradiation of the pelvis is possible in select patients to control local symptoms, such as bleeding, but carries an increased risk of bowel complications. For previously unirradiated sites of metastatic disease, 3,000 cGy in 10 fractions provides palliation of symptoms in the majority of patients.

Chemotherapy for Advanced/Recurrent Disease

Chemotherapy has traditionally been used for the palliative management of advanced or recurrent disease that can no longer be managed by surgery or radiation therapy (Table 3). Various factors complicate the use of chemotherapy in such patients, however. Prior radiation treatment can affect the blood supply to the involved field, which may result in decreased drug delivery to the tumor site. Pelvic irradiation also reduces bone marrow reserve, thus limiting the tolerable doses of most chemotherapeutic agents. Moreover, irradiation may produce its cytotoxic effect, in part, through a mechanism similar to that of alkylating agents; thus, it is thought to be cross-resistant with some chemotherapeutic agents. A significant number of patients with advanced disease may also have impaired renal function, further limiting the use of certain chemotherapeutic regimens.

TABLE 4Active agents as defined by a response rate of at least 15%

Single agents

Among the chemotherapeutic agents used for cervical cancer, cisplatin(Drug information on cisplatin) and ifosfamide have shown the most consistent activity as single agents (Table 4). The duration of response with any single agent is brief, ranging from 4 to 6 months, with survival ranging from 6 to 9 months.

Cisplatin. Cisplatin has been the most extensively evaluated single agent for cervical carcinoma. A dose of 100 mg/m² was shown to have a higher response rate than a dose of 50 mg/m² (31% vs 21%), but the higher dose was associated with increased toxicity; overall survival did not differ significantly between the two groups. A 24-hour infusion of cisplatin was tolerated better than a 2-hour infusion, with no difference in therapeutic efficacy.

TABLE 5Combination chemotherapy for advanced or recurrent cervical carcinoma

Ifosfamide. Ifosfamide produces response rates ranging from 33% to 50% in various dose schedules. A dosage of 1.5 g/m² over 30 minutes for 5 days (with mesna [Mesnex]) produced an overall response rate of 40% and a complete response rate of 20%.

Lower response rates are generally seen in patients who have had prior chemotherapy. Responses also are decreased in previously irradiated sites.

Taxanes. Paclitaxel and docetaxel (Taxotere) have been reported to be active in cervical cancer. A study of paclitaxel (170 mg/m² over 24 hours) showed an objective response rate of 17%, and another study of paclitaxel (250 mg/m² over 3 hours) demonstrated an objective response rate of 27%. Docetaxel (100 mg/m² over 1 hour) has yielded a response rate of 19%.

Camptothecins. Irinotecan and topotecan(Drug information on topotecan), semisynthetic camptothecins, have shown activity in patients with cervical cancer, even in patients who did not respond to prior chemotherapy and prior radiation therapy. The reported objective response rates were 21% and 19%, respectively.

Targeted therapies. Newer biologic agents are being actively studied. Two important receptors in cervical cancer include vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR). VEGF is a key promoter of tumor progression in cervical cancer. A GOG phase II study of 46 patients with metastatic cervical cancer explored the role of bevacizumab (Avastin), a recombinant humanized anti-VEGF monoclonal antibody. Eleven patients (24%) survived progression-free for at least 6 months, and five patients (11%) had objective radiographic responses. This finding compared favorably with results of historic phase II studies in this population. Results of another GOG phase II study testing cetuximab (Erbitux), a monoclonal antibody to the EGFR, in patients with persistent or recurrent disease did not show any significant clinical response. The 5 patients out of 38 who showed progression-free survival for 6 months had tumors with squamous cell histology, thus suggesting cetuximab activity may be limited to cervical cancer patients with squamous cell histology.

Combination regimens

Various combination chemotherapy regimens have been evaluated in phase II trials, and high response rates (> 50%) were noted, even in patients who had received prior radiation therapy. The results of some of these trials are summarized in Tables 5 and 6. In one study, a subset analysis showed a response rate of 72% with the combination of bleomycin, ifosfamide, and cisplatin as treatment for tumors located in previously irradiated sites. Neoadjuvant regimens of cisplatin combined with gemcitabine(Drug information on gemcitabine) in patients with locally advanced cervical cancer demonstrated very high activity, with a clinical response rate of 95%. Neoadjuvant ifosfamide and cisplatin, with or without paclitaxel, produced 87% and 82% response rates, respectively, among 146 evaluable patients in a randomized study.

A randomized trial was reported by Long et al. A total of 146 patients with advanced persistent or recurrent cervical cancer were treated with cisplatin (50 mg/m² IV every 21 days), and 147 patients were treated with topotecan (0.75 mg/m² IV during 30 minutes on days 1, 2, and 3 followed by cisplatin (50 mg/m² on day 1) repeated every 21 days. All regimens were administered for a maximum of six cycles for nonresponders or until disease progression or unacceptable toxicity prohibited additional chemotherapy. The complete response rate was 3% for cisplatin and 10% for the cisplatin-topotecan combination, and the complete and partial remission rates were 13% and 27%, respectively; the median progression-free survival was 2.9 months and 4.6 months, respectively. Chemotherapy remains palliative, with no longevity prolongation of survival in recurrent or metastatic disease.

A phase III GOG randomized trial explored four cisplatin-containing doublet combinations in stage IVB, recurrent or persistent cervical carcinoma. A total of 434 evaluable patients received cisplatin (50 mg/m² on day 1), combined with either paclitaxel (135 mg/m²) or vinorelbine (30 mg/m² on days 1 and 8) or gemcitabine (1,000 mg/m² on days 1 and 8) or topotecan (0.75 mg/m² on days 1, 2, and 3). Each cycle was repeated every 21 days. In the analysis, the cisplatin and paclitaxel regimen was considered the standard arm, and a 33% death reduction was considered to be a significant endpoint. In the final results, there was no survival difference seen among the four groups. Cisplatin-paclitaxel had the highest radiographic response rate (29.1%) and slightly higher survival rates (2.6 months longer), but still these results were not statistically better than those of the other treatment groups.

Recently, a phase III trial conducted by the Japanese Clinical Oncology Group compared palliative chemotherapy containing paclitaxel and carboplatin (TC) with paclitaxel and cisplatin (TP) as a standard treatment for patients with newly diagnosed stage IVB persistent or recurrent cervical cancer. The study was designed to demonstrate the non-inferiority of the TC regimen; the primary endpoint was overall survival. The median overall survival for TP was 18.3 months, and for TC, 17.5 months. The authors suggested that "the more feasible and less toxic TC can be recommended as the new standard treatment for stage IVB or recurrent cervical caner."

TABLE 6Phase III clinical trials in advanced or recurrent cervical cancer

Palliative care

Palliation of the dying cervical cancer patient is difficult. Pain due to recurrent pelvic disease can be extreme and requires skillful use of combinations of narcotics, sedatives, and anxiolytics. Fistula from the bladder or rectum demands meticulous local skin care and occasionally surgical diversion procedures in patients with reasonable expected longevity. This patient population often has limited resources, with dependent children requiring careful social service planning. A small percentage has concurrent HIV infection, making the infectious disease specialist part of the palliative care team. The tripod of care in advanced cervical cancer is the judicious use of chemotherapy and radiation therapy, palliation of the symptoms of advancing disease, and emotional and social support for the patient and family members.

In the follow-up of patients treated for carcinoma of the cervix, it is important to keep in mind that they are at risk for the development of secondary malignant tumors. In a study of more than 85,000 patients with squamous cell carcinoma and 10,280 with adenocarcinoma treated in Scandinavian countries and the United States, there were 10,559 second cancers (standardized incidence ratio [SIR] = 1.31) in the squamous cell carcinoma and 920 (SIR = 1.29) in the adenocarcinoma patients. Risk of lung cancer was increased in both groups of patients. SIRs for second cancers of the colon and soft tissues, melanoma, and non-Hodgkin lymphoma were significantly higher among the adenocarcinoma survivors than the squamous cell carcinoma survivors.

Carcinoma of the cervix and pregnancy. About 1% of patients with cervical cancer are pregnant at diagnosis. Most patients present with an abnormal cytology or vaginal bleeding. Colposcopy during pregnancy is used to rule out invasive carcinoma. This procedure and biopsies of suspicious lesions are safe for these patients. In patients with high-grade dysplasia, a conservative approach is reasonable. Conization during pregnancy was associated with fetal loss of 10% to 20% in some series.

More than 70% of cervical cancer cases diagnosed during pregnancy are stage I disease. Management requires a multidisciplinary approach, involving a gynecologist, radiation oncologist, perinatologist, and psychological counselor. Important elements in the therapeutic decision involve tumor size, tumor stage, gestational status, and the patient's desire to continue the pregnancy.

Invasive cancer in a pregnant woman (< 20 weeks) generally is managed immediately, with loss of the fetus, although there have been reports of delayed treatment in select patients with small tumors. The majority of patients are treated with a total or radical hysterectomy, which can be performed after a cesarean section and fetal delivery in women with pregnancy in the second or third trimester. An alternative is radiation therapy alone, for stage I/II disease, or combined with chemotherapy, for locally advanced disease. Spontaneous abortion usually occurs at about 4 weeks after initiation of pelvic irradiation (40 Gy). In patients whose cancer is diagnosed during the third trimester, fetal delivery is accomplished with a cesarean section or vaginal delivery, after which definitive treatment with radical surgery or irradiation is instituted. Several reports show comparable results with either therapeutic approach.