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© 2003 American Society for Clinical Oncology Small-Cell Carcinoma of the Cervix: Fourteen Years of Experience at a Single Institution Using a Combined-Modality Regimen of Involved-Field Irradiation and Platinum-Based Combination ChemotherapyFrom the Division of Medical Oncology, Division of Radiation Oncology, and Cancer Control Research, British Columbia Cancer Agency, Vancouver and Fraser Valley Clinics, British Columbia, Canada. Address reprint requests to Paul J. Hoskins, MD, British Columbia Cancer Agency, 600 West 10th Ave, Vancouver, BC, Canada, V5Z 4E6; e-mail: phoskins{at}bccancer.bc.ca.
Purpose: To determine the efficacy and toxicity of a combined-modality regimen of irradiation with platinum-based combination chemotherapy in small-cell carcinoma of the cervix (SCCC). Patients and Methods: Thirty-four patients with SCCC were seen and treated at the British Columbia Cancer Agency between May 1988 and November 2002. Two protocols were used, SMCC (May 1988 to December 1995) and SMCC2 (January 1996 to November 2002). Both protocols used cisplatin, etoposide, and involved-field irradiation (essentially pelvis plus or minus para-aortics) with concurrent chemotherapy. In addition, SMCC2 included carboplatin and paclitaxel, and the para-aortics were irradiated routinely. Results: Thirty-one patients received either SMCC (n = 17) or SMCC2 (n = 14), and three patients did not (disease too extensive, n = 1; patient refusal, n = 1; and alternative regimen, n = 1). For the 31 patients treated on one of the protocols, the 3-year overall and failure-free survival (FFS) rates were 60% and 57%, respectively. The results were equivalent for SMCC and SMCC2. Radiologic stage was the only independent predictor for FFS (80% at 3 years for stage I and II patients v 38% at 3 years for stage III and IV patients). Distant failure (28%) was the most common cause of failure, with local failure occurring in 13% of patients. The switch to SMCC2 did not improve efficacy but did lessen the toxicity. Conclusion: SCCC can be successfully treated in approximately 55% of patients with a combination of irradiation and platinum-based chemotherapy. Disease extent predicts for chance of curability.
SMALL-CELL CARCINOMA of the cervix (SCCC), which was first described in 1957, is a rare cancer comprising less than 3% of all cervical neoplasms.1–5 The behavior of SCCC is akin to small-cell lung cancer (SCLC) in that lymph node involvement is common (50% to 60%), vascular invasion is the norm, and relapse patterns show that it is hematogenously disseminated.4,6–8 Given this behavior, we have been treating SCCC in a similar fashion to SCLC. Therefore, irradiation, started early in the treatment regimen, is used for local control, and platinum-based chemotherapy is used for systemic control.9–11 In 1995, we reported on the initial 11 patients treated with this regimen.12 Essentially, local control was good, death was a result of distant metastases, Eastern Cooperative Oncology Group (ECOG) status and cervix size were prognostic, and the toxicity was high with resultant dose reductions and treatment delays. As a result, the regimen was modified. To try to improve the efficacy of the chemotherapy, paclitaxel was added because of its activity in SCLC.13 The irradiation component was modified by adding cisplatin (60 mg/m2 every 2 weeks) as a radiation sensitizer.14 In addition, the para-aortic area was irradiated routinely. We hoped to diminish the toxicity and need for treatment modifications by changing to a 3-week chemotherapy schedule, substituting carboplatin for cisplatin in the final two multiagent cycles, and giving the irradiation without concurrent multiagent chemotherapy, substituting single-agent cisplatin chemotherapy instead. In this article, we detail our institutional experience since 1988 with SCCC, when our multimodality approach was first instituted, updating the long-term results of our initial protocol. We also detail the design, results, and toxicity of our replacement protocol SMCC2 and provide the results of univariate/multivariate analyses of potential prognostic factors.
Patients All patients with SCCC diagnosed from May 1998 onward and who were referred to one of the clinics of the British Columbia Cancer Agency were identified both from the computerized, pathologic diagnosis–based patient database and from the pharmacy records (all institutional treatment protocols have a specific code). The histologic definition of SCCC was the definition used by the World Health Organization using light microscopy for small-cell cancer of the lung15 (ie, small cells, hyperchromatic nuclei, scant cytoplasm, and high nuclear-cytoplasmic ratio). Electron microscopy, testing for neuron-specific enolase, and silver staining were not used. Any small-cell component was sufficient for the patient to be included. The cancer was staged both clinically, according to the International Federation of Gynecology and Obstetrics staging system, and radiologically.16 Examination under anesthesia, cystoscopy, and proctoscopy were not routinely used. Surgical staging was not performed because our policy was to start treatment as soon as possible after the initial diagnostic biopsy, and we used irradiation, not surgery, for local control. Instead, computed tomography (CT) scan imaging of the abdomen and pelvis was used to try to identify additional sites of disease. The following tests were routine: complete blood count, electrolytes and creatinine, liver function tests (AST, lactate dehydrogenase, gamma-glutamyltransferase, and alkaline phosphatase), chest x-ray, and CT scan of the abdomen and pelvis. Bipedal lymphangiogram was used initially but was dropped in favor of CT scan. CT scan of the brain was performed initially, but because no cases of CNS involvement at diagnosis were found in the initial cohort, its use became optional. For the same reason, bone marrow biopsy and aspiration were dropped from the requirements.
Treatment
Exclusion criteria for SMCC2 were age greater than 70 years (unless ECOG performance status of 0 or 1), creatinine greater than 150 µmol/L (after hydration, stenting, or both), partial deafness, second- or third-degree heart block, inability to tolerate fluid loading, inability to receive irradiation, and a disease extent that could not be radioencompassed. Essentially, these criteria were similar to those used for SMCC, except that in the SMCC protocol, the age cutoff was 65 years, and heart block was irrelevant because paclitaxel was not used. The dose adjustments used in the SMCC protocol have previously been described.12 For SMCC2, there were no planned dose reductions, but instead, treatment at days 21, 98, and 126 was to be delayed until the neutrophil count was greater than 1 x 109/L and the platelet count was greater than 100 x 109/L. Renal dysfunction, hearing loss, and neuropathy were not expected to be a problem, and therefore, no dose reduction scheme for these indications was included in the protocol. In SMCC2, the radiotherapy was scheduled to start concurrently with the third cycle of chemotherapy (day 42). The radiotherapy regimen was 40 Gy of 10, 18, or 25 MV photons in 25 daily fractions to the pelvis and para-aortic lymph nodes. This regimen was followed by two intracavitary insertions if the cervix was present and technically amenable to brachytherapy, or an external-beam pelvic boost of 15 Gy in 7 daily fractions if the cervix was not suitable for brachytherapy, or the regimen was followed by an external-beam pelvic boost of 10 Gy in 5 daily fractions if a hysterectomy had been performed before protocol entry. The pelvis and para-aortic nodes were treated with anteroposterior/posteroanterior ports extending from midischium to the T12/L1 interspace and laterally to cover the true pelvis with a 2-cm margin. Blocking, determined by anatomy and CT scan, was used to limit normal tissue exposure. Brachytherapy was delivered with a standard, remote after-loading system using caesium 137 delivering 13.5 Gy to point A at 1 Gy/h in each of two implants timed at the end of teletherapy and 1 week later. External-beam boosts were delivered with lateral pelvic fields extending from midischium to L5/S1 and from the anterior symphysis to S2/3; again, blocking was used where appropriate. At the discretion of the treating radiation oncologist, prophylactic cranial radiotherapy of 25 Gy in 10 fractions after the completion of all chemotherapy was allowed. Prophylactic cranial radiotherapy was dropped from the protocol in September 1998. The irradiation regimen was slightly different between SMCC and SMCC2. In the original SMCC protocol, the approach to external-beam radiotherapy was to treat known disease plus one uninvolved nodal station with a minimum volume of pelvis and a maximum of pelvis and para-aortic nodes. Brachytherapy was to be used if possible. Radiotherapy doses were reduced to account for chemotherapy. In SMCC2, all patients were planned to receive pelvic and para-aortic radiotherapy because this was found to be tolerable in SMCC, and brachytherapy was delivered with no dose reduction.
Assessment of Results Overall survival (OS) was assessed from the date of the initial diagnostic biopsy to death from any cause. Failure-free survival (FFS) was measured from diagnosis to either progression/relapse or to the date of toxic death.
Patients Thirty-four women (median age, 43 years; range, 23 to 75 years) with SCCC (mixed histology, 29%) have been seen and treated at the British Columbia Cancer Agency since the inception of the SMCC protocol in May 1988 up until the present day. Patient characteristics are listed in Table 1  . The last woman was diagnosed on September 13, 2001, and the analysis was performed with follow-up data collected up to August 1, 2002. Twenty-nine women had a cervical biopsy alone, four had total abdominal hysterectomy and bilateral salpingo-oophorectomy, and one had a subtotal hysterectomy. Three of the five patients undergoing hysterectomy had their SCCC diagnosed as an incidental finding at the surgery. Seventeen patients received the SMCC protocol, 14 received the SMCC2 protocol, and three received other treatment (no treatment at patient’s request, n = 1; pelvic irradiation for palliation in the setting of widespread disease, n = 1; and cyclophosphamide/irradiation, n = 1).
Clinical staging significantly underestimated the true disease extent. With further imaging studies, 38% of patients (n = 13) were upstaged. There was a difference in the upstaging rate between the SMCC and SMCC2 patients, with 47% (eight of 17 patients) and 21% (three of 14 patients), respectively, being upstaged. This was most likely caused by the discontinuation of lymphangiography, which, unlike CT scan, can identify abnormal structure despite normal size. It was performed in five of the SMCC patients and in none of the SMCC2 patients. Therefore, a greater percentage of patients in the SMCC2 cohort were classified as stage IB (ie, lymph-node negative). Disease sites at diagnosis (all patients) were the cervix (n = 34), pelvic lymph nodes (n = 11), vagina (n = 4), uterus (n = 4), periurethral (n = 1), ovary (n = 2), para-aortic nodes (n = 8), bone (n = 1), hilar nodes (n = 1), and lung (n = 2). Ten of 17 SMCC patients had disease limited to the pelvis; in addition, six patients had involvement of para-aortic nodes, and one patient had systemic metastases. Twelve SMCC2 patients had disease limited to the pelvis, and two patients had involvement of para-aortic nodes and systemic metastases.
Treatment Outcomes
There was an apparent plateau to the survival curves (both OS and FFS) after the 30-month time point. For all 34 patients, the 3-year OS rate was 55%, and the 3-year FFS rate was 55% (Figs 3 and 4). There was no difference in outcomes between SMCC and SMCC2. The survival curves were overlapping; at 3 years, OS was 60%, and FFS was 57%.
In the univariate analysis, ECOG status (0 v  1), regimen (SMCC v SMCC2), and clinical stage were not significant factors for OS and FFS. Cervix size (< 5 cm) and radiologic stage (I or II) were positive predictive factors for OS and FFS; age (< 50 years) also predicted for OS (Table 3). Radiologic stage used clinical examination results, as well as the results of CT scanning and lymphangiography. Because lymphangiography was less often used in the SMCC2 cohort, with resultant understaging, stage migration likely will have slightly altered the true survival rates of the low-stage and high-stage groups.
Radiologic stage was the only independent predictor in the multivariate analysis for FFS (Fig 5 ), whereas age and radiologic stage both predicted for OS (Table 3 ). Relapse/progression rates by radiologic stage (excluding toxic deaths and death from other causes) were 25% (three of 12 patients), 0% (zero of four patients), 50% (three of six patients), and 64% (seven of 11 patients) for stages I, II, III, and IV, respectively.
Treatment Delivery for SMCC2 One patient treated with SMCC2 progressed rapidly and did not complete treatment, and one patient, aged 75 years, discontinued the chemotherapy after one cycle but did undergo the irradiation. The remaining 12 patients underwent the full protocol. Nine patients received full doses of all drugs, and 10 were treated on time. Thirteen of the 14 SMCC2 cohort patients were irradiated. Eleven had pelvis plus intracavitary and two had pelvis plus boost. Twelve patients also had para-aortic irradiation. In the original SMCC cohort, only eight patients (47%) had para-aortic irradiation. Twelve of 13 patients received their irradiation on time, and all 13 received full-dose irradiation. Three patients (21%) received cranial irradiation; whereas, in the SMCC protocol, seven patients (41%) received cranial irradiation.
Treatment Toxicity With SMCC2
A multimodality regimen of platinum-based chemotherapy with pelvic plus or minus para-aortic nodal irradiation was introduced as our routine treatment of SCCC in May 1989. Since then, 34 patients have been treated. Thirty-one patients received either the original SMCC variant (n = 17) or the subsequent SMCC2 protocol (n = 14). Two patients were treated with other regimens, and one patient refused all treatment. All three of these patients have died. The 3-year OS and FFS rates (failure is relapse, progression, or death from toxicity) for the SMCC and SMCC2 patients were 60% and 57%, respectively. There was a plateau to the survival curve from 3 years onward; so therefore, these patients are likely cured. The outcomes were the same for the two protocols and are superior to any other outcomes reported in the literature (Table 5 ).2,4,5,7,17–22 Comparison between series is problematic for all the well-known reasons of referral and selection bias. However, it does seem that those regimens that routinely use chemotherapy in addition to local treatments (ie, irradiation, surgery, or both) confer a superior outcome to regimens in which there is no use of chemotherapy, as evidenced in our study and others.21,22
Radiologic stage (ie, staging using imaging modalities and clinical examination) was the only independent predictor for FFS. Patients with central pelvic disease only (stage I or II) did significantly better (19% relapse rate, three of 16 patients) compared with patients with stage III or IV disease (59% relapse rate, 10 of 17 patients). The relapse rates/survival figures for these two groups will be slightly inaccurate because there was a decrease in the use of lymphangiography, resulting in understaging and stage migration. Age less than 50 years was also positively significant for OS. In our initial report, there were no episodes of pelvic failure, but with this larger series, it occurred in 13% of patients (four of 31 patients).12 This is a lower rate than the rates found in the three other series in which relapse rates were given. In the series from Sevin et al,7 four of the seven patients treated with hysterectomy and pelvic irradiation relapsed locally, and in the study by Sheets et al,4 five of eight patients treated with hysterectomy and pelvic irradiation relapsed. Sykes et al5 reported on 11 patients who were treated (seven had irradiation, two had surgery, and two received both modalities); seven of the patients relapsed, all of whom had a component of pelvic relapse. The only substantive differences between our regimen and the regimens in these other studies were the routine use of chemotherapy, given from the initiation of therapy, and the concurrent use of chemotherapy and irradiation. Our results indicate that routinely using surgery in addition to pelvic irradiation would not be helpful because the pelvic relapse rate was only 13%, and only two of the four relapses (one in the cervix and one in an iliac node) could have been potentially prevented by surgery. Distant (ie, hematogenously disseminated) disease was the major reason for failure, as reported previously.4,5,17 Our regimen change from SMCC to SMCC2 did not meet our goal of improving the efficacy of the chemotherapy, at least statistically, with six (35%) of 17 SMCC patients and three (21%) of 14 SMCC2 patients experiencing distant failure. Our other goal was to make the regimen more tolerable. In that, the change was a partial success. Patient admissions to hospital significantly decreased (from 60% to zero), and the drop in ECOG status during therapy was markedly less. Some of these improvements were a result of the advent of serotonin antagonists as antiemetics, but substituting carboplatin for cisplatin also had a major role, as has been shown in ovarian cancer. The major negative impact of SMCC2 was the greater rate of hematologic toxicity. However, this was of limited clinical relevance in this younger group of patients. One possible exception to this statement would be the fall in hemoglobin, with the majority of patients having a hemoglobin level below 110 g/dL. Given the hypothesis, currently under testing, that anemia adversely impacts irradiation control rates and survival after chemotherapy, there could have been a negative impact on outcome. The routine use of transfusion or erythropoietin in future patients to prevent such anemia makes sense while further data is awaited. The other downside to the SMCC2 protocol was the increased duration of treatment. Peripheral neuropathy was not a problem, with the caveat of the small numbers of patients, with the SMCC2 regimen, despite the use of concurrent cisplatin and 3-hourly paclitaxel. Because carboplatin and cisplatin have equivalent efficacy in SCLC, using carboplatin, not cisplatin, in future regimens would be sensible to minimize any potential for peripheral neuropathy. Cranial irradiation was not routinely used in these two protocols. The one CNS relapse that did occur was in a patient who did not receive cranial irradiation. However, because 23 (96%) of 24 nonirradiated patients did not relapse in the CNS and because cranial irradiation has important neurologic sequelae, we do not recommend its routine use. In summary, long-term survival for patients with SCCC can be achieved with a combined-modality treatment consisting of platinum-based chemotherapy and irradiation, especially for those patients with disease limited to the central pelvis. The change from the SMCC to the SMCC2 protocol did not improve the outcome, with the exception of a potentially lower distant relapse rate, but it did improve the regimen’s tolerability. Cisplatin plus etoposide with the early use of irradiation (the SMCC protocol) is generally regarded as the standard regimen for SCLC and, thus, by extrapolation, could be regarded as standard for SCCC. However, it was highly toxic, and therefore, the use and exploration of other platinum-based regimens (eg, SMCC2) makes sense. Because 40% of patients are still experiencing treatment failure, adding or substituting other agents may prove beneficial. Agents that could be combined with platinum analogues, based on their activity in SCLC, are the camptothecins, vinorelbine, gemcitabine, and the taxanes. In a recent phase III Japanese lung cancer study, there was superior survival for cisplatin plus irinotecan compared with cisplatin plus etoposide.23 However, adding a third drug, paclitaxel, in our study had no clear effect on efficacy, and this mirrors the much larger experience in SCLC, where no three-drug combination was superior to cisplatin plus etoposide.24,25 Maintaining hemoglobin levels is another route to follow in trying to improve outcome. Major improvements will likely rely on a better understanding of an individual patient’s underlying genetic abnormalities and the use of targeted therapies specific to these changes.
The authors indicated no potential conflicts of interest.
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23. Noda K, Nishiwaki Y, Kawahara M, et al: Irinotecan plus cisplatin compared with etoposide plus cisplatin for extensive small-cell lung cancer. N Engl J Med 346:85–91, 2002 24. Loehrer PJ Sr, Ansari R, Gonin R: Cisplatin plus etoposide with and without ifosfamide in extensive small-cell lung cancer: A Hoosier Oncology Group study. J Clin Oncol 13:2594–2599, 1995[Abstract] 25. Niell HB, Herndon JE, Miller AA, et al: Randomized phase III intergroup trial (CALGB 9732) of etoposide (VP-16) and cisplatin (DDP) with or without paclitaxel (TAX) and G-CSF in patients with extensive stage small cell lung cancer (ED-SCLC). Proc Am Soc Clin Oncol 21:293, 2002 (abstr 1169) Submitted January 16, 2003; accepted June 18, 2003.
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
