GYNECOLOGIC ONCOLOGY 47, 62-6.5 (1992)

Treatment of Small Cell Carcinoma of the Cervix with Cisplatin, Doxorubicin, and Etoposide

MITCHELL MORRIS, M.D., DAVID M. GERSHENSON, M.D., PATRICIA EIFEL, M.D., ELVIO G. SILVA, M.D., MICHELE F. MITCHELL, M.D., THOMAS W. BURKE, M.D., AND J. TAYLOR WHARTON, M.D.

Departments of Gynecology, Clinical Radiotherapy, and Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas

Received January 22, 1992

Between July 1986 and February 1991, 10 patients with small cell carcinoma of the cervix were prospectively treated with com- bination chemotherapy using cisplatin (50 mg/m*) and doxorub- icin (50 mg/m’) on Day 1 and etoposide (75 mg/m’) on Days l- 3. All patients underwent an extensive pretreatment metastatic survey and had histologic confirmation of small cell carcinoma prior to entry in the study. Seven patients had stage Ib, 1 stage Da, and 2 stage Ilb. Nine patients received chemotherapy at primary presentation and 1 was treated for recurrent disease. In 6 cases, chemotherapy was given and then followed by radiation therapy. Three patients received chemotherapy following radical hysterectomy and 1 was treated for persistent disease after ra- diation therapy. Patients received a median of four courses of chemotherapy (range 2-6). Neutropenia was the dose-limiting toxicity with 9 of 10 patients requiring a dose reduction. There was no instance of neutropenic sepsis or other major toxicity. Seven patients had measurable disease at the start of therapy. Three of these patients had a complete clinical response, 1 had a partial response, 2 had stable disease, and 1 had progressive disease (response rate = 57%). The median survival was 28 months. At the time of this report, 4 of 6 patients with stage Ib cancers given primary treatment on this regimen remained free of disease (with 28 months the median follow-up). Our pilot study indicates that this chemotherapy regimen has activity in small cell carcinoma of the cervix and should be further evaluated as an adjuvant to surgery or radiation in patients with early stage disease. 0 1992 Academic Press, Inc.

INTRODUCTION

Small cell carcinoma of the cervix is an uncommon gynecological malignancy, accounting for less than 5% of cervical cancers [l]. The histologic criteria for the diag- nosis of small cell carcinoma of the cervix have been the subject of some controversy, making the comparison of cases from different clinical series difficult. There is gen-

Presented at the 23rd Annual Meeting of the Society of Gynecologic Oncologists, San Antonio, TX, March 15-18, 1992.

era1 agreement, however, that these tumors are highly aggressive and characterized by early lymphatic dissem- ination and a high recurrence rate, particularly at extra- pelvic sites [2-51. Because of the tendency to early me- tastasis from even small lesions, regional therapy is unlikely to be curative unless systemic disease can be addressed at the same time.

Due to the rarity of small cell carcinoma of the cervix, there is limited information regarding the efficacy of ad- juvant chemotherapy [5,6]. For these reasons, we con- ducted a study to evaluate the efficacy of combining cis- platin, doxorubicin, and etoposide with surgery or irradiation in treating women with small cell cancer of the cervix.

MATERIALS AND METHODS

Between July 1986 and February 1991, we conducted a prospective clinical trial in which 10 patients with small cell carcinoma of the cervix were treated at The Univer- sity of Texas M. D. Anderson Cancer Center with a combination of cisplatin, doxorubicin, and etoposide. Prior to entry into the study, histologic confirmation of small cell carcinoma was made by one of the authors (E.G.S.). The criteria used for the diagnosis of small cell carcinoma of the cervix are fully described in another publication [7]. Small cell carcinoma was defined as a tumor will small basophilic cells, no keratinization, a high mitotic count with a characteristic cell and nuclear di- ameter and area. To be included in the study, the majority of the nuclei (>70%) had to be smaller than 19 pm in maximum dimension.

Patients underwent a pretreatment evaluation that in- cluded computed tomography of the brain, chest, abdo- men, and pelvis, bipedal lymphangiography, chest radio- graph, intravenous pyleogram, bone marrow aspirate and biopsy, bone scan, and cardiac scan in addition to routine

62

0090-8258/92 $4.00 Copyright 0 1992 by Academic Press, Inc. All rights of reproduction in any form reserved.

SMALL CELL CARCINOMA 63

TABLE 1 Patient Characteristics

Age of Patient patient Stage

Lesion size (cm) Histology

1 50 Ib 2 31 Ib 3 32 Ib 4 46 Ib 5 28 Ib 6 27 Ib I 34 Ib 8 40 IIa 9 61 IIb

10 56 IIb

4 Pure 1 Pure 2 Mixed 2 Mixed 4 Mixed 5 Pure 4 Pure 4 Pure 6 Pure 5 Pure

TX prior to

chemo Status at

chemo start

Rad hyst NED Rad hyst NED Rad hyst NED

None CED None CED None CED XRT CED None CED None CED None CED

Cycles chemo

6 N/E 6 N/E 6 N/E 2 Stable

3 CR 3 CR 2 Prog 2 Stable

4 CR 4 PR

Clinical response

Further therapy

None None XRT XRT XRT XRT None XRT XRT XRT

Current status

Follow-up (months)

NED 60

NED 54

DOD 14

NED 21

DOD 14

NED I

DOD II AWD 18 DOD 12 DOD 14

Note. N/E, not evaluable; CR, complete response; PR, partial response; Prog, progressive disease; Stable, stable disease; CED, clinical evidence of disease; NED, no evidence of disease; DOD, dead of disease; XRT, radiotherapy; Rad hyst, radical hysterectomy.

laboratory studies and EKG. Stage was assigned accord- ing to the clinical criteria established by the International Federation of Gynecology and Obstetrics (FIGO).

Chemotherapy was administered during a 3-day period and repeated every 28 days. On Day 1, patients were treated with cisplatin (50 mg/m*) given intravenously (IV) over 4 hr with vigorous hydration and doxorubicin (50 mg/m*) IV over 30 min. On each of Days 1-3, Etoposide (75 mg/m’) was given IV (225 mg/m* total dose). Che- motherapy was delayed when the granulocyte count was under 2000/p13 or the platelet count was less than 100,000/~13. Dose reductions of 20% were made when the granulocyte nadir was less than 500/p13 or the platelet count was less than 50,000/~1’.

Three groups of patients were eligible for this che- motherapy regimen. One group which included those pa- tients with a negative metastatic evaluation and with small-volume disease (lesion size 44 cm) and who had no medical contraindication to surgery were initially treated with radical hysterectomy and pelvic lymphade- nectomy. Paraortic lymph nodes were routinely sampled and other staging biopsies performed as indicated. Pa- tients then received chemotherapy every 28 days for a total of six planned cycles. At the conclusion of chemo- therapy, patients who had been found to have metastatic pelvic disease at the time of surgery were considered for consolidation radiation therapy with 45 Gy delivered to the whole pelvis and a boost to an area of involved nodes.

Patients were also eligible for protocol therapy when surgery was contraindicated due to a large tumor or for medical reasons, provided that there was no evidence of metastatic disease outside the pelvis. Patients in this sec- ond group were treated with three cycles of the regimen described above followed by standard pelvic radiation with curative intent. Cisplatin (20 mg/m*) was given weekly from the initiation of chemotherapy to completion (including brachytherapy).

A third category of eligible patients included those with disease disseminated outside the pelvis. These patients were treated with the regimen described above which was continued to tolerance or disease progression.

Patients who received prior chemotherapy were not eligible for this study. All patients who presented with primary small cell cancer of the cervix during the study period were entered on the protocol.

Complete clinical response to chemotherapy was de- fined as the disappearance of all clinical evidence of tumor for a minimum of 4 weeks. A partial response was defined as a 50% or greater decrease in the sum of the product of the diameters of the measured lesions. In addition, no simultaneous increase in the size of any existing lesion or appearance of new metastatic lesions could occur. Stable disease was defined as no change in the tumor size (less than a 50% decrease or a 25% increase in tumor volume). Progressive disease was defined as an increase of 25% or more in the size of any existing lesion or as the appearance of any new metastatic lesions. Patients were removed from the study if the disease progressed, if the toxic effects were unacceptable, or if they requested it.

Survival was calculated using the life-table analysis of Berkson-Gage [8].

RESULTS

The 10 patients (Table 1) entered on this clinical trial were observed for a median of 23 months (range, 7-60 months). The median age of the patients at entry was 37 years (range, 27-61 years). The distribution of the disease included 7 patients with stage Ib carcinoma, 1 with stage IIa, and 2 with stage IIb.

Seven patients had pure small cell carcinoma. The ma- jority of the nuclei in these cases were smaller than 19 pm in maximum dimension. Three cases were character-

64 MORRIS ET AL.

ized by tumor cells having nuclei smaller than 19 ,um in maximum dimension in at least 70% of the cells. The other 30% of the cells was composed of solid areas with cells having nuclie larger than 19 pm, or cells showing squamous or adenocarcinoma differentiation.

At the time of study entry, all patients had evaluable lesions. Nine patients presented for study without prior therapy. In one case a patient had metastatic disease following primary radiotherapy at another institution. All patients entered the study with a Karnofsky performance status equal to 100.

Prior to initiation of adjuvant chemotherapy, three pa- tients underwent radical hysterectomy. All had a com- plete resection of gross tumor and consequently were not evaluable for response to chemotherapy. One of these was found to have a positive pelvic lymph node and sub- sequently died from recurrent disease. Six patients under- went chemotherapy followed by radiation therapy be- cause of a large tumor volume. The one patient with persistent disease had undergone prior radiation therapy.

Patients received a median of 4 cycles of therapy (range, 2-6 cycles). The 10 patients received a total of 38 cycles of the combination chemotherapy. The dose- limiting toxicity was myelosuppression with 9 of 10 pa- tients requiring a dose reduction because of granulocy- topenia. No deaths related to treatment occurred. No patient required a red blood cell transfusion and no sig- nificant thrombocytopenia was detected. There were no cases of sepsis, ototoxicity, neurotoxicity, or cardiotoxicity.

Seven patients were evaluable for a response to che- motherapy. Of the seven, three patients had a complete response, and one had a partial response (response rate = 57%); two patients had stable disease during therapy and one patient had progressive disease.

With a median follow-up period of 23 months, the me- dian survival for the group of 10 patients was 28 months. At the time of this report, 4 patients were alive without disease at, respectively, 7, 21, 54, and 60 months after completion of therapy. One patient was alive with disease and 5 patients had died of disease.

DISCUSSION

For a number of years, it has been recognized that small cell carcinoma of the uterine cervix carries a poor prognosis with a tendency toward early and widespread dissemination [2,9,10]. While the majority of cervical can- cers may be successfully treated in a regional fashion with either radical surgery or radiation therapy, such local ap- proaches with small cell carcinoma have not been suc- cessful. In a review of 14 patients with early stage, sur- gically resectable lesions, Sheets and co-workers [3] found that 57% had lymph node metastasis. Twelve of the 14

were dead from disease at the time of their report, and the other 2 patients had recurrent disease. These dismal results illustrate the need for a primary therapy that ad- dresses both regional and systemic disease.

Because of its similar histologic appearance and pattern of metastatic spread, the clinical experience with small cell cancer of the lung is often discussed as a model for treating the similar cervical tumor. Like small cell cervical cancer, small cell cancer of the lung is a usually fatal disease characterized by early dissemination and rapid progression. Current investigational therapies utilize ad- juvant chemotherapy, usually including cisplatin and etoposide, sometimes in combination with other agents. Although the response rate of these lesions to chemo- therapy often exceeds 90%, the duration of response is often short and may have little impact on the disease process [ll-131. Adjuvant therapy for small cell lung can- cer has focused on early stage disease and utilizes a mul- tiagent therapy in an attempt to eradicate microscopic metastases prior to the emergence of drug-resistant clones.

Experience with adjuvant chemotherapy for small can- cer of the cervix is limited. Pazdur and co-workers [14] first suggested an adjuvant approach to small cell cervical cancer in a similar fashion to the lung tumor. Since then there have been six reports totaling nine patients who were treated with chemotherapy for small cell cancer of the cervix [3,5,6,15-171. Tabbara and colleagues treated three patients with small cell cancer of the cervix with a complex regimen of cisplatin, vincristine, methotrexate, doxorubicin, cyclophosphamide, and etoposide [6]. Two patients had a complete response and one had a partial response. O’Hanlan and co-workers reported on two pa- tients who were treated with adjuvant chemotherapy and radiation following radical hysterectomies. The patients were not evaluable for response but, at the time of that report, had survived, respectively, 28 and 47 months after therapy [5 1.

Our study observed 10 patients who were accrued in a 5-year period and conclusions regarding the response rate must be viewed in light of the small numbers and short follow-up period. Nonetheless, the observation that 4 of 7 evaluable patients responded to chemotherapy encour- aged us to report our results in hope of prompting a prospective cooperative group trial for small cell cancer of the cervix. That 4 of 6 patients with Stage Ib disease remained alive without disease following this treatment approach compares favorably to the poor results docu- mented by Sheets et al. [3]. Although the numbers are small, we believe these patient groups are roughly com- parable and there is a suggestion that adjuvant chemo- therapy may prolong disease-free survival.

The optimal therapy for a cooperative trial remains an open question. The response rate of 57% in our study

SMALL CELL

does not compare well to the results of some recent small cell lung cancer adjuvant trials. Is this due to the choice of chemotherapeutic agents in the present study, or is it related to the inherent biologic difference between lung cancer and cervical cancer? The results of our pilot study and the experience gained from adjuvant trials in small cell cancer of the lung should be used to design a pro- spective clinical trial in small cell carcinoma of the cervix.

REFERENCES

I. Scully, R. E., Aguirre, P., and DeLellis, R. A. Argyrophilia, se- rotonin. and peptide hormones in the female genital tract and its tumors, Int. J. Gynecol. Puthol. 3, 51-70 (1984).

2. van Nagell, .I. R., Powell, D. E., Gallion, H. H., Elliott, D. G., Donaldson, E. S., Carpenter, A. E., Higgins, R. V., Kryscio, R.. and Pavlik, E. J. Small cell carcinoma of the uterine cervix. Cancer 62, 158661593 (1988).

3. Sheets, E. E., Berman, M. L., Hrountas, C. K., Liao, S. Y., and DiSaia. P. J. Surgically treated, early-stage neuroendocrine small- cell cervical carcinoma, Obstet. Gynecol. 71(l). IO-14 (1988).

4. Gersell. D. J., Mazoujian, G., Mutch, D. G., and Rudloff, M. A. Small-cell undifferentiated carcinoma of the cervix: A clinicopath- ologic, ultrastructural, and immunocytochemical study of I5 cases, Am. J. Surg. Pathol. 12(9), 684-98 (1988).

5. O’Hanlan, K. A., Goldberg, G. L., Jones, J. G., Runowicz, C. D., Ehrlich. L., and Rodriguez-Rodriguez. L. Adjuvant therapy for neuroendocrine small cell carcinoma of the cervix: Review of the literature, Gynecol. Oncol. 43, 167-172 (1991).

6. Tabbara, I. A., Grosh, W. A., Andersen, W. A., Taylor, P. T., Hahn, S. S., and Stewart, F. M. Treatment of small-cell carcinoma of the cervix with weekly combination chemotherapy, Eur. 1. Cancer

26(6), 748-749 (1990).

CARCINOMA 65

7. Silva, E. G., Gershenson, D. M., Sneige, N., Brock, W. A., Saul, P., and Copeland, L. J. Small cell carcinoma of the cervix: Pa- thology and prognostic factors. Surg. Pathol. 2, 105-115 (1989).

8. SPSS-X. Statistical package for the social sciences (1988). 9. Wentz, W. B. Histologic grade and survival in cervical cancer. Ob-

stet. Gynecol. 18, 412-416 (1961). 10. Van Nagell, J. R.. Donaldson, E. S., Wood, E. G., Maruyama,

Y., and Utley, J. Small cell cancer of the uterine cervix, Cancer 40, 2243-2249 (1977).

Il. Aisner, J., Whitacre, M., Abrams, J., and Propert, K. Doxorubicin, cyclophosphamide, etoposide and platinum, doxorubicin, cyclo- phosphamide and etoposide for small-cell carcinoma of the lung, Semin. Oncol. 13, S54-S62 (1986).

12. Mitchell, E. P., Luikart, S. D., Van Echo, D. A., Propert, K., Modeas, C., Perry, M. C., and Green, M. Etoposide and cisplatin in untreated extensive small cell lung cancer: A dose escalation study, Proc. Am. Sot. C/in. Oncol. 7, 206 (1988).

13. Turisi, A. T., Glover, D. J., Mason, B., and Tester, W. Concurrent twice-daily multi-field radiotherapy and platinum-etoposide che- motherapy for limited small cell lung cancer, Lung Cuncer 7, 211 (1988).

14. Pazdur, R., Bonomi, P., Slayton, R., Gould, V. E., Miller, A., Jao, W., Dolan, T., and Wilbanks, G. Neuroendocrine carcinoma of the cervix: Implications for staging and therapy, Gynecol. 0~01. 12, 120-12X (1981).

15. Turner, W. A., Gallup, D. G., Talledo, 0. E., Otken, L. B., and Guthrie, T. H. Neuroendocrine carcinoma of the uterine cervix complicated by pregnancy: Case report and review of the literature, Obstet. Gynecol. 67, 8OS-83s (1986).

16. Seidel, R., and Steinfeld, A. Carcinoid of the cervix: Natural history and implications for therapy, Gynecol. Oncol. 30, 114-119 (1988).

17. Sutton, G. P., Siemers, E., Stehman, F. B., and Ehrlich, C. E. Eaton-Lambert syndrome as a harbinger of recurrent small-cell carcinoma of the cervix with improvement after combination che- motherapy, Obstet. Gynecol. 72, 516-518 (1988).