GYNECOLOGIC
ONCOLOGY
40, 7-11 (1991)
Induction Chemotherapy Followed by Radical Surgery in Cervical Cancer PETER
R. DOTTINO, M.D.,’ STEVEN C. PLAXE, M.D., ANNE MARIE BEDDOE, M.D., CAROLYN JOHNSTON, M.D., AND CARMEL J. COHEN, M.D.
Division
of Gynecologic
Oncology, Department of Obstetrics, Gynecology, and Reproductive Science, Mount Sinai Medical One Gustave L. Levy Place, Box 1173, New York, New York 10029
Center,
ReceivedMay 4, 1990
not improve survival [I]. Likewise, studies identifing patients with aortic lymph node metastases who were then treated with extended-field radiotherapy failed to demonstrate improved survival [2]. Therefore, to increase survival in patients with cervical carcinoma an effective method of treating lymph node metastases must be found. Squamous cell carcinomas of the cervix are known to be responsive to c&platinum-based chemotherapy. Reported response rates ranging from 30 to 90% [3-71 can be achieved; however, the duration of response is usually limited [4,8,9]. Responses to chemotherapy may be reduced by decreased vascular supply to the tumor secondary to previous irradiation or surgery. The use of induction chemotherapy as part of multimodality treatment offers some theoretical advantages in the treatment of advanced disease. Chemotherapy may shrink bulky tumors prior to surgical and radiation treatment, and may also reduce the incidence of lymph node metastases [lo-131. Following induction chemotherapy, radical surgery may be performed to remove residual central disease, evaluate lymph node status, and presumably improve cure. This study was undertaken to assess the feasibility of combined induction chemotherapy plus radical surgery in the treatment of cervical carcinoma. We treated 28 patients with stage 1B (>4 cm) through stage IVA cervical carcinoma, with induction chemotherapy followed by radical surgery sufficient to remove all pelvic disease. Fourteen patients with residual extrauterine disease found at laparotomy were treated with postoperative radiation therapy.
To evaluate the therapeutic potential of cytotoxic therapy in patients with squamous cell carcinoma of the cervix, 28 patients with disease clinically localized to the pelvis were treated with chemotherapy followed by radical pelvic surgery. Treatment consisted of c&platinum 50 mg/m’, mitomycin C 10 mg/m’, vincristine 1.0 mg/m’, and bleomycin 10 U IM given as a course (over 21 days) of induction chemotherapy followed by radical hysterectomy and pelvic and aortic lymphadenectomy in 26 patients and total pelvic exenteration in 2 patients. The stage distribution of the patients in the study was 4 stage IB, 6 stage IIA, 7 stage IIB, 1 stage IIIA, 11 stage IIIB, and 1 stage IVA. Two patients with stage IIIB cancer were found, at the time of laparotomy, to have carcinomatosis and were excluded from the final evaluation in this study. All patients achieved a clinical and histologic response to chemotherapy. There were 35% complete and 65% partial responses. After chemotherapy, at the time of surgery, 4 patients were found to be histologically free of disease, and the incidence of surgically documented nodal disease after chemotherapy was found to be 32%. There was no significant hematologic or pulmonary toxicity. Induction chemotherapy is well tolerated and may be beneficial in the management of some patients with cervical cancer who are at high risk for failure with conventional treatment. D 1991 Academic Press, Inc.
INTRODUCTION Traditional methods for the treatment of invasive cervical carcinoma include radiotherapy, radical surgery, or a combination of both methods. Although cure rates of 85-90% are attainable in early disease, the same is not true for more advanced stages. Studies examining prognostic factors in cervical cancer indicate that the presence of lymph node metastases is strongly related to survival. Kinney er al. found that in patients with resected early-stage disease, who had lymph node involvement, the addition of postoperative pelvic irradiation did ’
To
whom
reprint
requests
should
MATERIALS AND METHODS Between July 1987 and August 1989, 28 patients with invasive cervical carcinoma were admitted to the study.
be addressed.
7 009@8258/91 $1.50 Copyright Q 1991 by Academic Press, Inc. All rights of reproduction in any form reserved.
8
DOTTINO ET AL.
Staging was done according to the International Federation of Gynecology and Obstetrics (FIGO). Patients in this study with stage IB carcinomas were required to have tumors greater than 4 cm in diameter. Patients with evidence of hepatic, renal, cardiac, or pulmonary disease were ineligible for this protocol. All patients gave informed consent prior to the commencement of treatment. Pretreatment evaluation consisted of a history and physical examination, biopsy, and evaluation of tumor extension. Complete blood count and chemistry panel, chest films, computerized tomography, intravenous pyelography, and pulmonary function tests (including DLCO) were performed on all patients at the time of entry into the study. Patients were required to have both normal renal (creatine s 1.5 mg/dl) and pulmonary functions before treatment. Blood urea nitrogen, creatine, and complete blood counts were monitored weekly during the course of chemotherapy. Cystoscopy and sigmoidoscopy were performed when indicated. Each cycle of chemotherapy was administered as follows: c&Platinum Vincristine Mitomycin C Bleomycin
50 mg/m2 IV given on Days 1 and 21 1 mg/m2 IV given on Days 1 and 21 10 mg/m2 IV given on Day 1 10 U IM given on Days 1, 7, 14, and 21
All patients received 10 hr of prehydration before receiving c&platinum and were premeditated with metaclopromide and lorazepam. Diuretics were not routinely employed. Twenty-eight patients received one cycle of chemotherapy as outlined above. This was followed by surgery on Day 35. One patient with a large stage IIIB tumor and one patient with stage IVA disease received two and three additional cycles of chemotherapy, respectively, prior to surgery. Surgery consisted of radical hysterectomy with pelvic and aortic lymphadenectomy in 26 patients. In addition to radical hysterectomy, two patients required resection of the rectosigmoid to remove all gross pelvic disease. Primary reanastomosis was performed at the time of initial surgery in both of these patients. Two patients, one with stage IIIB and one with stage IVA disease, required total pelvic exenterations for removal of all pelvic disease. Histologic analysis of all surgical specimens assessed the extent of cervical, vaginal, and parametrial disease and the status of all surgical margins and lymph nodes. Clinical response to chemotherapy was evaluated as follows: complete clinical response (CR) was defined as disappearance of all measurable disease; partial response (PR) was defined as a decrease by at least 50% in the largest volume.
TABLE 1
Patient Characteristics (Median Age 56 Years, Range 36-68 Years) Number of patients
Stage IB HA IIB IIIA IIIB IVA Total Histology Well-differentiated squamous Moderately differentiated squamous Poorly differentiated squamous
%
4 6 I 1 9 I 28
14 21 25 3 32 3
3 5
10 17
20
71
Cervical biopsy specimens were taken on Days 1 and 14 to assess chemosensitivity. These results will be compared to the findings in the surgical specimens and reported separately. RESULTS All patients completed chemotherapy without incident. The median age in the series was 56 years (range 3668). Stage distribution is presented in Table 1. The stage IVA patient had a positive bladder biopsy. All patients had purely squamous lesions; 71% were poorly differentiated. The overall clinical response rate, in the cervix, to induction chemotherapy was 100%; 35% were complete and 65% were partial responses. All patients with complete clinical responses in the cervix had negative lymph nodes at laparotomy (Table 2). Of the 18 partial responders, nodal disease was found in 9 patients (Table a
Residual microscopic disease was present in the cervix of 24 patients. Two patients with stage IB, one with IIB, and one with IIIA disease had no microscopic residual tumor in the surgical specimens, including the lymph nodes. HISTOLOGICAL FINDINGS Stage
ZB
Of the four patients with stage IB disease, two had residual microscopic disease in the cervix following induction chemotherapy (Table 3). No disease was found in the vagina, parametrium, or pelvic or aortic lymph
PREOPERATIVE
INDUCTION
CHEMOTHERAPY
IN CERVICAL
9
CANCER
TABLE 2 Nodal Disease Relative to Clinical Response in the Cervix Partial responseh
Complete response” Number of patients
Stage IB IIA IIB IIIA IIIB IVA Total
Node +
Node -
0
4 6 7
3 2 3 I I 0 IO
0 0 0 0 0
9 1 28
Node +
Node -
0 0 4 0 5 0 9
I 4 0 0 3 I 9
y Clinical response is defined as disappearance of all measurable, visible disease in the cervix. ’ Partial response is defined as a decrease by at least 50% in the largest volume.
nodes in any patient with stage I disease. Median followup for this group is 24 months. All patients are alive and free of disease.
seven patients (57%). No aortic nodal disease was found in any patient. Those four with lymph node disease were given postoperative pelvic radiotherapy. Two of the four patients with pelvic node metastases have recurred and died of disease. One recurred at 10 months in the pelvis and the lung; the other recurred at 13 months in the lung and the brain. The median follow-up is 20 months.
Stage IZA All six stage IIA patients had disease present in the cervix after induction chemotherapy; however, no vaginal disease was identified in any of their surgical specimens. All pelvic and aortic lymph nodes were negative for tumor in these patients. One patient had microscopic tumor emboli in the proximal parametrium. Median follow-up for this group is 24 months. Two patients have had recurrences. The patient with microscopically positive parametrium recurred in the pelvis and chest at 20 months following surgery despite postoperative pelvic irradiation. The other patient who had negative vagina, parametrium, and nodes had a recurrence at 24 months after surgery in the thoracic spine.
Stage IIZA The patient with stage IIIA disease had no residual disease in the entire surgical specimen including the lymph nodes and this patient remains clinically free of disease 25 months postoperatively. Stage IlIB There were nine evaluable patients with stage IIIB disease and all patients were given postoperative pelvic radiotherapy. After induction chemotherapy all demonstrated a partial clinical response in the cervix. At the time of surgery all had residual disease in the cervix, and five of nine had residual parametrial disease. All distal parametrial resection margins were free. Two patients were found to have disease extending to the anterior surface of the rectosigmoid and had resection with reanastomosis at the time of radical hysterectomy. These are distinct from the two exenteration patients.
Stage IIB Six of the seven stage IIB patients had residual disease in the cervix. The other patient had no residual disease in the entire surgical specimen. The parametrium contained residual microscopic disease in two of seven patients (28%). Pelvic node disease was found in four of
TABLE 3 Histologic Findings of Disease after Induction Chemotherapy and Surgery Stage IB IIA IIB IIIA IIIB TVA
Number of patients
Cervix
Vagina
Parametrium
Pelvic nodes
Aortic nodes
4
2
0
0
0
0
5 7 I
5
0
1
0
0
6
I
2
4
0
0
0
0
0
9
9
6
5
5
I
I
0
0
0
0 I 0
10
DOTTINO
Pelvic nodal disease was found in five patients, one of whom also had aortic disease. Of these patients, three are dead of disease and two are alive with disease on salvage chemotherapy. The three patients who died of disease each required extensive surgery for disease clearance (large bowel resection [2], total exenteration [l]). The three patients who expired recurred at 8, 13, and 22 months, both in the pelvis and at distant sites. Of the four patients with negative nodes, two have recurred in the pelvis at 12 and 16 months. The other two patients with negative nodes remain alive and free of disease at 22 and 24 months. Stage WA The patient with stage IVA disease, by virtue of bladder involvement, had a supralevator total pelvic exenteration and primary colonic reanastomosis. At surgery residual disease was found only in the cervix; the bladder and the lymph nodes were negative. Despite this finding the patient suffered a recurrence at 7 months, in the liver, and expired without further therapy. There were no intraoperative or postoperative complications. We encountered dense fibrosis around the pelvic lymph node chains in all patients. In addition, we frequently found a fine reticular capillary network in both the nodal and the parametrial areas. No renal, pulmonary, or hematologic toxicity was encountered. Two patients (stages IB and IIA) developed ureteral strictures at 5 and 7 months after surgery. Both were treated by percutaneous nephrostomies and subsequent stent placement, and both remain alive without evidence of disease. DISCUSSION This pilot study was undertaken to assess the utility of preoperative induction chemotherapy in decreasing the incidence of lymph node metastases and reducing cervical tumor volume to facilitate surgical excision of locally advanced cervical cancer. Follow-up is needed to assess the effect of this treatment on survival in patients who are at high risk for failure with traditional therapy. Several other groups have attempted to evaluate preoperative platinum-based chemotherapy for advanced cervical carcinoma. Friedlander et al. reported a clinical response rate of 67% in untreated patients with advanced local disease [lo]. In this series of 30 patients, radical hysterectomy was performed in nine patients after induction chemotherapy. They found lymph node metastases in two of the nine patients; no mention is made of distribution of
ET AL.
stage in the study group. Follow-up in this study was 28 weeks. Valle et al. reported on 35 patients with stage IIIA and IIIB disease who were treated with c&platinum, adriamycin, and bleomycin preoperatively. No data on lymph node metastases were given but they did report five patients (14%) with histologically complete responses [14]. Follow-up in this study is also limited. Kim et al. reported on 54 patients with stage IB and II disease treated initially with chemotherapy followed by radical hysterectomy. They report a 20% overall incidence of positive nodes with a median follow-up of 36 months. All recurrences were found in the group with positive nodes. Their data suggested that preoperative chemotherapy in early-stage disease decreased tumor volume and improved 2-year survival [12]. Panici et al. reported using preoperative c&platinum, bleomycin, and methotrexate in 33 patients with stage IB through stage III cervical cancers. They found an overall clinical response rate of 75%. Of the 33 patients in this study, 25 had a radical hysterectomy, with pelvic and aortic lymphadenectomy. Four of the twenty-five patients, 12%, had complete pathologic responses. Lymph node metastases were found in only four patients; three had stage IIB disease and one was stage IIIA. None of five patients with stage IIIB disease had positive lymph nodes after chemotherapy. Both chemotherapy and surgery were tolerated. Long-term follow-up is not reported in this series [ 131. In our series of 28 patients, all showed a clinical response to induction chemotherapy; 35% had complete responses, and 65% had partial responses. Consistent with other series, we report four patients (14%) with histologically proven complete responses. Two of these patients had stage IB disease, one had stage IIB, and one had stage IIIA. Pelvic nodes were positive after chemotherapy in 9 of 28 patients (38%). Positive nodes were found in four of seven stage IIB patients and five of nine stage IIIB patients. All nine patients with involved nodes showed only a partial clinical response to chemotherapy. Of the nine patients with positive lymph nodes, all of whom received postoperative pelvic irradiation, two are alive without disease; both are stage IIB. Five patients, two with stage IIB and three with stage IIIB cancers, are dead of disease. The two other patients with positive nodes are alive with disease. The findings of this pilot study confirm that for patients with untreated cervical carcinoma, high clinical response rates can be achieved with platinum-based chemotherapy. Of those patients with a complete clinical response in the cervix, nine of ten are alive without evidence of disease with a median follow-up of 24 months. No patient who demonstrated a complete clinical response to che-
PREOPERATIVE
INDUCTION
CHEMOTHERAPY
motherapy had positive lymph nodes. Of the 18 patients who had a partial clinical response to chemotherapy, 7 are dead of disease, 4 are alive with disease, and 7 are without evidence of disease with a median follow-up of 24 months. This study shows that preoperative induction chemotherapy is well tolerated. In those patients who demonstrate complete clinical response to chemotherapy, particularly in earlier stages, there seems to be a lower than expected incidence of lymph node metastases [15191,which may improve survival. For those patients who were found, at the time of laparotomy, to have lymph node metastases or advanced local disease requiring either bowel resection or exenteration for disease clearance, long-term survival was not achieved even with the addition of postoperative pelvic irradiation. The study also confirms the feasibility of the use of induction chemotherapy prior to radical surgery in patients with locally advanced cervical carcinoma. If more active drug regimens can be designed to reliably increase the number of complete clinical responses, then the use of induction chemotherapy may translate into prolonged survival. Further investigations are currently underway.
REFERENCES 1. Kinney, W. K., Alvarez, R. K., Reid, G. C., Schray, M. F., Soong, S., Morley, G. W., Podratz, K. C., and Shingleton, H. M. Value of adjuvant whole pelvis irradiation after Wertheim hysterectomy for early stage squamous carcinoma of the cervix with pelvic node metastases: A mixed control study, Gynecol. On&. 34, 258-262 (1989). 2. Berman, M. L., Keys, H., Creasman, W., DiSaia, P., Bundy, B., and Blessing, J. Survival and patterns of recurrence in cervical cancer metastatic to periaortic lymph nodes. A Gynecologic Oncology Group study, Gyneco/. Oncol. 19, 8-16 (1984). 3. Cohen, C. J., Deppe, G., Castro-Marin, C. A., and Bruckner, H. W. Treatment of advanced squamous cell cancer of the cervix with cis-platinum(H) diammine dichloride (NSC-I 19875),Amer. J. Obsret. Gynecol. 130, 853-854 (1978). 4. Thigpen, T., Shingleton, H., Homesley, H., Lagasse, L., and Blessing, J. cis-Platinum in treatment of advanced or recurrent squamous cell carcinoma of the cervix. A Phase II study of the Gynecologic Oncology Group, Cancer 48, 899-903 (1981). 5. Cohen, C. J., Deppe, G., Yannopoulos, K., and Gusberg, S. G. Chemosensitivity testng with cis-platinum(I1) diammine dichloride. I. A new concept in the treatment of carcinoma of the cervix, Gynecol. Oncol. 13, 1-9 (1982). 6. Deppe, G., Cohen, C. J.. Yannopoulos, K., and Gusberg, S. B.
IN CERVICAL
CANCER
11
Chemosensitivity testing with cis-platinum(H) diammine dichloride. II. Preliminary experience in the treatment of carcinoma of the cervix, Gynecol. Oncol. 13, IO-18 (1982). 7. Kim, S. D., Moon, H., Hwang, Y. Y., and Cho, S. H. Preoperative adjuvant chemotherapy in the treatment of cervical cancer stage lb, Ha and Ilb with bulky tumor, Gynecol. Oncol. 29, 321332 (1988). 8. Giannone, L., Brenner, D. E., Jones, H. W., Greco, A., and Burnett. L. S. Combination chemotherapy for patients with advanced carcinoma of the cervix: Trial of mitomycin-C, vincristine, bleomycin and cisplatin, Gynecol. Oncol. 26, 178-182 (1987). 9. Friedlander, M. L., Kaye, S. B., Sullivan, H., Atkinson, K., EIliott, P., Coppleson, M., Houghton, R., Solomon, J., Green, D., Russell, P., Hudson, C. N., Langlands, A. O., and Tattersall, M. H. N. Cervical carcinoma: A drug responsive tumor experience with combined cisplatin, vinblastine and bleomycin therapy, Gynecoi. Oncol. 16, 275-281 (1983). 10. Friedlander, M. L., Atkinson, K., Coppleson, J. V. M., Elliot, P., Coreen, D., Houghton, R., Solomon, H. J., Russell, P., and Tattersall, M. H. N. The integration of chemotherapy into the management of locally advanced cervical cancer: A pilot study, Gynew/. Oncol. 19, l-7 (1984). 11. Sardi, J. E., DiPaola, G. R., Cachau, A., Ortiz, 0. C., Sananes, C., Giaroli, A., Martins, D., and Peluffo, M. A possible new trend in the management of carcinoma of the cervix uteri. Gynecol. Oncol. 25, 139-149 (1986). 12. Kim, D. S., Moon, H., Kim, K. T., Hwang, Y. Y., Cho, S. H., and Kim, S. R. Two year survival: Preoperative adjuvant chemotherapy in the treatment of cervical cancer stage Ib and II with bulky tumor, Gynecol. Oncol. 33, 225-230 (1989). 13. Panici, B. C., Scambia, G., Greggi, S., DiRoberto, P., Baiocchi, G., and Mancuso, S. Neoadjuvant chemotherapy and radical surgery in locally advanced cervical carcinoma: A pilot study, Ohstef. Gynecoi. 71, 344-348 (1988). 14. Valle, J. C.. Rezende, M. R., Werneck, C., Chui, C., and Figueiredoi, E. Neoadjuvant and adjuvant chemotherapy with adriamycin, bleomycin and cisplatin (ABC) and modified radical hysterectomy in cancer of the cervix, stage III, hoc. ASCO 4, 125 (1985) (Abstract). 15. Piver, M. S., and Chung, W. S. Prognostic significance of cervical lesion size and pelvic node metastases in cervical carcinoma, Obsfet. Gynecol.
46, 507-510 (1975).
16. Chung. C. K., Nahhas, W. A., Stryker, J. A., Curry, S. L., Abt. A. B., and Mortel, R. Analysis of factors contributing to treatment failures in stage IB and HA carcinoma of the cervix, Amer. J. Obsfet. Gynecol. 138, 550-556 (1980). 17. Burghardt, E., Picker, H., Haas, J., and Lahousen, M. Prognostic factors and operative treatment of stages IB to IIB cervical cancer, Amer. J. Obstef. Gynecol. 156, 988-996 (1987). 18. Zander, J., Baltzer, J., Lohe, K. J., Ober, K. C., and Kaufman, C. Carcinoma of the cervix: An attempt to individualize treatment, Amer. J. Obstet. Gynecol. 139, 752-759 (1981). 19. Noguchi, H., Shiozawa, I., Saka, Y., Yamazaki, T., and Fukuta, T. Pelvic lymph node metastases of uterine cervical cancer, Gynecol. Oncol. 27, 150-158 (1987).
ONCOLOGY
40, 7-11 (1991)
Induction Chemotherapy Followed by Radical Surgery in Cervical Cancer PETER
R. DOTTINO, M.D.,’ STEVEN C. PLAXE, M.D., ANNE MARIE BEDDOE, M.D., CAROLYN JOHNSTON, M.D., AND CARMEL J. COHEN, M.D.
Division
of Gynecologic
Oncology, Department of Obstetrics, Gynecology, and Reproductive Science, Mount Sinai Medical One Gustave L. Levy Place, Box 1173, New York, New York 10029
Center,
ReceivedMay 4, 1990
not improve survival [I]. Likewise, studies identifing patients with aortic lymph node metastases who were then treated with extended-field radiotherapy failed to demonstrate improved survival [2]. Therefore, to increase survival in patients with cervical carcinoma an effective method of treating lymph node metastases must be found. Squamous cell carcinomas of the cervix are known to be responsive to c&platinum-based chemotherapy. Reported response rates ranging from 30 to 90% [3-71 can be achieved; however, the duration of response is usually limited [4,8,9]. Responses to chemotherapy may be reduced by decreased vascular supply to the tumor secondary to previous irradiation or surgery. The use of induction chemotherapy as part of multimodality treatment offers some theoretical advantages in the treatment of advanced disease. Chemotherapy may shrink bulky tumors prior to surgical and radiation treatment, and may also reduce the incidence of lymph node metastases [lo-131. Following induction chemotherapy, radical surgery may be performed to remove residual central disease, evaluate lymph node status, and presumably improve cure. This study was undertaken to assess the feasibility of combined induction chemotherapy plus radical surgery in the treatment of cervical carcinoma. We treated 28 patients with stage 1B (>4 cm) through stage IVA cervical carcinoma, with induction chemotherapy followed by radical surgery sufficient to remove all pelvic disease. Fourteen patients with residual extrauterine disease found at laparotomy were treated with postoperative radiation therapy.
To evaluate the therapeutic potential of cytotoxic therapy in patients with squamous cell carcinoma of the cervix, 28 patients with disease clinically localized to the pelvis were treated with chemotherapy followed by radical pelvic surgery. Treatment consisted of c&platinum 50 mg/m’, mitomycin C 10 mg/m’, vincristine 1.0 mg/m’, and bleomycin 10 U IM given as a course (over 21 days) of induction chemotherapy followed by radical hysterectomy and pelvic and aortic lymphadenectomy in 26 patients and total pelvic exenteration in 2 patients. The stage distribution of the patients in the study was 4 stage IB, 6 stage IIA, 7 stage IIB, 1 stage IIIA, 11 stage IIIB, and 1 stage IVA. Two patients with stage IIIB cancer were found, at the time of laparotomy, to have carcinomatosis and were excluded from the final evaluation in this study. All patients achieved a clinical and histologic response to chemotherapy. There were 35% complete and 65% partial responses. After chemotherapy, at the time of surgery, 4 patients were found to be histologically free of disease, and the incidence of surgically documented nodal disease after chemotherapy was found to be 32%. There was no significant hematologic or pulmonary toxicity. Induction chemotherapy is well tolerated and may be beneficial in the management of some patients with cervical cancer who are at high risk for failure with conventional treatment. D 1991 Academic Press, Inc.
INTRODUCTION Traditional methods for the treatment of invasive cervical carcinoma include radiotherapy, radical surgery, or a combination of both methods. Although cure rates of 85-90% are attainable in early disease, the same is not true for more advanced stages. Studies examining prognostic factors in cervical cancer indicate that the presence of lymph node metastases is strongly related to survival. Kinney er al. found that in patients with resected early-stage disease, who had lymph node involvement, the addition of postoperative pelvic irradiation did ’
To
whom
reprint
requests
should
MATERIALS AND METHODS Between July 1987 and August 1989, 28 patients with invasive cervical carcinoma were admitted to the study.
be addressed.
7 009@8258/91 $1.50 Copyright Q 1991 by Academic Press, Inc. All rights of reproduction in any form reserved.
8
DOTTINO ET AL.
Staging was done according to the International Federation of Gynecology and Obstetrics (FIGO). Patients in this study with stage IB carcinomas were required to have tumors greater than 4 cm in diameter. Patients with evidence of hepatic, renal, cardiac, or pulmonary disease were ineligible for this protocol. All patients gave informed consent prior to the commencement of treatment. Pretreatment evaluation consisted of a history and physical examination, biopsy, and evaluation of tumor extension. Complete blood count and chemistry panel, chest films, computerized tomography, intravenous pyelography, and pulmonary function tests (including DLCO) were performed on all patients at the time of entry into the study. Patients were required to have both normal renal (creatine s 1.5 mg/dl) and pulmonary functions before treatment. Blood urea nitrogen, creatine, and complete blood counts were monitored weekly during the course of chemotherapy. Cystoscopy and sigmoidoscopy were performed when indicated. Each cycle of chemotherapy was administered as follows: c&Platinum Vincristine Mitomycin C Bleomycin
50 mg/m2 IV given on Days 1 and 21 1 mg/m2 IV given on Days 1 and 21 10 mg/m2 IV given on Day 1 10 U IM given on Days 1, 7, 14, and 21
All patients received 10 hr of prehydration before receiving c&platinum and were premeditated with metaclopromide and lorazepam. Diuretics were not routinely employed. Twenty-eight patients received one cycle of chemotherapy as outlined above. This was followed by surgery on Day 35. One patient with a large stage IIIB tumor and one patient with stage IVA disease received two and three additional cycles of chemotherapy, respectively, prior to surgery. Surgery consisted of radical hysterectomy with pelvic and aortic lymphadenectomy in 26 patients. In addition to radical hysterectomy, two patients required resection of the rectosigmoid to remove all gross pelvic disease. Primary reanastomosis was performed at the time of initial surgery in both of these patients. Two patients, one with stage IIIB and one with stage IVA disease, required total pelvic exenterations for removal of all pelvic disease. Histologic analysis of all surgical specimens assessed the extent of cervical, vaginal, and parametrial disease and the status of all surgical margins and lymph nodes. Clinical response to chemotherapy was evaluated as follows: complete clinical response (CR) was defined as disappearance of all measurable disease; partial response (PR) was defined as a decrease by at least 50% in the largest volume.
TABLE 1
Patient Characteristics (Median Age 56 Years, Range 36-68 Years) Number of patients
Stage IB HA IIB IIIA IIIB IVA Total Histology Well-differentiated squamous Moderately differentiated squamous Poorly differentiated squamous
%
4 6 I 1 9 I 28
14 21 25 3 32 3
3 5
10 17
20
71
Cervical biopsy specimens were taken on Days 1 and 14 to assess chemosensitivity. These results will be compared to the findings in the surgical specimens and reported separately. RESULTS All patients completed chemotherapy without incident. The median age in the series was 56 years (range 3668). Stage distribution is presented in Table 1. The stage IVA patient had a positive bladder biopsy. All patients had purely squamous lesions; 71% were poorly differentiated. The overall clinical response rate, in the cervix, to induction chemotherapy was 100%; 35% were complete and 65% were partial responses. All patients with complete clinical responses in the cervix had negative lymph nodes at laparotomy (Table 2). Of the 18 partial responders, nodal disease was found in 9 patients (Table a
Residual microscopic disease was present in the cervix of 24 patients. Two patients with stage IB, one with IIB, and one with IIIA disease had no microscopic residual tumor in the surgical specimens, including the lymph nodes. HISTOLOGICAL FINDINGS Stage
ZB
Of the four patients with stage IB disease, two had residual microscopic disease in the cervix following induction chemotherapy (Table 3). No disease was found in the vagina, parametrium, or pelvic or aortic lymph
PREOPERATIVE
INDUCTION
CHEMOTHERAPY
IN CERVICAL
9
CANCER
TABLE 2 Nodal Disease Relative to Clinical Response in the Cervix Partial responseh
Complete response” Number of patients
Stage IB IIA IIB IIIA IIIB IVA Total
Node +
Node -
0
4 6 7
3 2 3 I I 0 IO
0 0 0 0 0
9 1 28
Node +
Node -
0 0 4 0 5 0 9
I 4 0 0 3 I 9
y Clinical response is defined as disappearance of all measurable, visible disease in the cervix. ’ Partial response is defined as a decrease by at least 50% in the largest volume.
nodes in any patient with stage I disease. Median followup for this group is 24 months. All patients are alive and free of disease.
seven patients (57%). No aortic nodal disease was found in any patient. Those four with lymph node disease were given postoperative pelvic radiotherapy. Two of the four patients with pelvic node metastases have recurred and died of disease. One recurred at 10 months in the pelvis and the lung; the other recurred at 13 months in the lung and the brain. The median follow-up is 20 months.
Stage IZA All six stage IIA patients had disease present in the cervix after induction chemotherapy; however, no vaginal disease was identified in any of their surgical specimens. All pelvic and aortic lymph nodes were negative for tumor in these patients. One patient had microscopic tumor emboli in the proximal parametrium. Median follow-up for this group is 24 months. Two patients have had recurrences. The patient with microscopically positive parametrium recurred in the pelvis and chest at 20 months following surgery despite postoperative pelvic irradiation. The other patient who had negative vagina, parametrium, and nodes had a recurrence at 24 months after surgery in the thoracic spine.
Stage IIZA The patient with stage IIIA disease had no residual disease in the entire surgical specimen including the lymph nodes and this patient remains clinically free of disease 25 months postoperatively. Stage IlIB There were nine evaluable patients with stage IIIB disease and all patients were given postoperative pelvic radiotherapy. After induction chemotherapy all demonstrated a partial clinical response in the cervix. At the time of surgery all had residual disease in the cervix, and five of nine had residual parametrial disease. All distal parametrial resection margins were free. Two patients were found to have disease extending to the anterior surface of the rectosigmoid and had resection with reanastomosis at the time of radical hysterectomy. These are distinct from the two exenteration patients.
Stage IIB Six of the seven stage IIB patients had residual disease in the cervix. The other patient had no residual disease in the entire surgical specimen. The parametrium contained residual microscopic disease in two of seven patients (28%). Pelvic node disease was found in four of
TABLE 3 Histologic Findings of Disease after Induction Chemotherapy and Surgery Stage IB IIA IIB IIIA IIIB TVA
Number of patients
Cervix
Vagina
Parametrium
Pelvic nodes
Aortic nodes
4
2
0
0
0
0
5 7 I
5
0
1
0
0
6
I
2
4
0
0
0
0
0
9
9
6
5
5
I
I
0
0
0
0 I 0
10
DOTTINO
Pelvic nodal disease was found in five patients, one of whom also had aortic disease. Of these patients, three are dead of disease and two are alive with disease on salvage chemotherapy. The three patients who died of disease each required extensive surgery for disease clearance (large bowel resection [2], total exenteration [l]). The three patients who expired recurred at 8, 13, and 22 months, both in the pelvis and at distant sites. Of the four patients with negative nodes, two have recurred in the pelvis at 12 and 16 months. The other two patients with negative nodes remain alive and free of disease at 22 and 24 months. Stage WA The patient with stage IVA disease, by virtue of bladder involvement, had a supralevator total pelvic exenteration and primary colonic reanastomosis. At surgery residual disease was found only in the cervix; the bladder and the lymph nodes were negative. Despite this finding the patient suffered a recurrence at 7 months, in the liver, and expired without further therapy. There were no intraoperative or postoperative complications. We encountered dense fibrosis around the pelvic lymph node chains in all patients. In addition, we frequently found a fine reticular capillary network in both the nodal and the parametrial areas. No renal, pulmonary, or hematologic toxicity was encountered. Two patients (stages IB and IIA) developed ureteral strictures at 5 and 7 months after surgery. Both were treated by percutaneous nephrostomies and subsequent stent placement, and both remain alive without evidence of disease. DISCUSSION This pilot study was undertaken to assess the utility of preoperative induction chemotherapy in decreasing the incidence of lymph node metastases and reducing cervical tumor volume to facilitate surgical excision of locally advanced cervical cancer. Follow-up is needed to assess the effect of this treatment on survival in patients who are at high risk for failure with traditional therapy. Several other groups have attempted to evaluate preoperative platinum-based chemotherapy for advanced cervical carcinoma. Friedlander et al. reported a clinical response rate of 67% in untreated patients with advanced local disease [lo]. In this series of 30 patients, radical hysterectomy was performed in nine patients after induction chemotherapy. They found lymph node metastases in two of the nine patients; no mention is made of distribution of
ET AL.
stage in the study group. Follow-up in this study was 28 weeks. Valle et al. reported on 35 patients with stage IIIA and IIIB disease who were treated with c&platinum, adriamycin, and bleomycin preoperatively. No data on lymph node metastases were given but they did report five patients (14%) with histologically complete responses [14]. Follow-up in this study is also limited. Kim et al. reported on 54 patients with stage IB and II disease treated initially with chemotherapy followed by radical hysterectomy. They report a 20% overall incidence of positive nodes with a median follow-up of 36 months. All recurrences were found in the group with positive nodes. Their data suggested that preoperative chemotherapy in early-stage disease decreased tumor volume and improved 2-year survival [12]. Panici et al. reported using preoperative c&platinum, bleomycin, and methotrexate in 33 patients with stage IB through stage III cervical cancers. They found an overall clinical response rate of 75%. Of the 33 patients in this study, 25 had a radical hysterectomy, with pelvic and aortic lymphadenectomy. Four of the twenty-five patients, 12%, had complete pathologic responses. Lymph node metastases were found in only four patients; three had stage IIB disease and one was stage IIIA. None of five patients with stage IIIB disease had positive lymph nodes after chemotherapy. Both chemotherapy and surgery were tolerated. Long-term follow-up is not reported in this series [ 131. In our series of 28 patients, all showed a clinical response to induction chemotherapy; 35% had complete responses, and 65% had partial responses. Consistent with other series, we report four patients (14%) with histologically proven complete responses. Two of these patients had stage IB disease, one had stage IIB, and one had stage IIIA. Pelvic nodes were positive after chemotherapy in 9 of 28 patients (38%). Positive nodes were found in four of seven stage IIB patients and five of nine stage IIIB patients. All nine patients with involved nodes showed only a partial clinical response to chemotherapy. Of the nine patients with positive lymph nodes, all of whom received postoperative pelvic irradiation, two are alive without disease; both are stage IIB. Five patients, two with stage IIB and three with stage IIIB cancers, are dead of disease. The two other patients with positive nodes are alive with disease. The findings of this pilot study confirm that for patients with untreated cervical carcinoma, high clinical response rates can be achieved with platinum-based chemotherapy. Of those patients with a complete clinical response in the cervix, nine of ten are alive without evidence of disease with a median follow-up of 24 months. No patient who demonstrated a complete clinical response to che-
PREOPERATIVE
INDUCTION
CHEMOTHERAPY
motherapy had positive lymph nodes. Of the 18 patients who had a partial clinical response to chemotherapy, 7 are dead of disease, 4 are alive with disease, and 7 are without evidence of disease with a median follow-up of 24 months. This study shows that preoperative induction chemotherapy is well tolerated. In those patients who demonstrate complete clinical response to chemotherapy, particularly in earlier stages, there seems to be a lower than expected incidence of lymph node metastases [15191,which may improve survival. For those patients who were found, at the time of laparotomy, to have lymph node metastases or advanced local disease requiring either bowel resection or exenteration for disease clearance, long-term survival was not achieved even with the addition of postoperative pelvic irradiation. The study also confirms the feasibility of the use of induction chemotherapy prior to radical surgery in patients with locally advanced cervical carcinoma. If more active drug regimens can be designed to reliably increase the number of complete clinical responses, then the use of induction chemotherapy may translate into prolonged survival. Further investigations are currently underway.
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Chemosensitivity testing with cis-platinum(H) diammine dichloride. II. Preliminary experience in the treatment of carcinoma of the cervix, Gynecol. Oncol. 13, IO-18 (1982). 7. Kim, S. D., Moon, H., Hwang, Y. Y., and Cho, S. H. Preoperative adjuvant chemotherapy in the treatment of cervical cancer stage lb, Ha and Ilb with bulky tumor, Gynecol. Oncol. 29, 321332 (1988). 8. Giannone, L., Brenner, D. E., Jones, H. W., Greco, A., and Burnett. L. S. Combination chemotherapy for patients with advanced carcinoma of the cervix: Trial of mitomycin-C, vincristine, bleomycin and cisplatin, Gynecol. Oncol. 26, 178-182 (1987). 9. Friedlander, M. L., Kaye, S. B., Sullivan, H., Atkinson, K., EIliott, P., Coppleson, M., Houghton, R., Solomon, J., Green, D., Russell, P., Hudson, C. N., Langlands, A. O., and Tattersall, M. H. N. Cervical carcinoma: A drug responsive tumor experience with combined cisplatin, vinblastine and bleomycin therapy, Gynecoi. Oncol. 16, 275-281 (1983). 10. Friedlander, M. L., Atkinson, K., Coppleson, J. V. M., Elliot, P., Coreen, D., Houghton, R., Solomon, H. J., Russell, P., and Tattersall, M. H. N. The integration of chemotherapy into the management of locally advanced cervical cancer: A pilot study, Gynew/. Oncol. 19, l-7 (1984). 11. Sardi, J. E., DiPaola, G. R., Cachau, A., Ortiz, 0. C., Sananes, C., Giaroli, A., Martins, D., and Peluffo, M. A possible new trend in the management of carcinoma of the cervix uteri. Gynecol. Oncol. 25, 139-149 (1986). 12. Kim, D. S., Moon, H., Kim, K. T., Hwang, Y. Y., Cho, S. H., and Kim, S. R. Two year survival: Preoperative adjuvant chemotherapy in the treatment of cervical cancer stage Ib and II with bulky tumor, Gynecol. Oncol. 33, 225-230 (1989). 13. Panici, B. C., Scambia, G., Greggi, S., DiRoberto, P., Baiocchi, G., and Mancuso, S. Neoadjuvant chemotherapy and radical surgery in locally advanced cervical carcinoma: A pilot study, Ohstef. Gynecoi. 71, 344-348 (1988). 14. Valle, J. C.. Rezende, M. R., Werneck, C., Chui, C., and Figueiredoi, E. Neoadjuvant and adjuvant chemotherapy with adriamycin, bleomycin and cisplatin (ABC) and modified radical hysterectomy in cancer of the cervix, stage III, hoc. ASCO 4, 125 (1985) (Abstract). 15. Piver, M. S., and Chung, W. S. Prognostic significance of cervical lesion size and pelvic node metastases in cervical carcinoma, Obsfet. Gynecol.
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16. Chung. C. K., Nahhas, W. A., Stryker, J. A., Curry, S. L., Abt. A. B., and Mortel, R. Analysis of factors contributing to treatment failures in stage IB and HA carcinoma of the cervix, Amer. J. Obsfet. Gynecol. 138, 550-556 (1980). 17. Burghardt, E., Picker, H., Haas, J., and Lahousen, M. Prognostic factors and operative treatment of stages IB to IIB cervical cancer, Amer. J. Obstef. Gynecol. 156, 988-996 (1987). 18. Zander, J., Baltzer, J., Lohe, K. J., Ober, K. C., and Kaufman, C. Carcinoma of the cervix: An attempt to individualize treatment, Amer. J. Obstet. Gynecol. 139, 752-759 (1981). 19. Noguchi, H., Shiozawa, I., Saka, Y., Yamazaki, T., and Fukuta, T. Pelvic lymph node metastases of uterine cervical cancer, Gynecol. Oncol. 27, 150-158 (1987).
