GYNECOLOGIC
ONCOLOGY
43, 220-225
(1991)
Mitomycin-C/S-FU PHUC D. NGUYEN, *Division of Radiation $Division of Medical
and Radiation Therapy for Locally Advanced Uterine Cervical Cancer
M.D.,*
Oncology, Oncology,
BERCHMANS JOHN, M.D.,* ALAN K. MUNOZ, M.D.? ROBERTOYAZIGI, M.D.,? MATEEL GRAHAM, M.D.,* AND PATRICIA FRANKLIN, M.S.§ Department Department
of Radiology, tDiv&ion of Gynecology/Oncology, of Internal Medicine, and, BAcademic Computing Medical Center at Dallas, Dallas, Texas 75235
Received March
To assess the feasibility and effectivenessof combinedtherapy on locally advanced cervical cancer, we entered 38 patients into a study. The patientswere treated with mitomycin-C (10 mg/m*) on Days 1 and 30 and S-FU (1000mg/m*) on Days 1 to 4 and Days 30 to 33. In 5 weeks4500-5000cGy wasgiven concurrently, followed by radioactive implants. Twenty-six patients had an early-stagedisease(IB-IIB) and twelve had a late-stagedisease (IIIB-IVA). Eighty-seven percent (33/38) of the patients had a tumor measuring5 cm or more. The other 5 patients with a tumor size under 5 cm had biopsy-provenpositive pelvic nodes; 2 of these 5 patients had a pretherapy hysterectomy. Tumor response,complete(CR) vs partial (PR), was assessed in 36 patients 3 monthsafter completionof therapy. A CR was noted in 80% (29/36) of the patients. The PR status conferred a detrimental effect on the pelvic diseasecontrol (PDC), disease-free survival (DFS), and survival (S) while late stagecorrelatedwith the developmentof distant metastases(DM) and a poor DFS. PDC wasobtainedin 93%(27/29) of the patientswho had a CR, as comparedto only 43%(3/7) of thosewith a PR (P = 0.0228). The DFS and S rates were 59 and 77% for patients with a CR and 21 and 19% for thosewith a PR; respectiveP values were 0.0340and 0.0002.Eleven percent(3/26) of the patients with an early stagedevelopedDM, as comparedto 50% (6/12) of those with late stage,(P = 0.0016). The DFS rates were 80 and 37% for patients with an early and late stage, respectively (P = 0.0141). Four patients developedtransient neutropeniaand one had transient thrombocytopenia.The seconddoseof mitomycmC was omitted in 4 patients due to persistentneutropeniain 3 and to transfusion-relatedhepatitis in 1. Two percent (5/21) of the patients who had a staging laparotomy developed wound dehiscence.Three patients developed non-cancer-relatedsmall bowelobstructionrequiring surgery. We concludedthat this combined regimenwas well tolerated. Although it was effective in controlling the cancerin the pelvis, this regimenfailed to control DM in late-stagepatients. 0 1991 .4Eademic RW, I~C.
220
fxl90-8258/91$1.50
Copyright 0 1991 byAcademic Press, Inc. All rightsof reproduction in anyformresewed.
Department of Obstetrics and Gynecology, Services, University of Texas Southwestern
11, 1991
In locally advanced cervical cancer, failure to control pelvic disease has resulted in local spread, distant metastases, and decreased survival. Failure rates when irradiation alone was used have been reported as follows: 25% for stage IIB, 40% for stage III, and 65-75% for stage IV [l]. In an effort to improve these results, investigators have tried to combine chemotherapy and irradiation. Since 1973 the combination of mitomycin-C, 5-FU, and irradiation has shown improved local control in the management of squamous cell cancer of the anus. The combined therapy was well tolerated. In one study, the primary tumor control rate was 93% [2]. In 1984, the Princess Margaret Hospital in Toronto, Canada, published a pilot study using mitomycin-C, 5FU, and irradiation in advanced cervical cancer [3]. The optimal method of combining these two drugs with irradiation was not known. However, the clinical impression from this pilot study was that the response to the combined regimen occurred more rapidly and more completely than that seen in patients managed with irradiation alone. At our institution, a review of 18 patients with locally advanced cervical cancer treated with irradiation alone from 1983 to 1985 revealed a pelvic recurrence rate of 55% (10/l@ [4]. On the basis of these results, we initiated a study to evaluate the feasibility and effectiveness of combined modality therapy in a group of patients with locally advanced cervical cancer, i.e., patients with a tumor size larger than 5 cm and/or positive nodes. MATERIALS
AND METHOD
From 1985 to 1989, 38 patients with locally advanced carcinoma of the cervix were entered into a protocol com-
COMBINED
TREATMENT
OF UTERINE
bining mitomycin-C/5-FU and irradiation. All patients had squamous cell carcinoma except for 1, who had adenocarcinoma. All patients were available for analysis. The median patient age was 40 years (range, 25 to 67). The median follow-up was 20 months (range, 7 to 61). The distribution by FIG0 stage was IB, 9 (24%); IIB, 17 (44%); IIIB, 11 (29%); IVA, 1 (3%). Thirty-three patients (87%) had a tumor size of 5 cm or greater. The other 5 patients with a tumor size under 5 cm had positive nodes at laparotomy. Patient characteristics are included in Table 1. All patients underwent complete physical examination, blood counts, chest X ray, CT scan of the abdomen, cystoscopy, and proctoscopy. Patients were evaluated every 3 months for the first 2 years and every 6 months thereafter. CT scans were obtained every 6 months. The study endpoints were pelvic disease control (PDC), disease-free survival (DFS), survival (S), and development of distant metastases (DM), defined as recurrence outside the pelvis. Patients were stratified according to tumor size, less than 5 cm vs 5 cm and over in largest dimension; tumor stage, early (IB-IIB) vs late (IIIB-IVA); and tumor response. This was assessed at 3 months after completion of therapy. A complete response (CR) was defined as no clinical evidence of cancer in the pelvis and a partial response (PR) as reduction in tumor dimension but with clinically palpable disease in the pelvis. In patients who had a hysterectomy after therapy, CR was defined as no evidence of squamous cell cancer in the specimen and a patient was classified as having a PR when there was evidence of squamous cell cancer in the specimen. Probabilities of DFS and S curves were generated using the life-table method. The data were calculated from the time of the initiation of therapy. Significance between curves was determined according to the log-rank test. Fisher’s exact test was used to study the impact of tumor response, tumor size, and stage on PDC and on DM. Surgery
Early in the study 21 patients were subjected to a staging laparotomy to exclude those with positive periaortic nodes. The pelvic and periaortic nodes were inspected and biopsied even when they were not clinically suspicious. Two of these twenty-one patients had a hysterectomy at the time of laparotomy because the primary cancer measured 2 cm. In both cases bilateral microscopic involvement of pelvic nodes was found. However, when good tolerance to the combined therapy was observed, it was decided to treat the patients with positive periaortic nodes using extended field irradiation. Accordingly, staging laparotomy was not performed in the remaining patients. Five patients had an abdominal hysterectomy after therapy. One patient refused the radiation implant, one
CERVICAL
221
CANCER
TABLE 1 Patient Characteristics Patients entered Patients evaluable Median age Median follow-up Stage IB Stage IIB Stage IIIB Stage IVA Patients with tumor size >5 cm Patients with tumor size 0.999). Only the status of tumor response (CR vs PR) had a statistical impact on the PDC (P = 0.0028) (Table 2). Tumor size and stage had no detectable impact on the PDC. TABLE 3 Failure Outside Pelvis According to Tumor Parameters Tumor parameter Size
ONCOLOGY
43, 220-225
(1991)
Mitomycin-C/S-FU PHUC D. NGUYEN, *Division of Radiation $Division of Medical
and Radiation Therapy for Locally Advanced Uterine Cervical Cancer
M.D.,*
Oncology, Oncology,
BERCHMANS JOHN, M.D.,* ALAN K. MUNOZ, M.D.? ROBERTOYAZIGI, M.D.,? MATEEL GRAHAM, M.D.,* AND PATRICIA FRANKLIN, M.S.§ Department Department
of Radiology, tDiv&ion of Gynecology/Oncology, of Internal Medicine, and, BAcademic Computing Medical Center at Dallas, Dallas, Texas 75235
Received March
To assess the feasibility and effectivenessof combinedtherapy on locally advanced cervical cancer, we entered 38 patients into a study. The patientswere treated with mitomycin-C (10 mg/m*) on Days 1 and 30 and S-FU (1000mg/m*) on Days 1 to 4 and Days 30 to 33. In 5 weeks4500-5000cGy wasgiven concurrently, followed by radioactive implants. Twenty-six patients had an early-stagedisease(IB-IIB) and twelve had a late-stagedisease (IIIB-IVA). Eighty-seven percent (33/38) of the patients had a tumor measuring5 cm or more. The other 5 patients with a tumor size under 5 cm had biopsy-provenpositive pelvic nodes; 2 of these 5 patients had a pretherapy hysterectomy. Tumor response,complete(CR) vs partial (PR), was assessed in 36 patients 3 monthsafter completionof therapy. A CR was noted in 80% (29/36) of the patients. The PR status conferred a detrimental effect on the pelvic diseasecontrol (PDC), disease-free survival (DFS), and survival (S) while late stagecorrelatedwith the developmentof distant metastases(DM) and a poor DFS. PDC wasobtainedin 93%(27/29) of the patientswho had a CR, as comparedto only 43%(3/7) of thosewith a PR (P = 0.0228). The DFS and S rates were 59 and 77% for patients with a CR and 21 and 19% for thosewith a PR; respectiveP values were 0.0340and 0.0002.Eleven percent(3/26) of the patients with an early stagedevelopedDM, as comparedto 50% (6/12) of those with late stage,(P = 0.0016). The DFS rates were 80 and 37% for patients with an early and late stage, respectively (P = 0.0141). Four patients developedtransient neutropeniaand one had transient thrombocytopenia.The seconddoseof mitomycmC was omitted in 4 patients due to persistentneutropeniain 3 and to transfusion-relatedhepatitis in 1. Two percent (5/21) of the patients who had a staging laparotomy developed wound dehiscence.Three patients developed non-cancer-relatedsmall bowelobstructionrequiring surgery. We concludedthat this combined regimenwas well tolerated. Although it was effective in controlling the cancerin the pelvis, this regimenfailed to control DM in late-stagepatients. 0 1991 .4Eademic RW, I~C.
220
fxl90-8258/91$1.50
Copyright 0 1991 byAcademic Press, Inc. All rightsof reproduction in anyformresewed.
Department of Obstetrics and Gynecology, Services, University of Texas Southwestern
11, 1991
In locally advanced cervical cancer, failure to control pelvic disease has resulted in local spread, distant metastases, and decreased survival. Failure rates when irradiation alone was used have been reported as follows: 25% for stage IIB, 40% for stage III, and 65-75% for stage IV [l]. In an effort to improve these results, investigators have tried to combine chemotherapy and irradiation. Since 1973 the combination of mitomycin-C, 5-FU, and irradiation has shown improved local control in the management of squamous cell cancer of the anus. The combined therapy was well tolerated. In one study, the primary tumor control rate was 93% [2]. In 1984, the Princess Margaret Hospital in Toronto, Canada, published a pilot study using mitomycin-C, 5FU, and irradiation in advanced cervical cancer [3]. The optimal method of combining these two drugs with irradiation was not known. However, the clinical impression from this pilot study was that the response to the combined regimen occurred more rapidly and more completely than that seen in patients managed with irradiation alone. At our institution, a review of 18 patients with locally advanced cervical cancer treated with irradiation alone from 1983 to 1985 revealed a pelvic recurrence rate of 55% (10/l@ [4]. On the basis of these results, we initiated a study to evaluate the feasibility and effectiveness of combined modality therapy in a group of patients with locally advanced cervical cancer, i.e., patients with a tumor size larger than 5 cm and/or positive nodes. MATERIALS
AND METHOD
From 1985 to 1989, 38 patients with locally advanced carcinoma of the cervix were entered into a protocol com-
COMBINED
TREATMENT
OF UTERINE
bining mitomycin-C/5-FU and irradiation. All patients had squamous cell carcinoma except for 1, who had adenocarcinoma. All patients were available for analysis. The median patient age was 40 years (range, 25 to 67). The median follow-up was 20 months (range, 7 to 61). The distribution by FIG0 stage was IB, 9 (24%); IIB, 17 (44%); IIIB, 11 (29%); IVA, 1 (3%). Thirty-three patients (87%) had a tumor size of 5 cm or greater. The other 5 patients with a tumor size under 5 cm had positive nodes at laparotomy. Patient characteristics are included in Table 1. All patients underwent complete physical examination, blood counts, chest X ray, CT scan of the abdomen, cystoscopy, and proctoscopy. Patients were evaluated every 3 months for the first 2 years and every 6 months thereafter. CT scans were obtained every 6 months. The study endpoints were pelvic disease control (PDC), disease-free survival (DFS), survival (S), and development of distant metastases (DM), defined as recurrence outside the pelvis. Patients were stratified according to tumor size, less than 5 cm vs 5 cm and over in largest dimension; tumor stage, early (IB-IIB) vs late (IIIB-IVA); and tumor response. This was assessed at 3 months after completion of therapy. A complete response (CR) was defined as no clinical evidence of cancer in the pelvis and a partial response (PR) as reduction in tumor dimension but with clinically palpable disease in the pelvis. In patients who had a hysterectomy after therapy, CR was defined as no evidence of squamous cell cancer in the specimen and a patient was classified as having a PR when there was evidence of squamous cell cancer in the specimen. Probabilities of DFS and S curves were generated using the life-table method. The data were calculated from the time of the initiation of therapy. Significance between curves was determined according to the log-rank test. Fisher’s exact test was used to study the impact of tumor response, tumor size, and stage on PDC and on DM. Surgery
Early in the study 21 patients were subjected to a staging laparotomy to exclude those with positive periaortic nodes. The pelvic and periaortic nodes were inspected and biopsied even when they were not clinically suspicious. Two of these twenty-one patients had a hysterectomy at the time of laparotomy because the primary cancer measured 2 cm. In both cases bilateral microscopic involvement of pelvic nodes was found. However, when good tolerance to the combined therapy was observed, it was decided to treat the patients with positive periaortic nodes using extended field irradiation. Accordingly, staging laparotomy was not performed in the remaining patients. Five patients had an abdominal hysterectomy after therapy. One patient refused the radiation implant, one
CERVICAL
221
CANCER
TABLE 1 Patient Characteristics Patients entered Patients evaluable Median age Median follow-up Stage IB Stage IIB Stage IIIB Stage IVA Patients with tumor size >5 cm Patients with tumor size 0.999). Only the status of tumor response (CR vs PR) had a statistical impact on the PDC (P = 0.0028) (Table 2). Tumor size and stage had no detectable impact on the PDC. TABLE 3 Failure Outside Pelvis According to Tumor Parameters Tumor parameter Size
