- Email: [email protected]
Paclitaxel, ifosfamide and cisplatin (TIP) chemotherapy for recurrent or persistent squamous-cell cervical cancer
Annals of Oncology 10: 1171-1174,1999. © 1999 Kluwer Academic Publishers. Printed in the Netherlands.
Rapid publication Paclitaxel, ifosfamide and cisplatin (TIP) chemotherapy for recurrent or persistent squamous-cell cervical cancer G. Zanetta,1 F. Fei,1 G. Parma,2 M. Balestrino,3 A. Lissoni,1 A. Gabriele1 & C. Mangioni1 ^Department of Obstetrics and Gynecology, San Gerardo Hospital Monza, University of Milan; 2Department ofGynecology, European Institute of Oncology, Milan; Department of Gynecology, Clinica Malzoni, Avellino, Italy
51%-81%). Ten complete responders underwent subsequent surgery and seven had pathology-defined complete responses Purpose: The results of salvage chemotherapy for recurrent or (two in irradiated areas). The response rate was 52% in irradipersistent squamous-cell cervical cancer are unsatisfactory. ated and 75% in non-irradiated areas. Cisplatin and Ifosfamide are effective compounds in cervical The median survival for non-responders is 6 months, 9+ cancer. Paclitaxel has recently been tested with promising month for partial responders and 13+ for complete responders. results. The aim of this study was to assess the efficacy of a The most relevant side effect was myelotoxicity, with 91% of combination of paclitaxel, ifosfamide and cisplatin (TIP) for patients experiencing grade 3-4. One woman had life-threatpersistent/recurrent squamous-cell cervical carcinoma in a ening toxic effects. phase II trial. Conclusions: This combination is highly effective for salvage Patients and methods: Forty-five women were treated with treatment in non-irradiated patients. For irradiated women the the TIP regimen. Thirty-one had received prior irradiation. response rate is higher than that observed with other regimens Paclitaxel was given at a dose of 175 mg/m2, ifosfamide at a but further investigation is warranted. The toxicity is relevant dose of 5 g/m2, and cisplatin at a dose of 75 mg/m2 (50 mg/m2 but adequate hydration and prolonged infusion of ifosfamide in irradiated patients) at three-week intervals. make it acceptable. Results: We observed 15 clinical complete responses, 15 partial responses, 9 stable diseases and 6 progressions. The Key words: cervical cancer, chemotherapy, cisplatin, ifosfamide, objective response rate was 67% (95% confidence interval: paclitaxel, survival Summary
Introduction
Cervical carcinoma is a chemo-sensitive disease. In 1981 a study of the Gynecologic Oncology Group documented for the first time that some patients may achieve objective responses when they are treated with cisplatin [1] and in the succeeding ten years several studies were conducted with the aim of achieving higher response rates by combining cisplatin with several toxic agents, mainly mitomycin, bleomycin, the vinca derivatives, methotrexate and ifosfamide [2-5]. Unfortunately, despite some promising preliminary reports, all authors now agree that multi-drug regimens yield unsatisfactory results, with minimal impact on survival [6,7]. In 1996 a study of the Gynecologic Oncology Group documented that paclitaxel could yield a 17% objective response rate in recurrent cervical cancer [8]. Although this response rate does not seem high, the authors of the study noted that there is very little difference between it and the one observed when cisplatin initially appeared and they concluded that such a response rate made paclitaxel suitable for being tested in multi-drug regimens in the future.
In this paper we describe the results obtained in persistent and recurrent squamous cell cervical cancer with a combination of paclitaxel, ifosfamide and cisplatin (TIP). Patients and methods Forty-five consecutive patients with histologically confirmed recurrent or persistent squamous-cell carcinoma of the cervix were treated with the TIP regimen between April 1996 and December 1998. The patients ranged from 32-72 years of age, with a median of 50. Thirty-one patients had been treated previously with radiotherapy. Nine had received radiotherapy alone, seven had received surgery alone, twenty-nine had received various combined treatments. The tumor was in the pelvis in 21 women, in extrapelvic sites in 15 (20 lesions), and in both in 9, for a total of 59 sites, 23 of which had been previously treated with radiation. All women had measurable disease, either by diagnostic imaging or by physical exam. Initial evaluation of each patient included details of previous treatment, physical exam, assessment of performance status, hemogram, renal and liver function tests, ECG and chest X-rays. Diagnostic imaging (computed tomography, magnetic resonance and/or ultrasound) was done to determine the extent of the disease. All women were informed about the treatment schedule. Table 1 summarizes the main characteristics of the patients. Eligibility requirements were: pathology-confirmed diagnosis of
Downloaded from https://academic.oup.com/annonc/article-abstract/10/10/1171/209649 by guest on 10 April 2018
1172 Table 1. Patient characterisitics. Performance status 0 1
Previous treatment Radiation alone Surgery alone Combinations of surgery and radiation Combinations of chemotherapy and surgery Concurrent chemo-radiation Combinations of surgery, chemotherapy and radiation Chemotherapy followed by radiation Sites of tumor involvement In the radiation field only Outside the radiation field only Both Number of sites of tumor involvement 1 2
21 24 9 7 11 7 7 3 1 19 20 6 26 19
squamous-cell cervical carcinoma, age < 75 years, performance status (PS) < 2 according to the WHO criteria, neutrophil count of 2000/ml, platelet count of 100000/ml, normal liver and renal function, written informed consent. Only patients with a life expectancy of at least three months were eligible for treatment. The treatment required hospitalization for three days. Chemotherapy was given as follows : paclitaxel on day 1 was given at the dose of 175 mg/m2, as a three-hour infusion, preceded by premedication with methilprednisolone 250 mg i.v., 60 min before chlorpheniramine 10 mg i.m. and cimetidine 300 mg i.v., 30 min before. On day 2, cisplatin was administered in a 60-min infusion at the dose of 50 mg/m2 (31 irradiated patients) or 75 mg/m2 (14 nonirradiated patients patients) after prehydration with 1.5 1 of normal saline added with 10 mEq/1 of potassium chlorite and 10 mEq/1 of MgSO4, with post-hydration with 11 of 5% dextrose solution added with 20 mEq/1 of KG and 20 mEq/1 of MgSO4 given over two hours. After post-hydration, ifosfamide 5 g/m2 and mesna 5 g/m2 were infused i.v. over 24 hours in 1 1 of normal saline, followed, on day 3, by mesna 3 g/m2 given i.v. in 1 1 of normal saline over 24 hours. The treatment was repeated every three weeks for a minimum of two courses. Complete blood count and renal function tests were repeated weekly. One week of delay was planned if the neuthrophil count was less than 1500 mm3, or the platelet count less than 100,000 mm3. On the basis of physician judgment, recombinant human G-CSF, while not part of the standard treatment, was administered in instances of persistent grade 4 myelotoxicity or febrile neutropenia. Dose reductions were not planned but were permitted in instances of persistent slow recovery of the bone marrow function. Pelvic examination was performed before each course. Tumor response was assessed clinically and by diagnostic imaging every two courses. A minimum of two courses was planned before evaluation of response and a maximum of seven courses were given to responders. Response and toxicity were defined according to WHO criteria [9]. Follow-up procedures consisting of general and gynecologic examination and vaginal cytology were performed one month before the end of the treatment and every two months thereafter. Pelvic and abdominal CT scans or MRI were performed every three months in complete responders. Response duration was defined as the time from onset of objective response to the appearance of progressive disease. Survival was defined as the observed length of life from entry into the study until death or, for living patients, the date of last contact. Statistical evaluations were performed by means of the Chi-square test. As most studies on salvage therapy for cervical carcinoma describe
Downloaded from https://academic.oup.com/annonc/article-abstract/10/10/1171/209649 by guest on 10 April 2018
objective responses in 30%-40% of patients, this study was aimed at assessing an objective response rate of at least 40%. A sample size of not less than 33 patients was required to reject the hypothesis of response rate smaller than 40%, and this goal was achieved in June 1998. Nevertheless, due to good accrual and promising ad-interim analysis, we decided to continue the study until the end of 1998, when a total of 45 patients had been accrued.
Results Two hundred two courses were given, with a median of four courses per patient. We observed 15 complete responses (33%), 15 partial responses (33%), 9 stable diseases (20%) and 6 progressive diseases (13%). The overall response rate (complete + partial response) was 67% (95% confidence interval: After chemotherapy, 24 women received tailored salvage treatments (14 surgery, ten radiotherapy with or without concurrent chemotherapy) and 18 received palliative treatments (16 hormone and two other chemotherapy regimens). In particular, 10 clinical complete responders underwent surgery (4 radical colpectomies, 2 hysterectomies with lymphadenectomies, 4 pelvic and/ or para-aortic lymphadenectomies) and 7 were found to have pathology-defined complete responses, 2 of them in irradiated areas. We recorded 15 objective responses in 21 women with tumor in the pelvis alone (71%), 5 in 9 women with both pelvic and extra-pelvic disease (56%), and 10 in 15 women with distant metastases alone (67%). Prior irradiation to the site of recurrence was a negative factor in predicting response: 12 responses were recorded in 23 irradiated areas (52%) compared to 27 responses seen in 36 non-irradiated areas (75%) (P - 0.07 Chi-square test; P = 0.06 Fisher's test). When the interval since prior irradiation was considered, we observed that the response rate of irradiated targets was higher after longer intervals. Eight objective responses were recorded in thirteen women (69%) at an interval of more than twelve months since irradiation, and four objective responses in nine (44%) women after less than twelve months. Nevertheless, this difference lacked statistical significance. Eighteen patients had received prior platinum-based chemotherapy (only three in the neoadjuvant setting) and their response rate was 61% (11 of 18), irrespective of other treatments. With a median follow-up of 8 months for survivors, the median survival of complete responders is 13+ months, 9+ months for partial responders, and 6 months for non-responders. Several patients who achieved objective responses underwent additional salvage treatments but for those who received no further treatment the median duration of response was 7+ months. At the time of writing, 13 women had died of disease, one had died of pulmonary embolism with progressive
1173 Table 2. Toxicity according to WHO criteria. Toxicity
Granulocytopenia Anemia Thrombocytopenia Alopecia Nausea-emesis Renal Hepatic Mucositis Diarrhea Peripheral neurotoxicity Central neurotoxicity Myalgia-arthralgia Allergy
Grade 1
2
3
4
6 9 3 3 4 3 9 1 11 2
4 6 14 6 12 4 1 1 3 4 1
17 24 13 39 24 2 1 — -
24 9 9 6 -
disease one month after the start of treatment, 13 are alive with disease and 18 remain alive without evidence of disease. This regimen was rather toxic and myelotoxicity was the most relevant side effect. One woman died of pulmonary embolism with progressive disease after one course of chemotherapy. One woman with chronic hepatitis had reaxerbation requiring discontinuation of the treatment after two courses of chemotherapy. She was classified as a non-responder despite an approximately 40% objective reduction in size of the tumor and improvement in her symptoms. One woman experienced a life-threatening myelotoxicity requiring discontinuation of treatment. The toxic effects of chemotherapy are summarized in Table 2. In all, 10 women required an at least one-week delay in the planned treatment and nine women received myelostimulation with G-CSF.
Discussion Cisplatin is the cornerstone of chemotherapy for cervical carcinoma. This drug is usually utilized in neoadjuvant regimens and in salvage treatments [7,10-12]. When used as single-agent treatment, cisplatin may yield a 20%-25% objective response rate in recurrent cervical cancer [7]. Unfortunately, until now, the late 1990s, no combination with other cytotoxic drugs has proven effective in improving the survival of patients with advanced or recurrent disease [6, 7]. Higher response rates may be achieved but their duration is short and practically all patients ultimately die of the disease. In 1995 we analyzed the experience of our institution with single-agent and multi-drug salvage chemotherapy for cervical cancer [7]. We did observe a slightly higher response rate with some multi-drug regimens than with cisplatin alone but, in a multivariate analysis, multidrug treatment conferred no prognostic advantage over single-agent chemotherapy with cisplatin. We did observe, however, a significant increase in toxicity and
costs with multi-agent chemotherapy. At that time we concluded that new cytotoxic drugs should be tested rather than new combinations of the old drugs. The study published by the GOG in 1996 raised the hope that a new effective drug might have become available for the treatment in cervical cancer [9]. A subsequent study of the GOG reported an objective response rate of 46% in recurrent or advanced squamous-cell cervical carcinoma treated with a combination of paclitaxel and cisplatin [13]. In the current study we observe that the objective response rate is 67%, with a clinical complete response rate of 33%. Most importantly we report an objective response rate of 52% in irradiated areas and we observed seven cases of documented pathology complete remission (two of them in irradiated areas). We recognize that in our study population only 31 of 45 patients had received irradiation prior to salvage chemotherapy. In Italy a high proportion of patients with locally advanced cervical carcinoma currently receive neoadjuvant chemotherapy followed by radical surgery rather than pelvic irradiation or adjuvant chemotherapy instead of adjuvant irradiation. Although the advantages of this new therapeutic strategy need further investigation, our study shows that those patients who did not receive first-line irradiation have less fibrosis in case of local recurrence and seem to have better results in case of salvage chemotherapy. One might argue that recurrent cervical carcinomas include a wide variety of clinical situations, which are difficult to compare. However, we have demonstrated in the past that only previous irradiation, site of recurrence and response to treatment significantly affected the prognosis [7]. In this study population 68.8% of patients had received prior irradiation and 67% had persistencerecurrence in the pelvis. According to our data we believe that it is time to reconsider the potential of salvage chemotherapy in view of the improved objective response rate, possibly reflecting a prolonged survival of the patients observed with this combination, even if irradiated. With regard to the toxicity of this regimen, we recognize that myelotoxicity is severe, but in view of the dismal prognosis of such patients, it is acceptable. None of our patients died of toxicity, although discontinuation of treatment was needed in two women and one woman died of pulmonary embolism with progression of disease. We also note that other authors have described relevant toxicity with a regimen consisting of cisplatin and paclitaxel [14] delivered on an outpatient basis. Our regimen differs in that it required hospitalization for three days. Obviously, such a regimen means higher hospital costs and is technically less easy to perform. However, despite the inclusion of an additional myelotoxic agent such as ifosfamide, our regimen was not less tolerable than the two-drug regimen described by others. We also note that Granulocyte Colony Stimulating Factors were not routinely used in this study and this offsets most of the expenses of the prolonged hospitalization. Therefore,
Downloaded from https://academic.oup.com/annonc/article-abstract/10/10/1171/209649 by guest on 10 April 2018
1174 better hydration and longer infusion of ifosfamide make this regimen relatively more tolerable than other combinations. The GOG is now proposing a randomized trial aimed at comparing salvage treatment with cisplatin versus a regimen with cisplatin and paclitaxel. We believe that in the future an ideal study should include an experimental arm with the regimen described in this article.
8. 9. 10. 11.
References 1. Thigpen T, Shingleton H, Homesley H et al. Cis-platinum in treatment of advanced or recurrent squamous cell carcinoma of the cervix. A phase II study of the Gynecologic Oncology Group. Cancer 1981; 48: 899-903. 2. Picozzi VJ, Sikic RJ, Carlson RW et al. Bleomycin, mitomycin and cisplatin therapy for advanced squamous carcinoma of the uterine cervix: A phase II study of the Northern California Oncology Group. Cancer Treat Rep 1985; 69: 903-5. 3. Rustin GJS, Newlands ES, Southcott BM, Singer A. Cisplatin, vincristine, methotrexate and bleomycin (POMB) as initial or palliative chemotherapy for carcinoma of the cervix. Br J Obstet Gynaecol 1987; 94: 1205-11. 4. Hoskin PJ, Blake PR. Cisplatin, methotrexate and bleomycin (PMB) for carcinoma of the cervix: The influence of presentation and previous treatment upon response. Int J Gynecol Cancer 1991; 1:75-80. 5. Buxton EJ, Meanwell CA, Mould JJ et al. Phase II studies of bleomycin, ifosfamide and cisplatin in advanced and recurrent cervical carcinoma. Acta Oncol 1988; 27: 545-9. 6. Vermorken JB. The role of chemotherapy in squamous-cell carcinoma of the uterine cervix: A review. Int J Gynecol Cancer 1993; 3: 129-42. 7. Zanetta G, Torri W, Bocciolone L et al. Factors predicting response to chemotherapy and survival in patients with meta-
Downloaded from https://academic.oup.com/annonc/article-abstract/10/10/1171/209649 by guest on 10 April 2018
12.
13.
14.
static or recurrent squamous-cell cervical carcinoma. A multivariate analysis. Gynecol Oncol 1995; 58: 58-63. McGuire Wp, Blessing JA, Moore D et al. Paclitaxel has moderate activity in squamous cervix cancer. A Gynecologic Oncology Group study. J Clin Oncol 1996; 14: 792-5. Miller AB, Hoogstraten B, Staquet M, Winkler A. Reporting results of cancer treatment. Cancer 1981; 47: 207-14. Potter ME, Hatch K.D, Potter MY et al. Factors affecting the response of recurrent squamous-cell carcinoma of the cervix to cisplatin. Cancer 1989; 63: 1283-6. Sardi JE, Giaroli A, Sananes C et al. Long-term follow-up of the first randomized trial using neoadjuvant chemotherapy in stage Ib squamous carcinoma of the cervix. The final results. Gynecol Oncol 1997; 67: 61-9. Zanetta G, Landoni F, Colombo A et al. Three-year results after neoadjuvant chemotherapy, radical surgery and radiotherapy in locally advanced cervical carcinoma. Obstet Gynecol 1993; 82: 447-50. Rose PG, Blessing J, Gershenson DM, McGehee R. Paclitaxel and cisplatin as first-line therapy in recurrent or advanced squamous-cell carcinoma of the cervix. A Gynecologic Oncology Group (GOG) study. Gynecol Oncol 1999; 72: 461 (Abstr 69). Papadimitrou CA, Sarris K, Moulopoulos LA et al. Phase II trial of paclitaxel and cisplatin in metastatic and recurrent carcinoma of the uterine cervix. J Clin Oncol 1999; 17: 761-6.
Received 15 July 1999; accepted 25 August 1999.
Correspondence to:
G. Zanetta, MD Divisione Ostetricia e Ginecologia Ospedale San Gerardo di Monza Via Solferino 16 20052 Monza Italy E-mail: [email protected]
Rapid publication Paclitaxel, ifosfamide and cisplatin (TIP) chemotherapy for recurrent or persistent squamous-cell cervical cancer G. Zanetta,1 F. Fei,1 G. Parma,2 M. Balestrino,3 A. Lissoni,1 A. Gabriele1 & C. Mangioni1 ^Department of Obstetrics and Gynecology, San Gerardo Hospital Monza, University of Milan; 2Department ofGynecology, European Institute of Oncology, Milan; Department of Gynecology, Clinica Malzoni, Avellino, Italy
51%-81%). Ten complete responders underwent subsequent surgery and seven had pathology-defined complete responses Purpose: The results of salvage chemotherapy for recurrent or (two in irradiated areas). The response rate was 52% in irradipersistent squamous-cell cervical cancer are unsatisfactory. ated and 75% in non-irradiated areas. Cisplatin and Ifosfamide are effective compounds in cervical The median survival for non-responders is 6 months, 9+ cancer. Paclitaxel has recently been tested with promising month for partial responders and 13+ for complete responders. results. The aim of this study was to assess the efficacy of a The most relevant side effect was myelotoxicity, with 91% of combination of paclitaxel, ifosfamide and cisplatin (TIP) for patients experiencing grade 3-4. One woman had life-threatpersistent/recurrent squamous-cell cervical carcinoma in a ening toxic effects. phase II trial. Conclusions: This combination is highly effective for salvage Patients and methods: Forty-five women were treated with treatment in non-irradiated patients. For irradiated women the the TIP regimen. Thirty-one had received prior irradiation. response rate is higher than that observed with other regimens Paclitaxel was given at a dose of 175 mg/m2, ifosfamide at a but further investigation is warranted. The toxicity is relevant dose of 5 g/m2, and cisplatin at a dose of 75 mg/m2 (50 mg/m2 but adequate hydration and prolonged infusion of ifosfamide in irradiated patients) at three-week intervals. make it acceptable. Results: We observed 15 clinical complete responses, 15 partial responses, 9 stable diseases and 6 progressions. The Key words: cervical cancer, chemotherapy, cisplatin, ifosfamide, objective response rate was 67% (95% confidence interval: paclitaxel, survival Summary
Introduction
Cervical carcinoma is a chemo-sensitive disease. In 1981 a study of the Gynecologic Oncology Group documented for the first time that some patients may achieve objective responses when they are treated with cisplatin [1] and in the succeeding ten years several studies were conducted with the aim of achieving higher response rates by combining cisplatin with several toxic agents, mainly mitomycin, bleomycin, the vinca derivatives, methotrexate and ifosfamide [2-5]. Unfortunately, despite some promising preliminary reports, all authors now agree that multi-drug regimens yield unsatisfactory results, with minimal impact on survival [6,7]. In 1996 a study of the Gynecologic Oncology Group documented that paclitaxel could yield a 17% objective response rate in recurrent cervical cancer [8]. Although this response rate does not seem high, the authors of the study noted that there is very little difference between it and the one observed when cisplatin initially appeared and they concluded that such a response rate made paclitaxel suitable for being tested in multi-drug regimens in the future.
In this paper we describe the results obtained in persistent and recurrent squamous cell cervical cancer with a combination of paclitaxel, ifosfamide and cisplatin (TIP). Patients and methods Forty-five consecutive patients with histologically confirmed recurrent or persistent squamous-cell carcinoma of the cervix were treated with the TIP regimen between April 1996 and December 1998. The patients ranged from 32-72 years of age, with a median of 50. Thirty-one patients had been treated previously with radiotherapy. Nine had received radiotherapy alone, seven had received surgery alone, twenty-nine had received various combined treatments. The tumor was in the pelvis in 21 women, in extrapelvic sites in 15 (20 lesions), and in both in 9, for a total of 59 sites, 23 of which had been previously treated with radiation. All women had measurable disease, either by diagnostic imaging or by physical exam. Initial evaluation of each patient included details of previous treatment, physical exam, assessment of performance status, hemogram, renal and liver function tests, ECG and chest X-rays. Diagnostic imaging (computed tomography, magnetic resonance and/or ultrasound) was done to determine the extent of the disease. All women were informed about the treatment schedule. Table 1 summarizes the main characteristics of the patients. Eligibility requirements were: pathology-confirmed diagnosis of
Downloaded from https://academic.oup.com/annonc/article-abstract/10/10/1171/209649 by guest on 10 April 2018
1172 Table 1. Patient characterisitics. Performance status 0 1
Previous treatment Radiation alone Surgery alone Combinations of surgery and radiation Combinations of chemotherapy and surgery Concurrent chemo-radiation Combinations of surgery, chemotherapy and radiation Chemotherapy followed by radiation Sites of tumor involvement In the radiation field only Outside the radiation field only Both Number of sites of tumor involvement 1 2
21 24 9 7 11 7 7 3 1 19 20 6 26 19
squamous-cell cervical carcinoma, age < 75 years, performance status (PS) < 2 according to the WHO criteria, neutrophil count of 2000/ml, platelet count of 100000/ml, normal liver and renal function, written informed consent. Only patients with a life expectancy of at least three months were eligible for treatment. The treatment required hospitalization for three days. Chemotherapy was given as follows : paclitaxel on day 1 was given at the dose of 175 mg/m2, as a three-hour infusion, preceded by premedication with methilprednisolone 250 mg i.v., 60 min before chlorpheniramine 10 mg i.m. and cimetidine 300 mg i.v., 30 min before. On day 2, cisplatin was administered in a 60-min infusion at the dose of 50 mg/m2 (31 irradiated patients) or 75 mg/m2 (14 nonirradiated patients patients) after prehydration with 1.5 1 of normal saline added with 10 mEq/1 of potassium chlorite and 10 mEq/1 of MgSO4, with post-hydration with 11 of 5% dextrose solution added with 20 mEq/1 of KG and 20 mEq/1 of MgSO4 given over two hours. After post-hydration, ifosfamide 5 g/m2 and mesna 5 g/m2 were infused i.v. over 24 hours in 1 1 of normal saline, followed, on day 3, by mesna 3 g/m2 given i.v. in 1 1 of normal saline over 24 hours. The treatment was repeated every three weeks for a minimum of two courses. Complete blood count and renal function tests were repeated weekly. One week of delay was planned if the neuthrophil count was less than 1500 mm3, or the platelet count less than 100,000 mm3. On the basis of physician judgment, recombinant human G-CSF, while not part of the standard treatment, was administered in instances of persistent grade 4 myelotoxicity or febrile neutropenia. Dose reductions were not planned but were permitted in instances of persistent slow recovery of the bone marrow function. Pelvic examination was performed before each course. Tumor response was assessed clinically and by diagnostic imaging every two courses. A minimum of two courses was planned before evaluation of response and a maximum of seven courses were given to responders. Response and toxicity were defined according to WHO criteria [9]. Follow-up procedures consisting of general and gynecologic examination and vaginal cytology were performed one month before the end of the treatment and every two months thereafter. Pelvic and abdominal CT scans or MRI were performed every three months in complete responders. Response duration was defined as the time from onset of objective response to the appearance of progressive disease. Survival was defined as the observed length of life from entry into the study until death or, for living patients, the date of last contact. Statistical evaluations were performed by means of the Chi-square test. As most studies on salvage therapy for cervical carcinoma describe
Downloaded from https://academic.oup.com/annonc/article-abstract/10/10/1171/209649 by guest on 10 April 2018
objective responses in 30%-40% of patients, this study was aimed at assessing an objective response rate of at least 40%. A sample size of not less than 33 patients was required to reject the hypothesis of response rate smaller than 40%, and this goal was achieved in June 1998. Nevertheless, due to good accrual and promising ad-interim analysis, we decided to continue the study until the end of 1998, when a total of 45 patients had been accrued.
Results Two hundred two courses were given, with a median of four courses per patient. We observed 15 complete responses (33%), 15 partial responses (33%), 9 stable diseases (20%) and 6 progressive diseases (13%). The overall response rate (complete + partial response) was 67% (95% confidence interval: After chemotherapy, 24 women received tailored salvage treatments (14 surgery, ten radiotherapy with or without concurrent chemotherapy) and 18 received palliative treatments (16 hormone and two other chemotherapy regimens). In particular, 10 clinical complete responders underwent surgery (4 radical colpectomies, 2 hysterectomies with lymphadenectomies, 4 pelvic and/ or para-aortic lymphadenectomies) and 7 were found to have pathology-defined complete responses, 2 of them in irradiated areas. We recorded 15 objective responses in 21 women with tumor in the pelvis alone (71%), 5 in 9 women with both pelvic and extra-pelvic disease (56%), and 10 in 15 women with distant metastases alone (67%). Prior irradiation to the site of recurrence was a negative factor in predicting response: 12 responses were recorded in 23 irradiated areas (52%) compared to 27 responses seen in 36 non-irradiated areas (75%) (P - 0.07 Chi-square test; P = 0.06 Fisher's test). When the interval since prior irradiation was considered, we observed that the response rate of irradiated targets was higher after longer intervals. Eight objective responses were recorded in thirteen women (69%) at an interval of more than twelve months since irradiation, and four objective responses in nine (44%) women after less than twelve months. Nevertheless, this difference lacked statistical significance. Eighteen patients had received prior platinum-based chemotherapy (only three in the neoadjuvant setting) and their response rate was 61% (11 of 18), irrespective of other treatments. With a median follow-up of 8 months for survivors, the median survival of complete responders is 13+ months, 9+ months for partial responders, and 6 months for non-responders. Several patients who achieved objective responses underwent additional salvage treatments but for those who received no further treatment the median duration of response was 7+ months. At the time of writing, 13 women had died of disease, one had died of pulmonary embolism with progressive
1173 Table 2. Toxicity according to WHO criteria. Toxicity
Granulocytopenia Anemia Thrombocytopenia Alopecia Nausea-emesis Renal Hepatic Mucositis Diarrhea Peripheral neurotoxicity Central neurotoxicity Myalgia-arthralgia Allergy
Grade 1
2
3
4
6 9 3 3 4 3 9 1 11 2
4 6 14 6 12 4 1 1 3 4 1
17 24 13 39 24 2 1 — -
24 9 9 6 -
disease one month after the start of treatment, 13 are alive with disease and 18 remain alive without evidence of disease. This regimen was rather toxic and myelotoxicity was the most relevant side effect. One woman died of pulmonary embolism with progressive disease after one course of chemotherapy. One woman with chronic hepatitis had reaxerbation requiring discontinuation of the treatment after two courses of chemotherapy. She was classified as a non-responder despite an approximately 40% objective reduction in size of the tumor and improvement in her symptoms. One woman experienced a life-threatening myelotoxicity requiring discontinuation of treatment. The toxic effects of chemotherapy are summarized in Table 2. In all, 10 women required an at least one-week delay in the planned treatment and nine women received myelostimulation with G-CSF.
Discussion Cisplatin is the cornerstone of chemotherapy for cervical carcinoma. This drug is usually utilized in neoadjuvant regimens and in salvage treatments [7,10-12]. When used as single-agent treatment, cisplatin may yield a 20%-25% objective response rate in recurrent cervical cancer [7]. Unfortunately, until now, the late 1990s, no combination with other cytotoxic drugs has proven effective in improving the survival of patients with advanced or recurrent disease [6, 7]. Higher response rates may be achieved but their duration is short and practically all patients ultimately die of the disease. In 1995 we analyzed the experience of our institution with single-agent and multi-drug salvage chemotherapy for cervical cancer [7]. We did observe a slightly higher response rate with some multi-drug regimens than with cisplatin alone but, in a multivariate analysis, multidrug treatment conferred no prognostic advantage over single-agent chemotherapy with cisplatin. We did observe, however, a significant increase in toxicity and
costs with multi-agent chemotherapy. At that time we concluded that new cytotoxic drugs should be tested rather than new combinations of the old drugs. The study published by the GOG in 1996 raised the hope that a new effective drug might have become available for the treatment in cervical cancer [9]. A subsequent study of the GOG reported an objective response rate of 46% in recurrent or advanced squamous-cell cervical carcinoma treated with a combination of paclitaxel and cisplatin [13]. In the current study we observe that the objective response rate is 67%, with a clinical complete response rate of 33%. Most importantly we report an objective response rate of 52% in irradiated areas and we observed seven cases of documented pathology complete remission (two of them in irradiated areas). We recognize that in our study population only 31 of 45 patients had received irradiation prior to salvage chemotherapy. In Italy a high proportion of patients with locally advanced cervical carcinoma currently receive neoadjuvant chemotherapy followed by radical surgery rather than pelvic irradiation or adjuvant chemotherapy instead of adjuvant irradiation. Although the advantages of this new therapeutic strategy need further investigation, our study shows that those patients who did not receive first-line irradiation have less fibrosis in case of local recurrence and seem to have better results in case of salvage chemotherapy. One might argue that recurrent cervical carcinomas include a wide variety of clinical situations, which are difficult to compare. However, we have demonstrated in the past that only previous irradiation, site of recurrence and response to treatment significantly affected the prognosis [7]. In this study population 68.8% of patients had received prior irradiation and 67% had persistencerecurrence in the pelvis. According to our data we believe that it is time to reconsider the potential of salvage chemotherapy in view of the improved objective response rate, possibly reflecting a prolonged survival of the patients observed with this combination, even if irradiated. With regard to the toxicity of this regimen, we recognize that myelotoxicity is severe, but in view of the dismal prognosis of such patients, it is acceptable. None of our patients died of toxicity, although discontinuation of treatment was needed in two women and one woman died of pulmonary embolism with progression of disease. We also note that other authors have described relevant toxicity with a regimen consisting of cisplatin and paclitaxel [14] delivered on an outpatient basis. Our regimen differs in that it required hospitalization for three days. Obviously, such a regimen means higher hospital costs and is technically less easy to perform. However, despite the inclusion of an additional myelotoxic agent such as ifosfamide, our regimen was not less tolerable than the two-drug regimen described by others. We also note that Granulocyte Colony Stimulating Factors were not routinely used in this study and this offsets most of the expenses of the prolonged hospitalization. Therefore,
Downloaded from https://academic.oup.com/annonc/article-abstract/10/10/1171/209649 by guest on 10 April 2018
1174 better hydration and longer infusion of ifosfamide make this regimen relatively more tolerable than other combinations. The GOG is now proposing a randomized trial aimed at comparing salvage treatment with cisplatin versus a regimen with cisplatin and paclitaxel. We believe that in the future an ideal study should include an experimental arm with the regimen described in this article.
8. 9. 10. 11.
References 1. Thigpen T, Shingleton H, Homesley H et al. Cis-platinum in treatment of advanced or recurrent squamous cell carcinoma of the cervix. A phase II study of the Gynecologic Oncology Group. Cancer 1981; 48: 899-903. 2. Picozzi VJ, Sikic RJ, Carlson RW et al. Bleomycin, mitomycin and cisplatin therapy for advanced squamous carcinoma of the uterine cervix: A phase II study of the Northern California Oncology Group. Cancer Treat Rep 1985; 69: 903-5. 3. Rustin GJS, Newlands ES, Southcott BM, Singer A. Cisplatin, vincristine, methotrexate and bleomycin (POMB) as initial or palliative chemotherapy for carcinoma of the cervix. Br J Obstet Gynaecol 1987; 94: 1205-11. 4. Hoskin PJ, Blake PR. Cisplatin, methotrexate and bleomycin (PMB) for carcinoma of the cervix: The influence of presentation and previous treatment upon response. Int J Gynecol Cancer 1991; 1:75-80. 5. Buxton EJ, Meanwell CA, Mould JJ et al. Phase II studies of bleomycin, ifosfamide and cisplatin in advanced and recurrent cervical carcinoma. Acta Oncol 1988; 27: 545-9. 6. Vermorken JB. The role of chemotherapy in squamous-cell carcinoma of the uterine cervix: A review. Int J Gynecol Cancer 1993; 3: 129-42. 7. Zanetta G, Torri W, Bocciolone L et al. Factors predicting response to chemotherapy and survival in patients with meta-
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12.
13.
14.
static or recurrent squamous-cell cervical carcinoma. A multivariate analysis. Gynecol Oncol 1995; 58: 58-63. McGuire Wp, Blessing JA, Moore D et al. Paclitaxel has moderate activity in squamous cervix cancer. A Gynecologic Oncology Group study. J Clin Oncol 1996; 14: 792-5. Miller AB, Hoogstraten B, Staquet M, Winkler A. Reporting results of cancer treatment. Cancer 1981; 47: 207-14. Potter ME, Hatch K.D, Potter MY et al. Factors affecting the response of recurrent squamous-cell carcinoma of the cervix to cisplatin. Cancer 1989; 63: 1283-6. Sardi JE, Giaroli A, Sananes C et al. Long-term follow-up of the first randomized trial using neoadjuvant chemotherapy in stage Ib squamous carcinoma of the cervix. The final results. Gynecol Oncol 1997; 67: 61-9. Zanetta G, Landoni F, Colombo A et al. Three-year results after neoadjuvant chemotherapy, radical surgery and radiotherapy in locally advanced cervical carcinoma. Obstet Gynecol 1993; 82: 447-50. Rose PG, Blessing J, Gershenson DM, McGehee R. Paclitaxel and cisplatin as first-line therapy in recurrent or advanced squamous-cell carcinoma of the cervix. A Gynecologic Oncology Group (GOG) study. Gynecol Oncol 1999; 72: 461 (Abstr 69). Papadimitrou CA, Sarris K, Moulopoulos LA et al. Phase II trial of paclitaxel and cisplatin in metastatic and recurrent carcinoma of the uterine cervix. J Clin Oncol 1999; 17: 761-6.
Received 15 July 1999; accepted 25 August 1999.
Correspondence to:
G. Zanetta, MD Divisione Ostetricia e Ginecologia Ospedale San Gerardo di Monza Via Solferino 16 20052 Monza Italy E-mail: [email protected]