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Neoadjuvant chemotherapy with cisplatin, ifosfamide and paclitaxel for locally advanced squamous-cell cervical cancer
Annals of Oncology 9: 977-980, 1998. © 1998 Khtwer Academic Publishers. Primed in the Netherlands.
Original article Neoadjuvant chemotherapy with cisplatin, ifosfamide and paclitaxel for locally advanced squamous-cell cervical cancer G. Zanetta,1 A. Lissoni,1 A. Pellegrino,1 C. Sessa,2 N. Colombo,3 D. Gueli-Alletti4 & C. Mangioni1 1 Department ofObstetrics and Gynecology, San Gerardo Hospital, Monza, University of Milan, Italy; 2 Division of Oncology, Ospedale San Giovanni Bellinzona, Switzerland; 3Division of Gynecology, European Cancer Institute, Milan; ADepartment of Obstetrics and Gynecology, Ospedale Cervello, Palermo, Italy
Summary
Results: All patients are evaluable for response. Eleven achieved clinical complete responses, 21 had partial responses, five had stable disease and one had progression of disease. Of 34 patients who underwent surgery, six (16%) had pathologydocumented complete responses, seven (18%) had partial responses with only microscopic residual disease in the cervix, 19 had sub-optimal partial responses, and two had stable disease, for an overall response rate of 84% (95% confidence intervals (CI): 68.7%-94%). Grade 3-4 neutropenia was recorded for 27 (71%) patients, grade 3-4 thrombocytopenia for four (10.5%), and grade 2 peripheral neuropathy for two (2.5%). At a median follow-up of 16 months (range 7-22), 29 (76%) women are alive without recurrence, seven are alive with persistent/recurrent disease and two have died of their disease. Conclusions: According to pathology examination, this regimen yields a 34% complete and optimal partial response rate with acceptable toxicity, and it should be prospectively compared to other regimens.
Background: Neoadjuvant chemotherapy is increasingly being used for the treatment of bulky and locally-advanced cervical cancer. Cisplatin and ifosfamide are known to be effective in cervical cancer, while paclitaxel is one of the promising new drugs for the treatment of this neoplasm. Objective: To assess the toxic effects and antitumor activity of a multidrug neoadjuvant regimen consisting of cisplatin, ifosfamide, and paclitaxel in bulky and locally advanced cervical cancer. Patients and methods: Thirty-eight patients with pathologyconfirmed squamous-cell cervical cancer (27 IB2-IIA, two IIB, eight IIIB, one IVA) were prospectively enrolled in the study. Their treatment consisted of paclitaxel 175 mg/m2 given over three hours on day 1, cisplatin 50 mg/m2 (75 mg/m2 in 10 patients), ifosfamide 5 g/m2 in a 24-hour continuous infusion and mesna 5 g/m2 in a 24-hour continuous infusion on day 2, and mesna 3 g/m2 in a 24-hour continuous infusion on day 3. The course was repeated every three weeks for three courses and all of the patients, except those with disease progression or who were inoperable, were scheduled for radical hysterectomy Key words: cervical cancer, neoadjuvant chemotherapy, pacliand pelvic lymphadenectomy. taxel
Introduction
Patients and methods
Neoadjuvant chemotherapy for bulky or locally advanced cervical carcinoma has received increasing attention in the past decade [1-3]. Several compounds have been tested in squamous cell carcinoma [4, 5] and cisplatin is considered the most effective drug in this neoplasm in both neoadjuvant and salvage treatments. Most neoadjuvant regimens utilize cisplatin in combination with bleomycin and/or vinca alkaloid derivatives; ifosfamide has also been evaluated with promising results in neoadjuvant and salvage regimens [6-9]. More recently, paclitaxel has proven effective in human neoplasms of squamous type and preliminary results of good antitumour activity in cervical cancer have already been reported [10,11]. In this paper we describe our preliminary experience with a neoadjuvant regimen including cisplatin, paclitaxel and ifosfamide for cervical cancer.
From February 1996 to September 1997, 38 consecutive patients with locally advanced squamous cell cervical carcinoma were enrolled in this prospective pilot study. Pretreatment evaluation included history and physical examination, biopsy and evaluation of tumor extent, complete hematology and chemistry profiles, chest X-ray, tumor imaging by means of MRI, and urography. Lymphangiography was performed in 37 subjects. The main characteristics of the patients are summarized in Table 1. Eligibility requirements were a pathology-confirmed diagnosis of squamous-cell cervical carcinoma, age ^ 75 years, performance status (PS) < 2 according to the WHO criteria [12], neutrophil count of 2000/uL, platelet count of 100000/uL, normal liver and renal (24hour creatinine clearance > 6 0 ml/min) function, written informed consent. Chemotherapy was given as follows: paclitaxel on day 1 was given at the dose of 175 mg/m 2 as a three-hour infusion preceded by premedication with methilprednisolone 250 mg i.v. 60 min before and chlorpheniramine 10 mg i.m. and cimetidine 300 mg i.v. 30 min before. On day 2 cisplatin was administered as 60 min infusion at the dose of 50 mg/m 2 (28 patients) or 75 mg/m 2 (10 patients) after prehydration
Downloaded from https://academic.oup.com/annonc/article-abstract/9/9/977/222593 by guest on 09 January 2018
978 Table 2 sponse.
Table 1. Main characteristics of 38 patients. Age Median Range Stage Ib2-IIa a lib Illb IVa Preoperative node assessment Lymphangiography + Lymphangiography Lymphangiography not performed Tumor grade
a
44 27-71 27 2 8 1 7 30 1
1
4
2 3
16 18
> 4 cm diameter.
Clinical response
Correlation between clinical response and pathology re-
Pathology response No surgery
CR
Optimal PR
Suboptimal PR
PD NC PR CR
NC
Total
1 5 21 11
19
Table 3 Main toxicities in 38 patients. Number of patients with toxicity grade 0
1
2
3
4
_ 1 21 1 15 Leukopenia 7 20 11 Neutropenia with 1 1 of normal saline added with 10 mEq/1 of potassium chloride 1 3 12 12 10 and 10 mEq/1 of MgSO4, followed by a post-hydration with 1 1 of 5% Thrombocytopenia 3 35 Renal dextrose solution added with 20 mEq/1 of KC1 and 20 mEq/1 of 6 2 30 Peripheral neuropathy MgSO4 given over two hours. 1 32 Fever 5 After post-hydration, ifosfamide 5 g/m2 and mesna 5 g/m2 were 2 Nausea/vomiting 30 6 infused i.v. over 24 hours in 1 1 of normal saline, followed, on day 3, by 4 34 mesna 3 g/m 2 given i.v. in 1 1 of normal saline over 24 hours. Treatment Allergy 6 32 Mucositis was repeated every three weeks for a total of three cycles. Complete blood counts were performed weekly or more often in instances of toxicity, and blood count, serum creatinine and creatinine clearance were repeated before each cycle. Treatment was delayed by one week in instances of a granulocyte responses,fivehad stable disease and one showed tumour count of 1500/uL and/or platelet count of < 100000/uL; reduction of for an overall clinical response rate of 84% progression, doses was not planned. On the basis of physician judgment, recombi(95% CI: 68.7%-94%). Of 34 patients who underwent nant human G-CSF, while not part of the standard treatment, was administered in instances of persistent grade 4 myelotoxicity. surgery, six (16%) achieved pathology-documented comPelvic examination was performed before each course; tumor plete responses, seven (18%) optimal partial responses response was assessed clinically and by MRI after three courses. with negative nodes, four showed optimal response in Response and toxicity were defined according to WHO criteria [12]. the cervix with positive nodes, 15 macroscopic partial Optimal partial response was defined as a residual disease of less than and two stable disease, for an overall patholresponses, 5 mm of diameter or as in situ carcinoma of the cervix with negative nodes. ogy response rate of 84%. Table 2 shows the correlation Except in cases of progression or of stable disease of primarily between clinical and pathology responses. All of the unresectable tumor, all patients underwent radical hysterectomy and clinical partial responses were confirmed by pathology, pelvic lymphadenectomy three to four weeks after administration of while in five of 11 clinical CR only minimal residual the third cycle. Subsequent treatment consisted of external beam disease was found in the primary tumours. irradiation in patients with macroscopic positive nodes, parametrial involvement, cut-through or sub-optimal response, or, in patients with Grade 3-4 neutropenia occurred in 27 patients (71%), optimal partial response of primary tumor but still positive nodes, of grade 3-4 thrombocytopenia in four (10.5%), and grade two further cycles of chemotherapy. 2 peripheral neuropathy in two (5%, Table 3). No signifiFollow-up procedures with pelvic examination and vaginal cytolcant difference in toxicity was observed between the ogy were planned forl month after the end of the treatment and every patients receiving cisplatin at 50 mg/m2 and those retwo months thereafter. In patients without clinically evaluable disease ceiving 75 mg/m2. MRI or CT scan of pelvis and abdomen were repeated every three months. Five women (13%) required one-week delays in their The duration of partial and complete response was calculated from treatment and two (5%) required two-week delays; in the first documentation of response until documentation of recurboth of the latter the ifosfamide in the last courses was rence/progression. Survival was defined as the interval from entry into reduced by 25%. the study to death or to the date of last follow-up visit.
Results All patients completed the planned three courses of treatment and were evaluable for response and toxicity. Eleven achieved clinical complete responses, 21 partial
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Surgery consisted of class III radical hysterectomy [13] in 30 patients, class IV in two and anterior pelvic exenteration in two; nine women had lymphonodal metastases (five of them with preoperative positive lymphangiography and four with negative lymphangiography), two of them received additional cycles of chemotheraphy, while seven had external beam irradiation. All of the four women who did not have surgery received
979 external beam irradiation, and two of them have died of tumour recurrence. At a median follow-up of 16 months (range 7-22), 36 patients are alive, 29 of them (76%) without evidence of disease; the sites of recurrence, which occurred in patients with partial response only, were pelvis in four patients, groin in one and lung in two.
Discussion Neoadjuvant chemotherapy represents a promising alternative to surgery or radiotherapy as initial treatment of locally advanced cervical cancer because of the possibility, in responding patients, of obtaining wider uninvolved surgical margins. The impact on survival of this relatively new approach is still a matter of discussion, and different treatment strategies may be considered. Some authors have observed that neoadjuvant chemotherapy followed by radiation has yielded neither higher response rates nor longer survival [14], possibly due to the development of selective resistance to radiation after chemotherapy. The option of reducing the amount of tumor before surgical removal, however, remains theoretically and clinically attractive, the main limitation being the inability of the available regimens to achieve adequate tumour shrinkage. Some authors have reported that neoadjuvant chemotherapy followed by surgery may improve survival in locally advanced cervical cancer as compared to radical surgery [15, 16]. We had also previously reported that neoadjuvant platinum-based chemotherapy followed by radical surgery was associated with higher three-year survival rates than radiotherapy alone in locally advanced squamous-cell cervical cancer [17]. An up to 92% overall response rate has been reported for a variety of neoadjuvant regimens [14] with pathologycomplete responses in a limited number of cases. According to some authors, only patients in complete or optimal partial response (minimal foci of microscopic tumor in the removed uterus) can benefit significantly in terms of disease-free survival [2, 18]. In a retrospective analysis of our experience with neoadjuvant chemotherapy for locally advanced cervical carcinoma, achievement of an optimal response (absent or microscopic residual disease at surgery) was an independent favorable prognostic factor for survival for patients treated with cisplatin, bleomycin and vincristine (POB regimen) [19]. Kim et al. also described a 100% survival rate in patients achieving a complete pathology or optimal response (only microscopic foci of residual tumor) irrespective of the stage [2], while Giaroli et al. reported a diseasefree interval of 97.7% in patients with residual tumors smaller than 0.5 cm after neoadjuvant chemotherapy [18]. With the regimen of the present study, we observed a high rate (34%; 95% CI: 19.6%-51.4%) of complete and optimal partial responses, higher than the one we reported with the POB regimen [20]; this result suggests that the combination of cisplatin, paclitaxel and ifosfa-
Downloaded from https://academic.oup.com/annonc/article-abstract/9/9/977/222593 by guest on 09 January 2018
mide represents a very effective neoadjuvant regimen and may achieve greater control of the disease. Paclitaxel is an active drug in Mullerian tumors such as ovarian [21] and endometrial carcinomas [22]. Analogous to cisplatin, which was initially tested in ovarian cancer, then proven effective in endometrial cancer and eventually became the cornerstone of chemotherapy for cervical carcinoma, paclitaxel might find a role in the latter tumour type. Paclitaxel has not yet been tested extensively in cervical carcinoma [10, 11], but it showed an objective response rate of 17% in the only available large study, performed in advanced or recurrent squamous-cell carcinoma. This data supports the inclusion of paclitaxel in combination chemotherapies; the low dose (135 mg/m2) given to the majority of patients and the lack of information on response rate in irradiated areas render it difficult to assess its antitumour activity more precisely. Our report suggests that the use of paclitaxel in combination with cisplatin and ifosfamide is feasible and tolerable and results in a high response rate, particularly in terms of pathology-complete response. To prove the superiority of this combination and to define the impact of paclitaxel on survival, this regimen needs to be prospectively compared to standard multidrug treatments without taxanes. Toxicity appears to be acceptable in view of the facts that all of the patients received the three planned cycles, and that it was possible to complete all needed radiotherapies. Peripheral neuropathy was reported in only 5% of cases, mainly because of the short duration of treatment and of the low dose of cisplatin administered. Severe neutropenia, which occurred in 70% of the patients, was of greater concern; nevertheless, no related complications were reported. A prospective multicenter randomized trial comparing ifosfamide and cisplatin with/without paclitaxel is already ongoing.
References 1. Sardi JE, Di Paola GR, Cachau A et al. A possible new trend in the management of carcinoma of the cervix uteri. Gynecol Oncol 1986; 25: 139-49. 2. Kim DS, Moon H, Kim KTet al. Two-year survival: Preoperative adjuvant chemotherapy in the treatment of cervical cancer stage Ib and II with bulky tumor. Gynecol Oncol 1989; 33: 225-30. 3. Benedetti Panici P, Scambia G, Greggi S et al. Neoadjuvant chemotherapy and radical surgery in locally advanced cervical carcinoma: A pilot study. Obstet Gynecol 1988; 71: 344-8. 4. Thigpen T, Shingleton H, Homesley H et al. Cis dichlorodiamminoplatinum (II) in the treatment of gynecologic malignancies: Phase II trial by the Gynecologic Oncology Group. Cancer Treat Rep 1979; 63: 1549-55. 5. Zanetta G, Torri W, Bocciolone L et al. Factors predicting response to chemotherapy and survival in patients with metastatic or recurrent squamous cell cervical carcinoma. A multivariate analysis. Gynecol Oncol 1995; 58: 58-63. 6. Hanning EV, Dinh TV, Doherty MG. Ifosfamide with Mesna in squamous carcinoma of the cervix. Phase II results in patients with advanced or recurrent disease. Gynecol Oncol 1991; 43: 123-8.
980 7. Buxton EJ, Meanwell CA, Hilton C. Combination bleomycin, ifosfamide and cisplatin chemotherapy in cervical cancer. J Natl Cancer Inst 1989; 81: 359-61. 8. Zanetta G, Leventis C, Lomonico S et al. Bleomycin, ifosfamide and cisplatin chemotherapy in recurrent and persistent cervical cancer. A prospective study. Int J Gynecol Cancer 1995; 5: 56-60. 9. Bolis G, van Zainten-Przybysz I, Scarfone G et al. Determinants of response to a cisplatin-based regimen as neoadjuvant chemotherapy in stage IB-IIB invasive cervical cancer. Gynecol Oncol 1996; 63: 62-5. 10. Thigpen T, Vance RB, Khansur T. The platinum compounds and paclitaxel in the management of carcinomas of the endometrium and uterine cervix. Semin Oncol 1995; 22 (Suppl 12): 67-75. 11. Me Guire 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. 12. Miller AB, Hoogstraten B, Staquet et al. Reporting results of cancer treatment. Cancer 1981; 47: 207-14. 13. Piver MS, Rutledge F, Smith JP. Five classes of extended hysterectomy for women with cervical cancer. Obstet Gynecol 1974; 44: 265-72. 14. Tattersall MHN, Ramirez C, Coppleson H. A randomized trial comparing platinum-based chemotherapy followed by radiotherapy versus radiotherapy alone in patients with locally advanced cervical cancer. Int J Gynecol Cancer 1992; 2: 244-51. 15. Serur E, Mathews RP, Gates J et al. Neoadjuvant chemotherapy in stage IB2 squamous-cell carcinoma of the cervix. Gynecol Oncol 1997; 65: 348-56. 16. 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. 17. Benedetti-Panici P, Landoni F, Greggi S et al. Randomized trial
Downloaded from https://academic.oup.com/annonc/article-abstract/9/9/977/222593 by guest on 09 January 2018
18. 19.
20.
21.
22.
of neoadjuvant chemotherapy (NACT) followed by radical surgery (RS) vs exclusive radiotherapy (RT) in locally advanced squamous cell cervical cancer (LASCCC). An italian multicenter study. Int J Gynecol Cancer 1997; 7 (Suppl 2): 18. Giaroli A, Sananes C, Srdi JE et al. Lymph node metastases in carcinoma of the cervix uteri. Response to neoadjuvant chemotherapy and its impact on survival. Gynecol Oncol 1990; 39: 34-9. Colombo N, Gabriele A, Lissoni A et al. Neoadjuvant chemotherapy in locally advanced uterine cervical cancer: Correlation between pathological response and survival. Proc Am Soc Clin Oncol 1998; 17: 352. 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 Eisenhauer EA, Ten Bokkel-Huinik WW, Swenerton K.D et al. European-Canadian randomized trial of paclitaxel in relapsed ovarian cancer: high-dose versus low-dose and long versus short infusion. J Clin Oncol 1994; 12: 2654-66. Lissoni A, Zanetta G, Losa G et al. Phase II study of paclitaxel as salvage treatment in advanced endometrial cancer. Ann Oncol 1996; 7. 861-3.
Received 31 March 1998; accepted 23 June 1998. Correspondence to:
G. Zanetta, MD Divisione Ostetricia e Ginecologia Ospedale San Gerardo Via Solferino 16 20052, Monza Italy
Original article Neoadjuvant chemotherapy with cisplatin, ifosfamide and paclitaxel for locally advanced squamous-cell cervical cancer G. Zanetta,1 A. Lissoni,1 A. Pellegrino,1 C. Sessa,2 N. Colombo,3 D. Gueli-Alletti4 & C. Mangioni1 1 Department ofObstetrics and Gynecology, San Gerardo Hospital, Monza, University of Milan, Italy; 2 Division of Oncology, Ospedale San Giovanni Bellinzona, Switzerland; 3Division of Gynecology, European Cancer Institute, Milan; ADepartment of Obstetrics and Gynecology, Ospedale Cervello, Palermo, Italy
Summary
Results: All patients are evaluable for response. Eleven achieved clinical complete responses, 21 had partial responses, five had stable disease and one had progression of disease. Of 34 patients who underwent surgery, six (16%) had pathologydocumented complete responses, seven (18%) had partial responses with only microscopic residual disease in the cervix, 19 had sub-optimal partial responses, and two had stable disease, for an overall response rate of 84% (95% confidence intervals (CI): 68.7%-94%). Grade 3-4 neutropenia was recorded for 27 (71%) patients, grade 3-4 thrombocytopenia for four (10.5%), and grade 2 peripheral neuropathy for two (2.5%). At a median follow-up of 16 months (range 7-22), 29 (76%) women are alive without recurrence, seven are alive with persistent/recurrent disease and two have died of their disease. Conclusions: According to pathology examination, this regimen yields a 34% complete and optimal partial response rate with acceptable toxicity, and it should be prospectively compared to other regimens.
Background: Neoadjuvant chemotherapy is increasingly being used for the treatment of bulky and locally-advanced cervical cancer. Cisplatin and ifosfamide are known to be effective in cervical cancer, while paclitaxel is one of the promising new drugs for the treatment of this neoplasm. Objective: To assess the toxic effects and antitumor activity of a multidrug neoadjuvant regimen consisting of cisplatin, ifosfamide, and paclitaxel in bulky and locally advanced cervical cancer. Patients and methods: Thirty-eight patients with pathologyconfirmed squamous-cell cervical cancer (27 IB2-IIA, two IIB, eight IIIB, one IVA) were prospectively enrolled in the study. Their treatment consisted of paclitaxel 175 mg/m2 given over three hours on day 1, cisplatin 50 mg/m2 (75 mg/m2 in 10 patients), ifosfamide 5 g/m2 in a 24-hour continuous infusion and mesna 5 g/m2 in a 24-hour continuous infusion on day 2, and mesna 3 g/m2 in a 24-hour continuous infusion on day 3. The course was repeated every three weeks for three courses and all of the patients, except those with disease progression or who were inoperable, were scheduled for radical hysterectomy Key words: cervical cancer, neoadjuvant chemotherapy, pacliand pelvic lymphadenectomy. taxel
Introduction
Patients and methods
Neoadjuvant chemotherapy for bulky or locally advanced cervical carcinoma has received increasing attention in the past decade [1-3]. Several compounds have been tested in squamous cell carcinoma [4, 5] and cisplatin is considered the most effective drug in this neoplasm in both neoadjuvant and salvage treatments. Most neoadjuvant regimens utilize cisplatin in combination with bleomycin and/or vinca alkaloid derivatives; ifosfamide has also been evaluated with promising results in neoadjuvant and salvage regimens [6-9]. More recently, paclitaxel has proven effective in human neoplasms of squamous type and preliminary results of good antitumour activity in cervical cancer have already been reported [10,11]. In this paper we describe our preliminary experience with a neoadjuvant regimen including cisplatin, paclitaxel and ifosfamide for cervical cancer.
From February 1996 to September 1997, 38 consecutive patients with locally advanced squamous cell cervical carcinoma were enrolled in this prospective pilot study. Pretreatment evaluation included history and physical examination, biopsy and evaluation of tumor extent, complete hematology and chemistry profiles, chest X-ray, tumor imaging by means of MRI, and urography. Lymphangiography was performed in 37 subjects. The main characteristics of the patients are summarized in Table 1. Eligibility requirements were a pathology-confirmed diagnosis of squamous-cell cervical carcinoma, age ^ 75 years, performance status (PS) < 2 according to the WHO criteria [12], neutrophil count of 2000/uL, platelet count of 100000/uL, normal liver and renal (24hour creatinine clearance > 6 0 ml/min) function, written informed consent. Chemotherapy was given as follows: paclitaxel on day 1 was given at the dose of 175 mg/m 2 as a three-hour infusion preceded by premedication with methilprednisolone 250 mg i.v. 60 min before and chlorpheniramine 10 mg i.m. and cimetidine 300 mg i.v. 30 min before. On day 2 cisplatin was administered as 60 min infusion at the dose of 50 mg/m 2 (28 patients) or 75 mg/m 2 (10 patients) after prehydration
Downloaded from https://academic.oup.com/annonc/article-abstract/9/9/977/222593 by guest on 09 January 2018
978 Table 2 sponse.
Table 1. Main characteristics of 38 patients. Age Median Range Stage Ib2-IIa a lib Illb IVa Preoperative node assessment Lymphangiography + Lymphangiography Lymphangiography not performed Tumor grade
a
44 27-71 27 2 8 1 7 30 1
1
4
2 3
16 18
> 4 cm diameter.
Clinical response
Correlation between clinical response and pathology re-
Pathology response No surgery
CR
Optimal PR
Suboptimal PR
PD NC PR CR
NC
Total
1 5 21 11
19
Table 3 Main toxicities in 38 patients. Number of patients with toxicity grade 0
1
2
3
4
_ 1 21 1 15 Leukopenia 7 20 11 Neutropenia with 1 1 of normal saline added with 10 mEq/1 of potassium chloride 1 3 12 12 10 and 10 mEq/1 of MgSO4, followed by a post-hydration with 1 1 of 5% Thrombocytopenia 3 35 Renal dextrose solution added with 20 mEq/1 of KC1 and 20 mEq/1 of 6 2 30 Peripheral neuropathy MgSO4 given over two hours. 1 32 Fever 5 After post-hydration, ifosfamide 5 g/m2 and mesna 5 g/m2 were 2 Nausea/vomiting 30 6 infused i.v. over 24 hours in 1 1 of normal saline, followed, on day 3, by 4 34 mesna 3 g/m 2 given i.v. in 1 1 of normal saline over 24 hours. Treatment Allergy 6 32 Mucositis was repeated every three weeks for a total of three cycles. Complete blood counts were performed weekly or more often in instances of toxicity, and blood count, serum creatinine and creatinine clearance were repeated before each cycle. Treatment was delayed by one week in instances of a granulocyte responses,fivehad stable disease and one showed tumour count of 1500/uL and/or platelet count of < 100000/uL; reduction of for an overall clinical response rate of 84% progression, doses was not planned. On the basis of physician judgment, recombi(95% CI: 68.7%-94%). Of 34 patients who underwent nant human G-CSF, while not part of the standard treatment, was administered in instances of persistent grade 4 myelotoxicity. surgery, six (16%) achieved pathology-documented comPelvic examination was performed before each course; tumor plete responses, seven (18%) optimal partial responses response was assessed clinically and by MRI after three courses. with negative nodes, four showed optimal response in Response and toxicity were defined according to WHO criteria [12]. the cervix with positive nodes, 15 macroscopic partial Optimal partial response was defined as a residual disease of less than and two stable disease, for an overall patholresponses, 5 mm of diameter or as in situ carcinoma of the cervix with negative nodes. ogy response rate of 84%. Table 2 shows the correlation Except in cases of progression or of stable disease of primarily between clinical and pathology responses. All of the unresectable tumor, all patients underwent radical hysterectomy and clinical partial responses were confirmed by pathology, pelvic lymphadenectomy three to four weeks after administration of while in five of 11 clinical CR only minimal residual the third cycle. Subsequent treatment consisted of external beam disease was found in the primary tumours. irradiation in patients with macroscopic positive nodes, parametrial involvement, cut-through or sub-optimal response, or, in patients with Grade 3-4 neutropenia occurred in 27 patients (71%), optimal partial response of primary tumor but still positive nodes, of grade 3-4 thrombocytopenia in four (10.5%), and grade two further cycles of chemotherapy. 2 peripheral neuropathy in two (5%, Table 3). No signifiFollow-up procedures with pelvic examination and vaginal cytolcant difference in toxicity was observed between the ogy were planned forl month after the end of the treatment and every patients receiving cisplatin at 50 mg/m2 and those retwo months thereafter. In patients without clinically evaluable disease ceiving 75 mg/m2. MRI or CT scan of pelvis and abdomen were repeated every three months. Five women (13%) required one-week delays in their The duration of partial and complete response was calculated from treatment and two (5%) required two-week delays; in the first documentation of response until documentation of recurboth of the latter the ifosfamide in the last courses was rence/progression. Survival was defined as the interval from entry into reduced by 25%. the study to death or to the date of last follow-up visit.
Results All patients completed the planned three courses of treatment and were evaluable for response and toxicity. Eleven achieved clinical complete responses, 21 partial
Downloaded from https://academic.oup.com/annonc/article-abstract/9/9/977/222593 by guest on 09 January 2018
Surgery consisted of class III radical hysterectomy [13] in 30 patients, class IV in two and anterior pelvic exenteration in two; nine women had lymphonodal metastases (five of them with preoperative positive lymphangiography and four with negative lymphangiography), two of them received additional cycles of chemotheraphy, while seven had external beam irradiation. All of the four women who did not have surgery received
979 external beam irradiation, and two of them have died of tumour recurrence. At a median follow-up of 16 months (range 7-22), 36 patients are alive, 29 of them (76%) without evidence of disease; the sites of recurrence, which occurred in patients with partial response only, were pelvis in four patients, groin in one and lung in two.
Discussion Neoadjuvant chemotherapy represents a promising alternative to surgery or radiotherapy as initial treatment of locally advanced cervical cancer because of the possibility, in responding patients, of obtaining wider uninvolved surgical margins. The impact on survival of this relatively new approach is still a matter of discussion, and different treatment strategies may be considered. Some authors have observed that neoadjuvant chemotherapy followed by radiation has yielded neither higher response rates nor longer survival [14], possibly due to the development of selective resistance to radiation after chemotherapy. The option of reducing the amount of tumor before surgical removal, however, remains theoretically and clinically attractive, the main limitation being the inability of the available regimens to achieve adequate tumour shrinkage. Some authors have reported that neoadjuvant chemotherapy followed by surgery may improve survival in locally advanced cervical cancer as compared to radical surgery [15, 16]. We had also previously reported that neoadjuvant platinum-based chemotherapy followed by radical surgery was associated with higher three-year survival rates than radiotherapy alone in locally advanced squamous-cell cervical cancer [17]. An up to 92% overall response rate has been reported for a variety of neoadjuvant regimens [14] with pathologycomplete responses in a limited number of cases. According to some authors, only patients in complete or optimal partial response (minimal foci of microscopic tumor in the removed uterus) can benefit significantly in terms of disease-free survival [2, 18]. In a retrospective analysis of our experience with neoadjuvant chemotherapy for locally advanced cervical carcinoma, achievement of an optimal response (absent or microscopic residual disease at surgery) was an independent favorable prognostic factor for survival for patients treated with cisplatin, bleomycin and vincristine (POB regimen) [19]. Kim et al. also described a 100% survival rate in patients achieving a complete pathology or optimal response (only microscopic foci of residual tumor) irrespective of the stage [2], while Giaroli et al. reported a diseasefree interval of 97.7% in patients with residual tumors smaller than 0.5 cm after neoadjuvant chemotherapy [18]. With the regimen of the present study, we observed a high rate (34%; 95% CI: 19.6%-51.4%) of complete and optimal partial responses, higher than the one we reported with the POB regimen [20]; this result suggests that the combination of cisplatin, paclitaxel and ifosfa-
Downloaded from https://academic.oup.com/annonc/article-abstract/9/9/977/222593 by guest on 09 January 2018
mide represents a very effective neoadjuvant regimen and may achieve greater control of the disease. Paclitaxel is an active drug in Mullerian tumors such as ovarian [21] and endometrial carcinomas [22]. Analogous to cisplatin, which was initially tested in ovarian cancer, then proven effective in endometrial cancer and eventually became the cornerstone of chemotherapy for cervical carcinoma, paclitaxel might find a role in the latter tumour type. Paclitaxel has not yet been tested extensively in cervical carcinoma [10, 11], but it showed an objective response rate of 17% in the only available large study, performed in advanced or recurrent squamous-cell carcinoma. This data supports the inclusion of paclitaxel in combination chemotherapies; the low dose (135 mg/m2) given to the majority of patients and the lack of information on response rate in irradiated areas render it difficult to assess its antitumour activity more precisely. Our report suggests that the use of paclitaxel in combination with cisplatin and ifosfamide is feasible and tolerable and results in a high response rate, particularly in terms of pathology-complete response. To prove the superiority of this combination and to define the impact of paclitaxel on survival, this regimen needs to be prospectively compared to standard multidrug treatments without taxanes. Toxicity appears to be acceptable in view of the facts that all of the patients received the three planned cycles, and that it was possible to complete all needed radiotherapies. Peripheral neuropathy was reported in only 5% of cases, mainly because of the short duration of treatment and of the low dose of cisplatin administered. Severe neutropenia, which occurred in 70% of the patients, was of greater concern; nevertheless, no related complications were reported. A prospective multicenter randomized trial comparing ifosfamide and cisplatin with/without paclitaxel is already ongoing.
References 1. Sardi JE, Di Paola GR, Cachau A et al. A possible new trend in the management of carcinoma of the cervix uteri. Gynecol Oncol 1986; 25: 139-49. 2. Kim DS, Moon H, Kim KTet al. Two-year survival: Preoperative adjuvant chemotherapy in the treatment of cervical cancer stage Ib and II with bulky tumor. Gynecol Oncol 1989; 33: 225-30. 3. Benedetti Panici P, Scambia G, Greggi S et al. Neoadjuvant chemotherapy and radical surgery in locally advanced cervical carcinoma: A pilot study. Obstet Gynecol 1988; 71: 344-8. 4. Thigpen T, Shingleton H, Homesley H et al. Cis dichlorodiamminoplatinum (II) in the treatment of gynecologic malignancies: Phase II trial by the Gynecologic Oncology Group. Cancer Treat Rep 1979; 63: 1549-55. 5. Zanetta G, Torri W, Bocciolone L et al. Factors predicting response to chemotherapy and survival in patients with metastatic or recurrent squamous cell cervical carcinoma. A multivariate analysis. Gynecol Oncol 1995; 58: 58-63. 6. Hanning EV, Dinh TV, Doherty MG. Ifosfamide with Mesna in squamous carcinoma of the cervix. Phase II results in patients with advanced or recurrent disease. Gynecol Oncol 1991; 43: 123-8.
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Received 31 March 1998; accepted 23 June 1998. Correspondence to:
G. Zanetta, MD Divisione Ostetricia e Ginecologia Ospedale San Gerardo Via Solferino 16 20052, Monza Italy