Ann Oncol 1998 Zanetta 977 80

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 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 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. Downloaded from http://annonc.oxfordjournals.org/ by guest on November 27, 2013 Introduction 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. Patients and methods 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 all patients underwent radical hysterectomy and clinical partial responses were confirmed by pathology. 5 mm of diameter or as in situ carcinoma of the cervix with negative nodes. followed. 1 32 Fever 5 After post-hydration.v. ogy response rate of 84%. six (16%) achieved pathology-documented comPelvic examination was performed before each course. On the basis of physician judgment. seven (18%) optimal partial responses response was assessed clinically and by MRI after three courses. was administered in instances of persistent grade 4 myelotoxicity. recombi(95% CI: 68. 2 peripheral neuropathy in two (5%. nine women had lymphonodal metastases (five of them with preoperative positive lymphangiography and four with negative lymphangiography). in the first documentation of response until documentation of recurboth of the latter the ifosfamide in the last courses was rence/progression. Eleven achieved clinical complete responses. the study to death or to the date of last follow-up visit.978 Table 1. the cervix with positive nodes. with negative nodes. or. 2013 Results All patients completed the planned three courses of treatment and were evaluable for response and toxicity.org/ by guest on November 27. in patients with Grade 3-4 neutropenia occurred in 27 patients (71%). Survival was defined as the interval from entry into reduced by 25%. Number of patients with toxicity grade 0 1 2 3 4 2 3 a 16 18 > 4 cm diameter. 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. Table 3). reduction of for an overall clinical response rate of 84% progression. class IV in two and anterior pelvic exenteration in two. Treatment was delayed by one week in instances of a granulocyte responses. Main characteristics of 38 patients. Subsequent treatment consisted of external beam disease was found in the primary tumours. serum creatinine and creatinine clearance were repeated before each cycle. 44 27-71 27 2 8 1 7 30 1 4 Correlation between clinical response and pathology re- Clinical response Pathology response No surgery CR Optimal PR Suboptimal PR NC Total PD NC PR CR 19 1 5 21 11 Table 3 Main toxicities in 38 patients.5%). Treatment Allergy 6 32 Mucositis was repeated every three weeks for a total of three cycles. 21 partial Surgery consisted of class III radical hysterectomy [13] in 30 patients. and grade two further cycles of chemotherapy. two of them received additional cycles of chemotheraphy. and blood count. pelvic lymphadenectomy three to four weeks after administration of while in five of 11 clinical CR only minimal residual the third cycle. by 4 34 mesna 3 g/m 2 given i. All of the four women who did not have surgery received . in 1 1 of normal saline over 24 hours. Complete blood counts were performed weekly or more often in instances of toxicity. tumor plete responses.oxfordjournals. parametrial involvement. while not part of the standard treatment. MRI or CT scan of pelvis and abdomen were repeated every three months. for an overall patholresponses. irradiation in patients with macroscopic positive nodes. on day 3.7%-94%). _ 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. Of 34 patients who underwent nant human G-CSF. All of the unresectable tumor. four showed optimal response in Response and toxicity were defined according to WHO criteria [12].fivehad stable disease and one showed tumour count of 1500/uL and/or platelet count of < 100000/uL. 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. 15 macroscopic partial Optimal partial response was defined as a residual disease of less than and two stable disease. Age Median Range Stage Ib2-IIa a lib Illb IVa Preoperative node assessment Lymphangiography + Lymphangiography Lymphangiography not performed Tumor grade 1 Table 2 sponse. while seven had external beam irradiation. In patients without clinically evaluable disease ceiving 75 mg/m2. doses was not planned.v. cut-through or sub-optimal response. surgery. 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. ifosfamide 5 g/m2 and mesna 5 g/m2 were 2 Nausea/vomiting 30 6 infused i. Table 2 shows the correlation Except in cases of progression or of stable disease of primarily between clinical and pathology responses. Downloaded from http://annonc. of grade 3-4 thrombocytopenia in four (10. optimal partial response of primary tumor but still positive nodes. over 24 hours in 1 1 of normal saline. The option of reducing the amount of tumor before surgical removal. 43: 123-8. however. paclitaxel might find a role in the latter tumour type. while Giaroli et al. particularly in terms of pathology-complete response.6%-51. 18]. Benedetti Panici P. mide represents a very effective neoadjuvant regimen and may achieve greater control of the disease. Zanetta G.5 cm after neoadjuvant chemotherapy [18]. Neoadjuvant chemotherapy and radical surgery in locally advanced cervical carcinoma: A pilot study. Phase II results in patients with advanced or recurrent disease. performed in advanced or recurrent squamous-cell carcinoma. . 36 patients are alive. A multivariate analysis.4%) of complete and optimal partial responses. 16]. Hanning EV. which occurred in 70% of the patients. 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]. 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. 63: 1549-55. nevertheless. 58: 58-63. and two of them have died of tumour recurrence. Toxicity appears to be acceptable in view of the facts that all of the patients received the three planned cycles. remains theoretically and clinically attractive. 33: 225-30. Dinh TV. 29 of them (76%) without evidence of disease. but it showed an objective response rate of 17% in the only available large study. then proven effective in endometrial cancer and eventually became the cornerstone of chemotherapy for cervical carcinoma. 2013 References 1. Paclitaxel has not yet been tested extensively in cervical carcinoma [10. According to some authors. In a retrospective analysis of our experience with neoadjuvant chemotherapy for locally advanced cervical carcinoma. groin in one and lung in two. Thigpen T. Obstet Gynecol 1988. The impact on survival of this relatively new approach is still a matter of discussion. Di Paola GR. the main limitation being the inability of the available regimens to achieve adequate tumour shrinkage. Peripheral neuropathy was reported in only 5% of cases. 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Some authors have reported that neoadjuvant chemotherapy followed by surgery may improve survival in locally advanced cervical cancer as compared to radical surgery [15.org/ by guest on November 27. Kim et al. Kim DS. mainly because of the short duration of treatment and of the low dose of cisplatin administered. and different treatment strategies may be considered. Sardi JE. 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]. Ifosfamide with Mesna in squamous carcinoma of the cervix. At a median follow-up of 16 months (range 7-22). Factors predicting response to chemotherapy and survival in patients with metastatic or recurrent squamous cell cervical carcinoma. Severe neutropenia. 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