Efficacy and Toxicity of Neoadjuvant Chemotherapy Followed by Radiochemotherapy in Locally Advanced Cervical Cancer

original studies Efficacy and Toxicity of Neoadjuvant Chemotherapy Followed by Radiochemotherapy in Locally Advanced Cervical Cancer Nemes Adina 1, Nagy Viorica 1, 2, Todor Nicolae 1, Marita Andreea 1, Ordeanu Claudia 1, Rancea Alin 1, 2 1) Oncology Institute Prof.Dr.IonChiricuta Cluj-Napoca; 2) The IuliuHatieganu University of Medicine and Pharmacy Cluj-Napoca Background and aims: This study conducted in the Prof.Dr.IonChiricuta Oncology Institute, Cluj-Napoca (OICN) represents a nonrandomized, feasibility study in which the efficacy and toxicity of neoadjuvant chemotherapy (NACT) was analyzed before radiochemotherapy (RCT) in patients with locally advanced cervical cancer (LACC). Methods:In this study patients with histologically confirmed stage IIB-III cervical cancer treated in OICN between November 2010-September 2012 were included. Patients were administered two or three cycles of NACT two regimens Paclitaxel and Carboplatin (PC) or Topotecan and Cisplatin (TC),then they underwent concurrent RCT with Cisplatin or Carboplatin.External beam radiation therapy (EBRT) was administered at a total dose (TD) of 46Gy when patients were evaluated for surgery and those with favorable parametrial response were optionally operated.remaining patients underwent exclusive RCT up to a TD of 60Gy.Brachitherapy was associated to EBRT TD=10-20Gy. Local response was assessed at the end of NACT,at the end of RCT and for operated patients by the pathological outcome.results:in this study 112 patients with LACCwere included: stage IIB 31,stage IIIA 48 and stage IIIB 33 with a median age at diagnosis of 52 years.histology was mostly squamos cell carcinoma (86%).84 patients out of the 112 patients performed NACT with PC and 28 patients with TC.Tumor response evaluated at the end of NACT revealed a 53% objective response (OR= complete response(cr)+partial response(pr)): 81% OR for PC and 19% for TC (p=0.10). Complete response (CR) at the end of therapy was 29%:22% CR for the 65 patients that underwent exclusive RCT and 40% for the 47 patients that underwent surgery.the pathological CR (pcr) was obtained in 32 (68%) of the 47 patients that were operated. At a median follow-up of 17.4 months 98 patients (88%) presented CR,3 patients (3%) PR and 11 patients (10%) PD.Grade 1-2 hematological toxicity on all medullary lines were the most common hematological toxicity observed to NACT.Grade 3-4 anemia, leucopenia and neutropenia occurred in 6%, 8% and 27% of cases respectively. Conclusion: NACT administered before RCT brings a high response rate with manageable toxicity, but randomized, larger number and long term evaluation trials are necessary in order to confirm these data. Key words: advanced cervical cancer, neoadjuvant chemotherapy, local response Introduction Cevical cancer represents the second most common malignancy in women worldwide and it remains the second most common cause of cancer related death in women in Romania (1). Journal of Radiotheraphy & Medical Oncology September 2014 Vol. 20 No 1: 5-9 Address for correspondence: Adina Nemes Ion Chiricuta Oncology Institute 34-36 Republicii Str 400015 Cluj-Napoca, Romania Email: adina_mojo2003@yahoo.com Concurrent radiochemotherapy (RCT) represents the standard treatment for locally advanced cervical cancer (LACCC). With 5-year overall survival raging from 60% to 65% for stage IIB and from 25% to 50% for stage III, locally advanced cervical cancer is the most frequently diagnosed cervical cancer in Romania (2).Trying to improve the results of RCT as standard treatment in LACC, a potential benefit could be brought by neoadjuvant chemotherapy (NACT) before RCT. In literature there are several trials published regardingnact before surgery, but few trials about NACT before RCT. The advantages of NACT before RCT are tumor size reduction, increasedradiosensitivity, eradication of micrometastases and this represents an important

6 Nemes et al prognostic factor. In recent years NACT before RCT represented an important topic and it has been extensively studied, but as yet no consensus has been established. In this nonrandomized, feasibility study we analyzed the response and toxicity to NACT associated with RCT in patients with locally advanced cervical cancer treated in the Prof.Dr.IonChiricutaOncology Institute Cluj-Napoca (OICN). Material and methods Patients included in this study had histologically confirmed stage IIB-III cervical cancer (FIGO staging modified by MD Anderson Cancer Center) (3)treated in OICN between November 2010-September 2012. Before treatment all patients underwent several investigations as part of the initial workup: hematology and biochemistry profile, chest X-ray, abdominal and pelvic computed tomography (CT). All patients included in this study received NACT two or three cycles, two regimens Paclitaxel 175mg/m 2 and Carboplatin AUC5 (PC) or Topotecan 0.75mg/m 2 and Cisplatin 50mg/m 2 (TC) administered every three weeks. Three weeks after the completion of the last NACT cycle, patients started RCT. The radiosensitizer chemotherapeutic agents administered concurrently with external beam radiation therapy (EBRT) were Cisplatin two regimens (20mg/m 2 5 days every three weeks or 40mg/m 2 weekly) or Carboplatin AUC2. All patients underwent EBRT to a total dose (TD) of 46Gy; at 46Gy patients were evaluated for surgery and those with favorable parametrial response were optionally operated and underwent radical hysterectomy and pelvic lymph node dissection. Patients who did not undergo surgery continued with EBRT up to a TD of 60 Gy. EBRT was associated with brachytherapy TD 10 Gy/2fractions for patients who underwent surgery or 20 Gy/4 fractions for patients who underwent exclusive RCT. Tumor response was evaluated according to the WHO criteria (4) defined as complete response-cr, partial response-pr, stable disease-sd and progressive disease-pd by pelvic examination three weeks after the administration of the last NACT cycle, before RCT and at the end of RCT. For the operated patients the tumor response was confirmed by the pathological outcome. Pathological CR was defined as the absence of tumor cells in the cervix, parametrium, vaginal cuff and pelvic lymph nodes. National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.0 were used for the classification of recorded NACT related toxicities. Results 12 patients with locally advanced cervical cancer were included in this study: stage IIB 31 patients (28%), stage IIIA 48 patients (42%) and stage IIIB 33 patients (30%). Median age at diagnosis was 52 years (22-72 years old); the median tumor size was 4 cm (1-7 cm) and regarding the histology, 86% of tumors were squamos cell carcinomas, 8% adenocarcinomas and 6% were other histologies (adenosquamos carcinoma, clear cell carcinoma,small cell carcinoma) (Table I). Table I. Patients characteristics November 2010-september 2012 112 patients Age (years) min 22 max 72 median 52 FIGO stage IIB 31 (28%) IIIA 48 (42%) IIIB 33 (30%) Tumor size (baseline) min 1 max 7 median 4 Histological type squamos cell 86% carcinomas adenocarcinomas 8% other histologies 6% Follow-up min 3.8months max 32months median 17,4months 75% (84 patients ) out of the 112 patients performed NACT with PC and 25% ( 28 patients) performed NACT with TC. 59 patients (53%) achieved an objective response (OR= CR+PR) after the administration of NACT. Regarding the NACT regimen administered we observed a 81% OR for PC versus 19% for TC, without statistical significance (p=0.10) (Table II). When evaluating the response to NACT in comparison with the number of NACT cycles administered the OR was 56% with the administration of two cycles and 70% with the administration of three cycles of PC. For the TC regimen the OR after the administration of two cycles was 33% versus 40% after the administration of three cycles (Table III). Table II.Response to neoadjuvant chemotherapy (regimen) Therapeutical response at the end of neoadjuvant chemotherapy OR SD Total (CR+PR) Neoadjuvant chemotherapy regimen Paclitaxel + Carboplatin 48 (81%) 36 (68%) 84 Topotecan + Cisplatin 11 (19%) 17 (32%) Total 59 53 112 p=0.10 (NS) 28

Efficacy and toxicity of neoadjuvant chemotherapy followed by radiochemotherapy in locally advanced cervical cancer 7 Table III. Response to neoadjuvant chemotherapy (regimen and number of cycles administered) Therapeutical response at the end of neoadjuvant chemotherapy OR (CR+PR) SD Total Neoadjuvant Paclitaxel + Carboplatin 1 cycle 6 (100%) 6 chemotherapy regimen 2 cycles 25 (56%) 20 (44%) 45 3 cycles 23 (70%) 10 (30%) 33 Topotecan + Cisplatin 1cycle 1 (100%) 1 2 cycles 4 (33%) 8 (67%) 12 3 cycles 6 (40%) 9 (60%) 15 Total 59 (53%) 53 (47%) 112 From the 112 patients 65 performed exclusive RCT with a CR in 14 patients (22%) and 47 patients underwent surgery with a CR in 19 patients (40%), with a CR at the end of treatment of 29% (Table IV). Regarding the concurrent chemotherapy regimen administered, 90% of patients received Cisplatin 20mg/m 2 5 days every three weeks, 8% of patients received Cisplatin 40mg/m 2 weekly and 3% of patients received Carboplatin AUC2. Out of the 101 patients receiving Cisplatin 20mg/m 2 5 days every three weeks, 25 patients received 1 cycle, 69 patients received 2 cycles and 7 patients received 3 cycles. Table IV. Response to concurrent radio-chemotherapy Clinical response at the end of RCT CR non CR Total Surgery- 14 (22%) 51 (78%) 65 Surgery+ 19 (40%) 28 (60%) 47 Total 33 (29%) 79 (71%) 112 For the 47 patients that underwent surgery there was a 68% (32 patients) pcr observed. The pcr observed with the administration of 3 cycles of NACT for the operated patients was of 79% CR for the PC regimen and 56% CR for the TC regimen (Table V).When correlating the clinical and pathological CR for the operated patients an accuracy of 68% was obtained: clinically a 40% CR was observed (at the end of RCT) and histopathologically a 68% CR was observed (surgery was performed four to six weeks after the end of RCT). Table V. Correlation between pcr and NACT Histopathology Total pcr non pcr Paclitaxel + 1-2 cycles 11 (69%) 5 (31%) 16 Carboplatin 3 cycles 15(79%) 4 (21%) 19 Topotecan + 1-2 cycles 1 (33%) 2 (67%) 3 Cisplatin 3 cycles 5(56%) 4(44%) 9 Total 32 (68%) 15 (32%) 47 At a median follow-up of 17.4 months 98 patients (88%) presented CR, 3 patients (3%) PR and 11 patients (10%) PD. A strong correlation with the stage of the disease (stage IIB, IIIA and IIIB) was observed regarding the response to treatment 97% vs. 85% vs. 82% CR and 3% vs. 8% vs. 18% PD, respectively. Hematological toxicity to NACT was mild or moderate, most common toxicities were grade 1-2 on all medullary lines. Grade 3-4 anemia, leucopenia and neutropenia was observed in 6%, 8% and 27% of cases respectively, with a more severe toxicity as the administration of multiple cycles of NACT. There was 2% grade 3-4 anemia after the administration of one cycle of NACT and 4% after the administration of three cycles.grade 3-4 leucopenia was observed in 2% of cases after the administration of two cycles of NACT and in 6% of cases after the administration of three cycles of NACT. The most common grade 3-4 hematologic toxicity to NACT observed was neutropenia; it was observed in 4% of cases after the administration of one cycle of NACT, 8% of cases after the administration of two cycles of NACT and 15% of cases after the administration of three cyclesof NACT. When evaluating the influence of NACT on the possibility of administrating all required cycles of concomitant chemotherapy (CCT), we observed that 25 patients received only one cycle of concurrent Cisplatin. 10 patients out of the 25 patients presented grade 3-4 hematologic toxicity to NACT and 10 patients presented grade 3-4 hematologic toxicity to CCT. Only 3 patients out of the 25 patients presented grade 3-4 hematologic toxicity both to NACT and CCT.Regarding grade 3-4 hematologic toxicity to CCT in these patients, the most common toxicities recorded were leucopenia and neutropenia (Table VI). Discussion In recent years NACT before RCT represented an important topic as it may facilitate local therapy by tumor size reduction, increaseradiosensitivity and reduce the risk of relapse by the eradication of micrometastases. Eventhough there are many published trials with NACT before surgery,

8 Nemes et al Table VI. Hematological toxicity associated with NACT Hb Pl WBC N grade 1-2 grade 3-4 grade 1-2 grade 3-4 grade 1-2 grade 3-4 grade1-2 grade 3-4 after C1 25% 2% 9% - 7% - 14% 4% after C2 40% - 10% - 13% 2% 22% 8% after C3 44% 4% 17% - 27% 6% 25% 15% and recently data from several trials of NACT before RCT became available, no NACT regimen emerged. All NACT regimes are platinum based. The administration of triple regimes such as cisplatin, vincristine and bleomycin (VBP) or paclitaxel, cisplatin and ifosfamide (TIP) determined an OR raging from 84% up to 87.7% (5,6,7,8). Other regimens using irinotecan, mitomycin-c, etoposid or gemcitabine determined an 69.7%-95% OR (9,10,11). OR rates of up to 95% were obtained with the administration of paclitaxel combined with either cisplatin or carboplatin (12,13,14). Park et al reported a 39.5% CR, with a 11.6% pcr and 51.2% PR after the administration of three courses of paclitaxel and cisplatin in patients with stage IB2-IIB cervical cancer (13). In a phase II prospective study of topotecan and cisplatin as NACT in locally advanced cervical cancer (stage IB2-IIIB) Manci et al showed a 15.8% pcr and 73.7% ppr after the administration of three consecutive cycles of NACT (15). Recently published studies of NACT in LACC using dosedense paclitaxel and carboplatin administered weekly for six cycles reported an OR between 67.8%-70% (16,17). In our study we obtained a 53% OR to NACT: 81% OR for the PC regimen and 19% OR for the TC regimen. PC was found to be superior to TC in terms of OR with a 62% difference, but without statistical significance(p=0.10). The pcr observed in the 47 patients that underwent surgery was 68%. The superiority of the PC regimen was also revealed by the correlation between pcr and the administration of 3 cycles of NACT and the same RCT schedule: 79% pcr after the administration of three cycles of PC and a 56% pcr after the administration of three TC cycles, but without statistical significance (p=0.41). The number of NACT cycles administered proved to be important for the response to NACT. For the PC regimen the administration of three cycles proved to bring an improvement in terms of OR (56% after two cycles vs. 70% after three cycles ).For the TC regimen the OR was higher with the administration of three cycles than two cycles (40% vs. 33%). The CR to RCT in our study was obtained in 29% of the 65 patients that underwent RCT. ThepCR observed in the 47 patients that underwent surgery was 68% (32 patients). In a pilot study of NACT with weekly paclitaxel and carboplatin followed by chemoradiation in LACC, Singh et al reported a CR in 23 out of the 24 patients that underwent RCT, but this was a small study performed on only 28 patients (14). In a larger study performed on 46 patients McCormack et al showed a 85% OR to RCT in patients with LACC that received dose-dense NACT with PC (15). Hematologic toxicity during NACT and CCT represents an important issue, as it can influence the ability of delivering the standard treatment to patients with LACC. 11% of patients were reported to have developed grade 3-4 hematologic toxicity during NACT and 41% of patients were reported to have developed grade 3-4 hematologic toxicity during RCT in McCormack s study (17). The most common hematologic toxicity both to NACT and CCT reported is neutropenia. Sight et al reported a grade 3-4 neutropenia in 28.5% of patients during NACT and in 29% of patients during RCT (16). In our study grade 3-4 hematologic toxicity to NACT was recorded in 6% of cases anemia, 8% of cases leucopenia and 27% of cases neutropenia. The most common hematologic toxicity recorded was neutropenia, being recorded even after the administration of one cycle of NACT. NACT did not seem to influence the administration of the required number of CCT cycles as only 3 patients out of the 25 patients that received only one cycle of concurrent Cisplatin presented grade 3-4 hematologic toxicity both to NACT and CCT. Conclusions High response rates can be achieved with NACT in locally advanced cervical cancer with manageable toxicity. In our study the paclitaxel and carboplatin regimen proved to be superior to topotecan and cisplatin in terms of overall response rates. The administration of three cycles of paclitaxel and carboplatin seemed to bring a benefit in comparison with two cycles regarding tumor response. Given the various NACT regimens administered in several studies, heterogeneity of stages in these studies and the small number of patients included, randomized, larger number and long term evaluation trials are necessary in order to confirm these data. References 1. World Health Organization Report: Comprehensive Cervical Cancer Control: a Guide to Essential Practice. World Health Organization Web site 2006. Available at www.who.int/reproductive health/ publications/cervical_cancer_gep/index.htm 2. Quinn MA, Benedet JL, Odicino F, et al. Carcinoma of the cervix uteri. FIGO 6th Annual Report on the Results of Treatment

Efficacy and toxicity of neoadjuvant chemotherapy followed by radiochemotherapy in locally advanced cervical cancer 9 in Gynecological Cancer. Int J GynecolObstet 2006;95(Suppl 1):S43-S103 3. Eifel PJ. Problems with the clinical staging of carcinoma of the cervix. Semin Oncol 2004; 4(1):1 4. WHO Handbook for reporting results of cancer treatment. World Health Organization Offset Publication no.48, Geneva, 1979 5. Chang TC, Lai CH, Hong JH, et al. Randomized trial of neoadjuvantcisplatin, vincristine, bleomycin, and radical hysterectomy versus radiation therapy for bulky stage IB and IIAcervical cancer. J Clin Oncol 2000;18:1740-7. 6. Chang HC, Lai CH, Chou PC, et al. Neoadjuvant chemotherapy with cisplatin, vincristine, and bleomycin and radical surgery in early-stage bulky cervical carcinoma. Cancer Chemother Pharmacol 1992;30:281-5 7. Buda A, Fossati R, Colombo N, et al. Randomized trial of neoadjuvant chemotherapy comparing paclitaxel, ifosfamide, and cisplatin with ifosfamide and cisplatin followed by radical surgery in patients with locally advanced squamous cell cervical carcinoma: the SNAP01 (Studio Neo-AdjuvantePortio) Italian Collaborative Study. J Clin Oncol 2005;23:4137-45. 8. Zanetta G, Lissoni A, Pellegrino A, et al. Neoadjuvant chemotherapy with cisplatin,ifosfamide and paclitaxel for locally advancedsquamous cell-cervicalcancer. Ann Oncol 1998;9:977-80 9. Kokawa K, Nishimura R, Fujii T, Umesaki N. Neoadjuvant chemotherapy with irinotecan and mitomycin-c for locally advanced squamous cell carcinoma of the uterine cervix. Anticancer Res 2007;27:2721-7. 10. Bae JH, Lee SJ, Lee A, et al. Neoadjuvantcisplatin and etoposide followed by radical hysterectomy for stage IB-2B cervical cancer. GynecolOncol 2008;111:444-8. 11. Duenas-Gonzalez A, Lopez-Graniel C, Gonzalez-Enciso A, et al.concomitantchemoradiation versus neoadjuvant chemotherapy in locally advanced cervical carcinoma: results from two consecutive phase II studies. Ann Oncol 2002;13:1212-19. 12. Duenas-Gonzalez A, Lopez-Graniel C, Gonzalez-Enciso A, et al. A Phase II study of multimodality treatment for locally advanced cervical cancer: neodjuvant carboplatin and paclitaxel followed by radical hysterectomy and adjuvant cisplatinchemoradiation. Ann Oncol 2003;14:1278-84. 13. Park DC, Kim JH, Lew YO, et al. Phase II trial of neoadjuvant paclitaxel and cisplatin in uterine cervical cancer. GynecolOncol 2004;92:59-63. 14. Cho YH, Kim DY, Kim JH, el al. Comparative study of neoadjuvant chemotherapy before radical hysterectomy and radical surgery alone in stage IB2-IIA bulky cervical cancer. J Gynecol Oncol 2009;20: 22-27. 15. Manci N, Marchetti C, Di Tucci C, et al. A prospective phase II study of topotecan (Hycamtin R) and cisplatin as neoadjuvant chemotherapy in locally advanced cervical cancer. Gynecol Oncol 2011;122:285-290. 16. Singh RB, Chander S, Mohanti BK, et al. Neoadjuvant chemotherapy with weekly paclitaxel and carboplatin followed by chemoradiation in locally advanced cervical carcinoma: a pilot study. Gynecol Oncol 2013;129:124-8. 17. McCormack M, Kadalayil L, Hackshaw A, et al. A phase II study of weekly neoadjuvant chemotherapy followed by radical chemoradiation for locally advanced cervical cancer. Br J Cancer 2013;108:2464-2469.