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© 2002 American Society for Clinical Oncology
Neoadjuvant Chemotherapy Followed by Surgery in Locally Advanced Cervical CarcinomaInstituto Nacional de Cancerología, Instituto de Investigaciones Biomedicas, Universidad Nacional Autonoma de Mexico, Mexico City, Mexico To the Editor:The results of the phase III study comparing neoadjuvant chemotherapy followed by surgery versus radiation alone reported by Benedetti-Panici et al,1 in the January 1, 2002, issue of the Journal of Clinical Oncology, are a proof of principle that the scalpel is able to overcome the cross-resistance between chemotherapy and radiation, the basic principle being that residual disease after upfront chemotherapy is more adequately treated by removing it instead of giving sequential radiation. It is noteworthy that the results of most of the randomized studies of neoadjuvant chemotherapy followed by radiation have been negative,2 as opposed to the results achieved when surgery is used instead of radiation.3,4 Unfortunately, the results of the Benedetti-Panici study were published after the superiority of concomitant chemoradiation as compared with radiation alone had already been shown.5 Thus, the control arm in this phase III study is clearly not the proper comparison. Moreover, this study raises some concerns, among them being the use of different schedules of chemotherapy at different dose-intensities as well as the use of drugs that could now be considered as first-generation drugs, which are not the most active against cervical carcinoma. These facts are reflected in the low percentage of pathologic complete responses they report, as well as in the equal rate of systemic failures in both arms. Also of concern in this study were the high number of patients who did not complete the planned treatment in both arms and the dose of radiation to point A (median, 71 Gy) in the control arm, which is lower than that considered optimal (85 to 90 Gy). Nevertheless, even though we believe that the treatment was not optimal in either arm, the difference in survival was still significant. Despite all of these issues, this study clearly supports that suggestion that surgery is the best therapeutic modality to consolidate the response to neoadjuvant chemotherapy in locally advanced cervical carcinoma and it should be further explored. Specifically, phase III trials should now be performed to compare neoadjuvant chemotherapy followed by surgery against the new standard of treatment, concurrent chemoradiation in locally advanced cervical carcinoma. We have obtained results that support the neoadjuvant chemotherapy/surgery approach. From February 1999 to July 1999, we performed a phase II study in 41 patients using three 21-day courses of neoadjuvant gemcitabine and cisplatin at 1,000 mg/m2 on days 1 and 8 and 100 mg/m2 on day1, respectively, followed by surgery, or concomitant chemoradiation for the patients who remained nonoperable after induction chemotherapy.6 The results of this study are compared with the results from a similar population of 41 patients treated from August 1999 to December 1999 with the standard concurrent chemoradiation using 6-week cisplatin courses at 40 mg/m2 during external-beam radiation as well as with those from another comparable group of 41 patients treated with pelvic radiation alone from September 1998 to December 1998. The main clinicopathologic characteristics of patients in the three respective arms were as follows: mean age, 48, 44, and 49 years; squamous histology, 92%, 90%, and 87%; International Federation of Gynecology and Obstetrics (FIGO) stage IB2/IIA, 15%, 15%, and 13%; FIGO stage IIB, 49%, 41%, and 51%; FIGO stage IIIB, 36%, 44%, and 36%; and mean hemoglobin pretreatment level, 12.7, 11.9, and 12.9 g/dL. There were no statistically significant differences among the three arms for any of these parameters. Figure 1 shows the intent-to-treat analysis of survival at a median follow-up of 29 months (range, 2 to 30 months), 25 months (range, 3 to 30 months), and 30 months (range, 1 to 35 months). The survival probability for the neoadjuvant arm is 60% versus 65% for concomitant chemoradiation, which is not statistically significant. On the other hand, there was a trend for a better survival probability for both arms (neoadjuvant, P = .012; chemoradiation, P = .07) as compared with radiation alone.
Several issues should be addressed in order to optimize the results of the neoadjuvant chemotherapy/surgery approach, such as defining the role of adjuvant radiation therapy in operable cases and demonstrating that adding cisplatin to radiation in the adjuvant setting overcomes the cross-resistance between chemotherapy and radiation, as we suggest.7 In addition, the best chemotherapy combination for use as neoadjuvant treatment should be defined, and the value of the maximum-effort surgery for patients with a suboptimal response to induction treatment should be demonstrated. All these data would suggest that using a highly active neoadjuvant program coupled with aggressive surgery for patients with suboptimal responses to neoadjuvant therapy and postoperative chemoradiation could eventually yield better results than the new standard treatment. REFERENCES
1.
Benedetti-Panici P, Greggi S, Colombo A, et al: Neoadjuvant chemotherapy and radical surgery versus exclusive radiotherapy in locally advanced squamous cell cervical cancer: Results from the Italian Multicenter Randomized Study. J Clin Oncol 20: 179-188, 2002 2. Tierney JF, Stewart LA, Parmar MK: Can the published data tell us about the effectiveness of neoadjuvant chemotherapy for locally advanced cancer of the uterine cervix? Eur J Cancer 35: 406-409, 1999[CrossRef][Medline] 3. Sardi J, Sananes C, Giaroli A, et al: Neoadjuvant chemotherapy in cervical carcinoma stage IIB: A randomized controlled trial. Int J Gynecol Cancer 8: 441-450, 1998 4. Sardi J, Giaroli A, Sananes C, et al: Randomized trial with neoadjuvant chemotherapy in stage IIIB squamous carcinoma of the cervix uteri: An unexpected therapeutic management. Int J Gynecol Cancer 6: 85-93, 1996 5. Green JA, Kirwan JM, Tierney JF, et al: Survival and recurrence after concomitant chemotherapy and radiotherapy for cancer of the uterine cervix: A systematic review and meta-analysis. Lancet 358: 781-786, 2001[CrossRef][Medline]
6.
Duenas-Gonzalez A, Lopez-Graniel C, Gonzalez A, et al: A phase II study of gemcitabine and cisplatin combination as induction chemotherapy for untreated locally advanced cervical carcinoma. Ann Oncol 12: 541-547, 2001 7. Dueñas-Gonzalez A, Mota A, Lopez-Graniel C, et al: Feasibility of chemoradiation after induction chemotherapy for locally advanced cervical carcinoma. Arch Med Res 33: 201-202, 2002[CrossRef][Medline]
ResponseUniversity of Rome "Campus Bio Medico", Rome, Italy In Reply:The Italian multicenter randomized trial was designed in the late 1980s, when neoadjuvant chemotherapy (NACT) followed by radical surgery (RS) emerged as a valid alternative to standard therapy in the treatment of locally advanced cervical cancer. In fact, several pilot studies had reported encouraging results in terms of response and survival.1-6 Only recently have other strategies involving integrated therapies, particularly with regard to concomitant chemoradiotherapy, been investigated.7-9 On the basis of the promising results of these studies, a European prospective randomized study comparing NACT followed by RS with concomitant chemoradiation has been designed. With regard to the chemotherapy regimen, given our previous experience and data from several phase II trials,1-6,10-12 cisplatin-based NACT was used in our study.13 These data had clearly indicated cisplatin as the leading agent in the treatment of advanced cervical cancer. Moreover, in an excellent review, Vermorken14 noted that cisplatin combinations were superior to cisplatin alone (approximately 40% v 25%) with no evidence for a steep dose-response relationship. Only in the last years have preliminary results of phase II studies on the use of combinations including new drugs (paclitaxel, irinotecan, and so on) been reported.15-16 In particular, cisplatin/paclitaxel–containing regimens seem to be able to induce higher rates of pathologic "optimal" (complete + microscopic partial) response, with a likely impact on survival. Unexpectedly, our study, using a cisplatin-based NACT regimen, showed similar rates of distant relapse in both arms. Therefore, it could be speculated that the incorporation of paclitaxel (or of another active "second-generation" drug) into a cisplatin NACT regimen may decrease the incidence of systemic failures after the chemotherapy-surgery sequence. However, the lack of complete sterilization of distant micrometastases may be not only drug dependent but also related to the duration of NACT. The number of different centers (n = 14) participating in our study could have negatively affected the treatment. Nevertheless, in a multicenter setting, the 75% rate of treatment compliance is usually considered an acceptable rate. As better underlined in our article’s Discussion,1 the 70-Gy total dose at point A delivered in 62 days seems to be lower than that considered optimal radiotherapy in advanced cervical cancer. Nevertheless, based on the pattern of the radiotherapy centers participating in the trial, our opinion is that the administered doses were those usually given in Italy and in other European centers, at least during the study period. Our study is one of the few phase III trials to compare NACT followed by RS with radiotherapy alone, and it demonstrated a significant improvement of both overall and progression-free survival for the experimental arm, although significant only for the stages IB2 to IIB. It is now consequential to compare the chemosurgical approach with that based on the concomitant use of chemotherapy and radiation. Therefore, data reported by Duenas-Gonzales et al, although generated from a nonrandomized, partly retrospective study, are of interest. Indeed, several questions concerning the chemosurgical as well as chemoradiation approaches are still open. First, the treatment of patients with tumors not responsive to chemotherapy (and/or radiation) remains an unsolved problem and calls for alternative strategies. Second, if the role of adjuvant surgery after chemoradiation seems to be very limited, adjuvant (chemo)radiotherapy may be of value in selected patient subsets. Finally, the possible additional benefit of paclitaxel in both the NACT and chemoradiation setting should be ascertained. REFERENCES 1. Kim DS, Moon H, Kim KT, et al: Two-year survival: Pre-operative adjuvant chemotherapy in the treatment of cervical cancer stages IB and II with bulky tumor. Gynecol Oncol 33: 225-230, 1989[CrossRef][Medline] 2. Sardi J, Sananes C, Giaroli A, et al: Neoadjuvant chemotherapy in locally advanced carcinoma of the cervix. Gynecol Oncol 38: 486-493, 1990[CrossRef][Medline] 3. Eddy GL, Manetta A, Alvarez RD, et al: Neoadjuvant chemotherapy with vincristine and cisplatin followed by radical hysterectomy and pelvic lymphadenectomy for FIGO stage IB bulky cervical cancer: A Gynecologic Oncology Group pilot study. Gynecol Oncol 57: 412-416, 1995[CrossRef][Medline] 4. Namkoong SE, Park JS, Kim JW, et al: Comparative study of the patients with locally advanced stages I and II cervical cancer treated by radical surgery with and without preoperative adjuvant chemotherapy. Gynecol Oncol 59: 136-142, 1995[CrossRef][Medline] 5. Beneditti Panici P, Greggi S, Scambia G, et al: Long-term survival following neoadjuvant chemotherapy and radical surgery in locally advanced cervical cancer. Eur J Cancer 3: 341-346, 1998 6. Sananes C, Giaroli C, Soderini A, et al: Neoadjuvant chemotherapy followed by radical hysterectomy and preoperative adjuvant chemotherapy in the treatment of the cervix uteri: Long-term follow-up of a pilot study. Eur J Gynecol ncol 19: 368-373, 1998
7.
Morris M, Eifel PJ, Lu J, et al: Pelvic radiation with concurrent chemotherapy compared with pelvic and para-aortic radiation for high-risk cervical cancer. N Engl J Med 340: 1137-1143, 1999
8.
Rose PG, Bundy BN, Watkins EB, et al: Concurrent cisplatin-based radiotherapy and chemotherapy for locally advanced cervical cancer. N Engl J Med 340: 1144-1153, 1999
9.
Keys H, Bundy BN, Stehman FB, et al: Cisplatin, radiation, and adjuvant hysterectomy compared with radiation and adjuvant hysterectomy for bulky stage IB cervical carcinoma. N Engl J Med 340: 1154-1161, 1999 10. Benedetti Panici P, Greggi S, Scambia G, et al: Neoadjuvant chemotherapy and radical surgery in locally advanced cervical cancer: A pilot study. Obstet Gynecol 713: 341-348, 1988 11. Benedetti Panici P, Greggi S, Scambia G, et al: High-dose cisplatin and bleomycin neoadjuvant chemotherapy plus radical surgery in locally advanced cervical cancer: A preliminary report. Gynecol Oncol 41: 212-216, 1991[CrossRef][Medline] 12. Benedetti Pancic P, Greggi S, Baiocchi G, et al: Neoadjuvant chemotherapy and radical surgery in locally advanced cervical cancer. Cancer 67: 372-379, 1991[CrossRef][Medline]
13.
Benedette-Panici P, Greggi S, Colombo A, et al: Neoadjuvant chemotherapy and radical surgery versus exclusive radiotherapy in locally advanced squamous cell cervical cancer: Results from the Italian Multicenter Randomized Study. J Clin Oncol 20: 179-188, 2002 14. Vermorken JB: The role of chemotherapy in squamous cell carcinoma of the uterine cervix: A review. Int J Gynecol Cancer 3: 129-142, 1993[CrossRef][Medline]
15.
Zanetta G, Lissoni A, Pellegrino A, et al: Neoadjuvant chemotherapy with cisplatin, ifosfamide and paclitaxel for locally advanced squamous-cell cervical. Ann Oncol 9: 977-980, 1998 16. Sugiyama T, Nishida T, Kumagai S, et al: Combination therapy with irinotecan and cisplatin as neoadjuvant chemotherapy in locally advanced cervical cancer. Br J Cancer 81: 95-98, 1999[CrossRef][Medline]
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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