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High-dose cisplatin and bleomycin neoadjuvant chemotherapy plus radical surgery in locally advanced cervical carcinoma: A preliminary report
GYNECOLOGIC
ONCOLOGY
41, 212-216 (1991)
High-Dose Cisplatin and Bleomycin Neoadjuvant Chemotherapy Plus Radical Surgery in Locally Advanced Cervical Carcinoma: A Preliminary Report PIERLUIGI BENEDETTI PANICI, M.D., STEFANO GREGGI, M.D., PH.D., GIOVANNI SCAMBIA, M.D., GUGLIELMO RAGUSA, M.D., GABRIELA BAIOCCHI, M.D., FRANCESCO BATTAGLIA, M.D., FERDINAND~ CORONETTA, PH.D., AND SALVATORE MANCUSO, M.D.’ Department of Gynecology and Obstetrics, Universitd Cattolica de1 S. &ore,
8, largo Agostino Gemelli, 00168 Rome, Italy
Received October 10, 1990
One courseof chemotherapycontainingcisplatinand bleomycin asa neoadjuvanttreatment wasgiven to 26 consecutivepatients with previously untreated stageIB (bulky disease)-111 cervical carcinomaand followed by radical surgery. After chemotherapy responses weredetectedin 23 patients(5 completeand 18partial; overall, 88%) and permitted radical surgery in 21 cases(81%). Surgery consistedof type III-IV radical hysterectomy plus systematic para-aortic and pelvic lymphadenectomy. At histologic examination, completeresponses werefound in 5 (19%)and partial responses in 16 (62%) cases.The averagenumber of lymph nodesremoved was 61 (range, 38-118). A lower than expected incidenceof lymph node metastases was detected(2/21, 9.5%). The chemotherapy-inducedtoxicity was mainly representedby nauseaand vomiting. Chemotherapydid not seemto complicate surgery in these circumstances,even though moderate-degree postoperativecomplicationsoccurred in 48% of cases.Eighteen monthsmedianfollow-up time (range, 11-23) from hystological diagnosishas beenreachedin the operatedpatients, and no recurrenceshave beendetectedso far. o IWI Academic preps, IN.
INTRODUCTION Neoadjuvant chemotherapy has been recently investigated as a new therapeutic approach to locally advanced cervical cancer because of the disappointing results with conventional treatments, and data from different studies suggest that cervical cancer is in fact a chemosensitive tumor [l-5]. Our previous experience with neoadjuvant chemotherapy (NACT) consisted of a pilot study with three cycles of cisplatin (P), bleomycin (B), and methotrexate (M) followed by radical surgery in 75 patients with FIG0 stages IB-IIA (tumor volume >4 cm), IIB, ’ To whom correspondence and reprint requests should be addressed.
and III. Three-year disease-free survivals (DFS) of 89, 73, and 42% were observed in stages IB-IIA, IIB, and III, respectively [6,7]. On the basis of the reported survival rates after exclusive radiotherapy from our and other institutions [8-121, these data suggest improved therapeutic results with the new combined treatment and call for randomized trials comparing this new approach with conventional radiotherapy. Patient accrual in our previous study on PBM NACT was stopped in October 1988 and, until October 1989, the now ongoing randomized trial could not be started because of the need for data reviewing and protocol drafting. This left room for us to conduct a further study based on the following considerations: (1) Given the results from phase II-III trials on recurrent/advanced disease, cisplatin can be considered the most active drug in the treatment of cervical cancer [13,14]. (2) Experimental and clinical studies in solid tumors have demonstrated a steep dose-response relationship with cisplatin [15-171. (3) The escalation of cisplatin dosage has been made possible through a hypertonic vehicle of drug administration and intensive hydration schedules or glutatione addition, overcoming the doselimiting nephrotoxicity [18-201. (4) The onset of peripheral neuropathy, recognized as the major toxic effect induced by high-dose cisplatin, usually has been reported after a total dose of 400 mg/m2 [21]. (5) In our previous experience with PBM NACT, over 90% of responses were registered after the first two cycles, including all 10 complete responses confirmed by hystologic evaluation of surgical specimens. (6) One of the possible disadvantages of the regimen previously employed was the approximately 2-month period of time needed before a definitive treatment option could be undertaken. Keeping all the above
212 OO!W-8258/91 $1.50 Copyright 0 1991 All
rights
by Academic Press, of reproduction in any form
Inc. reserved.
NEOADJUVANT
in mind, we conducted a new pilot study on one cycle of high-dose (200 mg/m’) cisplatin and bleomycin NACT followed by radical surgery, trying to explore the effectiveness of a briefer, more intensive neoadjuvant treatment in locally advanced cervical carcinoma. PATIENTS AND METHODS
From October 1988 through October 1989, 26 consecutive patients with previously untreated stage IB-III cervical carcinoma were enrolled. The eligibility and exclusion criteria were those adopted in our previous study [6]. After clinical staging (FIGO) [22], NACT was given according to the following schedule: cisplatin, 40 mg/m*, for five days in 3% hypertonic saline (100 mEq NaCl/200 ml normal saline in a 2-hr infusion) with 6 liters normal saline/plus 120 mEq KC1 and 10 mEq CaMgCl/day started 12 hr before the first dose of cisplatin and continued until 12 hr after the last dose on Day 5; iv mannitol k furosemide was routinely used daily for promoting diuresis; and bleomycin, 15 mg iv bolus, on Days 1,2,8,9. Alizapride was routinely employed for antiemesis. Electrocardiogram; pulmonary, renal, and hepatic function tests; complete blood count; audiometry; and neurologic examination were performed to monitor the induced toxicity before and after 28 days from the start of chemotherapy. The World Health Organization (WHO) toxicity evaluation criteria were adopted [23]. Fifteen-twenty days from the end of chemotherapy (Day 9), patients were submitted to a clinical evaluation of response including the following procedures: cervical cytology, colposcopy; cervical and vaginal biopsy; transabdominal and transrectal pelvic ultrasonography; and gynecologic examination under general anesthesia. The WHO response evaluation criteria were adopted [23]. Patients were eligible for surgical treatment only if a tumor volume under 4 cm had been achieved and if vaginal and parametrial disease were judged radically resectable. Operative therapy consisted of radical hysterectomy (type III-IV) [24] plus systematic para-aortic and pelvic lymphadenectomy. Those patients still considered not amenable for radical surgery were submitted to conventional radiotherapy. After histopathological evaluation of surgical specimens, patients with complete response or without lymph node (N) metastases or involvement of surgical resection margins (SRM) received no further treatment. Patients with SRM imvolvement and/or positive N were scheduled to receive external or interstitial radiotherapy and/or two further cycles of PB chemotherapy (100 mg/m’ cisplatin, Day 1; 15 mg bleomycin, Days 1,9; q28 days). Follow-up procedures consisting of general and gynecologic examinations, colposcopy, and cervical cytology were performed 1 month from the end
213
CHEMOTHERAPY
TABLE 1 Patient Characteristics Median age, 53 (range, 25-64) Patients entered Clinically evaluable Pathologically evaluable
26( 100%) 26( 100%) 23 (88%)
FIG0 stages IB-IIA IIB III
6 (23%) 11 (42%) 9 (35%)
Histotype Squamous cell carcinoma Adenocarcinoma
21 (81%) 5 (19%)
Grade of differentiation Good Moderately good Poor Median follow-up, 18 months (range, 11-23)
3 (12%) 9 (35%) 14 (53%)
of the planned treatment and every 3 months thereafter. Furthermore, pelvic ultrasonography, intravenous pyelography, and chest X ray were performed at 1, 3, and 6 months, within 12 months, and every 6 months from the end of treatment, respectively. Table 1 summarizes the characteristics of the patients. In the report the endpoints selected for analysis were clinical response and operability rate, pathological response, and toxicity. Analysis was as of August 1990. RESULTS
All patients received 100% of the planned dose of both cisplatin and bleomycin. The evaluation of clinical response revealed 19% (5/26) CR, and 69% (18/26) PR, while the remaining 12% (3/26) of patients showed SD (Table 2). All 23 responding patients were submitted to laparotomy (median time from the start of chemotherapy, 33 days; range, 28-38) and in 21 (81%) radical operation was possible (type III, 15; type IV, 6). The remaining 2 patients were intraoperatively judged not amenable for radical surgery because of the presence of metastatic lesions on the sigmoid peritoneum in one case (IIIB) and on the wall of the ileum in the other (IIB), despite the objective responses in parametrial and cervical disease. Pathological evaluation of surgical specimens confirmed CR in 5 patients (19%) and PR in 16 (62%), resulting in an overall histologically proven response rate of 81% . The remaining 2 patients (8%) with documented extrapelvic spread of disease were considered progressive cases and subsequently submitted to radiotherapy. Among the operated patients, cervical lesions showed an overall response (CR + PR) rate of 87.5%, while vaginal and
214
BENEDETTI
PANIC1 ET AL.
TABLE 2 Responsein Relation to FIG0 Stage Clinical (n = 26)
Pathological (n = 23)
Stage
No. Pts
CR
PR
SD
CR
PR
P
IB-IIA IIB III
6 11 9
-
4 1
2 10 6
3
4 1 -
2 9 5
1 1
(1020%)
(lCf%)
Total (6&o)
(123%)
(I;%)
(6k)
(Si)
Note. CR, complete response; PR, partial response; SD, stable disease; P, progression.
parametrial lesions showed a response rate of 100%. Surgical resection margins were tumor-free in all patients. The mean number of resected nodes was 61 (range, 38118): 48 pelvic (range, 28-82) and 22 para-aortic (range, 10-43). Lymph node metastases were detected in two patients (IIB and IIIB) (9.5%) with positive external iliac nodes in both cases. All 5 patients not submitted to radical surgery were referred to radiotherapy: 1 (IIIB) died before starting treatment; 1 (IIB) of the 2 with extrapelvic disease died with progressive tumor after intracavitary radiotherapy, and the other (IIIB) is alive with evident disease 5 months after treatment; and the remaining 2 patients (IIIB) are still alive and well 5 and 6 months from treatment completion, respectively. Chemotherapy-induced toxicity was mainly represented by myelosuppression (maximum grade per patient: grade 1, 19.2%; grade II, 34.6%; grade III, 7.7%), consisting of anemia (grade I, 7.7%; grade II, 27%; grade III, 7.7%) and/or leukopenia (grade I, 27%; grade II, 11.5%) or grade I thrombocytopenia (7.7%). Grade I hair loss was detected in 27% of cases while grade II-III nausea and vomiting were detected in all patients. There were no relevant neurotoxic effects except for grade I peripheral neuropathy detected in 2 patients (7.7%). Audiographic changes-a drop of 15 dB or more in pure tone audiography in one or both ears at one or more frequenceswere detected at 4000-8000 Hz in 31% of cases (g/26). However, no patients presented clinically hearing loss. No lethal surgery-related complications occurred. Intraoperative complication occurred in 1 patient (4.8%) and consisted of hemorrhage (1500 ml) due to a laceration of the left common iliac vein which was immediately repaired. The following postoperative complications were seen in 10 patients (48%), lymphocysts (6), deep venous thromboses (4), urinary fistula (l), and pulmonary embolism (l), with a good outcome in all cases. Eighteen months median follow-up time (range, 11-23) from histological diagnosis has been reached among the operated patients, and no recurrences have been detected so far.
DISCUSSION Our data suggest that high-dose cisplatin and bleomycin NACT followed by radical surgery is a feasible treatment in patients with locally advanced cervical carcinoma. No relevant chemotherapy-induced side effects were detected, and the surgery-related complications that occurred seem to be due to the type of surgery rather than increased by prior chemotherapy, as found in our previous series [6,7]. Radical operation was possible after only one cycle of high-dose cisplatin and bleomycin chemotherapy in 81% of patients (21/26) with a pathological complete response in 5 patients (19%), partial response in 16 (62%), and negative margins at final pathology in all. Furthermore, the 9.5% incidence of lymph node metastases detected after pathological examination of a large number of specimens (median number of nodes resected, 61) seems to be lower than that expected in such a patient population [25,26], confirming a possible therapeutic role of NACT on lymph node metastatic disease as previously suggested [6,7,25]. These data confirm the high response rate to primary medical treatment reported in other series of patients with similar characteristics [l-5]. Complete clinical response rates after cisplatin-based NACT all are within a lo-20% range except for the 60% referred to by Rustin et al. [27] on a very limited number of patients, and the overall response rates vary from 53 to 80% [l7,281. Furthermore, as far as pathological response is concerned, our data are in accordance with those reported in the literature [l]. It is likely that dose intensity not only correlates with the outcome of adjuvant chemotherapy but actually contributes to it in other malignancies [15,29,30,31]. Therefore we postulated that it might also be important in cervical cancer and in a neoadjuvant setting. Interestingly, when compared with our previous experience, in the present study the total dose of cisplatin was reduced by approximately 30% while its average dose intensity increased by 50%. In this way, also, the time needed for the neoadjuvant treatment was reduced by
NEOADJUVANT
50%, significantly shortening the interval between diagnosis and the definitive therapeutic option (radical surgery could be performed approximately 1 month from the start of treatment). Even though our previous series treated with PBM chemotherapy and the present series are not correctly comparable, the response rates induced by the two regimens are likely to be equivalent [6,7] according to Sardi et al. [2]. On the other hand, these preliminary data do not allow a definitive analysis of treatment results and the effectiveness of a more intensive but reduced cisplatin total dosage on micrometastatic disease has to be evaluated after a longer follow-up. However with a median follow-up of 18 months no recurrences have been so far detected, compared with 14% at the same time in our previous series. It is not yet clear in fact whether therapeutic effects are associated with the AUC (or the steady-state concentration) of a drug, or if a high peak serum concentration is required for maximal effect [3234]. From literature data on NACT in cervical cancer, there was no clear evidence of a correlation between cisplatin-dose intensity (ranging from 12.5 to 50 mg/m*/week) and observed response [l-4,7,27,28]. On the other hand, these data are far from correctly comparable, and dose intensity analyses have generally suggested that dose intensification schedules in other solid tumors are advantageous [29-311. In conclusion, all that can be said at the present time is that improved therapeutic results could be obtained with NACT in locally advanced cervical cancer, and that the possibility dose intensification schedules are advantageous, at least in terms of a reduction of treatment duration, exists a randomized trial of PBM neoadjuvant chemotherapy followed by radical surgery versus radiotherapy alone in stage IIB-III patients is in the patient accrual phase now. Dose intensification modalities could be prospectively investigated in a neoadjuvant setting.
patients with locally advanced cervical cancer, Br. J. Obstet. 583-588
94,
(1987).
5. Friedlander, M. L., Atkinson, K., Coppleson, J. V. M., Elliot, P., Green, D., Houghton, R., Solomon, H. J., Russel, P., and Tattersal, M. H. N. The integration of chemotherapy into the management of locally advanced cervical cancer: A pilot study, Gynecol. Oncol. 6.
8.
9.
10.
11.
12.
13.
14.
15.
19, 1-7 (1984).
Benedetti Panici, P., Scambia, G., Greggi, S., Di Roberto, P. F., Baiocchi, G., and Mancuso, S. Neoadjuvant chemotherapy and radical surgery in locally advanced cervical carcinoma: A pilot study, Obstet.
7.
REFERENCES 1. Kim, D. S., Moon, H., Kim, K. T., Hwang, Y., Cho, S., and Kim, S. R. Two-year survival: Preoperative adjuvant chemotherapy in the treatment of cervical cancer stages IB and II with bulky tumor, Gynecol. Oncol. 33, 225-230 (1989). 2. Sardi, J. E., di Paola, G., Giaroli, A., Sananes, C., Gomez Rueda, N., Cachau, A., Vighi, S., and Burlando, S. Results of a phase II trial with neoadjuvant chemotherapy in carcinoma of the cervix utery, Gynecol. Oncol. 31, 256-261 (1988). 3. Weiner, S. A., Aristizabal, S., Alberts, D., Survit, E. A., and Deatherage-Deuser, R. N. A phase II trial of mitomycin, vincristine, bleomycin, and cisplatin (MOBP) as neoadjuvant therapy in high-risk cervical carcinoma, Gynecol. Oncol. 30, l-6 (1988). 4. Kirsten, F., Atkinson, K. H., Coppleson, J. V. M., Elliot, P. M., Green, D., Houghton, R., Murray, J. C., Russel, P., Solomon, H. J., Friedlander, M., Swanson, C. E., and Tattersal, M. H. N. Combination chemotherapy followed by surgery or radiotherapy in
215
CHEMOTHERAPY
Gynecol.
71, 344-348
(1988).
Benedetti Panici, P., Scambia, G., Baiocchi, G., Greggi, S., Ragusa, G., Gallo, A., Conte, M., Battaglia, F., Laurelli, G., Rabitti, C., Capelli, A., and Mancuso, S. Neoadjuvant chemotherapy and radical surgery in locally advanced cervical cancer: Prognostic factors for response and survival, Cancer 67, 372-379 (1991). Benedetti Panici, P., Di Roberto, P. F., Greggi, S., Margariti, P. A., Scambia, G., Bompiani, A., and Mancuso, S. Squamous cervical cancer at stage IB and II: A ten years experience, analysis of 231 cases, Eur. J. Gynaecol. Oncol. 8, 76-80 (1987). Di Saia, P. J., Bundy, B. N., Curry, S. L., Schlaert, J., and Thigpen, T. J. Phase III study on the treatment of women with cervical cancer stage IIB, IIIB and IVA (confined to the pelvis and/or periaortic nodes), with radiotherapy alone versus radiotherapy plus immunotherapy with intravenous Corinebacterium parvum: A Gynecologic Oncology Group Study Gynecol. Oncol. 26, 386-397 (1987). Montana, G. S., Fowler, W. C., Varia, M. A., and Walton, L. M. Analysis of results of radiation therapy for stage II carcionoma of the cervix, Cancer 55, 956-962 (1985). Montana, G. S., Fowler, W. C., Varia, M. A., Walton, L. A., Mack, Y., and Ma Shemanski, L. Carcinoma of the cervix, stage III results of radiation therapy, Cancer 57, 148-154 (1986). Utley, J. F., von Essen, C. F., Horn, R. A., and Moeller, J. H. High-dose rate after loading brachytherapy in carcinoma of the uterine cervix, Int. J. Radiat. Oncol. Biol. Phys. 10, 2259-2263 (1984). Thigpen, T., Shingleton, H., Homesley, H., La Gasse, L., and Blessing, J. cis-Dichlorodiammineplatinum (II) in the treatment of gynecologic malignancies: Phase II trials by the Gynecologic Oncology Group, Cancer Treat. Rep. 63, 1549-1555 (1979). Thigpen, T., Blessing, J., Shingleton, H., Di Saia, P., and Fowler, W. Cisplatin in the management of patients with advanced or recurrent squamous carcinoma of the cervix: Effects of prolonged infusion. Proc. Ann. Meeting ASCO 5, 116 (1986). Ozols, R. F., Corden, B. J., Jacob, J., Wesley, M. N., Ostchega, Y., and Young, C. High dose cisplatin in hypertonic saline, Ann. Intern.
Med.
100, 19-24
(1984).
16. Behrens, B. C., Grotzinger, K. R., and Hamilton, T. C., Cytoxicity of 3 cisplatin analogues in a drug sensitive and a new cisplatin resistant human ovarian cancer cell line, Proc. Am. Assoc. Cancer. Res. 26, 262 (1985). 17. Bruckner, H. W., Wallach, R., Cohen, C. J., Deppe, G., Kabakow, B., Ratner, L., and Holland, J. F. High-dose cisplatin for refractory ovarian cancer, Gynecol. Oncol. 12, 64-67 (1981). 18. Baker, C. H., and Wiltshaw, E. Use of high dose cis--dichIorodiammineplatinum (II) following failure of previous chemotherapy for advanced carcinoma of the ovary, Br. J. Obstet. Gynaecol. 88, 1192-1199 (1981). 19. Zunino, F., Pratesi, G., Micheloni, A., Cavalletti, E., Sala, F., and Tofanetti, 0. Protective effect of reduced glutathione against cisplatin-induced renal and systemic toxicity and its influence on the
216
BENEDETTI
therapeutic activity of the antitumor drug, Chem. Biol. Iteract. 70, 89-101 (1989). 20. Di Re, F., Bohen, S., Oriana, S., Spatti, G. B., and Zunino, T. Efficacy and safety of high-dose cisplatin and cyclophosfamide with glutathione protection in the treatment of bulky advanced epithelial ovarian cancer, Cancer Chemother. Pharmacol. 25,355-360 (1990). 21. Ozols, R. F., and Young, R. C. Chemotherapy of ovarian cancer, Semin. Oncol. 11, 251-263 (1984). 22. Petterson, F. (Ed.). Annual report on results of treatment of gynecological tumors, FIGO, Stockholm, Vol. 20 (1988). 23. World Health Organization. W. H. 0. handbook for reporting results of cancer treatment, W.H.O. Offset Publication 48, Geneva (1979). 24. Piver, M. S., Rutledge, F., and Smith, J. P. Five classes of extended hysterectomy for women with cervical cancer, Obstet. Gynecol. 44, 264 (1974). 2.5. Kim, D. S., Moon, H., and Kang, K. J. Primary chemotherapy and postoperative adjuvant chemotherapy in the treatment of squamous cell carcinoma of the uterine cervix, Gynecol. Oncol. 22,5964 (1985). 26. Dargent, D., Frobert, J. L., and Bean, G. V factor (tumor volume) and T factor (FIG0 classification) in the assessment of cervix cancer prognosis: The risk of lymph node spread, Gynecol. Oncol. 22,1522 (1985). 27. Rustin, G. J. S., Newlands, E. S., Southcott, B. M., and Singer,
PANIC1 ET AL,
28.
29. 30. 31 ’
32. 33. 34.
A. Cisplatin, vincristine, methotrexate, and bleomycin (POMB) as initial or palliative therapy for carcinoma of the cervix, Br. J. Obstet. Gynaecol. 94, 1205-1211 (1987). Symonds, R. P., Burnett, R. A., Habeshaw, T., Kaye, S. B., Snee, M. P., and Watson, E. R. The prognostic value of a response to chemotherapy given before radiotherapy in advanced cancer of the cervix, Br. J. Cancer 59, 473-475 (1989). Murray, N. The importance of dose and dose intensity in lung cancer chemotherapy, Semin. Oncol. Suppl. 14(4), 20-28 (1987). Hryniuk, W., Figueredo, A., and Goodyear, M. Applications of dose-intensity to problems in chemotherapy of breast and colorectal cancer, Semin. Oncol. Suppl. 14(4), 3-11 (1987). Ozols, R. F., Ihde, D. C., Linehan, W. M., Jacob, J., Ostchega, Y., and Young, R. C. A randomized trial of standard chemotherapy v a high-dose chemotherapy regimen in the treatment of poor prognosis nonseminomatous germ-cell tumors, J. Clin. Oncol. 6, 10311040 (1988). McVie, J. G. The role of pharmacokinetics in (combination) chemotherapy, Cancer Suppl. S4(6), 1175-1178 (1984). Powis, G. Dose dependent metabolism, therapeutic effect, and toxicity of anticancer drugs in man, Drug. Metab. Rev. 14, 1145-1163 (1983). Moore, M. J., and Erlichman, C. Therapeutic drug monitoring in oncology. Problems and potential in antineoplastic therapy, Clin. Pharmacokinet. 13, 205-227 (1987).
ONCOLOGY
41, 212-216 (1991)
High-Dose Cisplatin and Bleomycin Neoadjuvant Chemotherapy Plus Radical Surgery in Locally Advanced Cervical Carcinoma: A Preliminary Report PIERLUIGI BENEDETTI PANICI, M.D., STEFANO GREGGI, M.D., PH.D., GIOVANNI SCAMBIA, M.D., GUGLIELMO RAGUSA, M.D., GABRIELA BAIOCCHI, M.D., FRANCESCO BATTAGLIA, M.D., FERDINAND~ CORONETTA, PH.D., AND SALVATORE MANCUSO, M.D.’ Department of Gynecology and Obstetrics, Universitd Cattolica de1 S. &ore,
8, largo Agostino Gemelli, 00168 Rome, Italy
Received October 10, 1990
One courseof chemotherapycontainingcisplatinand bleomycin asa neoadjuvanttreatment wasgiven to 26 consecutivepatients with previously untreated stageIB (bulky disease)-111 cervical carcinomaand followed by radical surgery. After chemotherapy responses weredetectedin 23 patients(5 completeand 18partial; overall, 88%) and permitted radical surgery in 21 cases(81%). Surgery consistedof type III-IV radical hysterectomy plus systematic para-aortic and pelvic lymphadenectomy. At histologic examination, completeresponses werefound in 5 (19%)and partial responses in 16 (62%) cases.The averagenumber of lymph nodesremoved was 61 (range, 38-118). A lower than expected incidenceof lymph node metastases was detected(2/21, 9.5%). The chemotherapy-inducedtoxicity was mainly representedby nauseaand vomiting. Chemotherapydid not seemto complicate surgery in these circumstances,even though moderate-degree postoperativecomplicationsoccurred in 48% of cases.Eighteen monthsmedianfollow-up time (range, 11-23) from hystological diagnosishas beenreachedin the operatedpatients, and no recurrenceshave beendetectedso far. o IWI Academic preps, IN.
INTRODUCTION Neoadjuvant chemotherapy has been recently investigated as a new therapeutic approach to locally advanced cervical cancer because of the disappointing results with conventional treatments, and data from different studies suggest that cervical cancer is in fact a chemosensitive tumor [l-5]. Our previous experience with neoadjuvant chemotherapy (NACT) consisted of a pilot study with three cycles of cisplatin (P), bleomycin (B), and methotrexate (M) followed by radical surgery in 75 patients with FIG0 stages IB-IIA (tumor volume >4 cm), IIB, ’ To whom correspondence and reprint requests should be addressed.
and III. Three-year disease-free survivals (DFS) of 89, 73, and 42% were observed in stages IB-IIA, IIB, and III, respectively [6,7]. On the basis of the reported survival rates after exclusive radiotherapy from our and other institutions [8-121, these data suggest improved therapeutic results with the new combined treatment and call for randomized trials comparing this new approach with conventional radiotherapy. Patient accrual in our previous study on PBM NACT was stopped in October 1988 and, until October 1989, the now ongoing randomized trial could not be started because of the need for data reviewing and protocol drafting. This left room for us to conduct a further study based on the following considerations: (1) Given the results from phase II-III trials on recurrent/advanced disease, cisplatin can be considered the most active drug in the treatment of cervical cancer [13,14]. (2) Experimental and clinical studies in solid tumors have demonstrated a steep dose-response relationship with cisplatin [15-171. (3) The escalation of cisplatin dosage has been made possible through a hypertonic vehicle of drug administration and intensive hydration schedules or glutatione addition, overcoming the doselimiting nephrotoxicity [18-201. (4) The onset of peripheral neuropathy, recognized as the major toxic effect induced by high-dose cisplatin, usually has been reported after a total dose of 400 mg/m2 [21]. (5) In our previous experience with PBM NACT, over 90% of responses were registered after the first two cycles, including all 10 complete responses confirmed by hystologic evaluation of surgical specimens. (6) One of the possible disadvantages of the regimen previously employed was the approximately 2-month period of time needed before a definitive treatment option could be undertaken. Keeping all the above
212 OO!W-8258/91 $1.50 Copyright 0 1991 All
rights
by Academic Press, of reproduction in any form
Inc. reserved.
NEOADJUVANT
in mind, we conducted a new pilot study on one cycle of high-dose (200 mg/m’) cisplatin and bleomycin NACT followed by radical surgery, trying to explore the effectiveness of a briefer, more intensive neoadjuvant treatment in locally advanced cervical carcinoma. PATIENTS AND METHODS
From October 1988 through October 1989, 26 consecutive patients with previously untreated stage IB-III cervical carcinoma were enrolled. The eligibility and exclusion criteria were those adopted in our previous study [6]. After clinical staging (FIGO) [22], NACT was given according to the following schedule: cisplatin, 40 mg/m*, for five days in 3% hypertonic saline (100 mEq NaCl/200 ml normal saline in a 2-hr infusion) with 6 liters normal saline/plus 120 mEq KC1 and 10 mEq CaMgCl/day started 12 hr before the first dose of cisplatin and continued until 12 hr after the last dose on Day 5; iv mannitol k furosemide was routinely used daily for promoting diuresis; and bleomycin, 15 mg iv bolus, on Days 1,2,8,9. Alizapride was routinely employed for antiemesis. Electrocardiogram; pulmonary, renal, and hepatic function tests; complete blood count; audiometry; and neurologic examination were performed to monitor the induced toxicity before and after 28 days from the start of chemotherapy. The World Health Organization (WHO) toxicity evaluation criteria were adopted [23]. Fifteen-twenty days from the end of chemotherapy (Day 9), patients were submitted to a clinical evaluation of response including the following procedures: cervical cytology, colposcopy; cervical and vaginal biopsy; transabdominal and transrectal pelvic ultrasonography; and gynecologic examination under general anesthesia. The WHO response evaluation criteria were adopted [23]. Patients were eligible for surgical treatment only if a tumor volume under 4 cm had been achieved and if vaginal and parametrial disease were judged radically resectable. Operative therapy consisted of radical hysterectomy (type III-IV) [24] plus systematic para-aortic and pelvic lymphadenectomy. Those patients still considered not amenable for radical surgery were submitted to conventional radiotherapy. After histopathological evaluation of surgical specimens, patients with complete response or without lymph node (N) metastases or involvement of surgical resection margins (SRM) received no further treatment. Patients with SRM imvolvement and/or positive N were scheduled to receive external or interstitial radiotherapy and/or two further cycles of PB chemotherapy (100 mg/m’ cisplatin, Day 1; 15 mg bleomycin, Days 1,9; q28 days). Follow-up procedures consisting of general and gynecologic examinations, colposcopy, and cervical cytology were performed 1 month from the end
213
CHEMOTHERAPY
TABLE 1 Patient Characteristics Median age, 53 (range, 25-64) Patients entered Clinically evaluable Pathologically evaluable
26( 100%) 26( 100%) 23 (88%)
FIG0 stages IB-IIA IIB III
6 (23%) 11 (42%) 9 (35%)
Histotype Squamous cell carcinoma Adenocarcinoma
21 (81%) 5 (19%)
Grade of differentiation Good Moderately good Poor Median follow-up, 18 months (range, 11-23)
3 (12%) 9 (35%) 14 (53%)
of the planned treatment and every 3 months thereafter. Furthermore, pelvic ultrasonography, intravenous pyelography, and chest X ray were performed at 1, 3, and 6 months, within 12 months, and every 6 months from the end of treatment, respectively. Table 1 summarizes the characteristics of the patients. In the report the endpoints selected for analysis were clinical response and operability rate, pathological response, and toxicity. Analysis was as of August 1990. RESULTS
All patients received 100% of the planned dose of both cisplatin and bleomycin. The evaluation of clinical response revealed 19% (5/26) CR, and 69% (18/26) PR, while the remaining 12% (3/26) of patients showed SD (Table 2). All 23 responding patients were submitted to laparotomy (median time from the start of chemotherapy, 33 days; range, 28-38) and in 21 (81%) radical operation was possible (type III, 15; type IV, 6). The remaining 2 patients were intraoperatively judged not amenable for radical surgery because of the presence of metastatic lesions on the sigmoid peritoneum in one case (IIIB) and on the wall of the ileum in the other (IIB), despite the objective responses in parametrial and cervical disease. Pathological evaluation of surgical specimens confirmed CR in 5 patients (19%) and PR in 16 (62%), resulting in an overall histologically proven response rate of 81% . The remaining 2 patients (8%) with documented extrapelvic spread of disease were considered progressive cases and subsequently submitted to radiotherapy. Among the operated patients, cervical lesions showed an overall response (CR + PR) rate of 87.5%, while vaginal and
214
BENEDETTI
PANIC1 ET AL.
TABLE 2 Responsein Relation to FIG0 Stage Clinical (n = 26)
Pathological (n = 23)
Stage
No. Pts
CR
PR
SD
CR
PR
P
IB-IIA IIB III
6 11 9
-
4 1
2 10 6
3
4 1 -
2 9 5
1 1
(1020%)
(lCf%)
Total (6&o)
(123%)
(I;%)
(6k)
(Si)
Note. CR, complete response; PR, partial response; SD, stable disease; P, progression.
parametrial lesions showed a response rate of 100%. Surgical resection margins were tumor-free in all patients. The mean number of resected nodes was 61 (range, 38118): 48 pelvic (range, 28-82) and 22 para-aortic (range, 10-43). Lymph node metastases were detected in two patients (IIB and IIIB) (9.5%) with positive external iliac nodes in both cases. All 5 patients not submitted to radical surgery were referred to radiotherapy: 1 (IIIB) died before starting treatment; 1 (IIB) of the 2 with extrapelvic disease died with progressive tumor after intracavitary radiotherapy, and the other (IIIB) is alive with evident disease 5 months after treatment; and the remaining 2 patients (IIIB) are still alive and well 5 and 6 months from treatment completion, respectively. Chemotherapy-induced toxicity was mainly represented by myelosuppression (maximum grade per patient: grade 1, 19.2%; grade II, 34.6%; grade III, 7.7%), consisting of anemia (grade I, 7.7%; grade II, 27%; grade III, 7.7%) and/or leukopenia (grade I, 27%; grade II, 11.5%) or grade I thrombocytopenia (7.7%). Grade I hair loss was detected in 27% of cases while grade II-III nausea and vomiting were detected in all patients. There were no relevant neurotoxic effects except for grade I peripheral neuropathy detected in 2 patients (7.7%). Audiographic changes-a drop of 15 dB or more in pure tone audiography in one or both ears at one or more frequenceswere detected at 4000-8000 Hz in 31% of cases (g/26). However, no patients presented clinically hearing loss. No lethal surgery-related complications occurred. Intraoperative complication occurred in 1 patient (4.8%) and consisted of hemorrhage (1500 ml) due to a laceration of the left common iliac vein which was immediately repaired. The following postoperative complications were seen in 10 patients (48%), lymphocysts (6), deep venous thromboses (4), urinary fistula (l), and pulmonary embolism (l), with a good outcome in all cases. Eighteen months median follow-up time (range, 11-23) from histological diagnosis has been reached among the operated patients, and no recurrences have been detected so far.
DISCUSSION Our data suggest that high-dose cisplatin and bleomycin NACT followed by radical surgery is a feasible treatment in patients with locally advanced cervical carcinoma. No relevant chemotherapy-induced side effects were detected, and the surgery-related complications that occurred seem to be due to the type of surgery rather than increased by prior chemotherapy, as found in our previous series [6,7]. Radical operation was possible after only one cycle of high-dose cisplatin and bleomycin chemotherapy in 81% of patients (21/26) with a pathological complete response in 5 patients (19%), partial response in 16 (62%), and negative margins at final pathology in all. Furthermore, the 9.5% incidence of lymph node metastases detected after pathological examination of a large number of specimens (median number of nodes resected, 61) seems to be lower than that expected in such a patient population [25,26], confirming a possible therapeutic role of NACT on lymph node metastatic disease as previously suggested [6,7,25]. These data confirm the high response rate to primary medical treatment reported in other series of patients with similar characteristics [l-5]. Complete clinical response rates after cisplatin-based NACT all are within a lo-20% range except for the 60% referred to by Rustin et al. [27] on a very limited number of patients, and the overall response rates vary from 53 to 80% [l7,281. Furthermore, as far as pathological response is concerned, our data are in accordance with those reported in the literature [l]. It is likely that dose intensity not only correlates with the outcome of adjuvant chemotherapy but actually contributes to it in other malignancies [15,29,30,31]. Therefore we postulated that it might also be important in cervical cancer and in a neoadjuvant setting. Interestingly, when compared with our previous experience, in the present study the total dose of cisplatin was reduced by approximately 30% while its average dose intensity increased by 50%. In this way, also, the time needed for the neoadjuvant treatment was reduced by
NEOADJUVANT
50%, significantly shortening the interval between diagnosis and the definitive therapeutic option (radical surgery could be performed approximately 1 month from the start of treatment). Even though our previous series treated with PBM chemotherapy and the present series are not correctly comparable, the response rates induced by the two regimens are likely to be equivalent [6,7] according to Sardi et al. [2]. On the other hand, these preliminary data do not allow a definitive analysis of treatment results and the effectiveness of a more intensive but reduced cisplatin total dosage on micrometastatic disease has to be evaluated after a longer follow-up. However with a median follow-up of 18 months no recurrences have been so far detected, compared with 14% at the same time in our previous series. It is not yet clear in fact whether therapeutic effects are associated with the AUC (or the steady-state concentration) of a drug, or if a high peak serum concentration is required for maximal effect [3234]. From literature data on NACT in cervical cancer, there was no clear evidence of a correlation between cisplatin-dose intensity (ranging from 12.5 to 50 mg/m*/week) and observed response [l-4,7,27,28]. On the other hand, these data are far from correctly comparable, and dose intensity analyses have generally suggested that dose intensification schedules in other solid tumors are advantageous [29-311. In conclusion, all that can be said at the present time is that improved therapeutic results could be obtained with NACT in locally advanced cervical cancer, and that the possibility dose intensification schedules are advantageous, at least in terms of a reduction of treatment duration, exists a randomized trial of PBM neoadjuvant chemotherapy followed by radical surgery versus radiotherapy alone in stage IIB-III patients is in the patient accrual phase now. Dose intensification modalities could be prospectively investigated in a neoadjuvant setting.
patients with locally advanced cervical cancer, Br. J. Obstet. 583-588
94,
(1987).
5. Friedlander, M. L., Atkinson, K., Coppleson, J. V. M., Elliot, P., Green, D., Houghton, R., Solomon, H. J., Russel, P., and Tattersal, M. H. N. The integration of chemotherapy into the management of locally advanced cervical cancer: A pilot study, Gynecol. Oncol. 6.
8.
9.
10.
11.
12.
13.
14.
15.
19, 1-7 (1984).
Benedetti Panici, P., Scambia, G., Greggi, S., Di Roberto, P. F., Baiocchi, G., and Mancuso, S. Neoadjuvant chemotherapy and radical surgery in locally advanced cervical carcinoma: A pilot study, Obstet.
7.
REFERENCES 1. Kim, D. S., Moon, H., Kim, K. T., Hwang, Y., Cho, S., and Kim, S. R. Two-year survival: Preoperative adjuvant chemotherapy in the treatment of cervical cancer stages IB and II with bulky tumor, Gynecol. Oncol. 33, 225-230 (1989). 2. Sardi, J. E., di Paola, G., Giaroli, A., Sananes, C., Gomez Rueda, N., Cachau, A., Vighi, S., and Burlando, S. Results of a phase II trial with neoadjuvant chemotherapy in carcinoma of the cervix utery, Gynecol. Oncol. 31, 256-261 (1988). 3. Weiner, S. A., Aristizabal, S., Alberts, D., Survit, E. A., and Deatherage-Deuser, R. N. A phase II trial of mitomycin, vincristine, bleomycin, and cisplatin (MOBP) as neoadjuvant therapy in high-risk cervical carcinoma, Gynecol. Oncol. 30, l-6 (1988). 4. Kirsten, F., Atkinson, K. H., Coppleson, J. V. M., Elliot, P. M., Green, D., Houghton, R., Murray, J. C., Russel, P., Solomon, H. J., Friedlander, M., Swanson, C. E., and Tattersal, M. H. N. Combination chemotherapy followed by surgery or radiotherapy in
215
CHEMOTHERAPY
Gynecol.
71, 344-348
(1988).
Benedetti Panici, P., Scambia, G., Baiocchi, G., Greggi, S., Ragusa, G., Gallo, A., Conte, M., Battaglia, F., Laurelli, G., Rabitti, C., Capelli, A., and Mancuso, S. Neoadjuvant chemotherapy and radical surgery in locally advanced cervical cancer: Prognostic factors for response and survival, Cancer 67, 372-379 (1991). Benedetti Panici, P., Di Roberto, P. F., Greggi, S., Margariti, P. A., Scambia, G., Bompiani, A., and Mancuso, S. Squamous cervical cancer at stage IB and II: A ten years experience, analysis of 231 cases, Eur. J. Gynaecol. Oncol. 8, 76-80 (1987). Di Saia, P. J., Bundy, B. N., Curry, S. L., Schlaert, J., and Thigpen, T. J. Phase III study on the treatment of women with cervical cancer stage IIB, IIIB and IVA (confined to the pelvis and/or periaortic nodes), with radiotherapy alone versus radiotherapy plus immunotherapy with intravenous Corinebacterium parvum: A Gynecologic Oncology Group Study Gynecol. Oncol. 26, 386-397 (1987). Montana, G. S., Fowler, W. C., Varia, M. A., and Walton, L. M. Analysis of results of radiation therapy for stage II carcionoma of the cervix, Cancer 55, 956-962 (1985). Montana, G. S., Fowler, W. C., Varia, M. A., Walton, L. A., Mack, Y., and Ma Shemanski, L. Carcinoma of the cervix, stage III results of radiation therapy, Cancer 57, 148-154 (1986). Utley, J. F., von Essen, C. F., Horn, R. A., and Moeller, J. H. High-dose rate after loading brachytherapy in carcinoma of the uterine cervix, Int. J. Radiat. Oncol. Biol. Phys. 10, 2259-2263 (1984). Thigpen, T., Shingleton, H., Homesley, H., La Gasse, L., and Blessing, J. cis-Dichlorodiammineplatinum (II) in the treatment of gynecologic malignancies: Phase II trials by the Gynecologic Oncology Group, Cancer Treat. Rep. 63, 1549-1555 (1979). Thigpen, T., Blessing, J., Shingleton, H., Di Saia, P., and Fowler, W. Cisplatin in the management of patients with advanced or recurrent squamous carcinoma of the cervix: Effects of prolonged infusion. Proc. Ann. Meeting ASCO 5, 116 (1986). Ozols, R. F., Corden, B. J., Jacob, J., Wesley, M. N., Ostchega, Y., and Young, C. High dose cisplatin in hypertonic saline, Ann. Intern.
Med.
100, 19-24
(1984).
16. Behrens, B. C., Grotzinger, K. R., and Hamilton, T. C., Cytoxicity of 3 cisplatin analogues in a drug sensitive and a new cisplatin resistant human ovarian cancer cell line, Proc. Am. Assoc. Cancer. Res. 26, 262 (1985). 17. Bruckner, H. W., Wallach, R., Cohen, C. J., Deppe, G., Kabakow, B., Ratner, L., and Holland, J. F. High-dose cisplatin for refractory ovarian cancer, Gynecol. Oncol. 12, 64-67 (1981). 18. Baker, C. H., and Wiltshaw, E. Use of high dose cis--dichIorodiammineplatinum (II) following failure of previous chemotherapy for advanced carcinoma of the ovary, Br. J. Obstet. Gynaecol. 88, 1192-1199 (1981). 19. Zunino, F., Pratesi, G., Micheloni, A., Cavalletti, E., Sala, F., and Tofanetti, 0. Protective effect of reduced glutathione against cisplatin-induced renal and systemic toxicity and its influence on the
216
BENEDETTI
therapeutic activity of the antitumor drug, Chem. Biol. Iteract. 70, 89-101 (1989). 20. Di Re, F., Bohen, S., Oriana, S., Spatti, G. B., and Zunino, T. Efficacy and safety of high-dose cisplatin and cyclophosfamide with glutathione protection in the treatment of bulky advanced epithelial ovarian cancer, Cancer Chemother. Pharmacol. 25,355-360 (1990). 21. Ozols, R. F., and Young, R. C. Chemotherapy of ovarian cancer, Semin. Oncol. 11, 251-263 (1984). 22. Petterson, F. (Ed.). Annual report on results of treatment of gynecological tumors, FIGO, Stockholm, Vol. 20 (1988). 23. World Health Organization. W. H. 0. handbook for reporting results of cancer treatment, W.H.O. Offset Publication 48, Geneva (1979). 24. Piver, M. S., Rutledge, F., and Smith, J. P. Five classes of extended hysterectomy for women with cervical cancer, Obstet. Gynecol. 44, 264 (1974). 2.5. Kim, D. S., Moon, H., and Kang, K. J. Primary chemotherapy and postoperative adjuvant chemotherapy in the treatment of squamous cell carcinoma of the uterine cervix, Gynecol. Oncol. 22,5964 (1985). 26. Dargent, D., Frobert, J. L., and Bean, G. V factor (tumor volume) and T factor (FIG0 classification) in the assessment of cervix cancer prognosis: The risk of lymph node spread, Gynecol. Oncol. 22,1522 (1985). 27. Rustin, G. J. S., Newlands, E. S., Southcott, B. M., and Singer,
PANIC1 ET AL,
28.
29. 30. 31 ’
32. 33. 34.
A. Cisplatin, vincristine, methotrexate, and bleomycin (POMB) as initial or palliative therapy for carcinoma of the cervix, Br. J. Obstet. Gynaecol. 94, 1205-1211 (1987). Symonds, R. P., Burnett, R. A., Habeshaw, T., Kaye, S. B., Snee, M. P., and Watson, E. R. The prognostic value of a response to chemotherapy given before radiotherapy in advanced cancer of the cervix, Br. J. Cancer 59, 473-475 (1989). Murray, N. The importance of dose and dose intensity in lung cancer chemotherapy, Semin. Oncol. Suppl. 14(4), 20-28 (1987). Hryniuk, W., Figueredo, A., and Goodyear, M. Applications of dose-intensity to problems in chemotherapy of breast and colorectal cancer, Semin. Oncol. Suppl. 14(4), 3-11 (1987). Ozols, R. F., Ihde, D. C., Linehan, W. M., Jacob, J., Ostchega, Y., and Young, R. C. A randomized trial of standard chemotherapy v a high-dose chemotherapy regimen in the treatment of poor prognosis nonseminomatous germ-cell tumors, J. Clin. Oncol. 6, 10311040 (1988). McVie, J. G. The role of pharmacokinetics in (combination) chemotherapy, Cancer Suppl. S4(6), 1175-1178 (1984). Powis, G. Dose dependent metabolism, therapeutic effect, and toxicity of anticancer drugs in man, Drug. Metab. Rev. 14, 1145-1163 (1983). Moore, M. J., and Erlichman, C. Therapeutic drug monitoring in oncology. Problems and potential in antineoplastic therapy, Clin. Pharmacokinet. 13, 205-227 (1987).