|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
© 2000 American Society for Clinical Oncology Randomized Trial of Neoadjuvant Cisplatin, Vincristine, Bleomycin, and Radical Hysterectomy Versus Radiation Therapy for Bulky Stage IB and IIA Cervical CancerByFrom the Departments of Obstetrics and Gynecology (Division of Gynecologic Oncology)Pathology, Radiation Oncology, and Diagnostic Radiology, and Biostatistics Consulting Center, Chang Gung Memorial Hospital Linkou Medical Center, and Chang Gung Medical College, Taoyuan, Taiwan. Address reprint requests to Ting-Chang Chang, MD, MPH, Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital Linkou Medical Center, Taoyuan, Taiwan; email tinchang{at}ms4 hinet.net.
PURPOSE: To compare the efficacy of neoadjuvant chemotherapy (NAC) followed by radical hysterectomy with that of radiotherapy (R/T) for bulky early-stage cervical cancer.
PATIENTS AND METHODS: Women with previously untreated bulky (primary tumor RESULTS: Of the 124 eligible patients, 68 in the NAC arm and 52 in the R/T arm could be evaluated. The median duration of follow-up was 39 months. Thirty-one percent of patients in the NAC arm and 27% in the R/T arm had relapse or persistent diseases after treatment, and 21% in each group died of disease. Estimated cumulative survival rates at 2 years were 81% for the NAC arm and 84% for the R/T arm; the 5-year rates were 70% and 61%, respectively. There were no significant differences in disease-free survival and overall survival. CONCLUSION: NAC followed by radical hysterectomy and primary R/T showed similar efficacy for bulky stage IB or IIA cervical cancer. Further study to identify patient subgroups better suited for either treatment modality and to evaluate the concurrent use of cisplatin and radiation without routine hysterectomy is necessary.
CERVICAL CARCINOMA is the most common gynecologic malignancy in developing countries. Despite remarkable improvement in clinical management, the survival of cervical cancer patients has shown only minor progress in the last decade.1 Most investigators agree that cervical tumor size is a significant negative prognostic factor that is inversely correlated with both survival and time to recurrence. Bulky primary tumors (diameter  4 cm) in patients with International Federation of Gynecology and Obstetrics (FIGO) stage IB or IIA cervical carcinoma are associated with a higher incidence of nodal metastases as well as central, regional, and distant recurrences compared with smaller tumors.2-6 The high relapse rate in these patients demands further development of therapeutic modalities and has been a controversial issue since the late 1960s.7-10 Cisplatin is one of the most efficacious agents, with a high response rate in patients with advanced, recurrent, or metastatic cervical carcinoma.11-21 Since 1985, many clinical trials of adjuvant cisplatin-containing regimens for high-risk patients have been reported.22-26 However, far fewer phase II studies have assessed the efficacy of cisplatin-containing chemotherapy in a neoadjuvant setting for bulky early-stage cervical carcinoma. To the best of our knowledge, there has been no randomized phase III study comparing neoadjuvant chemotherapy (NAC) followed by radical hysterectomy with radiotherapy (R/T) for early-stage bulky cervical carcinoma. Initial surgery in patients with bulky cervical cancer was not considered because of the high incidence of lymph node metastasis and the difficulty in performing appropriate parametrial dissection and vaginal resection.
Sardi et al27 proposed a "quick" chemotherapy regimen of a combination of cisplatin, vincristine, and bleomycin to be administered at 10-day intervals. It showed a satisfactory reduction in tumor size, which allowed surgical resection to be accomplished in previously inoperable cases, with acceptable toxicity. More importantly, patients attained a superior survival compared with a nonrandomized control group given conventional therapy.28,29 The efficacy of this regimen was confirmed in our institute on FIGO stage IB and IIA bulky tumors before radical hysterectomy.30,31 Therefore, we initiated a randomized trial to compare the efficacy of "quick" cisplatin, vincristine, and bleomycin as NAC preceding radical hysterectomy and bilateral pelvic lymphadenectomy with that of primary R/T in patients with bulky (tumor dimension
Patients Eligible patients had to be previously untreated and have histologically confirmed squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma of the uterine cervix, FIGO stage IB or IIA, with tumor extending to the vagina within the upper one third of the vaginal wall. Bulky cervical tumor was defined as (a) a visible cervical tumor with the largest diameter 4 cm or (b) a cervix expanded to 4 cm as a result of tumor infiltration. If any suspicious lymph node was palpated, histologic or cytologic studies were required. Pelvic examination was performed to determine cervical tumor size, the presence of vaginal extension, and the status of the parametrial and rectovaginal septum. Contrast-enhanced computerized tomography (CT) or magnetic resonance imaging of the pelvis and abdomen was used to determine the nodal status and as a reference of the cervical tumor size. Patients with highly suspicious para-aortic and/or common iliac nodal involvement on the image study were excluded unless cytologic or histologic investigations were negative. Patients were also required to meet all of the following laboratory criteria: hemoglobin level 10 g/dL, WBC count 3,000/mm3 or absolute neutrophil count 1,500/mm3, platelet count 100,000/mm3, serum transaminase (AST, ALT) levels  60 IU/mL, total serum bilirubin level 1.5 mg/dL, serum creatinine level 1.5 mg/dL, and blood urea nitrogen level 20 mg/dL. Also deemed necessary were adequate cardiopulmonary function that could tolerate radical hysterectomy, the absence of concurrent malignancy or history of cancer other than nonmelanoma skin cancer, and an Eastern Cooperative Oncology Group performance status of 0 to 2. This trial was submitted to and approved by the Human Investigation and Medical Ethics Committee of Chang Gung Memorial Hospital, Taoyuan, Taiwan. Before randomization, informed consent was obtained from each patient.
Chemotherapy
Radiotherapy The postoperative R/T was given according to the protocol described by Tsai et al.35 By using techniques similar to those described above, the dose to the whole pelvis was 44 to 45 Gy, and that to the true pelvis was 50 to 54 Gy. After external irradiation, intravaginal brachytherapy was given in two to three fractions with a total dose of 4 to 6 Gy/0.5 cm below vaginal mucosa.
Radical Hysterectomy
Evaluation of Tumor Response and Follow-Up Clinically, a complete response (CR) was defined as the complete disappearance of cervical tumor by pelvic examination and/or image study at hysterectomy, negative serum squamous cell carcinoma antigen, and no appearance of a new lesion. A partial response (PR) required a more than 50% decrease of the product of the greatest length and the perpendicular width of the cervical tumor and no new lesion. Progressive disease was indicated by a more than 25% increase in the product of the greatest length and the perpendicular width of the cervical tumor or the appearance of a new lesion. Stable disease (SD) was defined as the state of response that was less than PR or progressive disease. Histologic CR was defined as no residual tumor in any surgical specimens of a patient with clinical CR after NAC. Serum levels of squamous cell carcinoma antigen and carcinoembryonic antigen were measured before treatment; if any marker was elevated, it would be measured again before each chemotherapy cycle, as well as before surgery in patients receiving NAC. These markers were also measured every other week in the patients of the R/T arm and at outpatient follow-up in both patient groups. Tumors were measured using CT or magnetic resonance imaging before and after treatment by an independent radiologist (K.-K.N.). The attending physician of each individual patient determined the necessity and modality of adjuvant therapy after protocol treatment. Toxicity was graded according to the National Cancer Institute common toxicity criteria.36 After completion of treatment, patients were examined every 2 months in the first year, every 3 months in the second year, and every 4 months for 3 years thereafter. After 5 years, patients were examined at least once every year. Pelvic and physical examinations were performed at every follow-up visit. Any suspicious lesion was biopsied or aspirated for histologic or cytologic examinations. A Papanicolaou smear of cervical and/or vaginal exfoliated cells was done at least every 6 months. Chest x-rays and CT scans of the abdomen, pelvis, and vagina were taken 12 months after the completion of treatment and could be repeated annually. All patients with suspicion of recurrence and those who died after entry onto this study were discussed at a weekly combined conference of gynecologic oncology, radiation oncology, gynecologic pathology, and diagnostic radiology.
Randomization and Statistical Considerations
From October 1991 to December 1998, a total of 124 patients were registered onto this study. Seventy were randomized to receive NAC followed by radical abdominal hysterectomy, and 54 were randomized to receive primary R/T. Two patients in each treatment arm were considered to be ineligible after review (one with a synchronous primary lung cancer, two with small-cell cervical cancer, and one with para-aortic lymph node metastasis). Thus, 68 patients remained on the NAC arm and 52 patients remained on the R/T arm. Analyses were based on these 120 eligible patients. The pretreatment characteristics are listed in Table 1. Although there was prospective stratification only for tumor size (4 to 6 cm or 6 cm), the two study groups were similar with respect to patient age, Eastern Cooperative Oncology Group performance status, tumor dimension, tumor type, FIGO stage, histologic diagnosis, and grade.
Treatment Administration The trial profile shows the flow of patients in the study and their last follow-up status (Fig 1). Three patients allocated to the NAC arm did not receive a hysterectomy: one patient had indurated parametria after NAC, was judged to be inoperable, subsequently received radiotherapy, and had persistent tumor after treatment. Another patient presented 3 months after the completion of NAC with a polypoid cervical tumor that extended to the lower third of her vaginal wall and was judged to be ineligible for surgical treatment. She then received R/T and achieved SD after treatment. The third patient took alternative medicine after the first chemotherapy course and returned 6 months later with a 5-cm tumor fixed to the left pelvic wall; she then received concurrent chemoradiation and had a CR. Three patients received treatment at other hospitals after their NAC.
Two patients allocated to the R/T arm did not complete the treatment: one discontinued therapy after receiving 8 Gy of pelvic irradiation and underwent hysterectomy at another hospital; the other patient opted for alternative medicine. After hysterectomy, six patients in the NAC arm underwent adjuvant chemotherapy for nodal metastasis in the dissected lymph nodes, and 19 patients had adjuvant R/T for deep cervical stromal invasion and/or parametrial invasion of the tumor under histologic study. Of the 50 patients who completed R/T, five patients underwent radical hysterectomy for persistent cervical tumor; one of the five also received chemotherapy after surgery for the presence of metastasis in the upper pelvic lymph nodes. Hysterectomy was abandoned in another patient because of extensive local disease. Patients in the NAC arm had a higher chance of receiving adjuvant therapy after scheduled treatment than those in the R/T arm (P = .0018).
Response
Toxicity
Disease-Free Survival Twenty-one patients (31%) in the NAC arm and 14 (27%) in the R/T arm relapsed or had persistent disease after treatment (Table 3). Ten patients had more than one relapse site at the diagnosis of their first relapse. Higher incidences of relapse over the vagina and over the lung were noted in the NAC arm, whereas the R/T arm showed a higher rate of para-aortic node relapse. The mean disease-free survival duration of 60.5 months (95% confidence interval [CI], 51.3 to 69.9 months) for the NAC arm was similar to that of 55.2 months (95% CI, 46.2 to 64.3 months) for the R/T arm. The median disease-free survival for the R/T arm was 67.7 months, and that for the NAC arm was not reached. The difference in disease-free survival for patients in the two treatment arms showed no statistical significance (P = .76) (Fig 2).
Survival The median duration of follow-up was 39 months. Fourteen patients (21%) in the NAC arm died of disease and one patient with diabetes mellitus died of urosepsis; 11 patients (21%) in the R/T arm died of disease and one died of unrelated disease. Overall survival (Fig 3) was similar for both arms (P = .77). The mean overall survival time was 67.7 months (95% CI, 59.4 to 76.1 months) for the NAC arm versus 62.2 months (95% CI, 53.9 to 70.6 months) for the R/T arm. Their median survival times were not reached. The 2-year survival rate was 81% (95% CI, 71% to 91%) for the NAC arm and 84% (95% CI, 72% to 95%) for the R/T arm, and the estimated 5-year survival rates were 70% (95% CI, 56% to 83%) and 62% (95% CI, 43% to 80%) for the NAC and R/T arms, respectively. Except for the aforementioned patient who had complete disappearance of the tumor over the cervix but lymph node metastasis, all patients who had a CR to NAC were alive with no evidence of disease at last follow-up. The effects of age (< 40 v 40 years; < 50 v 50 years; < 60 v 60 years), histologic diagnosis (squamous cell carcinoma v other diagnoses), and differentiation (well v moderate, poor, and undifferentiation; well and moderate v poor and undifferentiation) did not reach statistical significance.
Based on the results from our previous phase II study,30,31 induction chemotherapy involving two to three courses of cisplatin, vincristine, and bleomycin is effective in reducing tumor volume and facilitating surgical removal of bulky early-stage cervical tumors. This randomized trial was initiated to compare the efficacy and toxicity of NAC followed by radical hysterectomy with those of R/T alone in patients with bulky early-stage cervical carcinoma. To the best of our knowledge, this is the first report of a phase III trial focused on NAC and radical hysterectomy versus R/T for bulky early-stage cervical carcinoma. The disease-free survival and the overall survival of the patients who underwent NAC and hysterectomy did not differ significantly from those of patients treated with R/T alone. Patients in the NAC arm had a higher incidence of receiving adjuvant therapy, with either R/T or chemotherapy, after the scheduled treatment than those in the R/T arm, who received radical hysterectomy as the adjuvant therapy. The incidence of acute toxicity, mainly mild to moderate gastrointestinal and hematologic toxicity and urinary retention, was higher in the NAC arm than in the R/T arm, whereas the incidence of radiation cystitis, radiation proctitis, and lymphedema was higher in the R/T arm. The overall clinical response rate after NAC was 86.2%, including 24.6% CR and 61.6% PR, whereas a pathologic CR was present in only three patients (4.6%). These observations are comparable to our phase II study, which showed 24.2% CR and 60.6% PR and two patients with a pathologic CR among 39 patients who received two to three cycles of "quick" cisplatin, vincristine, and bleomycin before surgery.31 It has been noted that those who achieved a CR after NAC had superior survival than those with a PR or an SD. In this study and in our phase II study, a poor response of the primary tumor to subsequent irradiation was often observed in patients who did not receive a scheduled hysterectomy after NAC. We believe that after cisplatin the residual tumor is insensitive to subsequent irradiation. Cisplatin induces radioresistance in tumor cells,38 or this observation may be explained by tumor cells that survive after cisplatin with an inherent resistance to radiation. Hence, we propose that once NAC is applied, a definite surgical approach to radically remove the cervical residual tumor should be undertaken as the first priority. At the time of this writing, only two randomized controlled trials on early-stage bulky cervical cancer had been published. In the trial from the Gynecologic Oncology Group (GOG),39 women with bulky stage IB disease were randomly assigned to receive R/T alone or R/T with concurrent weekly cisplatin at 40 mg/m2 for up to six doses; all patients then underwent extrafascial hysterectomy. A marked reduction in the local recurrence rate (9% v 21%) and a slight decrease in the distant recurrence rate (10% v 13%) were observed in those who received concurrent radiation and cisplatin compared with those who received R/T alone. At a median follow-up of 36 months, 26% of the patients who had received R/T alone had died of disease; this is significantly higher than the 15% of patients who had received concurrent R/T and cisplatin. Our study differed from this GOG trial in that the GOG trial included only those patients with bulky stage IB cervical carcinoma and no radiographic evidence of lymphadenopathy. Our study included patients with bulky stage IB or IIA disease and did not exclude those with only pelvic lymph node enlargement. In our study, no routine hysterectomy was applied to our control group, and only six patients (12%) had residual tumors after R/T and had to undergo radical hysterectomy; in the GOG study, hysterectomy was part of the scheduled treatment for all patients. With similar follow-up periods, 79% of the patients in the R/T arm of our study were still alive, whereas in the GOG study, 74% of the patients treated with R/T followed by hysterectomy remained alive. Therefore, as mentioned in the Discussion of the GOG study, the value of hysterectomy in patients who have received an optimal regimen of R/T is doubtful. We believe it is only appropriate as a salvage therapy and that it should be undertaken with a more radical approach than an extrafascial hysterectomy. Sardi et al40 compared the efficacy of "quick" cisplatin, vincristine, and bleomycin as the NAC plus radical hysterectomy plus adjuvant radiotherapy with that of radical hysterectomy plus adjuvant R/T in the treatment of stage IB cervical cancer. A subgroup analysis specific to the patients with bulky tumors showed a statistically significant higher overall survival rate (80% v 60%) in the patient group who had NAC before surgery compared with the group not treated with NAC. In our trial, R/T was used as an optional adjuvant therapy. The overall survival of our NAC arm was 79%, and 28% of the patients in this arm received adjuvant R/T. Although the median follow-up period was longer in the study from Sardi et al (67 months) than in our study (39 months), we observed higher rates of late toxicities among patients who received both surgery and R/T than we did among patients who received only one local treatment modality, ie, either hysterectomy or R/T. Although NAC effectively reduces the primary tumor volume, 9% of the patients in the NAC arm had distant relapse as of this writing. This is only slightly lower than the 12% of patients with distant relapse in the R/T arm. However, 21% of the patients in the NAC arm and 12% in the R/T arm had local relapse. In contrast, in a randomized study of high-risk cervical cancer, a significant reduction in the distant relapse rate (14% v 33%) was observed in patients treated with pelvic radiation plus concurrent cisplatin and fluorouracil, compared with the control group treated with pelvic and para-aortic radiation.41 Another large-scale phase III trial of locally advanced cervical carcinomas also showed that radiation plus concurrent cisplatin-based chemotherapy consisting of either weekly cisplatin or a combination of cisplatin, fluorouracil, and hydroxyurea resulted in a lower frequency of lung metastasis (3% and 4%, respectively, v 10%) than radiation plus concurrent hydroxyurea.42 Moreover, in these two studies, reductions in local recurrence rates of 37% and 46% were noted in patients who received concurrent cisplatin as compared with those who did not. The decrease in both local and distant relapses resulted in significantly higher rates of progression-free and overall survival in the groups treated with concurrent cisplatin than in those treated without. These two large-scale studies and our own experience (data not shown) indicate that concurrent use of weekly cisplatin and R/T is significantly beneficial to patients with locally advanced cervical cancers, with acceptable increases in transient hematologic and gastrointestinal toxicities during and immediately after chemotherapy. When we considered the significant improvement in local control with the use of concurrent cisplatin and R/T for locally advanced cervical cancers and that only 11% of the patients in our R/T arm required hysterectomy, we hypothesized that concurrent cisplatin and R/T without routine hysterectomy may achieve similarly favorable results for early-stage bulky cervical carcinoma as cisplatin plus R/T followed by hysterectomy. Further studies are needed to confirm this hypothesis and to define the optimal regimen for these agents and other combinations.
Supported in part by grant no. NSC 86-2314-B182A-056 from the National Science Council, Executive Yuan, Taiwan. We thank Jacqueline Ming Liu, MD, Cancer Research Center, National Health Research Institutes, for her assistance in English editing and recommendations.
Presented at the Thirty-Fifth Annual Meeting of the American Society of Clinical Oncology, Atlanta, GA, May 15-18, 1999.
1. Pettersson F (ed): Carcinoma of the cervix, in Annual Report on the Results of Treatment in Gynecological Cancer. Stockholm, Sweden, International Federation of Gynecology and Obstetrics, 1988, pp 29-33
2.
Burghardt E, Pickel H: Local spread and lymph node involvement in cervical cancer. Obstet Gynecol 52:138-145, 1978 3. Chung CK, Nahhas WA, Stryker JA, et al: Analysis of factors contributing to treatment failures in stage IB and IIA carcinoma of the cervix. Am J Obstet Gynecol 138:550-556, 1980[Medline]
4.
Piver MS, Chung WS: Prognostic significance of cervical lesion size and pelvic node metastases in cervical carcinoma. Obstet Gynecol 46:507-510, 1975 5. Alvarez RD, Soong SJ, Kinney WK, et al: Identification of prognostic factors and risk groups in patients found to have nodal metastasis at the time of radical hysterectomy for early-stage squamous carcinoma of the cervix. Gynecol Oncol 36:130-135, 1989 6. Delgado E, Bundy B, Zaino R, et al: Prospective surgical-pathological study of disease-free interval in patients with stage IB squamous cell carcinoma of the cervix: A Gynecologic Oncology Group study. Gynecol Oncol 38:352-357, 1990[Medline] 7. Perez CA, Grigsby PW, Camel HM, et al: Irradiation alone or combined with surgery in stage IB, IIA, and IIB carcinoma of uterine cervix: Update of a nonrandomized comparison. Int J Radiat Oncol Biol Phys 31:703-716, 1995[Medline] 8. Durrance FY, Fletcher GH, Rutledge FN: Analysis of central recurrent disease in stages I and II squamous cell carcinomas of the cervix on intact uterus. AJR Radium Ther Nucl Med 106:831-838, 1969 9. Gallion HH, van Nagell JR Jr, Donaldson ES, et al: Combined radiation therapy and extra-fascial hysterectomy in the treatment of stage IB barrel-shaped cervical cancer. Cancer 56:262-265, 1985[Medline] 10. Rutledge FN, Wharton JT, Fletcher GH: Clinical studies with adjunctive surgery and irradiation therapy in the treatment of carcinoma of the cervix. Cancer 38:596-602, 1976[Medline] 11. Prestayko AW, D’Aoust JC, Issell BF, et al: Cisplatin (cis-diamminedichloroplatinum II). Cancer Treat Rev 6:17-39, 1979[Medline] 12. Vogl SE, Moukhtar M, Calanog A, et al: Chemotherapy for advanced cervical cancer with bleomycin, vincristine, mitomycin C, and cis-diamminedichloroplatinum (II) (BOMP). Cancer Treat Rep 64:1005-1007, 1980[Medline] 13. Alberts DS, Martimbeau PW, Surwit EA, et al: Mitomycin-C, bleomycin, vincristine, and cis-platinum in the treatment of advanced, recurrent squamous cell carcinoma of the cervix. Cancer Clin Trials 4:313-316, 1981[Medline] 14. Hall DJ, Diasio R, Goplerud DR: cis-Platinum in gynecologic cancer: II. Squamous cell carcinoma of the cervix. Am J Obstet Gynecol 141:305-308, 1981[Medline] 15. Thigpen T, Shingleton H, Homesley H, et al: Cis-platinum in treatment of advanced or recurrent squamous cell carcinoma of the cervix: A phase II study of the Gynecologic Oncology Group. Cancer 48:899-903, 1981[Medline] 16. Daghestani AN, Hakes TB, Lynch G, et al: Cervix carcinoma: Treatment with combination cisplatin and bleomycin. Gynecol Oncol 16:334-339, 1983[Medline] 17. Bloch B, Nel CP, Kriel A, et al: Combination chemotherapy with cisplatin and bleomycin in advanced cervical cancer. Cancer Treat Rep 68:891-893, 1984[Medline] 18. Friedlander ML, Atkinson K, Coppleson JV, et al: The integration of chemotherapy into the management of locally advanced cervical cancer: A pilot study. Gynecol Oncol 19:1-7, 1984[Medline] 19. Jobson VW, Muss HB, Thigpen JT, et al: Chemotherapy of advanced squamous carcinoma of the cervix: A phase I-II study of high-dose cisplatin and cyclophosphamide—A pilot study of the Gynecologic Oncology Group. Am J Clin Oncol 7:341-345, 1984[Medline]
20.
Bonomi P, Blessing JA, Stehman FB, et al: Randomized trial of three cisplatin dose schedules in squamous-cell carcinoma of the cervix: A Gynecologic Oncology Group study. J Clin Oncol 3:1079-1085, 1985 21. Coleman RE, Clarke JM, Slevin ML, et al: A phase II study of ifosfamide and cisplatin chemotherapy for metastatic or relapsed carcinoma of the cervix. Cancer Chemother Pharmacol 27:52-54, 1990[Medline]
22.
Wertheim MS, Hakes TB, Daghestani AN, et al: A pilot study of adjuvant therapy in patients with cervical cancer at high risk of recurrence after radical hysterectomy and pelvic lymphadenectomy. J Clin Oncol 3:912-916, 1985 23. Lai CH, Lin TS, Soong YK, et al: Adjuvant chemotherapy after radical hysterectomy for cervical carcinoma. Gynecol Oncol 35:193-198, 1989[Medline] 24. Killackey MA, Boardman L, Carroll DS: Adjuvant chemotherapy and radiation in patients with poor prognostic stage Ib/IIa cervical cancer. Gynecol Oncol 49:377-379, 1993[Medline] 25. Curtin JP, Hoskins WJ, Venkatraman ES, et al: Adjuvant chemotherapy versus chemotherapy plus pelvic irradiation for high-risk cervical cancer patients after radical hysterectomy and pelvic lymphadenectomy (RH-PLND): A randomized phase III trial. Gynecol Oncol 61:3-10, 1996[Medline] 26. Thomas GM: Adjuvant therapy after primary surgery for stage I-IIA carcinoma of the cervix. J Natl Cancer Inst Monogr 21:77-83, 1996 27. Sardi JE, di Paola GR, Cachau A, et al: A possible new trend in the management of the carcinoma of the cervix uteri. Gynecol Oncol 25:139-149, 1986[Medline] 28. Sardi J, Sananes C, Giaroli A, et al: Neoadjuvant chemotherapy in locally advanced carcinoma of the cervix uteri. Gynecol Oncol 38:486-493, 1990[Medline] 29. Sardi JE, di Paola GR, Giaroli A, et al: Results of a phase II trial with neoadjuvant chemotherapy in carcinoma of the cervix uteri. Gynecol Oncol 31:256-261, 1988[Medline] 30. Lai CH, Hsueh S, Chang TC, et al: Prognostic factors in patients with bulky stage IB or IIA cervical carcinoma undergoing neoadjuvant chemotherapy and radical hysterectomy. Gynecol Oncol 64:456-462, 1997[Medline] 31. 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 30:281-285, 1992[Medline] 32. Chang TC, Hsieh FS, Lai CH, et al: Comparison of the efficacy of tropisetron versus a metoclopramide cocktail based on the intensity of cisplatin-induced emesis. Cancer Chemother Pharmacol 37:279-285, 1996[Medline] 33. Hong JH, Tsai CS, Chang JT, et al: The prognostic significance of pre- and post-treatment SCC levels in patients with squamous cell carcinoma of the cervix treated by radiotherapy. Int J Radiat Oncol Biol Phys 41:823-830, 1998[Medline] 34. Hsu WL, Wu CJ, Jen YM, et al: Twice-per-day fractionated high versus continuous low dose rate intracavitary therapy in the radical treatment of cervical cancer: A nonrandomized comparison of treatment results. Int J Radiat Oncol Biol Phys 32:1425-1431, 1995[Medline] 35. Tsai CS, Lai CH, Wang CC, et al: The prognostic factors for patients with early cervical cancer treated by radical hysterectomy and postoperative radiotherapy. Gynecol Oncol 75:328-333, 1999[Medline] 36. National Cancer Institute: Guidelines for Reporting Adverse Drug Reactions. Bethesda, MD, National Cancer Institute, Division of Cancer Treatment, Cancer Therapy Evaluation Program, 1988 37. Lachin JM, Matts JP, Wei LJ: Randomization in clinical trials: Conclusions and recommendations. Control Clin Trials 9:365-374, 1988[Medline] 38. Poppenborg H, Munstermann G, Knupfer MM, et al: Cisplatin induces radioprotection in human T98G glioma cells. Anticancer Res 17:1131-1134, 1997[Medline]
39.
Keys HM, 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 40. Sardi JE, Giaroli A, Sananes C, et al: Long-term follow-up of the first randomized trial using neoadjuvant chemotherapy in stage Ib squamous carcinoma of the cervix: The final results. Gynecol Oncol 67:61-69, 1997[Medline]
41.
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
42.
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 Submitted July 6, 1999; accepted December 15, 1999. This article has been cited by other articles:
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2000 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
TOP
ABSTRACT
INTRODUCTION
2 test was used to test the association between discrete variables. 
