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© 2002 American Society for Clinical Oncology Retrospective Analysis of Carboplatin and Paclitaxel as Initial Second-Line Therapy for Recurrent Epithelial Ovarian Carcinoma: Application Toward a Dynamic Disease State Model of Ovarian CancerByFrom the Department of Medicine, Division of Developmental Chemotherapy, and Department of Gynecologic Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY. Address reprint requests to David Spriggs, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021; email: spriggsd{at}mskcc.org
PURPOSE: The majority of patients with epithelial ovarian cancer (EOC) who achieve a complete remission with front-line chemotherapy develop recurrent disease. Carboplatin and paclitaxel are used for patients with platinum-sensitive recurrent disease, although there is little information regarding the response and survival in unselected patients treated with this strategy. We sought to determine the outcomes for patients with EOC treated with carboplatin and paclitaxel at the time of first recurrence. In addition, we sought to define a new paradigm for disease transition in patients with EOC. PATIENTS AND METHODS: Eighty-nine patients were identified who had a complete response to front-line platinum-based chemotherapy for EOC, relapsed 6 months after completion of front-line chemotherapy, and were treated with carboplatin and paclitaxel as second-line therapy. RESULTS: Eighty-four cases were available for analysis of survival end points, and 66 were assessable for response. The median follow-up was 27 months. The overall response rate was 70%. The median progression-free interval for the cohort was 13 months (95% confidence interval [CI], 10.7 to 13.8 months). The 3-year survival rate was 72% (95% CI, 59.4 to 86.1%). Toxicity was limited, and no deaths from treatment were observed. Using this data, it is possible to construct a disease states model of EOC, which provides risk estimates for transitions between clinically distinct categories. CONCLUSION: Re-treatment with carboplatin and paclitaxel is effective as initial therapy in recurrent EOC. This should form the basis of a randomized trial to determine the best agents for initial treatment of relapse from EOC in potentially platinum-sensitive patients.
EPITHELIAL OVARIAN cancer (EOC) is the second most common gynecologic malignancy in the United States, with an estimated 25,200 new cases diagnosed in 1999.1 It is responsible for an estimated 14,500 deaths in women, more than those succumbing from cervical or uterine cancer combined.1 Despite ongoing research in screening, the majority of patients continue to be diagnosed with advanced-stage disease. For these patients, treatment consists of a combination of surgical debulking and chemotherapy. The Gynecologic Oncology Group (GOG) 111 study established cisplatin and paclitaxel as the standard front-line chemotherapy.2 Because this combination requires a 24-hour hospitalization and given the significant oto-, nephro-, and neurotoxicity associated with cisplatin, carboplatin was substituted for cisplatin in GOG 158, with an equivalent response rate and a better toxicity profile.3,4 A cumulative analysis of seven phase I/II trials, evaluating the combination of carboplatin and paclitaxel, showed an overall response rate of 81.4% with a complete response rate of 47.2%, further suggesting its equivalency with cisplatin and paclitaxel in the front-line therapy of ovarian cancer.5 Despite the high response rate to front-line therapy, the majority of patients will relapse and ultimately die of progressive disease. The options for treatment of recurrent disease have increased with the identification of several active second-line agents. However, no second-line agents are curative. The treatment-free interval (TFI) has been established as predictive for response to re-treatment with a platinum-containing regimen,6-8 although more recent data indicate it may not be an independent factor.9 It has been generally accepted that patients who have a treatment-free interval of less than 12, 13 to 24, and more than 24 months have a response rate of 26%, 33%, and 77%, respectively. Based on this data, carboplatin is often used as the initial second-line treatment in women who relapse after a prolonged interval. In addition, paclitaxel has documented activity in recurrent ovarian cancer as single-agent therapy.10,11 Given that the combination of a carboplatin and paclitaxel is now considered standard first-line therapy, both agents have also been used to treat women with recurrent disease. Few data exists regarding the outcomes in women treated with carboplatin and paclitaxel for recurrent ovarian cancer. We report the use of carboplatin and paclitaxel as the initial second-line treatment in women with recurrent EOC, fallopian tube, or primary peritoneal cancer (PPC) who were initially treated with a platinum-based regimen. The purpose of this study was to define the response rate, disease-free interval, and overall survival in this population. In addition, we sought to incorporate the data from this retrospective analysis into a new disease state model of EOC, which takes into account the increased duration of survival after achievement of subsequent remissions. Both PPC and fallopian tube cancers respond to paclitaxel and platinum in a clinically indistinguishable manner.12-14 Given the similarities in response and management of these diseases to ovarian cancer, they have been included in this analysis.
Patients with recurrent EOC, PPC, or fallopian tube cancer evaluated at our center between October 1993 and March 2000 were identified from our institutional database. All patients who met the following criteria were included in our cohort: (1) histologically confirmed diagnosis of an EOC, PPC, or fallopian tube cancer; (2) original treatment with a platinum-containing regimen; (3) achievement of a complete clinical remission defined as normalization of radiologic evidence of disease, CA-125, and physical examination after front-line therapy with remission duration of at least 6 months; (4) confirmation of relapse by clinical, histologic, biochemical, or radiographic measures; and (5) initial treatment of recurrent disease with carboplatin and paclitaxel. Patients treated with this combination at second or subsequent relapse were not included in this analysis. The diagnosis of recurrence was confirmed histologically in some patients but was not required. Patients with bidimensionally measurable disease by computed tomography (CT) or other radiographic means were considered measurable. For these patients, complete response to second-line treatment was defined as the disappearance of all evidence of disease for at least 1 month. Partial response was defined as reduction of at least 50% in the perpendicular diameters of the largest tumor mass for at least 1 month. Progression of disease was defined as a 50% or greater increase in the size of previously documented lesions or the appearance of new lesions during the observation period. Patients who were diagnosed with recurrence on the basis of CA-125 elevation more than 100 U/mL in the absence of measurable disease were considered assessable. Normalization of previously elevated levels of CA-125 (to < 35 units/mL) constituted evidence of a complete clinical response. Patients with a reduction of their CA-125 by at least 50%, but without normalization, were classified as having a partial response. All other responses were classified as stable disease. Any elevation greater than 75% of previously reported CA-125 constituted evidence of disease progression. Follow-up was measured from the initiation of second-line therapy to the date of last contact. Disease-free survival (DFS) was calculated in patients who achieved a complete response to second-line chemotherapy. It was defined as the time interval from the end of second-line treatment to the date of documented disease recurrence or last follow-up. Progression-free interval (PFI) was defined as the interval between the date of initiation of second-line therapy to date of documented relapse or last follow-up. Survival times were calculated from the date of initiation of second-line therapy to the date of last follow-up or death. Toxicity was measured based on the National Cancer Institute’s common toxicity criteria. Data was analyzed using S-Plus software (Insightful, Seattle, WA). DFS, PFI, and survival estimates were generated using Kaplan-Meier analysis.
Disease States Model for Ovarian Cancer
The purpose of this model is to better characterize homogenous groups of patients for clinical trials and to allow prognostic estimates for patients at various phases in their illness. In this model, patients enter into either the first complete remission state or the refractory disease state at the end of primary therapy. Both the probability of entry into remission or relapsed disease (P1S and P1R) are functions of initial stage, grade, and a variety of other biologic features. Note that these probabilities are overall risks and not rate constants. Some of these probabilities are well characterized by a number of randomized primary therapy trials. For example, using data from GOG 111 we can derive estimates of P1S and P1R.2 At the time of relapse, patients enter into either a potentially platinum-sensitive recurrent disease state or the refractory disease state, depending on the TFI, as described by Markman et al.8 For purposes of this analysis, a TFI of less than 6 months has been applied as the definition of refractory disease. Because this population has a lower response to nearly all chemotherapy agents (including cisplatin), this state is identified in the model as chemotherapy refractory disease. The estimated values for the risk of relapse from first clinical remission (P2S and P2R) are not readily available from the literature. Instead, most studies report a Kaplan-Meier estimate for time to progression for the entire population treated. Unfortunately, this analysis cannot provide estimates of these risks because the patients were selected for platinum sensitivity as part of the search criteria. However, the results of this retrospective study will be used to provide estimates within this model.
Chemotherapy
Patient Population
The demographics of this population are listed in Table 1. The median age at initial diagnosis of the women in this cohort was 51 years (range, 30 to 78 years). Seventy-eight (93%) of 84 patients had EOC. There were four cases (4.8%) of fallopian tube adenocarcinomas and two cases (2.4%) of PPC. Sixty-eight (81%) of 84 patients were stage III or IV at initial diagnosis. The majority of patients had papillary serous or endometrioid type adenocarcinomas.
Fifty-two (62%) of 84 patients were treated with cisplatin or carboplatin plus paclitaxel as first-line therapy. Fourteen patients (16.7%) were treated with a combination of platinum and cyclophosphamide, and 14 (16.7%) were treated with platinum-based, high-dose stem-cell protocols; 12 of these patients received paclitaxel as part of their high-dose chemotherapy protocol. Four patients were treated with a three-drug combination as upfront treatment (cyclophosphamide, doxorubicin, and cisplatin, n = 1; paclitaxel, doxorubicin, and cisplatin, n = 3). Fifty-two (62%) of 84 patients in this cohort underwent second-look surgery. Of these patients, 24 (48%) had a pathologic complete remission, and 27 (52%) had evidence of residual disease. The procedure was aborted in one patient because of significant adhesions from prior surgeries. Thirty-three (63%) of 52 patients underwent intraperitoneal therapy. The front-line management of the cohort is listed in Table 2.
The median TFI after front-line therapy was 22 months (range, 7 to 86 months). Fifteen patients (18%) had a TFI between 6 and 11 months, 32 (38%) had a TFI between 12 and 24 months, and 33 (39%) had a TFI greater than 24 months. In four patients, the TFI was not calculated because of incomplete data. Sixty-six (79%) of 84 patients had recurrent disease documented by CT or CT and elevated CA-125. In 11 patients (13%), recurrent disease was diagnosed by CA-125 alone. Of these patients, five of 11 had histologic confirmation of recurrent disease, and an additional three patients had abnormal CT scans but no measurable disease. Seven patients (8%) had evidence of recurrence on physical examination and underwent a surgical procedure. A total of 33 patients (39%) had histologic confirmation of recurrence. Twenty-one (25%) of 84 patients underwent second-look surgery at diagnosis of recurrent disease, all of whom had a TFI of greater than 12 months. In 18 patients, surgical resection was complete; these patients were not assessable at the start of second-line therapy. In the end, 66 patients (79%) were assessable for assessment of response, of which 58 had bidimensionally measurable disease. Four hundred fifty courses of carboplatin and paclitaxel were given (median, six courses; range, one to eight courses). Eighteen additional cycles of paclitaxel were administered.
Response Rates Results were similar when the analysis was restricted to patients with measurable disease only (n = 58). The overall response rate is 67% (37.9% CR + 29.3% PR), with 17.2% of patients having stable disease. The responses are similar when TFI is considered as well (TFI 6 to 11 months, 64%; 12 to 24 months, 71%; more than 24 months, 60%; Table 3, Fig 2). When analysis is restricted to patients treated with standard carboplatin or cisplatin and paclitaxel as initial therapy (n = 52), the overall response rate is 70% (43% CR + 27% PR), with 16% of patients having stable disease.
PFI The median PFI for the cohort was 13 months (95% confidence interval [CI], 10.7 to 13.8 months; Fig 3). When patients are stratified by their initial TFI of  24 months or more than 24 months a statistically significant difference was seen in the PFI, 10 versus 16 months, respectively (P = .001; Fig 4). In addition, the PFI was significantly greater in the subgroup that underwent surgical debulking at the time of relapse (n = 21) than the group who did not undergo debulking (n = 62), 17 versus 11 months, respectively (P = .04; Fig 5). For the 28 patients with a CR, the median disease-free interval was 13 months (95% CI, 10.4 to 32.1 months).
Overall Survival The median follow-up for the entire cohort is 27 months (range, 3.8 to 75.2 months). The 3-year survival rate was 72% (95% CI, 59.4% to 86.1%; Fig 6). The 3-year survival rates when stratified by initial TFI of 6 to 11, 12 to 24, and more than 24 months were 49%, 63%, and 84%, respectively (P = .29). The 3-year survival rate did not differ between those patients who underwent debulking surgery at first-relapse and those that did not.
Toxicity Toxicities were managed at the discretion of the treating physician by dose reduction, treatment cessation, or hospitalization. Initial second-line therapy with this combination was halted in seven (8.3%) of 84 patients. In one patient, therapy was stopped because of progressive sensory neuropathy. Five patients suffered an allergic reaction, of which one had anaphylaxis. All allergic reactions occurred during the second cycle of treatment. The final patient requested to come off treatment because of significant fatigue. There were no deaths reported with re-treatment. Six (7.1%) of 84 patients required hospitalization during their treatment. One patient was hospitalized twice with dehydration and grade 4 nausea and vomiting during her therapy. A second patient was hospitalized with herpetic mucositis in the setting of neutropenia. A third patient was hospitalized with an enterococcal urinary tract infection, during a time she was not neutropenic. She recovered well with appropriate antibiotics during her hospitalization and was able to receive her scheduled cycle of chemotherapy while an in-patient. A fourth patient was hospitalized for elective exploratory surgery after the completion of five cycles of therapy. Another patient was hospitalized for a small bowel obstruction felt secondary to adhesions. The final patient was hospitalized twice, once because of a partial small bowel obstruction and the second time for a community-acquired pneumonia.
Application of the Disease States Model
Despite the sensitivity of ovarian cancer to first-line chemotherapy, many women develop recurrent disease. The choice of treatment at relapse has been the focus of many phase II investigations, although the optimal second-line regimen has not been established. There is little published information regarding carboplatin and paclitaxel used as the initial second-line treatment in women with recurrent ovarian cancer after complete remission. In one study, Goldberg et al17 treated 49 patients with recurrent or persistent ovarian cancer after at least one platinum-containing regimen. The CR rate was 37%, and the overall response rate was 53%. The median overall survival was 12 months. However, only 19 of 38 assessable patients had platinum-sensitive disease.17 In a study by Rose et al,18 25 patients with platinum-sensitive recurrent ovarian cancer only were treated with carboplatin and paclitaxel. Using similar criteria for response, they reported a 70% CR rate and a 90% overall response rate. Median overall survival from the completion of secondary therapy was 10+ months.18 The median PFI and overall survival were not reached. In this retrospective study of platinum-sensitive patients who received carboplatin and paclitaxel as their initial second-line therapy, the complete response and overall response rate were 42% and 70%, respectively. The median PFI was 13 months. In 28 patients who achieved a complete response, DFS was 13 months. At the time of this report, the median follow-up for the cohort is 27 months, strongly suggesting that overall survival will exceed 2.5 years. Using Kaplan-Meier analysis, the 3-year overall survival is 72%. The 3-year overall survival and median PFI are similar, even when this analysis is restricted to patients who had measurable disease, 72% and 12 months, respectively. The activity of other chemotherapy agents in patients with platinum-sensitive disease at relapse have been published. McGuire et al19 reported a CR rate of 4.3% and an overall response rate of 33% to single-agent topotecan. The median PFI and median survival for the cohort were 9.6 and 20.2+ months, respectively. Gordon et al20 compared liposomal doxorubicin versus topotecan in a randomized trial of patients with relapsed ovarian cancer. Of 474 patients enrolled, 220 patients were considered platinum sensitive. The CR and overall response rates for platinum-sensitive patients treated with liposomal doxorubicin was 7.3% and 28.4%, respectively; for topotecan they were 9.0% and 28.8%, respectively. Median progression-free survival was approximately 7 and 6 months for doxorubicin and topotecan, respectively. Overall survival in this cohort with liposomal doxorubicin was 27 months and 18 months with topotecan (P = .008). Rose et al21 reported a CR rate of 14.6% and overall response rate was 34.1% in this population treated with oral etoposide. Median PFI was 6.3+ months, and median overall survival was 16.5+ months. Recently, the Nordic Gynecologic Oncology Group reported the results of paclitaxel in patients with advanced ovarian cancer previously treated with a platinum-based regimen.22 In the platinum-sensitive population, the CR rate was 25% and overall response rate was 40.6%. The median time to progression was 5.4 months, and the overall survival for all patients was 18.7 months. Lund et al22 reported an overall response rate with gemcitabine of 14% in platinum-sensitive patients. No complete responses were reported, although only eight of 50 patients in this cohort had platinum-sensitive disease. The median PFI was 2.8 months, and median overall survival was 6.2 months. These results are listed in Table 4.15,19-23
Our study represents the largest cohort of patients re-treated with this combination as first-line therapy at relapse. The vast majority of patients tolerated this therapy, and no deaths were reported. There was also a low incidence of peripheral neuropathy warranting cessation of therapy. Five of 84 patients experienced an allergic reaction to carboplatin during their second cycle, warranting discontinuation of therapy. Markman et al24 have reported a similar incidence of carboplatin-related allergic reactions. Several points are worth noting in this study. First, we chose to include a group of 11 patients treated for an elevated CA-125 based on criteria published by Rustin et al25 for use in clinical trials. Of this group, eight of 11 had findings consistent or suggestive of progression. In addition, Rose et al,18 in their report, used similar eligibility and response criteria.18 To have sufficient numbers for analysis, we chose less restrictive criteria for defining our cohort and required that they be treated with a platinum-containing regimen as upfront therapy. It is noteworthy that the overall response rates of this cohort and the subgroup treated with standard platinum plus paclitaxel as adjuvant treatment are almost identical. This suggests that the entire group of patients with platinum-sensitive disease at recurrence are more similar than different with regard to subsequent responses. Therefore, this analysis should still prove to be of benefit. Our median age is approximately 10 years younger than that of other clinical trials reported. Several large population-based studies have reported that younger women tend to live longer compared with an older cohort.26,27 In one GOG study, Thigpen et al26 concluded that age, volume of residual disease, and performance status were major prognostic variables, with poorer outcomes in women older than 69 years, which was not related to treatment differences. Other large studies have not found age to be a prognostic variable.28,29 Most studies define the age cutoff between the sixth and seventh decades, suggesting that between the fifth and sixth decades, there is no significant difference in outcome. In a recent report, Lee et al29 retrospectively looked at the outcome of women with ovarian cancer treated with platinum-based chemotherapy in three randomized phase III trials. Although age less than 40 years was found to be a significant prognostic variable, little difference in overall survival was seen in patients between 50 and 70 years old, suggesting that age becomes a prognostic variable only in women less than 40 or more than 70 years old.29 We chose to include patients treated with this strategy who had PPC and fallopian tube primaries. The inclusion of these patients in ovarian trials has been done in prior studies and is the practice of GOG in conducting ovarian cancer therapy trials. Given the similar response to carboplatin and paclitaxel in women with these tumors and the similar clinical behaviors of these tumors to ovarian cancer, we feel the inclusion of women with these primaries is appropriate.
Our results show that the response rate for patients with a TFI more than 24 months was lower than what was seen in patients with a TFI of 6 to 11 or 12 to 24 months (Fig 1). These results were not statistically significant but do run contrary to previously reported studies showing that the TFI is predictive of a subsequent response to platinum-containing regimens.6-8 However, Eisenhauer et al9 recently studied the results in individual trials involving five agents for predictors of second-response. In a multivariate analysis, the TFI was not an independent factor for response. Only when the TFI was used as a categorical measure of less than 6 or It is also noted that twenty of 84 patients underwent surgical debulking at the time of diagnosis of recurrence. Further analysis shows that when the patients in this cohort were stratified to a debulked versus nondebulked subgroup, no difference in 3-year survival was seen, although a difference in PFI was noted. The extended survival of this cohort reinforces the paradigm of ovarian cancer as a chronic disease. With a median follow-up of 27 months, it is evident that survival will be beyond 2 years. Our analysis suggests that more than 70% of patients will be alive beyond 3 years. It is impossible to know how much this treatment contributes to the long median overall survival versus the contribution of other agents delivered after the cancer recurs. Similarly, the relative value of immediate versus delayed platinum/taxane chemotherapy cannot be ascertained from this data. However, the apparent variance between this data and the nonplatinum/taxane therapy emphasizes the need for randomized trials in this population. Such trials are already appearing in the literature. A recently completed trial compared carboplatin plus epidoxorubicin versus carboplatin as second-line treatment in 190 women with carboplatin-sensitive ovarian cancer. The overall response rate and 3-year survival was 58% and 42% versus 55% and 29%, respectively, which did not reach statistical significance.30 Finally, this is the first application of the disease state model to ovarian cancer. Although it is possible to imagine a different formulation of the model, this first iteration allows a simple visualization of the ovarian cancer population. For example, not all authorities would separate the patients by platinum-free interval. A large retrospective analysis suggested that TFI was not an independent predictor of chemotherapy response, whereas the large randomized study of liposomal doxorubicin versus topotecan did support the platinum-free interval as an important variable in the prediction of response.9,20 The goal of the disease state formulation is to divide the affected population into clinically homogenous groups for purposes of prognosis and clinical trial participation. This grouping into disease states also allows additional research into clinical and biologic characteristics to guide patient management innovation. It is noteworthy that this disease state model identifies a new ovarian cancer group for clinical trials (the second remission group) and provides a framework for the understanding of the clinical behavior of such patients. The results of this retrospective analysis suggest that treatment with carboplatin and paclitaxel, as first-line therapy at relapse of ovarian cancer in women treated with a platinum-containing regimen initially, is associated with a high response rate and prolonged survival. These results should be interpreted cautiously given the heterogenous population included in this analysis but should form the basis of a randomized trial against single-agent carboplatin in the second-line setting. This would be important to identify an appropriate standard treatment for comparing investigational regimens.
Supported by grant no. PO1-CA52477-08. D.S.D. was partially funded by grant no. NIH-5-T32-CA-09207-24.
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McGuire WP, Hoskins WJ, Brady MF, et al: Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer. N Engl J Med 334: 1-6, 1996
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Neijt JP, Engelholm SA, Tuxen MK, et al: Exploratory phase III study of paclitaxel and cisplatin versus paclitaxel and carboplatin in advanced ovarian cancer. J Clin Oncol 18: 3084-3092, 2000 4. Ozols RF, Bundy BN, Fowler J, et al: Randomized phase III study of cisplatin/paclitaxel in optimal stage III epithelial ovarian cancer (a Gynecologic Oncology Group trial (GOG 158). Proc Am Soc Clin Oncol 18: 356a, 1999 (abstr 1373) 5. DuBois A, Neijt JP, Thigpen JT: First-line chemotherapy with carboplatin plus paclitaxel in advanced ovarian cancer: A new standard of care? Ann Oncol 10: S35-S41, 1999 (suppl 1) 6. Blackledge G, Lawton F, Redman C, et al: Response of patients in phase II studies of chemotherapy in ovarian cancer: Implications for patient treatment and the design of phase II trials. Br J Cancer 59: 650-653, 1989[Medline] 7. Gore ME, Fryatt I, Wiltshaw E, et al: Treatment of relapsed carcinoma of the ovary with cisplatin or carboplatin following initial treatment with these compounds. Gynecol Oncol 36: 207-211, 1990[CrossRef][Medline] 8. Markman M, Rothman R, Hakes T, et al: Second-line platinum therapy in patients with ovarian cancer previously treated with cisplatin. J Clin Oncol 9: 389-393, 1991[Abstract]
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Eisenhauer EA, Vermorken JB, van Glabbeke M: Predictors of response to subsequent chemotherapy in platinum pretreated ovarian cancer: A multivariate analysis of 704 patients. Ann Oncol 8: 963-968, 1997 10. McGuire WP, Rowinsky EK, Rosenshein NB, et al: Taxol: A unique antineoplastic agent with significant activity in advanced ovarian epithelial neoplasms. Ann Intern Med 111: 273-279, 1989
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Thigpen JT, Blessing JA, Ball H, et al: Phase II trial of paclitaxel in patients with progressive ovarian carcinoma after platinum-based chemotherapy: A Gynecologic Oncology Group study. J Clin Oncol 12: 1748-1753, 1994 12. Cormio G, Maneo A, Gabriele A, et al: Treatment of fallopian tube carcinoma with cyclophosphamide, adriamycin, and cisplatin. Am J Clin Oncol 20: 143-145, 1997[CrossRef][Medline] 13. Barakat RR, Rubin SC, Saigo PE, et al: Cisplatin-based combination chemotherapy in carcinoma of the fallopian tube. Gynecol Oncol 42: 156-160, 1991[CrossRef][Medline] 14. Gemignani M, Hensley ML, Cohen R, et al: Paclitaxel-based chemotherapy in carcinoma of the fallopian tube. Gynecol Oncol 80: 16-20, 2001[CrossRef][Medline] 15. Scher HI, Heller G: Clinical states in prostate cancer: Toward a dynamic model of disease progression. Urology 55: 323-327, 2000[CrossRef][Medline] 16. Gordon AN, Fleagle JT, Guthrie D, et al: Interim analysis of a phase III randomized trial of Doxil/Caelyx (D) versus Topotecan (T) in the treatment of patients with relapsed ovarian cancer. Proc Am Soc Clin Oncol 19: 380a, 2000 (abstr 1504) 17. Goldberg JM, Piver MS, Hempling RE, et al: Paclitaxel and cisplatin combination chemotherapy in recurrent epithelial ovarian cancer. Gynecol Oncol 63: 312-317, 1996[CrossRef][Medline]
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McGuire WP, Blessing JA, Bookman MA, et al: Topotecan has substantial antitumor activity as first-line salvage therapy in platinum-sensitive epithelial ovarian carcinoma: A Gynecologic Oncology Group study. J Clin Oncol 18: 1062-1067, 2000
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Gordon AN, Fleagle JT, Guthrie D, et al: Recurrent epithelial ovarian carcinoma: A randomized phase III study of pegylated liposomal doxorubicin versus topotecan. J Clin Oncol 19: 3312-3322, 2001 21. Rose PG, Blessing JA, Mayer AR, et al: Prolonged oral etoposide as second-line therapy for platinum-resistant and platinum-sensitive ovarian carcinoma: A Gynecologic Oncology Group study. J Clin Oncol 16: 405-410, 1998[Abstract]
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Lund B, Hansen OP, Theilade K, et al: Phase II study of gemcitabine (2',2'-difluorodeoxycytidine) in previously treated ovarian cancer patients. J Natl Cancer Inst 86: 1530-1533, 1994
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Markman M, Kennedy A, Webster K, et al: Clinical features of hypersensitivity reactions to carboplatin. J Clin Oncol 17: 1141, 1999
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Vergote I, Rustin GJ, Eisenhauer EA, et al: New guidelines to evaluate the response to treatment in solid tumors [ovarian cancer]—Gynecologic Cancer Intergroup. J Natl Cancer Inst 92: 1534-1535, 2000 26. Thigpen T, Brady MF, Omura GA, et al: Age as a prognostic factor in ovarian carcinoma: The Gynecologic Oncology Group experience. Cancer 71: 606-614, 1993[Medline] 27. Marsoni S, Torri V, Valsecchi MG, et al: Prognostic factors in advanced epithelial ovarian cancer: Gruppo Interregionale Cooperativo di Oncologia Ginecologica (GICOG). Br J Cancer 62: 444-450, 1990[Medline]
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Redman JR, Petroni GR, Saigo PE, et al: Prognostic factors in advanced ovarian carcinoma. J Clin Oncol 4: 515-523, 1986 29. Lee CK, Pires de Miranda M, Ledermann JA, et al: Out-come of epithelial ovarian cancer in women under 40 years of age treated with platinum-based chemotherapy. Eur J Cancer 35: 727-732, 1999 30. Bolis G, Scarfone G, Giardina G, et al: Carboplatin alone vs carboplatin plus epidoxorubicin as second-line therapy for cisplatin- or carboplatin-sensitive ovarian cancer. Gynecol Oncol 81: 3-9, 2001[CrossRef][Medline] Submitted December 14, 2000; accepted November 12, 2001. This article has been cited by other articles:
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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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ABSTRACT
INTRODUCTION
6 months was it important, and even then, it was highly correlated with tumor volume.
