www.OncologyReport.com 63
Articles by Bruce K. Dixon, Fran...
Gynecologic Malignancies ENDOMETRIAL CANCER
www.OncologyReport.com 65
Gynecologic Malignancies OVARIAN CANCER
Doxil Comparable t...
Maintenance Paclitaxel Fails to Improve Survival
www.OncologyReport.com 67
Canfosfamide Disappoints in Two Ovarian Cancer Trials
The ...
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THE ONCOLOGY REPORT (Fall 2007) :: Gynecologic Malignancies

  1. 1. www.OncologyReport.com 63 GYNECOLOGICMALIGNANCIES:CERVICALCANCER Gynecologic Malignancies Articles by Bruce K. Dixon, Fran Lowry, and Patrice Wendling Commentary by J. Tate Thigpen, M.D. Professor of Medicine Director, Division of Medical Oncology University of Mississippi Jackson CERVICAL CANCER Model Predicts Response to Cisplatin-Based Therapy Apredictive model based on five risk factors may help guide re- searchers and clinicians in the planning of chemotherapy for women with advanced or recurrent cervical can- cer, according to researchers with the Gynecologic Oncology Group. Using a pooled multivariate analysis of three published phase III Gyneco- logic Oncology Group (GOG) studies involving 816 patients evaluable for re- sponse, the investigators identified the following prognostic factors for de- creased patient response to cisplatin- based chemotherapy, Dr. David H. Moore said in an interview: • Performance status 1 or 2 (versus 0). • Being African American. • Cancer recurrence within, rather than outside, the pelvis. • Prior chemotherapy with primary radiation. • Time to recurrence of less than 1 year. With the exception of race, these fac- tors also were independently associated with increased risk of death, while pa- tient age under 50 years (which was dropped from the list) was predictive of poor response only with cisplatin monotherapy, said Dr. Moore of St. Francis Hospitals & Health Centers in Indianapolis. Patients with none of the five factors would be considered at low risk for poor response to cisplatin or cisplatin-con- taining therapy, while having two to three factors would imply medium risk and four or five would place the patient at high risk of poor response. The investigators used data from the GOG 110, 169, and 179 trials to de- velop the model. They validated it by analyzing the GOG 149 database of 428 patients in a published phase III trial of cisplatin plus ifosfamide vs. cis- platin/ifosfamide plus bleomycin. “That test upheld our model, so what we’re proposing within the GOG is that in future trials, this model should be used as a defined eligibility criterion such that, if you have a patient deemed at high risk, she should be moved into nonplatinum therapies or biologics,” Dr. Moore said in an interview. There’s also a message for clinicians, he added: “If a patient with cervical can- cer has a pelvic recurrence, has never had complete response with chemora- diation therapy, is African American, and has a performance status of 2, I think this person would be unlikely to derive any benefit from a platinum- based therapy and perhaps should be steered into an investigational trial.” Dr. Moore noted that response was chosen as the primary end point of the study because data from GOG protocols 110 and 169 showed that adding ifos- famide to cisplatin and paclitaxel to plat- inum significantly improved response rates but had no effect on survival. While topotecan improved survival in protocol 179, Dr. Moore cautioned that increasing numbers of patients en- tering such trials have received prior chemotherapy in addition to radiation. “Even though there’s an impact on sur- vival of the addition of an agent to plat- inum versus platinum alone, the ques- tion is, is it really better treatment, or have we pushed the response rates to single-agent cisplatin in our control group to such a low level that it’s not so much that our experimental arm is doing a lot better? Rather, it may be that our control arm is now doing so poorly that we see a survival advantage with the combination therapy,” he said. Discussant Dr. Robert L. Coleman said predictive modeling is important for hypothesis generation and for developing strata for future trials. “In addition, this type of analysis gives us valuable insight into anticipated outcomes,” said Dr. Coleman of University of Texas M.D. Anderson Cancer Center, Houston. Limitations of the study, he added, include artificially allocated equal weighting and use of factors not equal- ly represented in the individual trials from which they were derived. “Lastly, it’s not entirely clear that such model- ing will be applicable to cohorts not treated with platinum or in whom al- ternative strategies may be used, such as biologics,” he said. Meanwhile, the GOG cervix and vul- va committee is planning a chemother- apy protocol for patients with advanced, recurrent/metastatic cervical cancer, said Dr. Moore. “They do not intend to use this model in the next study for defin- ing eligibility. However, they intend to apply the model to see if its predictive value extends beyond platinum-con- taining regimens,” he said. The next study will be a four-arm tri- al with platinum being absent from two of those arms, Dr. Moore added. ■ Moore D.H. et al. Factors predictive of re- sponse to cisplatin-based chemotherapy in stage IVB persistent or recurrent cervical carcinoma: A multivariate analysis of three Gynecologic Oncology Group trials. Abstract 5534. In 1999, the National Cancer Insti- tute issued a clinical alert that de- clared cisplatin-based concurrent chemoradiation as the standard of care of patients with stages IB-IVA carcinoma of the cervix. The alert was based on the results of five ma- jor randomized trials that showed a 24%-51% reduction in mortality with this approach, as opposed to radiation alone or in combination with other radiosensitizers. Prior to that clinical alert, most patients with recurrent or disseminated dis- ease were chemotherapy naive and responded best to cisplatin-based chemotherapy. Gynecologic Oncology Group (GOG) studies since 1999 have shown a marked reduction in the response rate to cisplatin-based regimens; and the GOG phase II ef- fort has identified a number of ac- tive nonplatinum agents. These facts prompted Moore et al. to eval- uate the GOG database for patient- related characteristics that predict- ed a lower response to standard platinum-based chemotherapy. The study identifies five risk fac- tors that predict poor response to platinum-based chemotherapy for advanced or recurrent cervix carci- noma: performance status 1 or 2 vs. 0, African American ethnicity, recurrence in the pelvis as opposed to elsewhere, prior concurrent chemoradiation, and recurrence within 1 year of diagnosis. The in- vestigators suggest that presence of four or five of these factors identi- fies a high-risk patient who should be considered for nonplatinum- based chemotherapy or biologics rather than standard platinum- based regimens. However, while the study certain- ly suggests that patients with sever- al risk factors will not do as well with standard therapy, insufficient data for the superior efficacy of nonplatinum regimens in these pa- tients argues for clinical trials rather than for the use of nonplat- inum regimens as routine practice in these patients. The GOG has planned a study of nonplatinum regimens in this setting to begin the process of assessing whether these regimens represent a realistic and effective alternative approach for these high-risk patients. Until these data are available, the stan- dard of care for advanced or recur- rent disease should remain plat- inum-based combination chemotherapy. — J. Tate Thigpen, M.D. C o m m e n t a r y GOG analysis finds five risk factors based on published results of phase III trials. ‘In future trials … if you have a patient deemed at high risk, she should be moved into nonplatinum therapies or biologics.’ —Dr. Moore
  2. 2. 64 Fall 2007 • The Oncology ReportGYNECOLOGICMALIGNANCIES:ENDOMETRIALCANCER Gynecologic Malignancies ENDOMETRIAL CANCER No Benefit but More Toxicity With EBRT in Stage I Disease Women with stage I endome- trial cancer do not need ad- ditional treatment with ex- ternal beam radiation therapy. In fact, blended data from two trials suggest it may do more harm than good. The two trials—A Study in the Treat- ment of Endometrial Cancer (ASTEC) from the United Kingdom and the Na- tional Cancer Institute of Canada Clin- ical Trials Group EN.5 trial—found ex- ternal beam radiation therapy (EBRT) conferred no overall survival benefit af- ter complete surgical removal of all visible tumor, and that the associated toxicity was more than twice as com- mon, Dr. Ann Marie Swart said in a press briefing. Nor was EBRT of any benefit in reducing recurrence. Consequently, “external beam radia- tion therapy is not routinely recom- mended,” said Dr. Swart of the Medical Research Council Clinical Trials Unit, London, which funded ASTEC. The results were hailed by Dr. Julie R. Gralow of the University of Wash- ington, Seattle, who moderated the briefing. “This is very exciting news in the gynecologic oncology field. Almost 40,000 women in the United States alone are diagnosed with endometrial cancer and uterine cancer each year. About three-quarters of these women would qualify for this trial because their tumors are confined to the uterus. This is a lot of radiation we can avoid.” ASTEC and EN.5 started indepen- dently, but it was decided “very early on” to combine the analysis and moni- toring, Dr. Swart said. Between Octo- ber 1996 and April 2005, 905 women with stage I endometrial cancer were randomized to EBRT (452 patients re- ceiving 40-46 Gy in 20-25 fractions to the pelvis) or to no further treatment (453 patients) until recurrence. Brachytherapy to the vagina was given to 52% of the patients in both arms. At 51 months of follow-up, 5-year survival was 84%; 5-year disease-spe- cific survival 89%; and 5-year recur- rence-free survival 78% with no differ- ence between arms. However, 56% (253) of patients given EBRT experi- enced toxicity vs. 24% (109) in the no- EBRT arm; rates of grade 3/4 toxicity were 7% (32) and 3% (15), respectively. Dr. Swart noted the Post-Operative Radiation Therapy for Endometrial Car- cinoma (PORTEC-1) trial, and Gyne- cologic Oncology Grop (GOG)–99 tri- al had similar findings. “Looking at the results in over 2,000 women from these trials, the hazard ratio is 1.02, which equals a 0.2% difference in overall sur- vival in favor of EBRT. The good news from this trial is that women with ear- ly-stage endometrial cancer have quite good outcomes without EBRT, and these are women with a median age of about 65 years,” she said. ■ Orton J. et al. Adjuvant external beam radiotherapy (EBRT) in the treatment of endometrial cancer: Results of the ran- domised MRC ASTEC and NCIC CTG EN.5 trial. Abstract 5504. ‘The good news from this trial is that women with early-stage endometrial cancer have quite good outcomes without EBRT.’ Dr. Swart This study by Orton and colleagues- focused on what role, if any, exter- nal beam radiation therapy (EBRT) has in patients with intermediate- risk endometrial carcinoma. This was defined as including patients having either FIGO stage IA or IB, endometrial carcinoma that was ei- ther grade 3 or papillary serous his- tology, and all patients with stage IC or IIA disease. Overall survival for this group of patients has been estimated to be 85%, and this study produced a very similar 5-year survival of 84%. When disease-specific survival was evaluated, again there was no sig- nificant difference with an overall 5-year disease-specific survival of 89%. The only significant differ- ence favoring the use of EBRT was a decrease in the frequency of iso- lated vaginal or pelvic initial recur- rences; that is, 4% with EBRT vs. 7% without (hazard ratio 0.53, P = .038). The study also showed no evidence that the effect of EBRT was smaller or greater in subgroups defined by age, performance status, nodal involvement, depth of inva- sion, grade, or extent of disease. The investigators presented a meta-analysis of the three major randomized trials that looked at the role of EBRT in intermediate-risk endometrial carcinoma: this study, GOG 99, and the PORTEC study. None found radiation had an impact on overall survival, but toxicity was substantially greater. These three trials make a convincing case that there is no role for EBRT in interme- diate-risk endometrial carcinoma. — J. Tate Thigpen, M.D. C o m m e n t a r y Advanced Endometrial Cancer Treated With mTOR Inhibitor An experimental mTOR inhibitor produced partial remissions and disease stabilization in an open-label study enrolling chemotherapy-naive and previously treated patients with pro- gressive, advanced endometrial cancer. Dr. Nicoletta Colombo reported the mTOR (mammalian target of ra- pamycin) inhibitor AP23573 (Ariad Pharmaceuticals) was given to 45 women with advanced disease and doc- umented progression in the 3 months before study entry. The cohort included patients with mixed histologies. All but two had pre- vious chemotherapy, and 30 women had previously received pelvic radio- therapy. Median age was 67 years. The women received 12.5 mg of AP23573 as an intravenous infusion for 5 days every 2 weeks, reported Dr. Colombo of the European Institute of Oncology, Milan. Clinically beneficial responses were seen in 13 patients. “We observed 4 par- tial remissions, which represented 9% of the cohort, and 9 patients had stable disease lasting longer than 16 weeks, giving us a total clinical response of 29% in this heavily treated population,” Dr. Colombo said at a poster session. Of the four patients with partial re- sponses, two had adenocarcinomas, one had an adeno-clear cell carcinoma, and one had a papillary serous carcinoma. Treatment was discontinued before four cycles in 18 patients because of progres- sive disease (14), consent withdrawal (1), or unrelated adverse events (3). “This kind of drug activity in ad- vanced endometrial cancer is very in- teresting, especially in view of how well the women tolerated the treat- ment,” she said. About one-third of patients devel- oped fatigue, anemia, mucositis, or nau- sea and vomiting. Most adverse events were grades 1 or 2. There were 16 grade 3 or 4 events, mirroring rates in previ- ous AP23573 trials, Dr. Colombo said. Discussant Dr. Martin Gore said “en- dometrial cancer is crying out for mTOR inhibition.” He called the re- sponses in chemotherapy-naive patients encouraging and said they indicate mTOR inhibition would be a reason- able approach for any patient with ad- vanced endometrial cancer. “Even though it’s only two patients, two out of two responded, and I cer- tainly would be very comfortable in giv- ing this material to chemotherapy-naive patients if they have metastatic en- dometrial cancer. One can always give them chemotherapy down the line,” said Dr. Gore of the Royal Marsden Hospital, London. ■ Colombo N. et al. A phase II trial of the mTOR inhibitor AP23573 as a single agent in advanced endometrial cancer. Ab- stract 5516. This study by Colombo et al. identi- fies potentially interesting activity for a new mTOR inhibitor, AP23573. These data suggest that this agent should be evaluated fur- ther in combination with chemotherapy in patients not previ- ously exposed to systemic agents. One cannot, however, draw the conclusion that the agent has a role in the management of endometrial carcinoma when the objective re- sponse rate is less than 10% and the agent has not been shown to af- fect progression-free survival or overall survival in a randomized tri- al. The mTOR inhibitors are an in- teresting category of targeted agents with potential usefulness in endometrial carcinoma. We should anxiously await the next studies of this agent in this disease. In the in- terim, the optimal systemic therapy remains chemotherapy that in- cludes two or more of the following: anthracyclines, taxanes, and plat- inum agents. — J. Tate Thigpen, M.D. C o m m e n t a r y
  3. 3. www.OncologyReport.com 65 GYNECOLOGICMALIGNANCIES:OVARIANCANCER Gynecologic Malignancies OVARIAN CANCER Doxil Comparable to Gemcitabine in Phase III Trial Aphase III trial has reported gemcitabine was shown not to be superior to pegylated lipo- somal doxorubicin for patients with re- current ovarian cancer. Neither time to progression nor over- all survival was longer with pegylated liposomal doxorubicin (Doxil/PLD) in the 153-patient study. PLD was associ- ated with significantly less severe tox- icity, however, and significantly better quality of life scores, lead investigator Dr. Gabriella Ferrandina reported on behalf of the Multicentre Italian Trials in Ovarian Cancer (MITO) group. The researchers randomized 76 women to 40 mg/m2 of PLD over 1 hour on day 1 every 4 weeks, and 77 women to 1,000 mg/m2 of gemcitabine (Gemzar) over 30 minutes on days 1, 8, and 15 every 4 weeks. All patients had relapsed within 12 months from com- pletion of primary platinum/paclitaxel treatment or had evaluable lesions. The average age was 63 years in both groups. The number of delayed cycles was sig- nificantly more with gemcitabine than PLD (32 vs.13); the number of reduced cycles was similar (22 vs. 24). The study’s primary end point, median time to progression, was 16 weeks with PLD and 20 weeks with gemcitabine (P = .4). Median overall survival also was sim- ilar: 55 weeks in the PLD arm and 50 weeks in the gemcitabine arm (P = .17). Longer follow-up is needed to evaluate this secondary outcome fully, said Dr. Ferrandina, Catholic University, Rome. Three patients on PLD had a com- plete response, compared with two on gemcitabine. In addition, 8 patients on PLD and 15 on gemcitabine had partial responses. Among evaluable patients, overall response was 15.9% with PLD and 28.3% with gemcitabine. Among those treated with PLD, six patients had grade 3/4 leukopenia and five had grade 3/4 neutropenia. In con- trast, 15 patients treated with gemc- itabine had grade 3/4 leukopenia and 15 grade 3/4 neutropenia. The difference was statistically significant for both toxicities (P less than .05), the investi- gators reported. Grade 3/4 pruritic papular eruptions occurred in four pa- tients given PLD and none treated with gemcitabine (P = .06). Global quality of life scores were sig- nificantly higher among patients treat- ed with PLD (P less than .05). The dif- ference may reflect an easier dosing schedule for PLD, but still cannot be ig- nored, said discussant Dr. William P. McGuire, director of the Weinberg Cancer Institute, Franklin Square Hos- pital Center, Baltimore. Overall, the two drugs probably are equivalent in activity in platinum-re- sistant disease, although their toxicity profiles are different, Dr. McGuire said. Gemcitabine is approved in the Unit- ed States in combination with carbo- platin for advanced ovarian cancer that has relapsed at least 6 months after completion of platinum-based therapy. Doxil is approved for ovarian cancer that has progressed or recurred after pri- or platinum-based therapy. “The decision regarding choice of drugs should be based on a discussion with the patient, and depends more on the acceptance of specific toxicities than on real differences in terms of benefit,” Dr. McGuire said. ■ Ferrandina G. et al. A randomized phase III study of gemcitabine (GEM) versus pe- gylated liposomal doxorubicin (PLD) in progressive/recurrent ovarian cancer (OC). Abstract LBA5506. Ferrandina et al. randomized pa- tients with recurrent ovarian carci- noma who relapsed within 12 months of completing first-line pa- clitaxel/platinum to either pegylated liposomal doxorubicin (PLD) or gemcitabine regimens. The study was designed to show a 58% im- provement in time to progression with gemcitabine from a median of 12 weeks to 19 weeks. Overall response, median time to progression, and median survival were not statistically different. Quality of life was statistically supe- rior with PLD. Gemcitabine pro- duced more myelosuppression; PLD more hand-foot syndrome. Rational conclusions are that both agents have activity in plat- inum-resistant/refractory recurrent ovarian carcinoma and that neither agent has a major advantage over the other. Since most patients in this setting receive multiple single- agent therapies, gemcitabine and PLD will continue to have important roles in the management of these resistant/refractory patients. — J. Tate Thigpen, M.D. C o m m e n t a r y Serial CA125 Screening May Flag Early High-Risk Cancer Frequent serum CA125 testing in tandem with transvaginal sonogra- phy may be an effective screening method to detect ovarian cancer early in women at increased risk of the disease. When serial CA125 levels were ana- lyzed using the previously established risk of ovarian cancer algorithm (ROCA), the overall specificity was 99.7% and positive predictive value 13% among 2,343 high-risk women in a prospective pilot study. The results are encouraging because no proven strategy exists for these pa- tients, but larger studies are needed to validate the findings, Steven J. Skates, Ph.D., reported. “Serial CA125 testing essentially establishes a baseline value for each woman that personalizes the in- terpretation of each new CA125 result to determine if ultrasound is indicated at a particular time,” he said in an in- terview. The ROCA has previously shown greater positive predictive value and sensitivity than a single CA125 test when screening healthy postmenopausal women for ovarian cancer (J. Clin. On- col. 2005;23:7919-26). The current study defined high-risk women as those with a BRCA1 or BRCA2 mutation, or first- or second- degree relatives with a BRCA mutation or multiple breast or ovarian cancers, or women of Ashkenazi heritage and at least one first-degree or two second-de- gree relatives with breast or ovarian can- cer. Women with a prior diagnosis of ovarian cancer were excluded. Participants underwent CA125 test- ing every 3 months, and the risk of hav- ing ovarian cancer was recalculated af- ter each test based on the CA125 profile. Women with a greater than 1% risk were referred to ultrasound, and those with a greater than 10% risk to a gynecologic oncologist. Between July 2001 and September 2006, 19,549 CA125 tests were per- formed, totaling 6,284 woman-years of screening. Compliance was high, and the average number of CA125 tests was three per year. Of 628 referrals made to ultrasound, 414 were per- formed, resulting in 38 women (9%) undergoing study-indicated surgeries. Nine ovarian cancers were identified during screening—three were prevalent (one early stage, two late stage) and six were incident (five early stage, one late stage), reported Dr. Skates, ROCA Screening Study Group, Massachusetts General Hospital Cancer Center, Har- vard Medical School, in Boston. Three incident carcinomas were found on prophylactic oophorectomy in early stage. The ROCA detected two of the three remaining incident cases in early stage, and three of three prevalent cases. The positive predictive value of ROCA was higher at 22% in post- menopausal women, but is acceptable at 13% in high-risk women considering prophylactic oophorectomy after child- bearing, Dr. Skates said. He received grant support from Fujirebo Diagnos- tics Inc., a cosponsor of the study with the National Cancer Institute. ■ Skates S.J. et al. A prospective multi- center ovarian cancer screening study in women at increased risk. Abstract 5510. Ovarian carcinoma remains the ma- jor killer of women among gyneco- logic cancers, accounting for more than 60% of all deaths. This study by Skates et al. evaluated the effi- cacy of serial measurement of CA- 125 every 3 months and use of these values to calculate a risk of ovarian carcinoma. Among 38 women referred for surgery, nine ovarian carcinomas were discovered. Five were found in an early stage by the ROCA (Risk of Ovarian Cancer Algorithm), yielding a positive predictive value of 13%. It needs to be confirmed in a study large enough to find 30 cases. This pilot study is too small to draw definitive conclusions about the ROCA. We must be certain a screening test is truly of value in detecting early disease because a false-positive screening test for ovarian carcinoma usually results in a major invasive abdominal proce- dure. Use of serial CA125 measure- ments to screen for ovarian carcino- ma cannot be recommended for routine clinical use at this time. — J. Tate Thigpen, M.D. C o m m e n t a r y
  4. 4. 66 Fall 2007 • The Oncology ReportGYNECOLOGICMALIGNANCIES:OVARIANCANCER Maintenance Paclitaxel Fails to Improve Survival Maintenance paclitaxel after a complete response to initial therapy did not prolong sur- vival of women with advanced ovarian cancer in a phase III trial. No differences in progression-free sur- vival or overall survival were observed be- tween women randomized to observation and those given six courses of mainte- nance paclitaxel in the After-6 protocol 1 trial. The study enrolled women with advanced ovarian cancer that was in complete response to first-line platinum or paclitaxel chemotherapy. “The results of this trial do not sup- port the administration of maintenance paclitaxel to patients with carefully de- fined clinical or pathological complete response,” said lead investigator Dr. Pier F. Conte of the University of Mod- ena and Reggio Emilia, Modena, Italy. This is the fifth randomized trial to evaluate maintenance or consolidation chemotherapy in ovarian cancer, and only one has shown a positive result (J. Clin. Oncol. 2003;21:2460-5). Mark- man et al. reported that progression-free survival was significantly improved with 12 versus 3 cycles of maintenance paclitaxel. “There are now four of five negative trials in ovarian cancer, so I don’t know if we really need a meta-analysis,” com- mented discussant Dr. William P. McGuire, director of the Weinberg Cancer Institute, Franklin Square Hos- pital Center, Baltimore. Dr. McGuire hailed the After-6 trial for defining the increase in neurotoxi- city (28%) associated with six cycles of paclitaxel, something not reported in the longer Markman trial. “That was just with 6 cycles, so I can imagine with 12 cycles it would be significantly more,” he said. Between March 1999 and May 2006, 200 women with stages IIb-IV ovarian cancer in clinical or pathologic com- plete response after six courses of first- line platinum or paclitaxel chemother- apy were randomized to observation or to receive six cycles of intravenous pa- clitaxel 175 mg/m2 every 3 weeks. At admission, 47.5% of the women had a clinical response to first-line ther- apy as defined by a negative pelvic exam plus negative ultrasonography or CT scan and a CA-125 level less than 35 units since at least two courses. In addi- tion, 52.5% of women had a pathologic response as defined by a clinical response plus negative peritoneal cytology, and at least eight negative random biopsies. The median age was 59 years for 101 patients who received paclitaxel and 58 years for 99 patients in the control group. Overall, 63.5% of women had grade 3 tumors, 62.5% had stage IIIc disease, and 52.5% had no macroscop- ic disease after their first surgery. As of March 30, 2007, 107 patients (53.5%) had relapsed and 48 patients (24%) had died. Compliance with therapy was good, with 77% of patients completing the six cycles. Grade 3 sensory neuropathy was reported in 6.7% of treated patients and grade 2 in 21.3%, said Dr. Conte. The study’s primary outcome of me- dian progression-free survival was 34 months in the paclitaxel group and 30 months in the control group. Two-year progression-free survival was not sta- tistically different between groups (59% vs. 54%, P = .068). Median overall survival was 77 months in the paclitaxel maintenance arm. It has not been reached in the con- trol arm. Two-year overall survival was not statistically different between groups (87% vs. 90%, P = .13). Because 14 patients randomized to observation received maintenance pa- clitaxel, the investigators also per- formed a per protocol analysis. Again, progression-free survival and overall survival were not significantly different between groups, Dr. Conte said. In a Cox proportional hazard model, study arm, tumor grading, and clinical or pathologic response were not inde- pendent predictors of progression-free survival, while tumor stage and resid- ual disease were. Women with stage IIIc-IV tumors were three times more likely to progress (hazard ratio 3.10) than were those with lower-stage tu- mors, while women with macroscopic residual disease were nearly twice as likely to progress (HR 1.91) compared to those with no residual disease. The study was designed to enroll 250 patients, but accrual was stopped after an unplanned interim analysis showed the probability of observing a 15% im- provement in 2-year progression-free survival was less than 5%. The small size of the study and poor compliance in the control group were weaknesses of the study, Dr. McGuire observed. ■ Conte P.F. et al. Final results of After-6 protocol 1: A phase III trial of observation versus 6 courses of paclitaxel (Pac) in ad- vanced ovarian cancer patients in complete response (CR) after platinum-paclitaxel chemotherapy (CT). Abstract 5505. Only one previous randomized trial has shown a benefit for the ap- proach in this trial by the After 6 Italian Cooperative Group. An earli- er intergroup study by the South- west Oncology Group (SWOG) and the Gynecologic Oncology Group (GOG) demonstrated a highly signif- icant difference in median progres- sion-free survival (22 vs. 14 months, P = .0023) favoring 12 additional cycles of maintenance paclitaxel in advanced-disease pa- tients in a clinical complete re- sponse at the end of initial paclitax- el/platinum therapy. That trial also reported a nonsignificant difference in overall survival (53 vs. 46 months, P = .30). The temptation here is to con- clude that the After 6 trial refutes the earlier SWOG-GOG results. Sev- eral major differences and one par- ticular similarity between the two studies should be considered before such a conclusion is reached. First, the populations are differ- ent. The After 6 trial included pa- tients with a substantially better outlook, as is evidenced by the overall progression-free survival of 34 months, which is longer than that seen in GOG intraperitoneal studies of patients with small vol- ume disease (28 months being the longest in those trials). Half of the patients in the After 6 study had no macroscopic disease at the conclu- sion of their initial laparotomy, and only 20% had macroscopic disease greater than 2 cm. Furthermore, over half of the patients in the After 6 trial were documented to be in a pathologic complete response at the end of initial therapy. Second, this study used only six additional cycles of paclitaxel, whereas the SWOG-GOG trial gave 12 additional cycles to the experi- mental arm. The After 6 trial may actually demonstrate only that six additional cycles are not enough. At the very least, these results show that the oft-heard criticism of the SWOG-GOG trial’s not having a con- trol arm is a hollow criticism. If there is no difference between zero and six cycles, then there certainly is no difference between zero and three cycles. The three-cycle arm of the SWOG-GOG trial is, thus, a valid control arm. Finally, both this trial and the SWOG-GOG study suggest a much greater effect of maintenance therapy in those with excellent ini- tial responses. In the group with a pathologic complete response to initial therapy, the hazard ratio was 0.79 favoring the six cycles of maintenance paclitaxel. Similarly, in the SWOG-GOG trial, those pa- tients with a drop in their initial CA-125 to less than 10 experi- enced a statistically significant improvement in overall survival: 57 months vs. 41 months at the median. No final conclusion about the val- ue of maintenance paclitaxel in ovarian carcinoma can be reached on the basis of current evidence. The ongoing GOG study of mainte- nance taxane versus no further ther- apy in clinical complete responders should provide a basis for a final conclusion, but this study will need 4-6 more years of accrual and then further follow-up before results are available. For now, physicians should discuss the available studies openly and honestly with patients, so that the 75% of patients in a complete response after initial ther- apy can participate in the decision as to whether to take maintenance paclitaxel. — J. Tate Thigpen, M.D. C o m m e n t a r y ‘There are now four of five negative trials in ovarian cancer, so I don’t know if we really need a meta- analysis.’ —Dr. McGuire After-6 protocol 1 trial finds no benefit after complete response to initial therapy. Paclitaxel Maintenance Control Group (n = 101) (n = 99) Median progression-free survival 34 months 30 months 2-Year progression-free survival 59% 54% Median overall survival 77 months Not reached 2-Year overall survival 87% 90% Note: Differences were not statistically significant. Source: Dr. Conte Survival Comparisons in After-6 Protocol 1 Trial ELSEVIERGLOBALMEDICALNEWS
  5. 5. www.OncologyReport.com 67 GYNECOLOGICMALIGNANCIES:OVARIANCANCER Canfosfamide Disappoints in Two Ovarian Cancer Trials The experimental drug canfos- famide failed to achieve survival end points in two phase III tri- als in patients with platinum-refracto- ry or -resistant ovarian cancer. One study compared canfosfamide (TLK286, Telcyta) and carboplatin with pegylated liposomal doxorubicin (Dox- il) as second-line treatment in 247 pa- tients recruited at 66 sites. Dr. Peter G. Rose said progression-free survival was 3.5 months in both arms of the trial. A subgroup of 38 patients (19 in each arm) characterized by a drug-free peri- od of 6 months or longer responded more favorably to the combination, with an overall response rate of 31.6%. Drug-free period was defined as the time from last treatment with plat- inum-based chemotherapy to initiation of first study treatment. The second trial compared single- agent canfosfamide to topotecan (Hy- camtin) or pegylated liposomal dox- orubicin in 461 women with disease progression following second-line treat- ment with doxorubicin or topotecan. Dr. Ignace Vergote, University Leuven (Belgium), said median overall survival was 8.5 months for canfosfamide, 10.8 months with topotecan and 14.2 months with doxorubicin (P = .0001). Telik Inc. sponsored both studies. Dr. Rose’s group randomized 123 women to receive intravenous canfos- famide (750 mg/m2) in combination with carboplatin (AUC = 5) monthly, while 124 women received doxorubicin at 50 mg/m2 monthly. Though more frequent in the combination arm, hema- tologic toxicity was well managed with growth factor support or dose reduc- tions, according to the investigators. Grade 3/4 thrombocytopenia occurred in 33% of the women on canfosfamide and carboplatin. About 20% of both arms had grade 3/4 neutropenia. The combination’s failure to meet end points “may in part be due to the challenges of radiologic imaging inter- pretation in ovarian cancer as well as to the complex biology involved in plat- inum resistance and resensitization,” said Dr. Rose, a professor of reproduc- tive biology and oncology at Case West- ern Reserve University, Cleveland. Ac- cording to the independent radiology review, about one-fourth of patients may have been prematurely discontin- ued from study involvement, con- founding the analysis. Discussant Dr. Carol Aghajanian of Memorial Sloan Kettering Cancer Cen- ter said, “It’s unfortunate that the re- sponse rate is not reported—the authors explaining that response rate varied too much between clinician assessments and radiology review assessments—and it’s disappointing that the trial’s final results could not be analyzed.” In the trial reported by Dr. Vergote, 232 patients received canfosfamide at 1,000 mg/m2 intravenously every 3 weeks, while 229 patients received ei- ther topotecan at 1.5 mg/m2 daily for 5 days once every 3 weeks, or doxoru- bicin at 50 mg/m2 once monthly. In addition to worse overall survival, median progression-free survival was 2.3 months for canfosfamide and 4.3 months for topotecan or doxorubicin (P = .0001). The overall response rate was 11% for topotecan or doxorubicin and 4% for canfosfamide. “This study showed us that, as a sin- gle agent, canfosfamide doesn’t have a lot of cytostatic effects, but other stud- ies suggest that we may get better re- sults by using this drug in combina- tion,” he said. ■ Vergote I. et al. Single agent, canfosfamide (C, TLK286) vs. pegylated liposomal doxorubicin (D) or topotecan (T) in 3rd- line treatment of platinum (P)-refractory or resistant ovarian cancer (OC): Phase 3 study results. Abstract LBA5528. Rose P. et al. Phase 3 Study: Canfos- famide (C, TLK286) plus carboplatin (P) vs. liposomal doxorubicin (D) as 2nd-line therapy of platinum (P)-resistant ovarian cancer (OC). Abstract LBA 5529. Rose et al. evaluated the new agent canfosfamide (TLK-286 or Telcyta) in combination with carboplatin vs. pegylated liposomal doxorubicin (PLD) in patients with platinum-re- sistant disease. The rationale was the postulated mechanism of action for canfosfamide, which includes potentially reversing resistance to the platinum compounds. Further interest came from a phase II trial of canfosfamide plus cisplatin in patients with platinum-resistant dis- ease, which produced an astound- ingly high 56% response rate. The new study unfortunately showed no significant difference in overall efficacy between canfos- famide/carboplatin and PLD. It il- lustrates the difficulty of managing platinum-resistant ovarian carcino- ma patients and the importance of evaluating efficacy in large, ran- domized phase III trials rather than smaller phase II studies, which can provide important clues to potential activity but also can be misleading because of small numbers of pa- tients and the lack of a control arm. — J. Tate Thigpen, M.D. C o m m e n t a r y Nab-Paclitaxel Active in Platinum-Sensitive Recurrent Disease Nab-paclitaxel, an albumin-bound form of paclitaxel delivered in a nanoparticle, has shown a high response rate in a phase II evaluation of women with recurrent ovarian, peritoneal, or fallopian tube cancers. “In these patients with platinum- sensitive cancers, we determined that there was a 64% overall response rate, so the drug is very active in this disease, and toxicities were minimal and man- ageable,” Dr. Michael G. Teneriello re- ported in a poster. Nab-paclitaxel (Abraxane) is a Cre- mophor-free, injectable suspension that the Food and Drug Administration ap- proved in 2005 for the treatment of ad- vanced breast cancer. These preliminary efficacy and toxicity results are the first in patients with platinum-sensitive re- current disease, said Dr. Teneriello, Texas Oncology P.A., central Austin. The researchers tested a dose of 260 mg/m2 IV every 3 weeks in 47 patients with a median age of 65.5 years (42-84 years). Nearly all had a platinum-free interval of 1 year or longer, and all had only one prior treatment with up-front chemotherapy. Women who received a taxane within the previous 6 months were excluded. The investigators reported that the overall response rate among the 44 evaluable patients was 50%, including 13 complete responses (CR) and nine partial responses (PR). In patients fol- lowed by RECIST (Response Evaluation Criteria in Solid Tumors) only, overall response was 27% (one CR and two PR in 11 patients). In those followed by CA-125, overall response was 64% (five CR and two PR in 11 patients). Among patients meeting both RECIST and CA-125 criteria, it was 54.5% (seven CR and five PR in 22 patients). Medi- an time to response was 1.8 months. “Because nab-paclitaxel does not re- quire the Cremophor vehicle, there’s less toxicity, and the time of administration is reduced,” Dr. Teneriello said. “Neutropenia was the most common side effect, and we saw grade 3/4 neu- ropathy in [only] 9% of patients, which was reassuring because this drug is as- sociated with neuropathy,” he said. Oth- er side effects included fatigue, diarrhea, and dyspepsia (2% each); and grades 1- 2 alopecia (85%). At the time 46 patients remained alive. One death was related to pro- gressive disease. Response and survival analysis are ongoing, Dr. Teneriello said, adding that further studies are warranted. The study was supported in part by a grant from Abraxis BioScience Inc., a developer of Abraxane. ■ Teneriello M.G. et al. Results of a phase II evaluation of nanoparticle albumin bound paclitaxel (nab-paclitaxel) in plat- inum-sensitive patients with recurrent ovarian, peritoneal, or fallopian tube can- cer. Abstract 5525. ‘The drug is very active in this disease, and toxicities were minimal and manageable.’ Dr. Teneriello This study by Teneriello et al. pro- vides the first substantial data on a new taxane, nanoparticle albumin- bound paclitaxel (nab-paclitaxel), in ovarian carcinoma. It enrolled plat- inum-sensitive patients with recur- rent disease. The reported activity was similar to that of paclitaxel. As with paclitaxel, they fall short of those reported with platinum-based regimens in the platinum-sensitive setting. Hence, platinum-based combinations would remain the standard of care unless platinum compounds are specifically con- traindicated in a particular patient. The next logical step would seem to be an exploration of combina- tions with platinum compounds in either the platinum-sensitive setting or in front-line treatment. For this agent to assume a significant place in the therapeutic armamentarium, some specific advantage over pacli- taxel other than simply length of in- fusion would need to be demon- strated. — J. Tate Thigpen, M.D. C o m m e n t a r y