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ASCO 2000: Critical Commentaries |
Massachusetts General Hospital, Boston, Massachusetts, USA
Correspondence: Michael V. Seiden, M.D., Ph.D., Massachusetts General Hospital, Cox 640, 100 Blossom Street, Boston, Massachusetts 02114, USA. Telephone: 617-724-3123; Fax: 617-724-3166; e-mail: Seiden.Michael{at}MGH.Harvard.edu
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ABSTRACT |
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 Top Abstract Randomized Trials Evaluating...Additional Studies and ReviewSecond-Line Therapies in the...Additional Studies and ReviewNovel TherapiesOverall ConclusionsReferences |
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Key Words. Ovarian cancer • Treatment • ASCO
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RANDOMIZED TRIALS EVALUATING INITIAL THERAPY FOR OVARIAN CANCER |
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TopAbstractRandomized Trials Evaluating...Additional Studies and ReviewSecond-Line Therapies in the...Additional Studies and ReviewNovel TherapiesOverall ConclusionsReferences |
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Study Design and Results
This very large multinational European study was designed to better define the potential role of paclitaxel with carboplatin in the treatment of women with epithelial ovarian cancer. Specifically, patients were randomized approximately 2:1 to a control arm versus the treatment arm of paclitaxel 175 mg/m2 over 3 h followed by carboplatin at a calculated area under the concentration time curve (AUC) of six. The choice of control was left to choice of the institution's principal investigator, who could select either carboplatin AUC = 6 or alternatively, CAP (cyclophosphamide 500 mg/m2, adriamycin 50 mg/m2, and cisplatin 50 mg/m2). The allowance of two different control regimens is atypical, but was felt to be appropriate since the result of the ICON 2 study comparing single-agent carboplatin to CAP was not yet available for analysis at the initiation of ICON 3. (Fortunately, subsequent analysis has suggested equivalent survival for carboplatin compared to CAP [1]). Patients received assigned therapies every 21 days for six cycles. The primary endpoint of the trial was survival with the study stratified by the chosen control arm. The carboplatin versus paclitaxel and carboplatin subgroup contained 1,421 patients (943 treated with carboplatin and 478 with paclitaxel and carboplatin), and 636 were placed into the CAP versus paclitaxel and carboplatin subgroup (421 treated with CAP and 215 with paclitaxel and carboplatin).
Although not fully mature, the median follow-up is now 29 months, and the analysis of this trial currently supports the conclusions made during last year's ASCO meeting, namely that control therapy gives equivalent overall survival and progression-free survival (PFS) as carboplatin and paclitaxel. Table 1
demonstrates that women assigned to the control arm had a PFS of 16.2 months while those assigned to the paclitaxel arm had a PFS of 16.8 months. One-year survival rates were nearly identical. Two-year overall survival was 62% for those assigned to the control arm and 64% for those assigned to the paclitaxel arm (Table 2). Subgroup analysis of the individual control groups, stage, residual disease after primary debulking and age all failed to demonstrate a single subgroup that enjoyed statistically better survival with the paclitaxel-containing group. Early analysis suggested that pooling the centers with low patient accrual demonstrated a trend in these centers that favored the control therapy.
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While the ICON 3 trial does not support the inclusion of paclitaxel into the upfront treatment of epithelial ovarian cancer, on balance, the total body of clinical trial evidence still supports paclitaxel with carboplatin as the standard first-line regimen in women with ovarian cancer who require systemic therapy. Nevertheless, it is probably reasonable to consider that paclitaxel and carboplatin may not be vastly superior to treatment with carboplatin followed subsequently by paclitaxel. Indeed, similar conclusions have been suggested by GOG 132 [4] that suggested cisplatin followed by paclitaxel was equivalent to cisplatin and paclitaxel. Indeed, ICON 3, GOG 132, and several of the second-line studies discussed below suggest that doublet and triplet therapy may not be superior to sequential single-agent therapy.
Multicenter Phase II/III Trial of Oxaliplatin plus Cyclophosphamide versus Cisplatin plus Cyclophosphamide in Advanced Chemonaïve Ovarian Cancer Patients: Final Results. JL Misset, P Vennin, P Chollet, J Pouillart, D Frober, M Castera, M Fabr, E Cortesei, E Gamelin, G Dupont-Andre, A Laadem, J Otero (ABSTRACT 1502).
Study Design and Results
Oxaliplatin is a platinum analog with activity in ovarian cancer. Work done both prior to and after the initiation of this trial demonstrates that this compound crosslinks a bulkier side chain to the DNA helix, potentially explaining its activity in cisplatin and carboplatin-resistant cell lines in vitro. In addition, it has activity in cisplatin-resistant cells with documented mismatch repair defects [5-7]. This study evaluates the safety and toxicity profile of oxaliplatin at 130 mg/m2 with cyclophosphamide at 1,000 mg/m2 compared to cisplatin at 100 mg/m2 with the same dose of cyclophosphamide. Both doublets are repeated on a 21-day schedule. Since cyclophosphamide doses are equivalent in both arms, this serves as a direct comparison of the oxaliplatin with cisplatin. Although not powered to definitely answer an efficacy endpoint, response rate, PFS and overall survival were examined as secondary endpoints.
The trial enrolled 177 women between 1992 and early 1996 with stage II, III, and IV ovarian cancer, with 85 evaluable patients in the oxaliplatin arm and 92 patients in the cisplatin arm. Compared to the cisplatin arm, the oxaliplatin arm had fewer dose delays, less hematologic toxicity and fewer withdrawals from the treatment plan. Specifically 18% of the woman assigned to cisplatin were withdrawn from treatment for toxicity concerns compared to only 2% of patients on the oxaliplatin arm. Table 3 reviews the incidence of various grade III/IV toxicities, all of which favored oxaliplatin. Moderate grade I/II neuropathy was more common with oxaliplatin compared to cisplatin, but was reversible within one year.
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Commentary
This study demonstrates that oxaliplatin can be delivered with cyclophosphamide with acceptable toxicity and indeed it appears to be less toxic than cisplatin (at a dose of 100 mg/m2). Available response and survival data suggest this will be a very active doublet in ovarian cancer. The trial was started prior to the conclusion of GOG 111 [2] and the general availability of paclitaxel; hence the comparison of the oxaliplatin to cisplatin-cyclophosphamide is less relevant today than it was in 1992. Also, the dose of cisplatin (100 mg/m2) is higher than necessary. At the current time there are several relevant questions. How does oxaliplatin-paclitaxel compare to carboplatin-paclitaxel? Will the increased neurtoxicity of oxaliplatin be problematic when combined with paclitaxel? While alternating or combining carboplatin with cisplatin has not provided increased therapeutic efficacy, the different mechanism of resistance to oxaliplatin compared to cisplatin and carboplatin makes it possible that alternating oxaliplatin doublets with carboplatin doublets may be efficacious. Evaluating these possibilities will require further toxicity studies and eventually further randomized studies.
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ADDITIONAL STUDIES AND REVIEW |
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A Phase II Study of Docetaxel and Carboplatin in the Treatment of Suboptimally Debulked Stage III and Stage IV Ovarian Carcinoma. JA Ruiz, I Smith, A Wertheim, A Troxel, P Rosenman, KH Antman, A Tiersten (ABSTRACT 1593).
Effective First Line Therapy of Ovarian Cancer with Cisplatin and Prolonged Topotecan Infusion —a NYGOG/ ECOG Study. J Speyer, H Hochster, S Wadler, C Runowicz, J Michalak, J Mandeli, A Fields, P Anderson, J Sorich, H Wasserstrom, R Wallach, F Muggia (ABSTRACT1503).
Paclitaxel, Topotecan, and Cisplatin Combination Chemotherapy in Advanced Ovarian Cancers. Results of a Pilot Study. D Coeffic, EC Antoine, MA Rocher, JP Spano, JP Grapin, I Lorenzi, E Mularoni, G Auclerc, D Nizri, M Delgado, D Khayat (ABSTRACT1601).
The ASCO 2000 had numerous posters exploring the efficacy and toxicity of novel doublets such as gemcitabine with cisplatin, docetaxel with cisplatin, and topotecan with carboplatin, as well as novel triplets incorporating either topotecan or doxil into the taxol and platinum backbone. All of these regimens demonstrate efficacy and acceptable toxicity if dosed appropriately. Further definition of the activity of these doublets and triplet regimens will require randomized trials comparing the novel regimen to carboplatin with paclitaxel.
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SECOND-LINE THERAPIES IN THE TREATMENT OF RECURRENT/PERSISTENT OVARIAN CANCER |
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Interim Analysis of a Phase II Randomized Trial of Doxil/Caelyx versus Topotecan in the Treatment of Patients with Relapsed Ovarian Cancer. A Gordon, J Fleagle, D Guthrie, D Parkin, M Gore, A Lacave, D Mutch (ABSTRACT1504).
Study Design and Results
Both topotecan and doxil have activity in ovarian cancer including disease that is considered paclitaxel- and platinum-resistant. This study was performed to evaluate the toxicity and response to these two agents in a randomized trial. Near equal numbers of woman with potentially platinum-sensitive and platinum-resistant recurrent ovarian cancer were included. Women randomized to topotecan received 1.5 mg/m2 per day for five consecutive days repeated on a 21-day cycle while those randomized to doxil received 50 mg/m2 on a 28-day schedule. A total of 104 sites have enrolled 481 patients, although this interim analysis includes only the first 237 patients.
Review of the patient population reveals good balance between the known prognostic factors. Response rates, time to progression as well as overall survival are equivalent in the two groups (Table 4). Not surprisingly, both drugs demonstrated significantly better activity in the subgroup with potentially platinum-sensitive disease. Curiously, survival of the platinum-sensitive group with doxil was 86 weeks compared to 63 weeks for the topotecan arm (p = 0.012). Toxicity data demonstrated that topotecan had a much higher rate of grade III/IV neutropenia, thrombocytopenia, anemia, need for G-CSF, erythropoietin, and blood transfusion, while doxil had a higher rate of grade III/IV palmar-plantar erythrodysethesia and stomatitis (Table 5).
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Finally, response rates of 7% to 12% in platinum-resistant disease are far from satisfactory and highlight the need for new agents in this difficult patient population.
An Updated Analysis of a Randomized Study of Single Agent Paclitaxel Given Weekly versus Every Three Weeks to Patients with Ovarian Cancer Treated with Prior Platinum Therapy. H Andersson, K Bowman, M Ridderheim, P Rosenberg, B Sorbe, U Puistola, G Horvath (ABSTRACT1505).
Study Design and Results
Since the late 1980s, it has been apparent that paclitaxel has activity in recurrent ovarian cancer [8]. Now, nearly 15 years later, debate still persists about the best dose and schedule of this drug. In particular, frequent low-dose administration of the drug may have enhanced endothelial toxicity that provides antiangiogenesis activity with this schedule compared to the more traditional once every three-week schedule. Swedish investigators performed a phase III comparative study of these two schedules to better understand the activity and toxicity of these two paclitaxel schedules.
To minimize the potential effect of dose intensity, patients on the weekly schedule started on 67 mg/m2/week while patients on the q three-week schedule were treated with 200 mg/m2/3 week, which calculates to identical dose intensity. Depending on toxicity, patients could be either dose de-escalated or dose escalated. The primary endpoint was overall response rate, and patients were allowed only one prior platinum-containing regimen. Patients had not received paclitaxel prior to study entry. Two hundred and six eligible patients were evaluated with approximately 50% of patients defined as platinum-resistant. Patients treated on the weekly schedule achieved a dose intensity of 77 mg/m2/week of paclitaxel, while those on every three-week paclitaxel had a median-dose intensity of 72 mg/m2/week. The three-week paclitaxel schedule had significantly more leukopenia, neutropenia, and alopecia while there was more nail toxicity with weekly taxol. Response rates were essentially identical at 37% with a very similar time to progression.
Commentary
This study confirms that both weekly and every three-week paclitaxel have significant activity in ovarian cancer. There appears to be no major therapeutic advantage to weekly paclitaxel when compared to approximately 210 mg/m2/week of paclitaxel. It is not clear how this weekly schedule would compare to the more typical dose of 175 mg/m2 every three weeks although the differences, if any, would presumably be modest. While the every three-week schedule offers advantages of convenience, the weekly schedule is a viable alternative when concerns about myelosuppression or hair loss are important. In addition, milder myelosuppression with equal efficacy may allow the weekly schedule of paclitaxel to be more easily combined with other active, but myelotoxic drugs, such as gemcitabine and topotecan.
Randomized Trial Comparing Paclitaxel + Epirubicin Versus Paclitaxel as Second-Line Therapy for Advanced Ovarian Cancer Patients in Early Progression after Platinum-Based Therapy. V Torri, I Floriani, A Tinazzi, PF Conte, A Ravaioli, MG Cantù, R Rossi, L Grassi, G Parma, N Colombo, M Negri (ABSTRACT 1506).
Study Design and Results
There is very little known regarding the value of single-agent therapy versus doublet or triplet drug therapy in the treatment of recurrent epithelial ovarian cancer. To begin to address this issue, several institutions in Italy compared the efficacy and toxicity of single-agent paclitaxel with the combination of epirubicin and paclitaxel in a group of women all defined to have platinum-resistant epithelial ovarian cancer.
This was a large study with 227 women who were enrolled a mean of three months from the completion of primary platinum-based therapy. While approximately 50% of the patients had received only single-agent carboplatin, about 25% of woman had had a previous anthracycline with their initial therapy. All women were paclitaxel-naïve. Paclitaxel was delivered at 175 mg/m2 every three weeks in both arms, while the women assigned to the doublet arm also received epirubicin at 80 mg/m2.
The women received four cycles of therapy. Those demonstrating stable or responding disease then received two additional cycles, assuming toxicity was acceptable. Paclitaxel single-agent therapy was completed in 70% of patients, although 11% of patients required dose reduction or dose delay. Only 59% of patients completed the doublet regimen as scheduled. Grade 3 or 4 neutropenia was much higher in doublet arm (41%) than in the single-agent arm (18%). Response rates were statistically identical in the two arms with no difference in progression-free or overall survival. As suggested in earlier studies, patients with platinum-resistant ovarian cancer carry a poor prognosis with median survival of only 12 months from study entry.
Commentary
This study demonstrates that paclitaxel has activity in platinum-resistant ovarian cancer and that the combination of epirubicin with paclitaxel is more toxic and no more efficacious then paclitaxel alone. To date there are no studies that demonstrate that two agents are superior to single-agent or sequential single agents in the treatment of recurrent ovarian cancer. Since some preclinical models suggest synergy of certain doublets, this concept requires further study in the setting of clinical trials, although current data would suggest that single-agent therapy is appropriate in the care of women not participating in a clinical study.
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ADDITIONAL STUDIES AND REVIEW |
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TopAbstractRandomized Trials Evaluating...Additional Studies and ReviewSecond-Line Therapies in the...Additional Studies and ReviewNovel TherapiesOverall ConclusionsReferences |
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Study Design and Results
The relatively recent availability of docetaxel, gemcitabine, topotecan [9], irinotecan, doxil, as well as further exploration into the efficacy of etoposide [10], epirubicin, and mitoxantrone provide fertile ground for evaluating novel doublets and schedules for delivering these agents in combination. Once again this year ASCO had a large number of presentations evaluating the potential efficacy and toxicity of these doublets. Several investigators have successfully defined deliverable doses and schedules of these doublets in women with recurrent ovarian cancer. None of the reported doublets appeared to be clearly superior to single-drug therapy, with the possible exception of mitoxantrone and paclitaxel.
The mitoxantrone and paclitaxel study explored two different schedules of mitoxantrone and paclitaxel in 33 heavily treated patients of whom 28 were regarded to be platinum-refractory. The regimen was myelotoxic and approximately half of the patients required G-CSF support. An overall response rate was 69% with 12 complete remissions. PFS was 9.5 months with an encouraging overall survival of 20.5 months. This response is more than double those seen with many other salvage regimens using similar drugs such as doxorubicin with paclitaxel or epirubicin and paclitaxel. The reasons for the superior response are not clear and the trial will require confirmation in other clinical centers.
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NOVEL THERAPIES |
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Study Design and Results
This phase II study done by the Texas Oncology Group evaluates Irofulven (MGI-114), a novel agent related to a mushroom-derived illudin toxin that has demonstrated broad activity in vitro and in vivo against several tumor types including epithelial ovarian cancer. This study evaluated the activity and toxicity of Irofulven at 11 mg/m2 given daily for five sequential days and repeated on 28-day cycles. The study is limited to 16 women with platinum-resistant ovarian cancer. At least one partial remission (PR) has been reported with a second awaiting confirmation. Toxicity of the five-day schedule is considerable and included nausea/vomiting, fatigue, and mental status problems (psychosis).
Commentary
Dr. Eddie Reed and colleagues at the United States National Cancer Institute have also evaluated Irofulven [11]. In the American Association of Cancer Research 2000 meeting in San Francisco, Dr. Reed reported a phase II study of Irofulven in women with heavily pretreated (but not necessarily formally platinum-resistant) ovarian cancer. In that study, shortening the schedule to four days of Irofulven led to considerably less toxicity and preserved activity with an approximate 35% response rate with activity in woman with platinum-sensitive as well as platinum-resistant tumors. These studies suggest that this drug merits further investigation to optimize drug schedule, dose, and efficacy.
A Phase I Trial of AD p53 for Ovarian Cancer Patients: Correlation with p53 and Anti-Adenovirus AB Status. JK Wolf, D Bodurka-Bevers, J Gano, MT Deavers, C Levenback, L Ramondetta, P Ramirez, D Fightmaster, DM Gershenson (ABSTRACT 1510).
Phase I Trial of Intraperitoneal ONYX-015 Adenovirus in Patients with Recurrent Ovarian Cancer. PA Vase, M Seiden, V O'Neill, S Campos, S Johnston, J Davis, D Kin, SB Aye, LN Schulman (ABSTRACT 1512).
Study Design and Results
These two studies were designed to evaluate the feasibility and toxicity of delivering intraperitoneal adenovirus to women with recurrent ovarian cancer. The study by Wolf and colleagues evaluated an adenovirus carrying the human p53 gene with the hypothesis that insertion of the p53 gene into p53-deficient ovarian carcinoma cells would reestablish an important cell checkpoint. Insertion of a wild-type p53 is postulated to reinstate apoptotic pathways and potentially reestablish sensitivity to more conventional chemotherapy agents. Alternatively, the second study evaluated Onyx-015 virus which is a modified adenovirus that is missing the E1b gene. E1b loss impairs viral replication in wild-type cells but not in p53 mutant or null cells. In theory viral replication in tumor cells should cause cellular destruction while sparing normal tissues.
Both studies evaluated the toxicities associated with intraperitoneal delivery of adenovirus over five sequential days. Dose-limiting toxicities in both studies included fatigue, fever, and abdominal pain (particularly with the Onyx-015 virus). Many patients on the Onyx-015 trial had symptoms consistent with a viral syndrome suggesting viral replication. One PR was seen in the p53 adenovirus trial. A second patient had stable disease and is continuing on her fourteenth cycle of therapy. No responses were seen in the 16 patients treated with Onyx-015, although two patients defined as having platinum-resistant ovarian cancer at the time of trial enrollment responded to subsequent carboplatin after Onyx-015 administration. The appropriate daily dose of the replication incompetent p53 adenovirus is unclear but may be 3 x 1012 pfu, while the dose-limiting toxicity for the replication impaired Onyx-015 virus was between 1 x 1010 pfu and 1 x 1011 pfu daily dose.
Commentary
The therapeutic role of viral-based intraperitoneal treatment strategies in ovarian cancer requires more investigation. These two studies demonstrate that the approach is feasible and reasonably well tolerated. The p53 adenovirus trial demonstrated that patients do develop very elevated antibody titers to adenovirus during repeat administrations, and that attempts to isolate adenovirus in tumor or peritoneal fluid in the Onyx-015 trial were difficult. Taken together these findings suggest that immune clearance of adenovirus-based approaches may limit efficacy; further modification of the adenovirus or the use of alternative vectors may be necessary.
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OVERALL CONCLUSIONS |
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REFERENCES |
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