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  • The Oncologist ASCO 1999: Critical Commentaries Progress in Gynecologic Oncology RICHARD T. PENSON, MICHAEL V. SEIDEN Division of Hematology and Oncology, Massachusetts General Hospital, Boston, Massachusetts, USA Key Words. Gynecologic oncology · ASCO · Review · Ovarian cancer · Cervical cancer INTRODUCTION Oncology Group (GOG) 164, a study that investigates Downloaded from www.TheOncologist.com by on October 29, 2010 The gynecologic oncology presentations at the 1999 high-dose chemotherapy as consolidation for first-line ASCO meeting in Atlanta continue to focus on defining the treatment for ovarian cancer, has been closed because of optimal treatment strategies for women with advanced poor accrual. Further information on the role of high-dose gynecologic malignancies. While there were no dramatic therapy in this disease awaits the completion of random- shifts in treatment paradigms at ASCO, a large number of ized trials ongoing in Europe. well-controlled randomized trials addressed key areas and defined standard of care. Indeed, 10 of the 43 clinical tri- STANDARD FIRST-LINE CHEMOTHERAPY FOR als presented were phase III trials that randomized a total OVARIAN CANCER of 5,664 patients. These studies add incrementally to both Dr. Robert Ozols of the Fox Chase Cancer Center in our knowledge base and improved outcomes. The most Philadelphia presented a phase III study comparing cis- important data were from trials of patients with ovarian platin and paclitaxel versus carboplatin and paclitaxel in cancer. Two randomized studies provided evidence that patients with optimally debulked stage III epithelial ovar- optimal first-line chemotherapy is paclitaxel 175 mg/m 2 ian cancer [2]. It was designed as an equivalency study in over 3 h and carboplatin AUC 4 - 7.5. An increasing num- previously untreated patients with no residual tumor ber of studies examined the incorporation of relatively new greater than 1 cm. The patient’s surgeon also selected agents into first-line therapy. No studies addressed the whether the patient would be evaluated by second look potential role of intraperitoneal treatment. Lastly, although operation at completion of six cycles of treatment. The the role of high-dose chemotherapy in ovarian cancer is schedule of paclitaxel was 175 mg/m2 over 3 h in the car- uncertain, for the most active agents the dose response boplatin and paclitaxel arm while the cisplatin/paclitaxel curves in ovarian cancer and breast cancer are similar. regimen gave paclitaxel as a 135 mg/m 2 dose over 24 h. High-dose chemotherapy in breast cancer was reviewed in The study was designed to detect a 30% difference in out- ASCO’s plenary session. Four studies evaluating high- come between the two arms and enrolled 840 patients. The dose therapy were presented and in general the results were combination of carboplatin and paclitaxel was associated not encouraging. A single study, presented by Dr. with more thrombocytopenia and pain, but cisplatin and Bezwoda of South Africa demonstrated a disease-free and paclitaxel caused a higher incidence of neutropenia, fever, overall survival advantage for up-front tandem transplant, and gastrointestinal toxicity, as well as metabolic toxici- which raises the issue of whether immediate high-dose ties. Although neurotoxicity was similar in both arms of chemotherapy may overcome drug resistance and avoid the this study, the follow-up is short (19.1 months). To date induction of resistance by moderate doses of the same there have been 419 recurrences. Although it was a little agents [1]. While no specific randomized data were pre- early for survival analysis, progression-free survival was sented for ovarian cancer, it is notable that Gynecologic 22 months in both arms. Indeed, the relative risk of failure Correspondence: Michael V. Seiden, M.D., Ph.D., Division of Hematology and Oncology, Massachusetts General Hospital, Boston, Massachusetts 02114, USA. Telephone: 617-724-3123; Fax: 617-724-3166; e-mail: Seiden.Michael@MGH.Harvard.edu Accepted for publication July 6, 1999. ©AlphaMed Press 1083-7159/99/$5.00/0 The Oncologist 1999;4:293-298
  • 294 Progress in Gynecologic Oncology on carboplatin and paclitaxel was 0.90 with 95% confi- for progression-free survival was 0.95 favoring carbo- dence intervals of 0.75 to 1.1, suggesting that it may even platin and the hazard ratio for overall survival was 1.17 be slightly superior to cisplatin and paclitaxel. The relative (confidence intervals 0.92 to 1.19). The study supported risk of death was 0.85 for carboplatin and paclitaxel and, the routine use of carboplatin because of the significantly though the confidence intervals were very broad, a signif- improved quality of life reported using the EORTC ques- icant survival advantage may develop with time for carbo- tionnaire (p = 0.0048). platin and paclitaxel, which is clearly a more convenient Clearly the equal progression-free and overall sur- outpatient based regimen. vival reported in GOG 158 and the AOG study, and the A point of controversy was the selection of the carbo- better toxicity profile and improved quality of life for platin dose of AUC = 7.5, a dose defined in a previous patients receiving carboplatin and paclitaxel establish phase I study done at Fox Chase Cancer Center. In the ear- this regimen as the standard of care for first-line lier trial, this dose was associated with a 75% response rate. chemotherapy. This conclusion was directly challenged This dose was higher than the apparently adequate doses by the Third International Collaborative Oncology investigated in two prior randomized controlled studies [3, Neoplasm Study (ICON 3), the largest randomized con- 4]. Specifically, two randomized trials from Europe demon- trol study ever conducted in ovarian cancer. Two thou- Downloaded from www.TheOncologist.com by on October 29, 2010 strating that carboplatin dosed at an AUC of 6 was equiva- sand seventy-four patients were randomized in what were lent to carboplatin at an AUC of 12 (U.K. study) [3] and a essentially two trials [6]. Paclitaxel 175 mg/m 2 over 3 h study suggested equivalency of carboplatin at AUCs of 4 with carboplatin (AUC = 6) was compared with a control and 8 (Danish study) [4]. These two studies suggest that the arm of either carboplatin as a single agent (AUC of 6 AUC dose of 7.5, in GOG 158, is excessive. based on the calculated GFR [glomerular filtration rate] A secondary objective of the study was to define the or 5 if estimated) or CAP chemotherapy (500 mg/m 2 potential benefit of a second look procedure. The assign- cyclophosphamide, 50 mg/m 2 adriamycin, and 50 mg/m 2 ment was not randomized, but made pretherapy by the cisplatin). The inclusion of two different control regi- surgeon, presumably after discussion with the patient, and mens reflected controversy regarding the effectiveness of hence is subject to bias. Second look operation (SLO) in CAP versus carboplatin. Prior to enrolling patients, each patients with optimally debulked disease had no impact on one of 130 centers in eight nations selected one of the progression-free survival. Three hundred ninety-nine control arms; the intent was to include such a large num- patients did not have SLO, while 395 were selected for ber of patients that there would be sufficient power to second look procedure. Of 395 patients who had SLO, 136 address the questions posed in subgroup analysis. Early were positive and of this group, 123 went on to have treat- analysis suggests progression-free survival and overall ment that was not specified by the trial. Treatments for the survival are equivalent for paclitaxel and carboplatin as subgroup of women with positive second look procedures compared to the outcomes of the two control arms. included continuation of carboplatin and paclitaxel, The study has a number of methodological weaknesses intraperitoneal treatment, high-dose chemotherapy with including limited follow-up (18 months) and a design with bone marrow transplantation, and whole abdominal radio- two different control arms. Nevertheless, this very large therapy at the discretion of the patient and physician. study is difficult to reconcile with GOG 111 [7], a study There was no evidence that the information gained by the that found a significant survival advantage favoring the second look operation impacted positively on survival regimen of paclitaxel and cisplatin over cytoxan and cis- although this was not a randomized comparison. Hence it platin. Dr. William McGuire, in discussion of ICON 3, is possible that a subset of patients might benefit or that evaluated subsets within ICON 3 and demonstrated that the alternative salvage therapies may be worthwhile in this study did support the hypothesis that patients with subopti- patient population. mally debulked tumor (residual disease >2 cm) may have Dr. Dubois presented a confirmatory phase III trial benefited from paclitaxel-based therapy. In the subopti- that compared paclitaxel 185 mg/m2 over 3 h with either mally debulked group, a 44% mortality gave greater statis- carboplatin AUC 6 or cisplatin 75 mg/m2 as first-line tical power, and in this group, there appeared to be a survival treatment of epithelial ovarian cancer [5]. Nausea and advantage for carboplatin and paclitaxel when compared to neuropathy were more common in the group treated with single-agent carboplatin (p = 0.05) or the CAP combination cisplatin—19% versus 7% (nausea) and 19% versus 8% (p = 0.03). The fact that GOG 132 (cisplatin versus cis- (neuropathy), respectively. During follow-up, patients platin/paclitaxel versus paclitaxel [8]) and ICON 3 suggest receiving carboplatin appeared to have at least a 20% no benefit from the addition of paclitaxel, compared with lower instance of any grade neuropathy. The hazard ratio GOG 111 and OV 10 (cisplatin/cyclophosphamide versus
  • Penson, Seiden 295 cisplatin/paclitaxel [9]) may be explained by other sources required use of neupogen. Ten percent of cycles were asso- of bias. The availability of paclitaxel for women who ciated with fever and neutropenia and 23% had grade IV relapse after non-Taxol based primary therapy poses a thrombocytopenia, highlighting the issue of combining problem in all trials except for GOG 111. Indeed, in GOG myelosuppressive agents. 132, 48% of patients were immediately treated with a sec- The use of agents sequentially versus concurrently is ond-line agent, half of whom received paclitaxel. Salvage attracting increasing attention. The Norton-Simon hypoth- therapy essentially converted this randomized study into an esis predicts that sequential treatment is more likely to investigation of sequential treatment that showed no clear eliminate drug-resistant clones. However, although this advantage for concurrent versus sequential therapy. approach is supported both by mathematical models and Though the addition of paclitaxel may reduce the dose clinical experiments, the impact of new agents has not yet intensity of platinum, the most active agent in ovarian can- translated into a significant improvement for patients. cer, 9 of 10 randomized controlled trials suggest no advan- Dr. Hoskins reported the results of a phase II study in 44 tage of platinum dose intensity at the investigated doses. patients using sequential doublets [14]. Cisplatin 50 Finally, there may be a genuine population difference mg/m2 on day 1 and topotecan 0.75 mg/m2 on days 1 between European patients with ovarian cancer and through 5 for four cycles and then followed by four cycles patients from the United States. of paclitaxel 135 mg/m2 over 24 h and cisplatin 75 mg/m2 Downloaded from www.TheOncologist.com by on October 29, 2010 A number of studies investigated novel up-front dou- (day 2) as first-line treatment for advanced ovarian cancer. blets (Abstract 1378), triplets (Abstracts 1379, 1397, and Although the doses of cisplatin and topotecan appear low, 1418), or quadruplets (Abstracts 1391 and 1417) and novel the regimen was based on a phase I study that showed syn- schedules (Abstracts 1416 and 1419). Although weekly ergistic myelosuppression. Fever and neutropenia occurred paclitaxel appears particularly active in recurrent disease, in approximately 10% of patients and was equally distrib- Rosenberg et al. from Finland reported a phase III study of uted between the two doublets of the study. Significant weekly paclitaxel 67 mg/m2 over 1 h versus 200 mg/m2 activity was demonstrated in a group of women with stage (equivalent dose intensity) given as a 3-h infusion on a IV or suboptimally debulked ovarian carcinoma. Seven per- three-week schedule [10]. The time to progression with the cent of patients progressed on cisplatin and topotecan, and three-week schedule was significantly longer; 8.3 months, 5% progressed on cisplatin and paclitaxel. In reviewing compared with 5.5 months for the weekly schedule. these novel combinations, discussants warned that the non- However, the weekly schedule was associated with a better surgical assessment of response, small clinical trial size, and toxicity profile. It has also been investigated in first-line lack of follow-up on durability of response made it difficult treatment. The regimen of paclitaxel, at a relatively high and perhaps dangerous to become enthusiastic about the high dose of 100 mg/m2 over 1 h and carboplatin weekly at an response rates. AUC of 2 over 24 h was evaluated by Bremer et al. in 26 Dr. Young presented GOG 95, a randomized clinical patients [11]. This was associated with tolerable toxicity and trial of adjuvant treatment of women with early stage complete remissions (CRs) in four of seven suboptimally ovarian cancer (FIGO I-IIA) [15]. This study evaluated debulked patients. 205 patients with high-risk ovarian cancer, defined as Hansen et al. presented data on 28 patients in a phase II early stage disease with stage IC, IIC or grade II-III stage study of the triplet combination of gemcitabine 800 mg/m2 on IA and B patients. Earlier studies in this patient popula- days 1 and 8, carboplatin AUC-5 on day 1, and paclitaxel 175 tion have compared intraperitoneal 32P with melphalan, mg/m2 over 3 h on day 1 [12]. For a first-line combination this both of which were associated with an 80% progression- had a remarkable response rate of 100% with 60% CRs. Eight free survival. Radioactive phosphorus was preferred of 28 patients had relapsed at a median follow-up of 12 because of the leukemogenic toxicity of melphalan [16]. months. Hematological toxicity was considerable with platelet Subsequently, Bolis et al. have reported a randomized trial transfusions required in three patients, one patient being admit- of 32P and cisplatin, which again had similar activity but ted twice for fever and neutropenia. Gemcitabine dosing was cisplatin was associated with less toxicity [17]. An ongo- delayed in eight patients. Other triplets included the addition of ing study, ICON I has randomized early stage patients to epirubicin (Abstract 1418) and the inclusion of ifosfamide or immediate platinum-based therapy or treatment at relapse epirubicin (Abstract 1396), both with significant hematologi- and should be analyzed soon. Young et al. reported a rel- cal toxicity and high response rates. A four-drug regimen was atively high failure rate and poor compliance for 32P. presented by Tung et al. with the CTEC protocol that com- There was no statistically significant difference between bined cyclophosphamide, paclitaxel, etoposide, and carbo- cisplatin and cyclophosphamide and 32P for progression- platin [13]. This regimen was myelosuppressive even with the free interval. However, a trend favored systemic therapy
  • 296 Progress in Gynecologic Oncology and, in light of logistical issues complicating 32P adminis- OVARIAN CANCER tration, Dr. Young recommended that platinum-based FIGO IC - IV AND IA AND B IF GRADE ≥ II treatment should be the treatment of choice for patients with high-risk early stage ovarian cancer. Surgical debulking OVARIAN CANCER: AFTER FIRST-LINE THERAPY? Carboplatin and Paclitaxel A burgeoning number of new agents have activity in ovarian cancer, a chemotherapy-sensitive disease marked Response* No Response by repeated recurrence. Although there has been an improvement in five-year survival in the United States for all stages of the disease from 32% in 1960 to 46% in Relapse 1992, it has essentially become a chronic disease associ- >1 year <1 year ated with very significant morbidity [18]. In an educa- tional session, Dr. Thigpen outlined treatment options for Further therapy: Investigational Therapy: Etoposide Phase I or II clinical trial second line therapy using A) the same drugs, carboplatin Topotecan Downloaded from www.TheOncologist.com by on October 29, 2010 and paclitaxel; B) alternative cytotoxics; C) high-dose Doxil chemotherapy using peripheral blood stem cell supported Gemcitabine Tamoxifen high-dose systemic therapy or intraperitoneal therapy, Navelbine and D) alternative modalities such as radiation, biologics, Docetaxel and gene therapy. Oxaliplatin Irinotecan One of the difficulties in comparing the relative Capecitabine worth of different treatments has been quantifying the Ifosfamide Alternate schedule degree of persisting chemosensitivity. Dr. Markman’s definition of chemoresistant disease as progression or Figure 1. Treatment algorithm for ovarian cancer. relapse within six months of completing platinum-based treatment has been most widely used [19]. The likeli- hood of responding to second-line treatment depends upon A) prior response; B) number of prior lines of ther- Kettering Cancer Center (MSKCC) dying postopera- apy, and C) duration of progression-free or disease-free tively, before leaving hospital and with a high rate of fis- survival. Four drugs, etoposide, topotecan, doxil, and tula complications [20]. gemcitabine, have efficacy in both platinum- and pacli- Dr. Markman reviewed the rationale for dose intensity in taxel-resistant disease. Other active agents include the second-line treatment for ovarian cancer. At least nine tamoxifen, vinorelbine, docetaxel, oxaliplatin, irinotecan, randomized controlled studies have now shown that doubling capecitabine, and ifosfamide (Fig. 1). of dose intensity of platinum fails to impact disease-free or Dr. Hoskins reviewed the role of surgery for recurrent overall survival, and studies of paclitaxel suggest that there is or persistent epithelial ovarian cancer. There are no data a greater effect from schedule than dose [21]. Whereas high- suggesting any benefit from SLO immediately after first- dose systemic treatment may increase the dose by 1/2 to 1 line treatment in terms of outcome. However, SLO is log, intraperitoneal treatment may increase local concentra- again an increasingly common procedure in clinical tri- tions of cytotoxics from 1 to 3 logs. However, there is lim- als, where negative SLO may be an important endpoint ited systemic exposure, and treatment is associated with and an early surrogate for disease-free survival. In local toxicity, increased cost, and a detrimental effect on the selected patients with drug-sensitive disease it is common quality of life. practice to resect residual masses and consolidate with The panel was asked about two interesting and topical further chemotherapy. In this setting, as in interval issues. The treatment of an asymptomatic patient with rising debulking, there may be a benefit for suboptimally CA125 is common practice but is not supported by data that debulked patients. SLO has clearly not helped in patients show any more then a lead time effect. Few patients accept who have progressive disease or who are initially opti- watchful waiting. Secondly, the role of herceptin in ovarian mally debulked (GOG 158), and the role of further cancer was discussed. Over 500 patients have being screened surgery for recurrence is still incompletely defined. for the GOG study of single-agent herceptin, and only 25 Palliative surgery for obstruction has a very limited role patients with HER-2/neu positive tumors have been treated, and is risky with 46% of patients at Memorial Sloan suggesting a lower incidence of HER-2/neu positivity than
  • Penson, Seiden 297 in breast cancer, perhaps between 5% and 10%. There is a Table 1. Recent randomized controlled trials of concurrent considerable interest in the agent, and despite a disappointing chemoradiation therapy for cervical cancer response rate, the study continues to accrue. Relative risk Additional topics of clinical interest included Dr. of death, Markman’s review of carboplatin-associated hypersensitiv- Schema versus RT ity reactions [22]. These reactions appeared to be mediated Rose et al. [23] Cis/RT versus Cis/Hydrea/ 0.61 and 0.58 5FU/RT versus Hydrea/RT through an antigen-specific IgE mechanism in which car- Keys et al. [24] Cis/ RT versus RT 0.54 boplatin may act as a hapten rather than producing the com- plement-mediated acute hypersensitivity reaction that is Morris et al. [25] Cis/5FU/RT versus RT 0.52 characteristic of paclitaxel. Although carboplatin reactions SWOG 8797 Cis/RT versus RT 0.50 [www.sgo.org] had similar clinical characteristics to the reactions to pacli- GOG 85 [in press] Cis/5FU/RT versus RT 0.72 taxel, they occurred later, typically after six to eight cycles. Although paclitaxel rechallenge is reasonable with steroids and antihistamines, in two of three patients who were receive cisplatin 240 - 320 mg/m2 in six to eight weeks fol- rechallenged with carboplatin, there were severe reactions lowed by radical hysterectomy and pelvic lymphadenectomy and, in one case, a fatal reaction upon rechallenge with cis- Downloaded from www.TheOncologist.com by on October 29, 2010 or external beam radiotherapy to a total dose of 70 Gy at point platin, suggesting that there is cross-reactivity between the A. The median follow-up was 47 months. There was a pre- analogs. dicted 15% overall survival benefit for neoadjuvant chemotherapy and surgery. Dr. Sardi also presented at the CERVICAL CANCER SCREENING educational session and updated his data, which suggest an In an educational session, Drs. Parhan and Seshadri overall survival advantage for neoadjuvant cisplatin, vin- reviewed the difficult issue of screening for cervical can- cristine, and bleomycin in stage IB2 patients with a p value of cer in the developing world. Seventy percent of patients <0.01 in subset analysis. However, in reviewing Abstract who are found to have cervical cancer in India are diag- 1377, Dr. Eiffel reminded the audience that the control arm in nosed with advanced stage disease and only 10% of the this neoadjuvant study involved a suboptimal radiotherapy patients are operable. This is a clearly important finding dose without concurrent cisplatin. Indeed, the recent reporting with approximately 500,000 cases of cervical cancer of five randomized controlled trials (Table 1) that all show a worldwide. In some sub-Saharan and African nations, cer- clear survival advantage for the combination of chemotherapy vical cancer is the leading cause of death in women aged and radiotherapy over radiotherapy alone now redefines stan- 33 to 44. Treatment of early stage disease in the third dard therapy for women with locally advanced or local world tends to be by immediate cryotherapy. The applica- regional cervical cancer. tion of low technology screening strategies was discussed. These include unaided visual inspection, use of 3% to 5% ENDOMETRIAL CANCER acetic acid, which whitens areas of nuclear proliferation Drs. Barakat and Runowicz presented data on the effect and density, and magnification using speculoscopy. of adjuvant tamoxifen on the endometrium in women with Increased diagnostic sensitivity is typically traded for breast cancer and the role of screening for endometrial can- poorer specificity. There are very significant issues of cer at MSKCC and in a subgroup analysis for the NSABP limited access and poor acceptance for screening pro- breast cancer prevention trial [P1] [26, 27]. Although the grams and cervical screening still has a low priority in latter was confounded by the use of endometrial aspiration community clinics because of the social stigma, the belief prior to ultrasonography, both studies drew similar conclu- that cancer cannot be cured and confusion between Pap sions. Endometrial cancer is rare and relatively low risk, smear testing and sterilization. The availability of an particularly in premenopausal women. During the P1 study, effective vaccine, and public health education programs to 36 of 6,681 patients on tamoxifen developed endometrial reduce the incidence of human papillomavirus (HPV) cancer. However, 15 patients of the 6,707 on placebo also infection, are likely to have a greater impact on early stage developed endometrial cancer. The value of screening is disease than will attempts to decrease the false positive not proven and screening beyond an annual gynecological rate of refined screening tests. assessment has to be questioned. Dr. Benedetti-Panici presented a study of neoadjuvant chemotherapy and radical surgery versus radiotherapy, in ACKNOWLEDGMENT squamous cell carcinoma of the cervix [23]. This phase III We gratefully acknowledge the cooperation of Kirin trial commenced in 1990 and randomized 441 patients to Pharmaceuticals and Excerpta Medica, Japan.
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  • Progress in Gynecologic Oncology Richard T. Penson and Michael V. Seiden Oncologist 1999;4;293-298 This information is current as of October 29, 2010 Updated Information including high-resolution figures, can be found at: & Services http://www.TheOncologist.com/cgi/content/full/4/4/293 Downloaded from www.TheOncologist.com by on October 29, 2010