Reports

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

15th International Meeting of the European Society of Gynecological Oncology

Berlin, Germany / October 28-November 1, 2007

According to Dr. Gavin Stuart, Dean, Faculty of Medicine, University of British Columbia, Vancouver, “A fairly large number of trials have shown that pegylated liposomal doxorubicin (PLD) provides clinical benefit and reduced toxicity in both ovarian and breast cancer. The remaining questions in women with ovarian cancer are when to use it and at what dose.” Early-stage ovarian carcinoma is generally asymptomatic, so most women are diagnosed with advanced-stage disease, which inversely correlates with survival.

Single-agent PLD has emerged as a treatment option for patients who relapse within six months after treatment, whereas a platinum/taxane combination is well established for women who fail after 12 months. Optimal therapy for the partially platinum-sensitive population who relapse between six and 12 months, however, remains unclear. Earlier trials have provided evidence that less toxic, non-platinum-based agents may be effective in some platinum-sensitive patients.

“We did a phase II study to look at that particular time period,” Dr. Stuart explained, “and used a relatively low 30 mg/m2 dose of PLD in combination with carboplatin AUC 5 mg/mL/min every four weeks, which is known to be well tolerated in those patients.”

Eligibility criteria in this multicentre, single-arm phase II trial included measurable disease in women who had been given taxane/platinum combination therapy previously.

The multicentre Canadian trial enrolled 58 patients, median age 59.1 years, with measurable disease who had been given one to 12 cycles of paclitaxel/carboplatin (PC) combination therapy previously and had achieved a progression-free interval of greater than six but less than 12 months. During the study, 75% of patients received six or more cycles of PLD, 16% were given one to two cycles and 9% received three to five cycles (Figure 1). The primary outcome measure was response according to Response Evaluation Criteria in Solid Tumors (RECIST).

Figure 1. Cycles of PLD/Carboplatin Received (n=58)

Reporting results, Dr. Patti Power, Dr. H. Bliss Murphy Cancer Centre and Professor of Obstetrics and Gynecology, Memorial University of Newfoundland, St. John’s, noted, “Response rates were very impressive in this setting and the toxicity profile of the drug regimen was quite remarkable. This patient group achieved a median progression-free interval of 8.8 months (range 5.6-12), while the objective response rate was 45% (4% complete response [CR] and 41% partial response [PR]). Another 33% attained disease stabilization (SD) for longer than six months, for an overall clinical benefit (CR+PR+SD) of 78%. Moreover, the response rate for patients with measurable cancer antigen-125 (CA-125) was 64% (27% CR and 37% PR), with an additional 17% achieving SD beyond six months, for an overall clinical benefit of 81%.”

Dr. Power added that median time to progression was 10.5 months (range 1.6 to 22.5) and median survival had not been reached at the time of the last analysis (Figure 2). Thirteen patients with SD experienced an increase in CA-125 after two cycles that eventually decreased to below baseline values.

Compared to expected response rates to any combination of compounds in recurrent ovarian cancer, Dr. Power commented, the 45% response rate in this study was highly promising. “Generally, if you get a response rate like that, it is at the expense of your toxicity profile, yet hardly any of these 58 patients experienced significant toxicity. It was extremely well tolerated,” she remarked. The most frequent grades 3 and 4 toxicities were neutropenia (21%), thrombocytopenia (16%) and constipation (10%), which were not life-threatening, generally manageable, or resolved after drug interruption. Two patients developed grade 2 alopecia and only one case of grade 3 palmar-plantar erythrodysesthesia (PPE) was reported. No patient has discontinued therapy due to PPE.

Almost all the other side effects commonly associated with chemotherapy combinations in patients in this setting such as nausea/vomiting and fatigue were virtually non-existent or minimal. Unlike standard therapy, the PLD/carboplatin (PLD/C) combination did not cause notable hair loss. Dr. Power considered that to be an especially important quality-of-life issue among women who have already been through hair loss and are experiencing it again with recurrence of their cancer.

“We did not have any episodes of cardiotoxicity with the formulation of doxorubicin encapsulated in pegylated liposomes, not even mild ones, although standard doxorubicin, being a derivative of [doxorubicin hydrochloride], is highly cardiotoxic,” she noted. “In fact, this combination was so well tolerated that there are no huge red flags. You do not get the cardiotoxicity that you did with regular doxorubicin and you are not dealing with the neurotoxicity that comes with [paclitaxel].”

Drs. Stuart and Power emphasized individually that the Canadian trial included only patients who suffered recurrences at between six months and a year, which they called an unpredictable group in terms of responses to chemotherapy. Another unique feature of the study was the relatively low 30 mg/m2 dose of PLD used. In general, ovarian cancer patients who recur in less than six months do not respond to platinum-containing regimens at all, whereas those whose cancer recurs after 12 months are platinum-sensitive and will benefit from further platinum-containing treatment. On the other hand, optimal treatment for the partially platinum-sensitive population relapsing within the narrow six- to 12-month therapeutic window has not been defined.

F
ree Survival* (n=58)

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In Dr. Power’s view, this trial demonstrating PLD/C to be a safe and effective alternative for women with partially platinum-sensitive relapsed ovarian cancer is an important complement to the CALYPSO (Caelyx in Platinum-Sensitive Ovarian Patients) trial. This is an international, randomized, controlled phase III trial comparing the toxicity and efficacy of PLD/C to that of the standard PC combination in comparable patients. It is the largest trial ever undertaken in platinum-sensitive disease, and includes participation by 18 centres in Canada which contributed 76 patients.

“This is going to be a landmark paper,” Dr. Power affirmed. “Efficacy in the Canadian trial was an objective response rate of 45%, and that is an essential end point of the CALYPSO trial, along with a secondary one pinpointing toxicity. I think it will be a positive study for PLD. Even if the response rates to the two drug regimens are just equivalent, we will opt for the PLD combination because PC will still be less well-tolerated; patients will continue to lose their hair and nerve function in their fingers and toes. Results should be available in about 18 months.”

This interim analysis from the ongoing CALYPSO phase III trial , based on data from 200 of the 976 enrolled patients with epithelial ovarian cancer in late relapse, was reported here. The multiple authors, including Dr. Mark Heywood, National Cancer Institute of Canada-Clinical Trials Group, noted that the patients were randomized to intravenous (i.v.) carboplatin AUC 5 day 1 plus i.v. paclitaxel 175 mg/m2/3-h (PC) day 1, q3 weeks or carboplatin plus i.v. PLD 30 mg/m2 (PLD/C) day 1, q4 weeks, for at least six cycles. They pointed out that while the primary study end point is progression-free survival, the question of toxicity between the two regimens is also of crucial importance.

Among the investigators, Dr. Andreas du Bois, Horst-Schmidt-Klinik, Wiesbaden, Germany, reported that early treatment termination due to toxicity occurred in 13 of 98 patients in the group given PC vs. two of 102 receiving the PLD/C combination, and dose reductions were required in 20% to 30% of patients in both arms. Neutropenia, although infrequently associated with infection, was similar in both arms (grade 3 to 4: 37% PLD/C, 48% PC). Grade 3 to 4 anemia and thrombocytopenia occurred more frequently in the PLD/C arm than the PC arm (nine vs. five patients and 19 vs. five patients, respectively), which caused more frequent cycle delays in 23% of the patient cohort.

Hand and foot syndrome was the only non-hematologic toxicity occurring with greater frequency in the PLD/C treatment arm than the PC arm. PC induced more grade 2 alopecia than did PLD/C, as well as more cases of neuropathy, allergic reactions and
ble 1).

Table 1. CALYPSO: Major Non-hematological Toxicities

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This interim analysis of the first 200 patients in the CALYPSO trial concluded that although the overall frequency of toxicities in general was low, toxicity profiles differ between the two treatment regimens.

Case Studies

Dr. Nicoletta Colombo, European Institute of Oncology, University of Milan-Bicocca, Italy, and Prof. Ignace Vergote, Head, Department of Obstetrics/Gynaecology and Gynaecologic Oncology, Catholic University of Leuven, Belgium, presented two case studies that could be typical of those seen in day-to-day practice.

Case 1: A 60-year-old woman with moderate performance status (PS) with undifferentiated ovarian cancer FIGO stage IIIC and CA-125 630 U/mL had residual tumour of about 5 mm on the serosal surface of the small intestine. CA-125 was not carried out post-operatively. First-line chemotherapy consisted of six courses of carboplatin/docetaxel. Follow-up at eight months for abdominal discomfort revealed no pelvic mass but “rough tissue” at the apex vagina and Douglas pouch. The patient demands effective treatment while maintaining quality of life and will not accept surgery or any emetogenic regimen and has a strong preference not to lose her hair again. Chemotherapy options include single-agent carboplatin, PLD or topotecan; combinations of carboplatin/gemcitabine, PC, PLD/C or bevacizumab alone or in combination. Dr. Colombo asked the audience for their recommendations.

She told delegates that she typically subdivides patients such as this into those who are partially platinum-sensitive with a platinum-free interval of six to 12 months or those who have truly platinum-sensitive recurrent disease when the platinum-free interval extends to beyond 12 months. She noted that this patient would belong in the first group.

“Is the patient’s quality-of-life request for not losing her hair or enduring nausea/vomiting an acceptable therapeutic restriction?” she asked. “I think we should consider the toxicity profile when choosing chemotherapy in the salvage setting. We now have options for her, among which are some active drugs that do not cause hair loss and nausea/vomiting, so we should consider patient preference and give the patients some choice.”

She continued, “Would we provide only palliative care because the patient is not curable? The aims of second-line chemotherapy are different from refractory disease in which only palliation can be achieved. In patients with partially sensitive recurrent disease, I think we can hope to have some impact on time to progression and maybe even overall survival. PLD is particularly effective in this group of patients compared to topotecan, for example, with survival curves definitely superior in patients with a platinum-free interval between six and 12 months. Palliative care may not be an acceptable option for these patients.”

Dr. Colombo concluded that patients could now be offered effective agents which do not cause nausea/vomiting and alopecia. Although the disease is probably not curable, second-line chemotherapy may prolong survival, so palliative care need not be considered for these patients. There are now results from randomized comparisons indicating that PLD is more effective and less toxic than topotecan, and that PLD is equally effective but less toxic than gemcitabine. Regarding drug combinations, she stated that PC and carboplatin/gemcitabine are superior to single-agent carboplatin, but associated toxicity would be unacceptable to the patient under discussion. Finally, bevacizumab-targeted therapy is active but likely too toxic in heavily pretreated individuals; consequently it may be preferable to use such drugs up front and in combination with chemotherapy.

Case 2: Prof. Vergote described the case of a 60-year-old woman with serous ovarian cancer, FIGO stage IIC (T2c, Nx) with a CA-125 of 120 U/mL with no visible residual tumour following resection of two peritoneal nodules in the Douglas pouch which reduced CA-125 to 49 U/mL. First-line chemotherapy consisted of six courses of PC. More than a year later, the patient’s CA-125 rose to 85 U/mL without observable liver or lung metastases, mediastinal lymph node involvement, ascites or pleural effusion, which suggested para-aortic lymph nodes.

Discussing treatment strategy for this patient, Prof. Vergote noted that this patient had undergone surgery but was not optimally staged. About 58% of these patients have para-aortic metastasis, so the patient should have para-aortic lymphadenectomy and he believed a second debulking procedure would be in order.

Combination platinum-based chemotherapy has been established as standard treatment in platinum-sensitive relapse, he stated. At two years, there is a 9% improvement in overall survival, so there was no question in Prof. Vergote’s mind that this patient should get combination chemotherapy based on carboplatin. Gemcitabine/carboplatin has been introduced as an alternative for PC in platinum-sensitive ovarian cancer patients based on superior results for progression-free survival compared to carboplatin alone. On the other hand, he noted there are little data on PLD in combination with carboplatin aside from the recent ongoing Canadian CALYPSO studies. He cited a phase II GINECO trial (Ferrero et al. Ann Oncol 2007;18(2):263-8), where 51% of patients on PLD/C developed grade 3 to 4 neutropenia, 12% reported grade 2 to 3 mucositis and 11% had PPE grade 2 or higher. Although not randomized, this trial demonstrated a surprising response rate of 63% and median progression-free survival of 9.4 months, with a median overall survival of 32 months.

Prof. Vergote concluded that combination platinum-based chemotherapy can improve progression-free and overall survival in relapsed platinum-sensitive ovarian cancer patients. Gemcitabine/carboplatin and PLD/C have the advantage of not increasing neurotoxicity and are associated with less alopecia. Most patients, including the one under discussion, typically receive previous paclitaxel and in these cases, he stated a preference for PLD/C or gemcitabine/carboplatin.