Exploring palliative treatment outcomes in women with advanced or recurrent ovarian clear cell carcinoma.

OBJECTIVE: Clear cell carcinoma (CCC) of the ovary is increasingly recognized as responding poorly to chemotherapy (CT). This review examines the outcomes achieved with a variety of CT regimens, looking for evidence of activity that might guide the development of more effective treatments. METHODS: A retrospective chart review of all cases of CCC referred to the BC Cancer Agency (BCCA) between 2000 and 2008 was conducted. Data were collected from those with primarily advanced disease and from those who recurred after adjuvant treatment. Outcomes were measured using broad definitions of treatment benefit (any objective or subjective evidence of disease control) in order to reflect the real-life use of palliative therapy. RESULTS: There were 158 women with pure CCC. First-line therapy for advanced disease was delivered to 33 patients. Second- and third-line treatment was delivered to 47 and 25 patients, respectively. The total number of treatment courses was 105: 88 CT-alone courses, 14 radiation therapy (RT)-alone and 3 combined modality. Treatment benefit was recorded in 24% of patients receiving CT, 64% of patients receiving RT, and each who received combined modality treatment. There was no CT drug class identified as obviously efficacious. CONCLUSION: Most patients with advanced or recurrent CCC have a low benefit-to-failure ratio from palliative CT. The role of RT and targeted agents must be explored to improve clinical outcomes for such patients.

Histotype predicts the curative potential of radiotherapy: the example of ovarian cancers.

BACKGROUND: To explore the influence of ovarian cancer histotype on the effectiveness of adjuvant radiotherapy (RT). METHODS: A review of a population-based experience included all referred women with no reported macroscopic residuum following primary surgery who underwent adjuvant platin-based chemotherapy (CT), with or without sequential RT, and for whom it was possible to assign histotype according to the contemporary criteria. RESULTS: Seven hundred and three subjects were eligible, of these 351 received RT. For those with apparent stage I and II tumors, the cohort with clear cell (C), endometrioid (E), and mucinous (M) disease who additionally received RT exhibited a 40% reduction in disease-specific mortality and a 43% reduction in overall mortality. CONCLUSIONS: The curability of those with stage I and II C-, E-, and M-type ovarian carcinomas was enhanced by RT-containing adjuvant therapy. This benefit did not extend to those with stage III or serous tumors. These findings necessitate reassessments of the role of RT and of the nonselective surgical and CT approaches that have characterized ovarian cancer care.

A phase II study of erlotinib (OSI-774) given in combination with carboplatin in patients with recurrent epithelial ovarian cancer (NCIC CTG IND.149).

OBJECTIVES: Approximately 50% of ovarian cancers have elevated levels of epidermal growth factor receptor (EGFR) which correlates with a poor prognosis. Preclinical evidence suggests that EGFR tyrosine kinase inhibitors (TKIs), such as erlotinib (OSI-774), may potentiate the anti-tumour effects of cytotoxic agents, including carboplatin. Blocking EGFR could thus potentially reverse drug resistance. The primary objective of the study was to assess the response rate to the addition of erlotinib in patients with recurrent ovarian cancer who were receiving carboplatin. METHODS: Patients enrolled on this study had either local or advanced recurrent ovarian cancer with measurable disease. They may have had up to 2 prior chemotherapy regimens, one of which must have contained platinum, and they must have responded to prior platinum therapy. Patients were stratified by platinum sensitivity and were treated with erlotinib 150 mg daily on a continuous dosing schedule, and carboplatin at an AUC of 5 every 21 days. RESULTS: Fifty patients with recurrent ovarian cancer entered the study, 33 in the platinum-sensitive arm and 17 in the platinum-resistant arm. Of patients evaluable for response, there were 14 partial responses (PR) of 30 evaluable for response (57% objective response rate (ORR)) in the platinum-sensitive arm, and 1 PR of 14 evaluable for response (7% ORR) in the platinum-resistant arm. CONCLUSIONS: The combination of erlotinib and carboplatin was active in patients with platinum-sensitive disease, but not in platinum-resistant disease. The toxicities seen were those expected with carboplatin and erlotinib.

A pilot phase 2 study of oregovomab murine monoclonal antibody to CA125 as an immunotherapeutic agent for recurrent ovarian cancer.

This prospective, open-label, pilot phase 2 study examined the clinical and immunologic effects of oregovomab (OvaRex) in heavily pretreated patients with recurrent ovarian cancer (OC). Thirteen women were administered intravenous oregovomab (2 mg) at weeks 0, 2, 4, 8, and 12, followed by quarterly doses for up to 2 years or disease progression. Concomitant chemotherapy was not permitted. Eligibility criteria included recurrence after one or more platinum-based chemotherapy regimens, CA125 >35 U/mL, evaluable or measurable disease. Tumor burden was evaluated by physical or radiologic methods pretreatment, weeks 12, 24, and every 24 weeks thereafter. Immune responses, including antibodies and T cells to oregovomab and CA125, were demonstrated in over half the patients. Stabilization of disease and survival >2 years was observed in 3 of 13 patients and coincided with robust immune responses. Shrinkage of marker lesions was not observed; however, four patients showed decreases in CA125 levels. Treatment was well tolerated without serious adverse events or discontinuations due to therapy. This pilot study supports immunologic activity and safety of oregovomab in recurrent OC. Further study of this agent in the consolidation and adjuvant setting is ongoing to establish its clinical utility.

Phase II multicenter open-label study of carboplatin and pegylated liposomal doxorubicin in uterine and cervical malignancies.

The results of a multicenter phase II study investigating carboplatin and pegylated liposomal doxorubicin (PLD) in patients with recurrent/metastatic uterine and cervical malignancies (UCM) are presented here. Fifty-three subjects with measurable, untreated, advanced UCM were enrolled. Fifty-one were evaluable for response. Prior combined-modality treatment was permitted if a component of primary therapy. Patients received carboplatin AUC = 5 with PLD 35 mg/m(2) intravenously once every 4 weeks. Overall response rate was 33% (35% stable disease). Overall survival (OS) at six months was 86% (95% CI 76%-96%). Six-month progression-free survival (PFS) was 43% (95% CI 30%-57%). Median PFS was 22.9 weeks (range 16.0-35.3) and median OS was 49.1 weeks (range 41.4-75.1). The most frequent grade 3-4 nonhematological adverse events were: abdominal pain (n = 7), fatigue (4), vomiting (4), nausea (3), and shortness of breath (3). There was 1 report of grade 3 hand-foot syndrome and none of grade 4. Twelve patients had first infusion reactions with only 1 discontinuing treatment. Grade 3-4 neutropenia occurred in 26/230 cycles (11.3%). There were no treatment-related deaths. The combination of carboplatin and PLD is well tolerated with sufficient activity to justify additional evaluation in clinical trials and might be suited to the addition of a taxane.

Carboplatin and paclitaxel for advanced and recurrent cervical carcinoma: the British Columbia Cancer Agency experience.

BACKGROUND: One of the most active chemotherapy combinations in advanced or recurrent cervical cancer is cisplatin-paclitaxel. However, this palliative regimen is associated with significant toxicity. Carboplatin-paclitaxel is thus an attractive option. METHODS: Patients with advanced or recurrent carcinoma of the cervix treated with carboplatin-paclitaxel from April 2000 were included in the study. Starting doses of carboplatin-paclitaxel were: AUC 5-6 and 155-175 mg/m(2), respectively, repeated every 28 days. RESULTS: Twenty-five women treated with this combination were identified. Twenty-three women (92%) had prior treatment with pelvic radiotherapy and 14 (56%) had had concurrent radio-sensitizing cisplatin. There was a 20% PR and a 20% CR rate (10/25). The median progression-free survival for the entire group was 3 months. Responders had a median PFS of 16 months. Fourteen patients (56%) had died of disease progression. The median overall survival (OS) was 21 months. Common toxicities included: grade 1 or 2 anemia, 68%; grade 3 or 4 anemia, 32%; grade 3 or 4 neutropenia, 32%; and grade 1 or 2 peripheral neuropathy, 24%. ECOG PS did not change significantly while on treatment. Eighty-four percent of treatments were delivered on time, and 96% at full dose. CONCLUSIONS: Carboplatin-paclitaxel is an active combination in advanced and recurrent cervical cancer. In this predominantly pre-irradiated group, the combination was deliverable, well tolerated, and the most commonly observed toxicity was anemia.

Long-term follow-up confirms a survival advantage of the paclitaxel-cisplatin regimen over the cyclophosphamide-cisplatin combination in advanced ovarian cancer.

Two independent and consecutive randomized clinical trials, conducted by the American Gynecological Oncology Group and by an European-Canadian Intergroup, have shown superiority, in clinical response rate, progression-free survival, and overall survival, of a cisplatin-paclitaxel regimen over cisplatin-cyclophosphamide given as first-line chemotherapy for women with advanced epithelial ovarian cancer. The results of these studies, published with a median follow-up of about 3 years, have been updated with a 6.5-year follow-up: In each case, an 11% absolute gain in survival favoring the paclitaxel arm is shown; this advantage remains both statistically and clinically significant and supports a role for paclitaxel in frontline chemotherapy for advanced ovarian cancer.

Small-cell carcinoma of the cervix: fourteen years of experience at a single institution using a combined-modality regimen of involved-field irradiation and platinum-based combination chemotherapy.

PURPOSE: To determine the efficacy and toxicity of a combined-modality regimen of irradiation with platinum-based combination chemotherapy in small-cell carcinoma of the cervix (SCCC). PATIENTS AND METHODS: Thirty-four patients with SCCC were seen and treated at the British Columbia Cancer Agency between May 1988 and November 2002. Two protocols were used, SMCC (May 1988 to December 1995) and SMCC2 (January 1996 to November 2002). Both protocols used cisplatin, etoposide, and involved-field irradiation (essentially pelvis plus or minus para-aortics) with concurrent chemotherapy. In addition, SMCC2 included carboplatin and paclitaxel, and the para-aortics were irradiated routinely. RESULTS: Thirty-one patients received either SMCC (n = 17) or SMCC2 (n = 14), and three patients did not (disease too extensive, n = 1; patient refusal, n = 1; and alternative regimen, n = 1). For the 31 patients treated on one of the protocols, the 3-year overall and failure-free survival (FFS) rates were 60% and 57%, respectively. The results were equivalent for SMCC and SMCC2. Radiologic stage was the only independent predictor for FFS (80% at 3 years for stage I and II patients v 38% at 3 years for stage III and IV patients). Distant failure (28%) was the most common cause of failure, with local failure occurring in 13% of patients. The switch to SMCC2 did not improve efficacy but did lessen the toxicity. CONCLUSION: SCCC can be successfully treated in approximately 55% of patients with a combination of irradiation and platinum-based chemotherapy. Disease extent predicts for chance of curability.

Phase II study of CGP 69846A (ISIS 5132) in recurrent epithelial ovarian cancer: an NCIC clinical trials group study (NCIC IND.116).

OBJECTIVE: ISIS 5132 is a 20-base phosphorothioate DNA oligonucleotide against human c-raf kinase, a downstream effector of ras oncogene function. C-raf kinase is a molecule in the MAP kinase signaling cascade which is essential for cellular proliferation, the overexpression of which leads to malignant expression. Activity of this compound was documented in a woman with ovarian cancer in a Phase I study. METHODS: We evaluated ISIS 5132 at a dose of 4 mg/kg/day by continuous venous infusion, administered for 21 days q 4 weeks in 22 patients with recurrent ovarian cancer in a standard two-stage Phase II design. Three patients were ineligible; 19 patients are evaluable for toxicity and 16 for response. All patients had previously received systemic therapy for ovarian cancer (6 had one and 13 had two prior regimens). Patients were treated with a median of two cycles and 79% of the patients received >90% planned dose intensity. RESULTS: ISIS 5132 was well tolerated with no episodes of Grade 3 or 4 hematologic or biochemical (creatinine, AST, bilirubin) toxicity. There were six episodes of grade 3 nonhematologic toxicity in 4 patients thought to be treatment related (lethargy 2; anorexia 1; abdominal pain 2; shortness of breath 1). No responses were seen in the 16 patients who are evaluable for response; 4 had stable disease for a median of 3.8 months and 12 patients had documented progressive disease. CONCLUSION: ISIS 5132 at 4 mg/kg/day as a single agent did not show activity in recurrent ovarian cancer.

Paclitaxel and carboplatin, alone or with irradiation, in advanced or recurrent endometrial cancer: a phase II study.

PURPOSE: To evaluate the efficacy of carboplatin plus paclitaxel in primarily advanced or recurrent endometrial cancers. PATIENTS AND METHODS: Four distinct patient groups received carboplatin (area under the curve, 5 to 7) plus paclitaxel 175 mg/m(2) for 3 hours at 4-week intervals: group 1 (n = 21), patients with primarily advanced, nonpapillary serous cancers; group 2 (n = 20), the same as group 1 but with papillary serous cancers; group 3 (n = 18), recurrent, nonpapillary serous cancers; and group 4 (n = 4), recurrent, papillary serous cancers. Involved-field irradiation was used in groups 1 and 2 for those with radioencompassable disease. RESULTS: Sixty-three patients were treated. Response rates to chemotherapy in the assessable patients in the four groups were 78% (95% confidence interval [CI], 51% to 100%); 60% (95% CI, 35% to 85%), 56% (95% CI, 34% to 78%), and 50%, respectively. Nineteen patients (90%) in group 1 also were irradiated, and the median failure-free survival time for all 21 patients was 23 months, with a 62% 3-year overall survival rate. Eleven patients (55%) in group 2 were irradiated, and the median failure-free survival time for all 18 patients was 18 months, with a 39% 3-year overall survival rate. The median failure-free interval in the patients in group 3 was 6 months, with a 15-month median overall survival time. Toxicity was manageable, reversible, and predominantly hematologic. Two patients developed neutropenic fever, and three patients, including these two, were hospitalized for complications. CONCLUSION: Carboplatin-paclitaxel is an efficacious, low-toxicity regimen for managing primarily advanced or recurrent endometrial cancers.

Randomized intergroup trial of cisplatin-paclitaxel versus cisplatin-cyclophosphamide in women with advanced epithelial ovarian cancer: three-year results.

BACKGROUND: A randomized trial conducted by the Gynecologic Oncology Group (GOG, study #111) in the United States showed a better outcome for patients with advanced ovarian cancer on the paclitaxel-cisplatin regimen than for those on a standard cyclophosphamide-cisplatin regimen. Before considering the paclitaxel-cisplatin regimen as the new "standard," a group of European and Canadian investigators planned a confirmatory phase III trial. METHODS: This intergroup trial recruited 680 patients with broader selection criteria than the GOG #111 study and administered paclitaxel as a 3-hour instead of a 24-hour infusion; progression-free survival was the primary end point. Patient survival was analyzed by use of the Kaplan-Meier technique. Treatment effects on patient survival were estimated by Cox proportional hazards regression models. All statistical tests were two-sided. RESULTS: The overall clinical response rate was 59% in the paclitaxel group and 45% in the cyclophosphamide group; the complete clinical remission rates were 41% and 27%, respectively; both differences were statistically significant (P =.01 for both). At a median follow-up of 38.5 months and despite a high rate of crossover (48%) from the cyclophosphamide arm to the paclitaxel arm at first detection of progression of disease, a longer progression-free survival (log-rank P =.0005; median of 15.5 months versus 11.5 months) and a longer overall survival (log-rank P =. 0016; median of 35.6 months versus 25.8 months) were seen in the paclitaxel regimen compared with the cyclophosphamide regimen. CONCLUSIONS: There is strong and confirmatory evidence from two large randomized phase III trials to support paclitaxel-cisplatin as the new standard regimen for treatment of patients with advanced ovarian cancer.

Intergroup collaboration in ovarian cancer: a giant step forward.

The rather slow evolution of so-called "optimal chemotherapy" for ovarian cancer is the result of suboptimal randomised clinical trials, not having the statistical power to identify truly superior regimens, and of the lack of systematic comparisons of new agents with relevant control arms. There is little doubt that we need international collaboration to move the field forward in a timely and coherent manner. European and transatlantic collaboration represents the beginning of the process and point to the success that can await us if the drive to work together remains strong. A similar organisation as for breast cancer (Breast International Group, BIG) needs to be established for ovarian cancer.

Gliomatosis peritonei with malignant transformation.

A 13-year-old girl underwent a right salpingo-o-ophorectomy and partial omentectomy for an ovarian tumor that on microscopic examination was a grade 1 immature teratoma. Mature glial implants were found in the omentum (Stage III). No additional treatment was given. Ten months later, grade 0 and grade 1 peritoneal glial implants were found on laparotomy. Chemotherapy with four cycles of vincristine/cisplatin/etoposide/bleomycin was administered. A second laparotomy 4 months later showed persistence of grade 0 and grade 1 peritoneal glial implants. The patient was well for the next 7 years, after which time she presented with a pelvic mass that on microscopic examination was a malignant neuroectodermal tumor resembling a glioblastoma multiforme. The tumor did not respond to debulking and chemotherapy, and the patient died 6 months later, 8 years after her initial presentation. This case represents the second report of malignant transformation of peritoneal glial implants.

Cisplatin/etoposide chemotherapy for recurrent or primarily advanced cervical carcinoma.

Thirty-eight women with primarily advanced (n = 10) or recurrent (n = 28) cervical carcinoma were treated with cisplatin (30 mg/m2/day intravenously) and etoposide (60 mg/m2/day intravenously) for 3 days followed by oral etoposide, 50 mg daily for 7 days, repeated at 28-day intervals. The response rate was 39% (95% confidence limits 24-55%) with response duration of 5 to 36 months. The main toxicities were neutropenia (21% developing neutropenic fever), alopecia, stomatitis, and nausea and vomiting. Despite this all responders had maintained or improved quality of life as defined by symptoms and performance status.

"MECCA": a developmental, dose-intensive, non-cross-resistant platinum-based chemotherapy for advanced ovarian cancer.

Twenty-nine women, ages 30-58 years, with advanced ovarian carcinoma were treated with a developmental combination chemotherapy regimen consisting of mitomycin C, etoposide, cisplatin, and carboplatin (MECCA). This protocol utilized the concepts of dose intensity, front-end loading, non-cross-resistance, and synergy. The median overall survival was 37 months with a 27% 5-year survival; the median failure-free survival was 15 months with a 14% 5-year failure-free rate. The predominant toxicity was hematologic and there was one toxic death (cardiac failure). The overall survival results are superior to our previous experience.

A phase I study of bi-weekly paclitaxel/cisplatin as initial therapy for advanced ovarian cancer. A study of the National Cancer Institute of Canada Clinical Trials Group.

PURPOSE: Given the potential for improved outcomes, a phase I trial was initiated to develop a paclitaxel/cisplatin regimen that could be delivered every two weeks to women with newly diagnosed advanced ovarian cancer. PATIENTS AND METHODS: From 1992 to 1994, 29 (28 eligible) patients were enrolled in a dose-seeking trial. All received 60 mg/m2 of cisplatin preceded by paclitaxel infused over three hours. The paclitaxel dose was excalated from an initial level of 90 mg/m2 by 10 mg/m2 increments in successive cohorts of patients. RESULTS: At 120 mg/m2 of paclitaxel, the dose-limiting toxicity was granulocytopenia which prevented retreatment on time. The recommended dose level was therefore paclitaxel 110 mg/m2 infused over three hours with cisplatin 60 mg/m2, repeated bi-weekly for eight cycles. CONCLUSION: This bi-weekly schedule of paclitaxel/cisplatin provides no advantage in terms of dose-intensity nor total dose of paclitaxel in comparison to more common regimens given tri-weekly.

Taxol is active in platinum-resistant endometrial adenocarcinoma.

Taxol, 170 mg/m2 by 3-h infusion every 3 weeks, was administered to seven patients with primarily advanced or recurrent endometrial cancer with progressive disease on platinum analogues. By standard response criteria, there were three clinical responders (43%; 95% confidence limits, 6-80%) and one disease stabilization. All three responses were clinical partial responses. The response duration ranged from 3 to 7 months. These preliminary results suggest that taxol is active in patients with platinum-resistant endometrial adenocarcinoma.

Platinum plus cyclophosphamide plus radiotherapy is superior to platinum alone in 'high-risk' epithelial ovarian cancer (residual negative and either stage I or II, grade 3, or stage III, any grade).

Patients with epithelial ovarian cancer (EOC) referred to our institution are stratified into risk groups based on their stage, grade and presence of residual cancer, with a specific treatment policy for each group. One-hundred and thirty-one patients with no visible residual tumor following primary surgery and either stage I, grade 3; stage II, grade 3; or stage III, any grade EOC were treated between November 1983 and the end of December 1991. Regimen A (cisplatin 75 mgm-2 and cyclophosphamide 600 mgm-2 intravenously every 4 weeks for 6 cycles with abdominopelvic irradiation between cycles 3 and 4) was used until April 1989 and was then replaced with Regimen B (cisplatin 75 mgm-2 intravenously every 3 weeks for 6 cycles). The 5-year actuarial overall and failure-free survivals were 78% and 64% respectively. Multivariate analysis identified increasing stage and treatment with Regimen B as independent adverse prognostic factors for failure-free survival. The importance of treatment regimen reached statistical significance for the stage I patients (P = 0.04) but not stage II (P = 0.11) or stage III (P = 0.79). It is possible to undertreat EOC as shown by the inferior results achieved with Regimen B (single agent cisplatin) compared to Regimen A (cisplatin-cyclophosphamide, irradiation). This effect of treatment regimen was particularly important for the lower-stage patients. Our postulate is that treatment resistant clones are less regularly present in lower-stage patients, and that a certain minimum amount of treatment is required to eliminate all the sensitive cancer.

Small cell carcinoma of the cervix treated with concurrent radiotherapy, cisplatin, and etoposide.

A multimodality regimen of four cycles of cisplatin and etoposide with concurrent locoregional radiotherapy (XRT) has been, since May 1988, the standard therapy for women with small cell carcinoma of the cervix (SCCC). Prophylactic cranial irradiation was to be used in all but primary progressors. All 11 patients (median age 47; 4 with pure SCCC and 7 with mixed histology) seen by us were treated with this regimen. Only 1 patient progressed while on treatment. The 3-year overall and failure-free survivals were 28%. Four patients remain alive in first remission; the remaining 7 died (2 from toxicity, 5 from cancer). Although not statistically significant due to the small numbers, it appeared that the chance of long-term survival depended both on the amount of the cancer as indicated by the FIGO stage and size of the primary and also the performance status. The toxicity was significant with 70% experiencing severe neutropenia and 40% being admitted for control of emesis. This regimen is only appropriate for those women in whom all of the apparent tumor can be encompassed within a radiation field and who, in addition, have a performance status of 0 or 1. For the remainder it does not offer any chance of long-term survival and its toxicity renders it antipalliative.