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.

Breast cancer 1 (BRCA1) protein expression as a prognostic marker in sporadic epithelial ovarian carcinoma: an NCIC CTG OV.16 correlative study.

BACKGROUND: Breast cancer 1 (BRCA1) protein inactivation in sporadic ovarian carcinoma (OC) is common and low BRCA1 expression is linked with platinum sensitivity. The clinical validation of BRCA1 as a prognostic marker in OC remains unresolved. PATIENTS AND METHODS: In 251 patient samples from the NCIC CTG clinical trial, OV.16, BRCA1 protein expression was determined by immunohistochemistry. RESULTS: For all patients, when BRCA1 score was analyzed as a continuous variable, there was no significant correlation between BRCA1 protein expression and progression-free survival (PFS) [adjusted hazard ratio (HR) = 1.15 (0.96-1.37), P = 0.12] or response rate [HR = 0.89 (0.70-1.12), P = 0.32]. In the 116 patients with minimal residual disease (RD), higher BRCA1 expression correlated significantly with worse PFS [HR = 1.40 (1.04-1.89), P = 0.03]. Subgroup analysis divided patients with minimal RD into low (BRCA1 ≤2.5) and high (BRCA1 >2.5) expression groups. Patients with low BRCA1 expression had a more favorable outcome [median PFS was 24.7 and 16.6 months in patients with low and high BRCA1, respectively; HR = 0.56 (0.35-0.89), P = 0.01]. CONCLUSIONS: This study suggests that BRCA1 protein is a prognostic marker in sporadic OC patients with minimal RD. Further research is needed to evaluate BRCA1 as a predictive biomarker and to target BRCA1 expression to enhance chemotherapeutic sensitivity.

CA 125 normalization with chemotherapy is independently predictive of survival in advanced endometrial cancer.

OBJECTIVE: Changes in CA 125 with chemotherapy predict outcome for epithelial ovarian cancer. There is no such data for advanced endometrial cancer. METHOD: Retrospective review of all women receiving carboplatin and paclitaxel for advanced endometrial cancer at any of the institutions of the British Columbia Cancer Agency between September 1995 and September 2006. RESULTS: 185 newly diagnosed women were treated. Univariable analysis for progression-free survival identified as adverse predictors: grade 3, positive residual, age > 60, deep myometrial invasion, increasing stage/substage, papillary serous subtype, presence of cervical involvement, ECOG 1 or greater, CA 125 above 35 either preoperatively or at start of cycle 1 and CA 125 greater than 24 at the start of cycle 3. Upon multivariate analysis, CA 125 above 24 at cycle 3, grade 3 and positive residual remained as independent predictors. The single most important factor identified by decision tree analysis was CA 125 level at cycle 3. CONCLUSION: As with epithelial ovarian cancer, changes in CA 125 are highly predictive of outcome for advanced, chemotherapy treated endometrial cancer.

Preoperative tumor markers at diagnosis in women with malignant mixed müllerian tumors/carcinosarcoma of the uterus.

CA125 is a well-recognized marker for endometrial cancer. Uterine malignant mixed müllerian tumors (MMMTs) are increasingly being recognized as an aggressive adenocarcinoma, not a sarcoma. There are no data in the literature regarding CA125 in this malignancy. One hundred twelve women with surgically staged MMMT, diagnosed between July 1990 and September 2005, had a retrospective chart review performed. Preoperative CA125 levels were available in 29 (26%) women. Seventeen (49%) women had levels above the upper limit of normal of 35 kmicro/L. Mean levels increased with increasing surgical stage: stage I 53.4 kmicro/L; stage II 122.5 kmicro/L; stage III 147.1 kmicro/L; and stage IV 428.4 kmicro/L. Elevated levels of CA19-9, CEA, and CA15-3 were found in 8%, 12%, and 25%, respectively.

Inadequate Rates of BRCA Testing with its Negative Consequences for Women with Epithelial Ovarian Cancer and their Families: an Overview of the Literature.

Fifteen per cent of women with epithelial ovarian cancer possess inherited mutations in the BRCA genes. Knowledge of her BRCA status is important to her and her family. Poly(ADP-ribose) polymerase (PARP) inhibitors provide a new therapeutic option for her. For her family it provides the opportunity for the prevention of what otherwise is often a lethal disease. To access these opportunities, the mandatory first step is testing the woman with the cancer. However, referral rates for genetic counselling and subsequent BRCA testing are low, in the of 10-30% range. The current paradigm needs the patient to be referred to genetics, be counselled and then undergo testing. Such an ad hoc process will never be 100% successful. Removing the human element by using reflex tumour testing as part of the routine pathological analysis is an obvious solution. Now 100% of women carrying mutations will be identified. Subsequent testing within the family would identify all the carriers, who would then be eligible for risk-reducing surgery. The current process for this is also flawed, with significant drop off at each stage, as it involves the woman with epithelial ovarian carcinoma and a mutation providing the information to her family who then in turn need to be referred or make an appointment for genetic counselling/testing and then, finally, if carrying the mutation, make a decision about risk-reducing surgery. Process improvements and education can help to diminish these roadblocks. The relevant available literature has been reviewed in order to provide an extensive overview of this broad topic with actual rates of counselling/testing at each step, the uptake of risk-reducing surgery and some solutions to make the process more effective. The value of PARP inhibitors and surgical prevention are also discussed, but in a more condensed format.

Oral etoposide is active against platinum-resistant epithelial ovarian cancer.

PURPOSE: To determine whether etoposide (VP16) is more effective when administered on a chronic schedule, women with clinically defined platinum-resistant epithelial ovarian cancer (EOC) were studied. PATIENTS AND METHODS: Thirty-one eligible women were treated with oral VP16. The first seven received a dose that varied depending on their body-surface area, but this proved too toxic, and so a fixed dose of 100 mg orally per day for 14 days every 3 weeks was used for the other subjects. RESULTS: The response rate was 26% (95% confidence interval [CI], 11% to 41%). The 28 women with cancer that had progressed while they were receiving a platinum analog had a response rate of 21% (95% CI, 6% to 36%). Response durations were short. CONCLUSION: When administered on this chronic schedule, VP16 has activity against platinum-resistant EOC.

Prognostic variables in patients with diffuse large-cell lymphoma treated with MACOP-B.

One hundred twenty-six patients with diffuse large-cell lymphoma were treated with methotrexate with leucovorin, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin (MACOP-B) between April 1981 and June 1986. Univariate and multivariate analyses were performed using overall survival as of September 1989 as the end point. Four independent negative predictors of survival were identified: presence of B symptoms; more than two involved lymph node sites; more than one extranodal site (variables related to tumor burden), and age older than 60, a variable related to the patient's ability to tolerate treatment. Each variable contributed the same relative risk of dying and, accordingly, this simple predictive formula was developed empirically: (4-N) x 30 = the approximate percentage of chance of survival at 5 years. "N" is the number of predictive variables present. The same four predictors were also found to be significant by multivariate analysis when only those patients achieving a complete response were analyzed.

Ten-year outcome of patients with advanced epithelial ovarian carcinoma treated with cisplatin-based multimodality therapy.

PURPOSE: At the end of the 1970s it was thought that advanced epithelial ovarian cancer (EOC) could be cured by multimodality treatment using surgery, cisplatin-based combination chemotherapy, and radiotherapy (RT). Such multimodality treatment was used as standard therapy at our institution. Our long-term results are reviewed. PATIENTS AND METHODS: One hundred ninety-five previously untreated patients with stage III or IV EOC were treated between April 1979 and December 1982. All patients were to have debulking surgery, when feasible, followed by the administration of doxorubicin and cisplatin at 50 mg/m2 every 3 weeks until a total dose of doxorubicin of 450 mg/m2 had been reached. RT was used in addition in patients with disease remaining after the chemotherapy. Maintenance chemotherapy with oral cyclophosphamide and hexamethylmelamine (altretamine) was administered to patients who did not have a documented histologic complete remission. RESULTS: The 10-year overall and failure-free survivals were 4% and 8%, respectively. The median overall survival was 2 years. The achievement of a histologic complete response (n = 32) did not equate to cure because 20 (63%) of the patients eventually relapsed. Multivariate analysis identified residual disease of greater or less than 2 cm as the only independent prognostic factor. CONCLUSIONS: Our multimodality treatment program was noncurative for the majority of the patients. Innovative therapies are needed before we can hope to cure such disease.

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.

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.

Dose-dense paclitaxel in advanced ovarian cancer.

Carboplatin and paclitaxel, delivered on a 3-weekly basis, is the historical standard for the management of advanced epithelial ovarian cancers (EOC). Increased dose intensity, the inclusion of additional active cytotoxic agents and lengthening treatment duration have failed to improve the outcomes seen with standard doses of carboplatin and paclitaxel in the treatment of EOC. Dose-dense (i.e. weekly) delivery of paclitaxel may exploit anticancer mechanisms such as anti-angiogenesis and the induction of apoptosis. Tumour regrowth may be more effectively impaired by the dose-dense delivery of paclitaxel. Non-randomised studies of dose-dense chemotherapy in EOC have been promising, particularly in heavily pretreated and platinum-resistant disease, with reported response rates as high as 60%. Dose-dense paclitaxel also seems to be well tolerated. These observations led to a number of comparative trials of dose-dense paclitaxel chemotherapy, three have been reported and four are ongoing. This review explores the rationale behind dose-dense delivery of paclitaxel and evaluates the results of completed phase III trials.

A phase II trial of intravenous etoposide (VP-16-213) in epithelial ovarian cancer resistant to cisplatin or carboplatin: clinical and serological evidence of activity.

Etoposide (VP16) was administered intravenously at a dose of 150 mg/m2 daily for 2 days every 2 weeks to 24 patients with progressing epithelial ovarian carcinoma which was resistant to platinum analogues. Using standard response criteria there were five clinical partial responses (21%, 95% confidence limits 5-37%) and three disease stabilizations. However, the aim of our study was to determine if etoposide was non-cross-resistant with platinum analogues and therefore we also developed additional response criteria based on serial CA 125 levels. This was to enable us to differentiate within the heterogeneous group of responses that form the stable disease category. Nine of 23 patients (39%, 95% confidence limits 19-59%) demonstrated a fall (all rising prior to etoposide) and of these, three had a serologic partial remission (65% or greater fall). The serologic and clinical responses were strongly correlated. Falling CA 125 levels occurred in the eight patients with either clinical partial responses or disease stabilizations.

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.

'Moderate-risk' ovarian cancer (stage I, grade 2; stage II, grade 1 or 2) treated with cisplatin chemotherapy (single agent or combination) and pelvi-abdominal irradiation.

We placed patients with invasive epithelial ovarian cancer into four distinct prognostic groups: 'low', 'moderate', 'high' and 'extreme' risk. The 'moderate-risk' group contained all residual negative, stage I and II patients with two exceptions: stage Ia or b, grade 1 cancers and grade 3 cancers. They were treated with primary surgery, usually including bilateral salpingo-oophorectomy, hysterectomy and omentectomy. Chemotherapy was then given (cisplatin at 100 mg m-2 every 2 weeks for three cycles) followed by pelvi-abdominal irradiation (2250 cGy in 10 fractions to the pelvis and 2250 cGy in 22 fractions to the whole abdomen including pelvis). An early cohort with ascites or positive washings instead received six cycles of cisplatin and cyclophosphamide at 75 mg m-2 and 600 mg m-2 every 4 weeks with the same pelvi-abdominal irradiation sandwiched between cycles 3 and 4. One-hundred and nine patients were treated between November 1983 and December 1989. Median follow-up was 4.7 years (range 0.7-9 years). The 5-year actuarial overall and failure-free survivals were 81% and 76%, respectively. Chronic toxicity, although usually minor, included 15% with peripheral neuropathy or ototoxicity and 23% with chronic abdominal complaints. Our combined-modality results are similar to those obtained by other centers utilizing either pelvi-abdominal irradiation alone or cisplatin-based chemotherapy alone.

A phase II trial of mitomycin in patients with epithelial ovarian carcinoma resistant to cisplatin or carboplatin.

Intravenous bolus mitomycin was given at a dose of 10-12 mg/m2 to patients with epithelial ovarian cancer resistant to cisplatin or carboplatin. There were three (12%) partial responses and no complete responses in the 25 patients so treated.

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.

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.

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.