Montana Cancer Consortium

2031 Background: The mammalian target of rapamycin (mTOR) functions within the PI3K/Akt pathway as a critical modulator of cell survival. Preclinical studies in GBM indicate that the combination of mTOR inhibitors, such as everolimus (RAD001), with either radiation therapy (RT) or temozolomide (TMZ) provide increased tumor cell killing. Methods: Newly diagnosed GBM pts were eligible for the study. RAD001 was dosed orally at 70 mg/week weekly, starting 1 week prior to RT/TMZ, and continued throughout RT/TMZ, adjuvant TMZ and then until progression. This was a single arm phase II design powered to detect a true overall survival at 12 months (OS12) of 73% (vs 58% in historical controls). Secondary endpoints were toxicity, response rate, and time to progression (TTP). A subgroup of patients with measurable residual disease were eligible for the PET imaging component of the study, consisting of an 18FLT-PET/CT scan performed before and after the initial two doses of RAD001 but before the first dose of RT or TMZ. Results: 103 patients were accrued to phase II of which 100 were evaluable. The median age was 60.5 years (23-81), median ECOG PS was 1, 46 patients had GTR, 33 STR, and the remainder had biopsy at diagnosis. Treatment tolerance was acceptable: 17% patient had at least one grade 3 hematologic toxicity; 14% had at least one grade 4 hematologic toxicity, 42% had at least one grade 3 non-heme toxicity, while 12% had at least one grade 4 non-heme toxicity. No increased incidence of infectious complications was observed and there were no treatment related deaths. Median PFS was 5.3 months (1.3-21.4), with 22 patients progression free. Mature OS data will be available at the meeting. MGMT methylation status analysis is ongoing. Of the pts who had evaluable FLT-PET data, three of eight (37.5%) had a drop in SUVmax >25% after two treatments of RAD001. Conclusions: RAD001 with standard of care chemoradiation had moderate toxicity. Serial 18FLT-PET was feasible for evaluating drug-induced changes in tumor proliferation following RAD001. Final outcome data and association of MGMT status with outcome will be reported at the meeting.

Lymphedema of the arms can be a serious consequence of local and regional therapy in women with breast cancer. Coumarin has been reported to be effective for the treatment of women with lymphedema; we undertook a study in which we attempted to replicate those findings. We studied 140 women with chronic lymphedema of the ipsilateral arm after treatment for breast cancer. The women received 200 mg of oral coumarin or placebo twice daily for six months and then the other treatment for the following six months. The end points of the study consisted of the volume of the arm (calculated from measurements of hand and arm circumference) and the answers on a questionnaire completed by the patient about symptoms potentially related to lymphedema. The volumes of the arms at 6 and 12 months, were virtually identical, regardless of whether coumarin or placebo was given first. After six months, the average volume of the affected arm increased by 21 ml during placebo treatment and 58 ml during coumarin treatment (P=0.80). In addition, answers to patient-completed questionnaires were similar in the two treatment groups. After six months only 15 percent of the women in the coumarin group and 10 percent of those in the placebo group reported that the study medication had helped a moderate or large amount (P=0.19). Coumarin was well tolerated, except that it resulted in serologic evidence of liver toxicity in 6 percent of the women. Coumarin is not effective therapy for women who have lymphedema of the arm after treatment for breast cancer.

We prospectively treated 46 patients with favorable myelodysplastic syndrome classified as refractory anemia (RA), refractory cytopenia (RC), or refractory anemia with ringed sideroblasts (RARS). These patients received one of two schedules of 13-Cis-Retinoic Acid (low dose 80 mg daily for 6 months vs. high dose 200 mg po daily for 3 months), or Danazol (800 mg po daily for 3 months), and were crossed over to the alternative drug in the absence of response or at progression. Using strict criteria of response we found little objective evidence of activity for either compound. Only two minor responses were seen among 22 patients treated with low dose 13-CRA, 1 response among 20 cases that received high dose 13-CRA, and 1 partial response and 1 minor response to Danazol among 34 cases. Neither 13-Cis-Retinoic Acid nor Danazol appear active enough in patients with favorable myelodysplastic syndrome to justify their use.

Doxorubicin generally is considered to be the most effective single chemotherapeutic agent for the treatment of breast cancer. The major cumulative dose-limiting toxicity is cardiac toxicity, which may be related to the formation of free radicals with subsequent lipid peroxidation, leading to membrane damage. The anthrapyrazoles, of which piroxantrone is a member, were synthesized in an attempt to eliminate this toxicity. A Phase II clinical trial was conducted in 30 women with metastatic breast cancer in whom piroxantrone was administered at a dose of 160 mg/m2 by 1-hour infusion. The planned cycle length for retreatment was 3 weeks. Measurable metastatic disease and failure on one prior chemotherapy regimen, but no prior anthracycline exposure, were required for response evaluation. Twenty-nine patients were evaluable for response, and 6 (21% and 95% confidence intervals: 10-43%) achieved an objective response (1 complete, 5 partial responses), with a median response duration of 244 days. The median time-to-disease progression for all patients was 124 days. Eight patients received cumulative doses of piroxantrone approaching or exceeding 1000 mg/m2, and all had reductions in the resting left ventricular ejection fraction (LVEF). The estimated median decrease in LVEF at 1000 mg/m2 was 16%, with a range of 10-28%. Clinical findings of congestive heart failure developed in two patients. Piroxantrone had definite antitumor activity in women who had metastatic breast cancer and failure on prior chemotherapy that did not include an anthracycline. The 95% confidence interval for response probability was broad, but the level of activity observed was relatively low. The clear association with cardiac toxicity combined with the relatively low efficacy led to the conclusion that piroxantrone cannot be recommended for further development as therapy for women with breast cancer. Further study of other anthrapyrazoles is necessary to determine if the promise of this new class of agents can be fulfilled.

In this study, we evaluated the role of alternating chemotherapy with or without etoposide (VP-16) in patients with extensive-stage small-cell carcinoma (SCC) of the lung. All patients received initial treatment with CMC [cyclophosphamide, methotrexate, and chloroethyl-cyclohexyl-nitrosourea (CCNU)]. Four weeks after initial treatment, patients were stratified by performance score, central nervous system (CNS) metastasis, age, and response to initial CMC therapy and randomized to receive AO (doxorubicin and vincristine) or AVO (doxorubicin, VP-16, and vincristine) alternating with CMC. One hundred eighty-two eligible patients were treated with the initial cycle of CMC and 98 responded (54%). One hundred fifty-four patients were randomized to either AO/CMC or AVO/CMC. The response rates to AO/CMC and AVO/CMC were similar (72 vs. 68%). The time to progression and survival were not significantly different on the two treatment regimens. Toxicity was significantly greater for patients receiving AVO/CMC with six treatment-related deaths. Etoposide as used in this regimen did not significantly influence response rates, time to progression, or survival of patients with extensive small-cell lung cancer.