Matthew Volm

Preoperative Twice-Weekly Paclitaxel With Concurrent Radiation Therapy Followed by Surgery and Postoperative Doxorubicin-Based Chemotherapy in Locally Advanced Breast Cancer: A Phase I/II Trial

PURPOSE Preoperative chemotherapy is the conventional primary treatment in locally advanced breast cancer (LABC). We investigated the safety and efficacy of primary twice-weekly paclitaxel and concurrent radiation (RT) before modified radical mastectomy followed by adjuvant doxorubicin-based chemotherapy. PATIENTS AND METHODS Stage IIB (T3N0) to III LABC patients were eligible. Primary chemoradiation consisted of paclitaxel, 30 mg/m(2) delivered intravenously for 1 hour twice weekly for a total of 8 to 10 weeks, and concurrent RT (45 Gy at 1.8 Gy/fraction). Modified radical mastectomy was performed at least 2 weeks after completion of chemoradiation or on recovery of skin toxicity. Postoperatively, patients who responded to paclitaxel and RT received four cycles of doxorubicin/paclitaxel, whereas patients who did not respond received doxorubicin/cytoxan. RESULTS Forty-four patients were accrued. Toxicity from paclitaxel/RT included grade 3 skin desquamation (7%), hypersensitivity (2%), and stomatitis (2%). Postsurgery complications occurred in six patients (14%). The only grade 4 toxicity of postmastectomy chemotherapy was hematologic (10%). Grade 3 toxicities were leukopenia (24%), infection (22%), peripheral neuropathy (17%), arthralgia and pain (17%), stomatitis (12%), fatigue (10%), esophagitis (5%), and nausea (2%). Overall clinical response rate to preoperative paclitaxel and RT was 91%. Thirty-four percent of patients achieved a pathologic response in the mastectomy specimen: 16% pathologic complete responses (clearance of invasive cancer in the breast and axillary contents) and 18% pathologic partial responses (< 10 residual microscopic foci of invasive breast cancer). CONCLUSION Twice-weekly paclitaxel with concurrent RT is a feasible and effective primary treatment for LABC. Future studies should compare primary chemoradiation to chemotherapy in LABC.

Effect of Highly Active Antiretroviral Therapy on Survival in Patients With AIDS-Associated Pulmonary Kaposi’s Sarcoma Treated With Chemotherapy

PURPOSE Kaposis sarcoma (KS) is the most common AIDS-related malignancy. Pulmonary involvement by KS (PKS) has carried a poor prognosis with median reported survival ranging from 3 to 10 months. We studied whether the introduction of highly active antiretroviral therapy (HAART; triple antiretroviral therapy including a protease inhibitor and two reverse transcriptase inhibitors) has been associated with improved survival for AIDS patients with PKS. PATIENTS AND METHODS A retrospective study was performed of 37 consecutive patients with PKS and human immunodeficiency virus infection in the tumor registry at a large municipal hospital in New York City between 1994 to 1997. There were 16 patients from 1994 to 1995 (pre-HAART period) and 21 patients from 1996 to 1997 (post-HAART period). The primary end point was survival, which was defined as time from start of chemotherapy until death from any cause. RESULTS Patients were analyzed by the date of diagnosis (pre- v post-HAART period) and whether or not they received HAART. Kaplan-Meier analysis showed significantly better survival in patients diagnosed in the post-HAART period (P =.0025). Additional Kaplan-Meier analysis indicated that patients on HAART had substantially better survival (P <.0001). Cox multivariate analyses showed that HAART therapy was associated with a reduced risk of death (hazard ratio = 0.09; 95% confidence interval, 0.03 to 0.69). CONCLUSION In patients with AIDS-associated PKS and undergoing chemotherapy, administration of HAART was associated with increased survival.

Phase II trial of RAD001 plus carboplatin in patients with triple-negative metastatic breast cancer.

293 Background: RAD001 is an oral mTOR inhibitor that has exhibited activity in breast cancer. Triple negative breast cancer cells are unable to repair double stranded DNA breaks and hence have sensitivity to platinum agents that cause interstrand cross-links. Rapamycin acts synergistically with platinum agents to induce apoptosis and inhibit proliferation in at least two different breast cancer cell lines (including ER/PR negative cell lines). We propose that combination RAD001 and carboplatin may have activity in triple-negative breast cancer. METHODS The primary objective of the study is to determine clinical benefit (complete remission; CR, partial remission; PR and stable disease; SD) and the toxicity of this combination in women with triple negative metastatic breast cancer who had received 0-3 prior chemotherapy regimens for metastatic disease. Prior carboplatin was allowed. Women with treated brain metastasis were eligible. Secondary objectives were to determine progression free survival. According to the original study plan, carboplatin AUC 6, was to be given intravenously every three weeks. 5 mg of RAD001 was to be given daily with a 3 patient run-in and then 10 mg daily if there were no dose-limiting toxicities. Due to a surprising amount of thrombocytopenia with this combination the dose of carboplatin was first amended to AUC 5 and most recently to AUC 4 with 5 mg of RAD001 (and no plan to escalate to 10 mg). RESULTS Eleven patients of a planned 25 have been recruited thus far. Median age is 62. Median number of prior regimens is 1. Of the 6 patients assessable for response at this time, four have SD and two have had a PR. 1 SD was achieved in a patient progressing on prior carboplatin at study entry. Five of 7 patients assessable for toxicity had grade 3 or 4 thrombocytopenia and 2 patients had grade 3 neutropenia. All patients have had treatment held and/or dose reductions secondary to hematological toxicity. There have been no non-hematological grade 3 or 4 toxicities. CONCLUSIONS Clinical benefit was observed in all 6 evaluable patients. Dose limiting thrombocytopenia was an unexpected side effect requiring protocol amendment. We continue to accrue study subjects at the amended dosing.

Phase I study of amifostine as a cytoprotector of the gemcitabine/cisplatin combination in patients with advanced solid malignancies.

Our objective was to evaluate the role of amifostine as a cytoprotector in patients with solid tumors receiving the myelosuppressive regimen of gemcitabine/cisplatin combination. Patients with advanced solid tumors were randomized to gemcitabine–amifostine–cisplatin (GAP) or gemcitabine–cisplatin (GP) in Cycle 1 (C1) and then were crossed over to the other treatment in Cycle 2 (C2). Amifostine at 740 mg/m2, followed by gemcitabine and cisplatin, were given for 2 consecutive weeks, every 4 weeks. Two GP combinations were studied: G 1000 mg/m2 and P 40 mg/m2 days 1, 8 (high dose), and G 800 mg/m2 and P 30 mg/m2 days 1, 8 (low dose). Forty patients were enrolled. Of the 19 patients treated with high-dose GP, 11 (nine patients GP in C1 and GAP in C2, two patients GAP in C1 and GP in C2) completed 2 cycles of therapy. Of the eight non-evaluable patients, five patients dropped out due to toxicity or refusal after treatment with amifostine in C1. Of the 21 patients treated with low-dose GP, 15 (eight patients GP in C1 and GAP in C2, seven patients GAP in C1 and GP in C2) were likewise evaluable. The incidence of grade 3 or 4 hematologic toxicities was similar for GP and GAP during the first 2 cycles of treatment, and there were no statistically significant differences in mean absolute neutrophil count, hemoglobin level and platelet levels between the cycles in each arm. We conclude that amifostine, at 740 mg/m2, does not lead to less myelosuppression when combined with gemcitabine/cisplatin chemotherapy regimens and may possibly contribute to subjective intolerance.

Efficacy of RAD001/carboplatin in triple-negative metastatic breast cancer: A phase II study.

108 Background: Triple-negative breast cancer cells are unable to repair double stranded DNA breaks and have sensitivity to platinum agents. Rapamycin acts synergistically with platinum agents to induce apoptosis and inhibit proliferation in breast cancer cell lines. RAD001 (oral mTOR inhibitor) and Carboplatin combination may have activity in triple-negative breast cancer. METHODS The primary objective is to estimate clinical benefit (complete remission (CR) + partial remission (PR) + stable disease (SD) lasting >6 months) and toxicity of the combination in triple negative metastatic breast cancer patients who have had 0-3 prior chemotherapy regimens. This design has > 80% power to test the null hypothesis i.e. clinical benefit rate is ≤ 10% vs. alternative hypothesis that clinical benefit rate is ≥ 30%. Prior carboplatin is allowed. Women with treated brain metastasis are eligible. Originally, carboplatin AUC 6 was to be administered every 3 weeks along with daily 5mg of RAD001 with a 3 patient run-in and then 10 mg daily. Due to a surprising amount of thrombocytopenia, the dose of carboplatin was first amended to AUC 5 and most recently to AUC 4 with 5 mg of RAD001 (no escalation to 10 mg). RESULTS 23 out of 25 patients have been recruited. Median age is 59. Thus far, there have been 1 CR, 5 PRs, 8 SDs and 6 PDs. One SD was achieved in a patient progressing on single agent carboplatin at study entry. Median duration of response is 13 weeks (range: 6-74 weeks). 5 patients had grade 3/4 thrombocytopenia and 4 patients had grade 3 neutropenia (no febrile neutropenia). 13 patients had treatment held and/or dose reductions secondary to hematological toxicity. Since dosing amendment for carboplatin to AUC 4 the regimen has been well tolerated (only 1 patient with grade 3 neutropenia and thrombocytopenia). 1 patient had grade 3 dehydration. The estimated clinical benefit rate is 45% (95% C.I.: 23%, 67%). Median time to progression or death is 85 days from start of treatment. CONCLUSIONS Our study has met the primary end point of demonstrating clinical benefit in triple-negative metastatic breast cancer. Dose-limiting thrombocytopenia was an unexpected side effect requiring protocol amendment. Patient accrual continues at the amended dosing.

A phase II trial of DTIC with thalidomide (thal) in metastatic melanoma (MM)

7543 Background: Single agent DTIC has a response rate of 10-20% in metastatic melanoma. In an attempt to improve disease response, thalidomide was added to standard dose DTIC in patients with MM. METHODS Eligibility: Stage IV MM, ECOG performance status 0-1, no prior chemotherapy, no brain mets and adequate hematologic and organ function. Patients received DTIC 1000 mg/m2 IV every 3 weeks with thal 200 mg daily at night (hs). Thal doses were escalated in 100 mg increments every 3 weeks as tolerated. Responses were assessed after 3 cycles. RESULTS 15 patients were accrued between 6/00 and 7/03 (IV1a-2, IV1b-7, IV1c-6). 6 patients had prior adjuvant vaccine or immunotherapy and 9 had no prior adjuvant therapy. LDH was elevated in 8/15. Ages ranged from 30-77. M:F=8:7. Thal doses ranged from 200-400 mg/d. The median tolerated dose of thal was 200 mg/d. Patients received 1-18 cycles of therapy (median = 5). Responses were as follows: complete-0, partial-1( in subcutaneuos tissue), stable-4, progression-5 with 5 patients not evaluable for response. 2 early withdrawl due to toxicity and 3 deaths due to rapidly progressive disease. Grade III/IV toxicity attributed to DTIC was neutropenia and thrombocytopenia. Grade III/IV toxicity due to thal was severe constipation, peripheral neuropathy, fatigue, peripheral edema and rash. CONCLUSIONS Thal added to DTIC does not appear to improve response rates in MM and is poorly tolerated in escalating doses greater than 200 mg/d. [Table: see text].

Tc-99m LL-2 Fab' monoclonal antibody imaging in acquired immune deficiency syndrome-related lymphoma

Both systemic and primary central nervous system (CNS) non‐Hodgkins lymphomas (NHL) occur in people with acquired immune deficiency syndrome (AIDS). The radiographic manifestations may be similar to other neoplasms and opportunistic infections that are also found frequently in AIDS. Furthermore, these diseases may coexist with NHL in the AIDS patient.

Combined Modality Therapy in Locally Advanced Breast Cancer

The management of locally advanced breast cancer requires the integration of surgery, chemotherapy, and radiation therapy. This chapter summarizes the existing experience and addresses some of the remaining issues in combined modality therapy of locally advanced and inflammatory breast cancer.

P1-17-07: Phase II Trial of RAD001 Plus Carboplatin in Patients with Triple-Negative Metastatic Breast Cancer.

Background: RAD001 is an oral mTOR inhibitor that has exhibited activity in breast cancer. Triple negative breast cancer cells are unable to repair double stranded DNA breaks and hence have sensitivity to platinum agents that cause interstrand cross-links. Rapamycin acts synergistically with platinum agents to induce apoptosis and inhibit proliferation in at least two different breast cancer cell lines (including ER/PR negative cell lines). We propose that combination RAD001 and carboplatin may have activity in triple-negative breast cancer. Methods: The primary objective of the study is to determine clinical benefit (complete remission (CR) + partial remission (PR) + stable disease (SD)) and the toxicity of this combination in women with triple negative metastatic breast cancer who have had 0–3 prior chemotherapy regimens for metastatic disease. Secondary objectives are to determine progression free survival as well as investigating the relationship between pretreatment sensitivity (biopsy at baseline) and clinical response (biopsy post 2 cycles) using IHC staining for abundance of key proteins in the Akt-mTOR pathway and their activity using surrogate phosphorylation site-specific antibodies (Akt and phospho-serine 473, phospho-threonine and phospho-threonine 308 Akt; mTOR and phospho-serine 2448 mTOR; ribosome protein S6 kinase (S6K) and phospho-threonine 378 S6K; 4E-BP1 and phospho-serine 65 4E-BP1). Prior carboplatin is allowed. Women with treated brain metastasis are eligible. According to the original study plan, carboplatin AUC 6, was to be given intravenously every three weeks. Five mg of RAD001 was to be given daily with a 3 patient run-in and then 10 mg daily if there were no dose-limiting toxicities. Due to a unexpected amount of thrombocytopenia with this combination the dose of carboplatin was first amended to AUC 5 and most recently to AUC 4 with 5 mg of RAD001 (and no plan to escalate to 10 mg). Results: Fourteen patients of a planned 25 have been recruited thus far. Median age is 58.5. Median number of prior regimens is 2 (0-3). Of the 7 patients assessable for response at this time, there have been 2 PR9s and 5 patients with SD. One SD was achieved in a patient progressing on single agent carboplatin at study entry. Median duration of SD + PR is 28.5 weeks (5 patients have ongoing response ranging from 8–46.5 weeks). Five of 8 patients assessable for toxicity had grade 3 or 4 thrombocytopenia and 2 patients had grade 3 neutropenia. No cases of febrile neutropenia were observed. Four patients have required blood transfusion and one patient has required platelet transfusion. All patients have had treatment held and/or dose reductions secondary to hematological toxicity, however, since amended carboplatin dose the regimen has been very well tolerated with only one out of six patients) with grade 3 neutropenia and grade 3 thrombocytopenia. There have been no non-hematological grade 3 or 4 toxicities. Conclusions: Clinical benefit was observed in all 7 assessable patients. Dose limiting thrombocytopenia was an unexpected side effect requiring protocol amendment. We continue to accrue study subjects at the amended dosing. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-17-07.

Thalidomide (Thal) tolerance in patients treated with transarterial chemoembolization (TACE) for hepatocellular carcinoma (HCC)

4255 Background: Most HCCs are hypervascular and appropriate for treatments that target tumor angiogenesis. Tumor vascularity may be mechanically disrupted by TACE yet biologic disruption is preferable. As Thal has anti-angiogenic properties we studied the combination of Thal and TACE in patients with HCC. Thals tolerance in patients (pt) with a variety of illnesses is not well-established. We therefore reviewed Thals tolerability in pts with liver disease and HCC undergoing Adriamycin (Adria) Lipiodol (Lip) TACE. METHODS 56 pts with HCC have been enrolled. All pts had total bili < 3, and transaminases ≤ 5 X nl. Thal was initiated at a dose(ds) of 200 mg/d and ds escalations or decreases were permitted as tolerated. After 28 days Thal was discontinued and pts underwent a Adria Lip collagen TACE after which Thal was restarted. RESULTS The mean pt age was 58.4 yrs. The m/f ratio was 46/10. All pts had hepatitis B or C, or alcoholic liver disease. 15 pts recieved liver transplants. 8 pts were removed from study for Thal toxicity (tox). 4, 1 and 3 of the 8 pts were withdrawn for grade (gr) II-III neurologic (neuro), gr I gastrointestinal (gastro) and gr ≥ III other Thal toxs, respectively. 42 pts have undergone TACE. 24 pts remained on 200 mg/d and 18 pts were ds escalated to 250-500 mg/d prior to TACE. There were 42 Thal ds increases and 32 ds reductions. The first post TACE ds was reduced for TACE related constitutional tox in 8 pts. 13 of 18 pts ds escalated prior to TACE required ds reductions after TACE. There were more ds reductions due to Thal tox after TACE then before it (28 vs 4, p = 0.0002), and more pts were reduced to ≤ 150 mg/d as a result of Thal tox after TACE then prior to it. (19 vs 5 p = 0.0007). 47.1 %, 3.7 % and 18.8 % of ds reductions were prompted by constitutional, gastro and neuro Thal tox, respectively. 41.5%, 45.2% and 13.2% of the ds reductions resulted from gr I, II and III Thal toxs. CONCLUSIONS 1.0 Initial Thal ds of 200 mg/d are tolerable in HCC pts with minimal liver dysfunction. 2.0 Ds escalations > 200 mg often result in subsequent ds reductions. 3.0 Ds reductions are more frequent after TACE when some pts may tolerate only 50-150 mg/d. No significant financial relationships to disclose.