Jason McCoy

International prognostic scoring system for Waldenstrom macroglobulinemia

Recently, many new drugs have been developed for the treatment of Waldenström macroglobulinemia (WM). To optimize the treatment according to the prognosis and to facilitate the comparison of trials, we developed an International Prognostic Scoring System for WM in a series of 587 patients with clearly defined criteria for diagnosis and for initiation of treatment. The median survival after treatment initiation was 87 months. Five adverse covariates were identified: advanced age (>65 years), hemoglobin less than or equal to 11.5 g/dL, platelet count less than or equal to 100 x 10(9)/L, beta2-microglobulin more than 3 mg/L, and serum monoclonal protein concentration more than 7.0 g/dL. Low-risk patients (27%) presented with no or 1 of the adverse characteristics and advanced age, intermediate-risk patients (38%) with 2 adverse characteristics or only advanced age, and high-risk patients (35%) with more than 2 adverse characteristics. Five-year survival rates were 87%, 68%, and 36%, respectively (P < .001). The ISSWM retained its prognostic significance in subgroups defined by age, treatment with alkylating agent, and purine analog. Thus, the ISSWM may provide a means to design risk-adapted studies. However, independent validation and new biologic markers may enhance its significance.

Prognostic impact of cytogenetic and interphase fluorescence in situ hybridization-defined chromosome 13 deletion in multiple myeloma: early results of total therapy II.

Summary. Cytogenetic abnormalities of chromosome 13 (CA 13) and those detected by fluorescence in situ hybridization (FISH 13) have both been associated with poor prognosis in multiple myeloma (MM) patients. The prognostic implications of CA, FISH 13 and other standard laboratory parameters were examined in the first 231 patients enrolled in Total Therapy II, an intensive cytotoxic chemotherapy programme with tandem autotransplants. Three‐year projections of event‐free survival (EFS) and overall survival (OS) were 71% and 77% respectively. CA 13 was detected in 14% and significantly correlated with FISH 13 (present in 51%), tumour burden, proliferative activity and lactic dehydrogenase (LDH). Both EFS and OS were significantly shorter in patients with CA 13, FISH 13, LDH ≥ 190 U/l, β2 microglobulin ≥ 4 mg/l and C reactive protein ≥ 4·0 mg/l; other CA was an additional risk factor for OS. Two‐thirds of CA 13 patients were identified by FISH 13 and plasma‐cell‐labelling index (PCLI) ≥ 0·4%; however, PCLI failed to identify additional risk groups in FISH subsets. Although present in considerably fewer patients, CA 13 imparted more rapid relapse (61% at 3 years) and death (43% at 3 years) than FISH 13 (38% and 35%; P = 0·02 and 0·1 respectively) and should be part of the initial work‐up of patients with MM.

Gefitinib therapy in advanced bronchioloalveolar carcinoma: Southwest Oncology Group Study S0126.

PURPOSE Advanced bronchioloalveolar carcinoma (BAC) is a distinct subtype of non-small-cell lung cancer (NSCLC) for which there is currently no optimal therapy. Based on preclinical and clinical data suggesting relevance of the epidermal growth factor receptor (EGFR) axis in BAC, the Southwest Oncology Group initiated a phase II trial (S0126) to evaluate the EGFR tyrosine kinase inhibitor gefitinib in chemotherapy-naïve and chemotherapy-pretreated patients with advanced BAC. METHODS A total of 136 eligible and assessable patients (101 untreated, 35 previously treated) received gefitinib 500 mg daily until progression or prohibitive toxicity. RESULTS The median age was 68.0 years (range, 34.3 to 88.6); 51% were female; 89% had a performance status (PS) of 0% or 1% and 11% had a PS of 2. The Response Evaluation Criteria in Solid Tumors response rate was 17%, with 6% complete responses (CRs) among 69 previously untreated patients with measurable disease, and 9% with no CRs among 22 pretreated patients. Median survival was 13 months for both chemo-naïve (95% CI, 8 to 18) and previously treated patients (95% CI, 6 to 17). Overall survival at 3 years was 23% (95% CI, 14% to 32%). Toxicity consisted mainly of rash and diarrhea, but 2% of patients died of presumed interstitial lung disease. Exploratory subset analyses revealed improved survival among women (P = .031), patients developing a rash (P = .003), never-smokers (P = .061), and patients with a PS of 0 or 1 (P = .015). CONCLUSION Gefitinib is an active agent in advanced stage BAC. Several subsets demonstrate significantly improved clinical outcomes.

Phase I Study of Tirapazamine Plus Cisplatin/Etoposide and Concurrent Thoracic Radiotherapy in Limited-Stage Small Cell Lung Cancer (S0004): A Southwest Oncology Group Study

Purpose: To determine the feasibility and a recommended phase II dose of tirapazamine when combined with chemoradiotherapy in limited-stage small cell lung cancer (LSCLC). Experimental Design: Concurrent chemoradiotherapy consisted of two cycles of cisplatin, etoposide, and once-daily radiation to 61 Gy. Tirapazamine (260 mg/m2) was given 1 h before cisplatin with planned dose escalation to 330 mg/m2 in the absence of dose-limiting toxicity, defined as ≥33% esophagitis (grade 3 or above). Consolidation therapy consisted of two cycles of tirapazamine (330 mg/m2), cisplatin, and etoposide. Complete responders received prophylactic cranial irradiation. Results: Thirty patients were enrolled at the 260 mg/m2 tirapazamine dose. All had performance status of 0–1. By comparison with S9713, a predecessor Southwest Oncology Group study in LSCLC that used the same concurrent chemoradiotherapy without tirapazamine, the present trial showed a higher rate of grade 3–4 esophagitis (34% versus 22%), vomiting (34% versus 23%), and febrile neutropenia (7% versus 2%). The consolidation phase was relatively well tolerated, with grade 4 neutropenia in 44% and febrile neutropenia in 5% of patients. There were two treatment-related deaths: one from neutropenic fever and one from respiratory infection. The overall response rate was 80%, and the median survival was 22 months. Conclusions: Protocol-defined dose-limiting toxicity was observed at the initial tirapazamine dose, precluding dose escalation. Compared with S9713, the addition of tirapazamine increased the incidence of vomiting, neutropenia, and febrile neutropenia, although the overall toxicity profile remained acceptable. In view of the observed favorable survival, further study of tirapazamine in LSCLC is warranted.

Survival after relapse following tandem autotransplants in multiple myeloma patients: the University of Arkansas total therapy I experience

Summary. Despite the superiority of high‐dose (compared with standard) treatment in multiple myeloma, relapses still occur. We evaluated relapse patterns, salvage treatments employed and outcome in patients given tandem transplants on our total therapy I protocol. We focused on 146 patients (of 231 enrolled) who received tandem autotransplants ≤12 months apart and survived ≥2 months after the second transplant. With a median follow‐up of 9 years after enrollment, 31 (21%) patients remain in complete or stable partial remission. Ninety‐five (65%) patients received therapy for relapsing myeloma. The median time from the first transplant to relapse was 2·9 years. The median overall survival from relapse was 2·4 years. In one‐quarter (23/95) of cases, the postrelapse interval exceeded the interval from the first transplant to relapse. On multivariate analysis, the presence of any cytogenetic abnormalities [P < 0·001, Hazard Ratio (HR): 3·84] and β‐2 microglobulin levels  > 4 mg/l at relapse (P < 0·001, HR: 2·87) were significant for poor survival after relapse. The median survival after relapse was 5·1, 1·3 and 0·7 years in patients with none (44%), one (46%) and two (10%) poor‐risk factors, respectively. In conclusion, a sizeable fraction of myeloma patients relapsing after tandem autotransplants without poor‐risk features enjoyed meaningful survival prolongation when appropriately treated.

Gemcitabine and Irinotecan for Patients with Untreated Extensive Stage Small Cell Lung Cancer: SWOG 0119

Introduction: To evaluate the activity of a nonplatinum-, nonetoposide-containing regimen for patients with extensive stage small cell lung cancer. Methods: Patients with untreated extensive stage small cell lung cancer were treated with gemcitabine 1000 mg/m2 and irinotecan 100 mg/m2 on days 1 and 8 of a 21-day cycle for a maximum of six cycles. Patients with brain metastases were eligible if asymptomatic or controlled after radiation. Results: Eighty-four eligible patients with untreated extensive stage small cell lung cancer with adequate organ function and a performance status of 0–2 were accrued. The median age was 64 years (range, 42–85) and 45 (54%) were women. Six cycles were completed by 28 (33%) patients. Some degree of diarrhea occurred in 57% (grade 3/4, 18%). Other grade 3/4 toxicities were neutropenia (26%), anemia (10%), thrombocytopenia (8%), febrile neutropenia (5%), fatigue (11%), nausea (10%), and vomiting (8%). The response rate was 32% (95% confidence interval: 22%–43%) among the 81 patients with measurable disease. The median survival was 8.5 months (95% confidence interval: 7.0–9.8) with 1- and 2-year survival rates of 26% and 7%, respectively. Salvage therapy data were captured by prospective collection, and only 50% of patients were treated secondarily. Conclusion: The overall response rate with the combination of gemcitabine and irinotecan was disappointing, and the median survival rate was lower than expected. Further development of this combination in small cell lung cancer is not recommended.

Phase II Trial of Paclitaxel, Carboplatin, and Topotecan with G-CSF Support in Previously Untreated Patients with Extensive Stage Small Cell Lung Cancer: Southwest Oncology Group 9914

Purpose: This phase II study (S9914) evaluated the efficacy and toxicity of the three-drug combination of paclitaxel, carboplatin, and topotecan with granulocyte colony–stimulating factor support in previously untreated patients with extensive stage small cell lung cancer. Patients and Methods: Patients with newly diagnosed extensive stage small cell lung cancer received topotecan 1.0 mg/m2 intravenously on days 1 through 4; paclitaxel 175 mg/m2 intravenously on day 4, and carboplatin AUC = 5 intravenously on day 4, treatments were repeated every 21 days for a maximum of six cycles. All patients also received granulocyte colony–stimulating factor 5 &mgr;g/kg/day beginning on day 5 of each cycle. Results: A total of 88 patients were enrolled on the study; 79 patients were assessable for survival and toxicity and 74 patients for response. Objective response was observed in 50 patients (68%; 95% confidence interval [CI]: 56%–78%) with nine patients (12%) achieving a complete response. Median progression-free survival was 7 months (95% CI: 6–8 months) and median overall survival was 12 months (95% CI: 11–14 months). The 1- and 2-year survival rates were 48% (95% CI: 37%–59%) and 20% (95% CI: 11%–29%), respectively. The most common toxicities were hematologic. Grade 3 and 4 neutropenia was noted in 17 (22%) and 27 (34%) patients, respectively. Febrile neutropenia developed in only four patients. Two patients (3%) died of treatment-related causes. Conclusion: The combination of paclitaxel, carboplatin, and topotecan combined with granulocyte colony–stimulating factor support is an active and reasonably well-tolerated regimen for the treatment of extensive stage small cell lung cancer.