Tarun Kewalramani

American Society of Clinical Oncology 2008 Clinical Practice Guideline Update: Use of Chemotherapy and Radiation Therapy Protectants

PURPOSE To update a clinical practice guideline on the use of chemotherapy and radiation therapy protectants for patients with cancer. METHODS An update committee reviewed literature published since the last guideline update in 2002. RESULTS Thirty-nine reports met the inclusion criteria: palifermin and dexrazoxane, three reports (two studies) each; amifostine, 33 reports (31 studies); and mesna, no published randomized trials identified since 2002. RECOMMENDATIONS Dexrazoxane is not recommended for routine use in breast cancer (BC) in adjuvant setting, or metastatic setting with initial doxorubicin-based chemotherapy. Consider use with metastatic BC and other malignancies, for patients who have received more than 300 mg/m(2) doxorubicin who may benefit from continued doxorubicin-containing therapy. Cardiac monitoring should continue in patients receiving doxorubicin. Amifostine may be considered for prevention of cisplatin-associated nephrotoxicity, reduction of grade 3 to 4 neutropenia (alternative strategies are reasonable), and to decrease acute and late xerostomia with fractionated radiation therapy alone for head and neck cancer. It is not recommended for protection against thrombocytopenia, prevention of platinum-associated neurotoxicity or ototoxicity or paclitaxel-associated neuropathy, prevention of radiation therapy-associated mucositis in head and neck cancer, or prevention of esophagitis during concurrent chemoradiotherapy for non-small-cell lung cancer. Palifermin is recommended to decrease severe mucositis in autologous stem-cell transplantation (SCT) for hematologic malignancies with total-body irradiation (TBI) conditioning regimens, and considered for patients undergoing myeloablative allogeneic SCT with TBI-based conditioning regimens. Data are insufficient to recommend use in the non-SCT setting.

Pretransplantation functional imaging predicts outcome following autologous stem cell transplantation for relapsed and refractory Hodgkin lymphoma.

To identify prognostic factors for patients transplanted for relapsed or refractory Hodgkin lymphoma we carried out a combined analysis of patients followed prospectively on 3 consecutive protocols at Memorial Sloan-Kettering Cancer Center. One hundred fifty-three patients with chemosensitive disease after ICE (ifosfamide, carboplatin, and etoposide)-based salvage therapy (ST) proceeded to high-dose chemoradiotherapy followed by autologous stem cell transplantation (ASCT). Patients were evaluated with computed tomography and functional imaging (gallium or fluorodeoxyglucose-positron emission tomography) prior to ST and again before ASCT. Functional imaging status before ASCT was the only factor significant for event-free survival (EFS) and overall survival by multivariate analysis and clearly identifies poor risk patients (5-year EFS 31% and 75% for FI-positive and negative patients respectively). Administration of involved-field radiotherapy with ASCT was marginally significant for EFS (P = .055). Studies evaluating novel STs, conditioning regimens, post-ASCT maintenance, or allogeneic stem cell transplantation are warranted for patients who fail to normalize pre-ASCT functional imaging.

Effectiveness of high dose chemoradiotherapy and autologous stem cell transplantation for patients with biopsy-proven primary refractory Hodgkin's disease.

Prospective randomized studies have determined that high dose therapy and autologous stem cell transplantation (ASCT) is the standard treatment for patients with chemosensitive relapsed Hodgkins disease (HD); however, the role of this approach in patients with primary refractory disease has been controversial. This report is an integrated analysis of 75 consecutive patients with biopsy‐confirmed primary refractory HD, who were treated with high dose chemoradiotherapy (HDT) and ASCT at the Memorial Sloan Kettering Cancer Center. The patients underwent conventional dose cytoreductive chemotherapy followed by HDT and ASCT. At a median follow‐up of 10 years for surviving patients, the event‐free survival (EFS), progression‐free survival (PFS) and overall survival (OS) rates were 45%, 49% and 48% respectively. Only chemosensitivity to standard‐dose second‐line chemotherapy (SDSC) predicted for a better survival, thus responding patients had an EFS, PFS and OS of 60%, 62% and 66%, respectively, versus 19%, 23% and 17% for patients who had a poor response to SDSC (P < 0·001). While patients with chemosensitive disease have an excellent outcome with HDT and ASCT, novel approaches are needed to cure HD patients who fail front‐line and second‐line chemotherapy.

Risk‐adapted autologous stem cell transplantation with adjuvant dexamethasone ± thalidomide for systemic light‐chain amyloidosis: results of a phase II trial

High‐dose melphalan (MEL) with autologous stem cell transplant (SCT) is an effective therapy for systemic AL amyloidosis (AL), but treatment‐related mortality (TRM) has historically been high. We performed a phase II trial of risk‐adapted SCT followed by adjuvant dexamethasone (dex) and thalidomide (thal) in an attempt to reduce TRM and improve response rates. Patients (n = 45) with newly diagnosed AL involving ≤2 organ systems were assigned to MEL 100, 140, or 200 mg/m2 with SCT, based on age, renal function and cardiac involvement. Patients with persistent clonal plasma cell disease 3 months post‐SCT received 9 months of adjuvant thal/dex (or dex if there was a history of deep vein thrombosis or neuropathy). Organ involvement was kidney (67%), heart (24%), liver/GI (22%) and peripheral nervous system (18%), with 31% having two organs involved. TRM was 4·4%. Thirty‐one patients began adjuvant therapy, with 16 (52%) completing 9 months of treatment and 13 (42%) achieving an improvement in haematological response. By intention‐to‐treat, overall haematological response rate was 71% (36% complete response), with 44% having organ responses. With a median follow‐up of 31 months, 2‐year survival was 84% (95% confidence interval: 73%, 94%). Risk‐adapted SCT with adjuvant thal/dex is feasible and results in low TRM and high haematological and organ response rates in AL patients.

Outcomes for patients who fail high dose chemoradiotherapy and autologous stem cell rescue for relapsed and primary refractory Hodgkin lymphoma.

Most patients with Hodgkin lymphoma (HL) are cured with first and second‐line treatment; however, the outcome is unknown for those who fail high dose chemoradiotherapy with autologous stem cell transplant (HDT‐ASCT). This report is an analysis of patients with relapsed and primary refractory HL who were treated with HDT‐ASCT and failed due to progression of disease (POD). Two hundred and two patients received HDT‐ASCT at Memorial Sloan Kettering Cancer Center for relapsed or refractory HL between December 1994 and 2005 and 71 failed due to POD. The median survival following HDT‐ASCT failure was 25 months. Only 16 (23%) of the 71 patients are currently alive, nine of whom are in remission. Multivariate analysis revealed two factors associated with poor outcome: relapse within 6 months of HDT‐ASCT and primary refractory disease. The only factor associated with improved survival was the ability to receive a second transplant, in particular, reduced intensity allogeneic transplant (RIT). Novel therapies are needed for patients who fail HDT‐ASCT, particularly those with primary refractory disease and those who relapse within 6 months of HDT‐ASCT. Future studies should focus on prospectively evaluating RIT following HDT‐ASCT failure in patients with remission duration from HDT‐ASCT of >6 months.

Autologous transplantation for relapsed or primary refractory peripheral T-cell lymphoma

Autologous transplantation (ASCT) is the standard of care for chemosensitive relapsed or primary refractory aggressive lymphoma, but little is known about its efficacy in the subset of patients with peripheral T‐cell lymphoma (PTCL). We undertook a retrospective review of patients with PTCL who underwent ASCT for relapsed or refractory disease after responding to second‐line therapy, excluding patients with indolent histologies and those with anaplastic lymphoma kinase (ALK) expressing anaplastic large cell lymphoma. The results of 24 patients with PTCL were compared with those of 86 consecutive patients with chemosensitive relapsed or primary refractory diffuse large B‐cell lymphoma (DLBCL). With a median follow‐up time of 6 years for surviving patients with PTCL and DLBCL, the 5‐year progression‐free survival (PFS) rates for PTCL and DLBCL patients were 24% and 34% respectively (P = 0·14); the corresponding overall survival (OS) rates were 33% and 39% respectively. There were no significant differences between the two groups with respect to time to disease progression or survival after progression. The second‐line age‐adjusted international prognostic index was the only variable prognostic for PFS and OS in a multivariate analysis. The outcome of ASCT for patients with chemosensitive relapsed or primary refractory PTCL is similar to that for patients with DLBCL.

Progressive disease following autologous transplantation in patients with chemosensitive relapsed or primary refractory Hodgkin's disease or aggressive non-Hodgkin's lymphoma

Summary:To determine the outcome of patients with chemosensitive relapsed or primary refractory Hodgkins disease (HD) or aggressive non-Hodgkins lymphoma (NHL) whose disease progresses after autologous stem cell transplantation (ASCT), we reviewed the records of 82 patients with HD and 139 patients with NHL transplanted between 1993 and 2000. Disease progression occurred in 25 patients with HD and 66 patients with NHL, with median times to progression (TTP) of 3.8 and 5.1 months, respectively. Median survival times following ASCT failure were 26 and 7.7 months for patients with HD and NHL, respectively. The second-line international prognostic index (sIPI) and the TTP (before or after 3 months from ASCT) independently were predictive of survival for NHL patients. In addition, treatment with rituximab for patients with B cell NHL was associated with improved survival (median 28.6 vs 4.1 months, P=0.003), independent of the sIPI and TTP. Prognostic factors for patients with HD were not identified. Only two patients, one of whom was among six patients who received second autologous transplants, remain disease-free. The uniformly poor outcome associated with disease progression after ASCT should prompt efforts to assess the feasibility and utility of detecting and treating post transplant residual disease during a minimal disease state, before overt progression.

High‐dose chemo‐radiotherapy for relapsed or refractory Hodgkin lymphoma and the significance of pre‐transplant functional imaging

We previously reported that three risk factors (RF): initial remission duration <1 year, active B symptoms, and extranodal disease predict outcome in relapsed or refractory Hodgkin lymphoma (HL). Our goal was to improve event‐free survival (EFS) for patients with multiple RF and to determine if response to salvage therapy impacted outcome. We conducted a phase II intent‐to‐treat study of tailored salvage treatment: patients with zero or one RF received standard‐dose ifosfamide, carboplatin, and etoposide (ICE); patients with two RF received augmented ICE; patients with three RF received high‐dose ICE with stem cell support. This was followed by evaluation with both computed tomography and functional imaging (FI); those with chemosensitive disease underwent high‐dose chemoradiotherapy and autologous stem cell transplantation (ASCT). There was no treatment‐related mortality. Compared to historical controls this therapy eliminated the difference in EFS between the three prognostic groups. Pre‐ASCT FI predicted outcome; 4‐year EFS rates was 33% vs. 77% for patients transplanted with positive versus negative FI respectively, P = 0·00004, hazard ratio 4·61. Risk‐adapted augmentation of salvage treatment in patients with HL is feasible and improves EFS in poorer‐risk patients. Our data suggest that normalisation of FI pre‐ASCT predicts outcome, and should be the goal of salvage treatment.

Phase I/II trial assessing bendamustine plus bortezomib combination therapy for the treatment of patients with relapsed or refractory multiple myeloma

Bendamustine, active in multiple myeloma (MM), is a bifunctional mechlorethamine derivative with alkylating properties. Bortezomib, approved to treat MM, is effective in combination with alkylators. The tolerability and efficacy of bendamustine plus bortezomib in relapsed/refractory MM was assessed in an open‐label, dose‐escalating, phase I/II study. Patients aged ≥18 years received intravenous bendamustine 50, 70, or 90 mg/m2 (days 1 and 4) plus bortezomib 1·0 mg/m2 (days 1, 4, 8, and 11) for up to eight 28‐day cycles. No dose‐limiting toxicity was observed after cycle 1; bendamustine 90 mg/m2 plus bortezomib 1·0 mg/m2 was designated the maximum tolerated dose (MTD). The most common grade 3/4 adverse events were leucopenia (58%), neutropenia (50%), lymphopenia (45%), and thrombocytopenia (30%). Primary efficacy measure was overall response rate (ORR), which was the combined complete response (CR), very good partial response (VGPR), partial response (PR), and minimal response (MR). ORR was 48% (one CR, two VGPR, nine PR, and seven MR) for all 40 enrolled patients, 52% (16/31) at the MTD (90 mg/m2), and 42% and 46% for prior use of bortezomib (n = 31) or alkylators (n = 28) respectively. Bendamustine plus bortezomib was well tolerated with promising efficacy in this heavily pretreated population.

Doxorubicin and dexamethasone followed by thalidomide and dexamethasone is an effective well tolerated initial therapy for multiple myeloma.

Among the drug combinations designed for the initial treatment of multiple myeloma, none has been unequivocally shown to be superior. However, a regimen leading to a high response rate and a low incidence of adverse events is highly desirable. We report the results of a phase II clinical trial involving 45 patients with Durie–Salmon stage II and III multiple myeloma. Doxorubicin and dexamethasone were given for 2 or 3 months followed by thalidomide and dexamethasone for 2 months (AD–TD regimen) with prophylactic antibiotics and daily aspirin (81 mg/d). Among the 42 patients whose response could be assessed, 38 responded to therapy (90·5%). The intent‐to‐treat response rate was 84·4% with seven complete responses (CR 15·5%), nine near complete responses (nCR 20·0%), and 22 partial responses (PR 48·9%). Two patients had stable disease (4·4%), and two progression of disease (4·4%). Normalization of the free light chain ratio after one or two cycles of treatment was highly predictive of achievement of CR or nCR. Patients tolerated the treatment well although five patients developed thromboembolic complications (11%). AD–TD administered with low dose aspirin for deep vein thrombosis prophylaxis was well tolerated and yielded a high response rate with minimal treatment‐related morbidity.