Matthew J. Matasar

Duration of Adjuvant Chemotherapy for Colon Cancer and Survival Among the Elderly

PURPOSE In randomized trials, patients with stage III colon cancer who received 6 months of fluorouracil (FU)-based adjuvant chemotherapy had better survival than patients who did not. However, little is known about the predictors of, or the survival associated with, duration of chemotherapy in the community. PATIENTS AND METHODS The linked Surveillance, Epidemiology, and End Results-Medicare database was used to identify individuals > or = 65 years of age diagnosed with stage III colon cancer between 1995 and 1999. We used logistic and Cox proportional hazards regression models to analyze factors associated with early discontinuation of FU-based chemotherapy among these elderly colon cancer patients. RESULTS Among 1,722 patients who received 1 to 7 months of FU-based chemotherapy, older age, being unmarried, and having comorbid conditions were associated with receiving less than 5 months of treatment. Among the 1,579 patients who survived > or = 8 months, the 1,091 (69.1%) who received 5 to 7 months of treatment had lower overall (hazard ratio [HR], 0.59; 95%, CI 0.49 to 0.71) and colon cancer-specific (HR, 0.53; 95% CI, 0.43 to 0.66) mortality than the 488 (30.9%) who received 1 to 4 months of treatment. CONCLUSION More than 30% of elderly patients who initiated FU-based chemotherapy for stage III colon cancer and survived for at least 8 months discontinued treatment early. Mortality rates among such patients were nearly twice as high as among patients who completed 5 to 7 months of treatment. If the association we observed between duration of treatment and survival is confirmed, additional investigation is warranted to determine whether dose-intensity, cumulative dose, or other factors related to receipt of full adjuvant treatment are responsible.

Phase II Study of Bendamustine in Relapsed and Refractory Hodgkin Lymphoma

PURPOSE Limited data exist regarding the activity of bendamustine in Hodgkin lymphoma (HL). This phase II study evaluated the efficacy of bendamustine in relapsed and refractory HL. PATIENTS AND METHODS Patients with relapsed and refractory HL who were ineligible for autologous stem-cell transplantation (ASCT), or for whom this treatment failed, received bendamustine 120 mg/m(2) as a 30-minute infusion on days 1 and 2 every 28 days with growth factor support. The primary end point was overall response rate (ORR). A secondary end point was referral rate to allogeneic stem-cell transplantation (alloSCT) for patients deemed eligible for alloSCT at the time of enrollment. RESULTS Of the 36 patients enrolled, 34 were evaluable for response. Patients had received a median of four prior treatments, and 75% had relapsed after ASCT. The ORR by intent-to-treat analysis was 53%, including 12 complete responses (33%) and seven partial responses (19%). The response rate among evaluable patients was 56%. Responses were seen in patients with prior refractory disease, prior ASCT, and prior alloSCT; however, no responses were seen in patients who relapsed within 3 months of ASCT. The median response duration was 5 months. Five patients (20% of those eligible) proceeded to alloSCT after treatment with bendamustine. Grade ≥ 3 adverse events were infrequent and most commonly included thrombocytopenia (20%), anemia (14%), and infection (14%). CONCLUSION This study confirms the efficacy of bendamustine in heavily pretreated patients with HL. These results support current and future studies evaluating bendamustine combinations in relapsed and refractory HL.

R-MPV followed by high-dose chemotherapy with TBC and autologous stem-cell transplant for newly diagnosed primary CNS lymphoma

High-dose methotrexate-based chemotherapy is the mainstay of treatment of primary central nervous system lymphoma (PCNSL), but relapses remain frequent. High-dose chemotherapy (HDC) with autologous stem-cell transplant (ASCT) may provide an alternative to address chemoresistance and overcome the blood-brain barrier. In this single-center phase-2 study, newly diagnosed PCNSL patients received 5 to 7 cycles of chemotherapy with rituximab, methotrexate (3.5 g/m(2)), procarbazine, and vincristine (R-MPV). Those with a complete or partial response proceeded with consolidation HDC with thiotepa, cyclophosphamide, and busulfan, followed by ASCT and no radiotherapy. Primary end point was 1-year progression-free survival (PFS), N = 32. Median age was 57, and median Karnofsky performance status 80. Following R-MPV, objective response rate was 97%, and 26 (81%) patients proceeded with HDC-ASCT. Among all patients, median PFS and overall survival (OS) were not reached (median follow-up: 45 months). Two-year PFS was 79% (95% confidence interval [CI], 58-90), with no events observed beyond 2 years. Two-year OS was 81% (95% CI, 63-91). In transplanted patients, 2-year PFS and OS were 81%. There were 3 treatment-related deaths. Prospective neuropsychological evaluations suggested relatively stable cognitive functions posttransplant. In conclusion, this treatment was associated with excellent disease control and survival, an acceptable toxicity profile, and no evidence of neurotoxicity thus far. This trial was registered at www.clinicaltrials.gov as NCT00596154.

PET-adapted sequential salvage therapy with brentuximab vedotin followed by augmented ifosamide, carboplatin, and etoposide for patients with relapsed and refractory Hodgkin's lymphoma: a non-randomised, open-label, single-centre, phase 2 study

BACKGROUND Pre-transplantation (18)F-fluorodeoxyglucose (FDG) PET-negativity is one of the strongest predictors of outcome after high-dose therapy and autologous stem-cell transplant (HDT/ASCT) for patients with relapsed or refractory Hodgkins lymphoma. In this study, we assessed the feasibility and activity of PET-adapted salvage therapy with brentuximab vedotin, followed by augmented ifosfamide, carboplatin, and etoposide (ICE). METHODS In this non-randomised, open-label, single-centre, phase 2 trial, we enrolled patients with relapsed or refractory Hodgkins lymphoma who had failed one previous doxorubicin-containing chemotherapy regimen. All patients received weekly infusions of 1·2 mg/kg brentuximab vedotin on days 1, 8, and 15 for two 28 day cycles. After completion of brentuximab vedotin treatment, patients received a PET scan. Patients who achieved PET-negative status (a Deauville score of 1 or 2) proceeded directly to HDT/ASCT; those with persistent abnormalities on PET received two cycles of augmented ICE (augICE; two doses of ifosfamide 5000 mg/m(2) in combination with mesna 5000 mg/m(2) continuous infusion over 24 h, days 1 and 2; one dose of carboplatin AUC 5, day 3; three doses of etoposide 200 mg/m(2) every 12 h, day 1) before consideration for HDT/ASCT. Only patients with persistent abnormalities on PET after brentuximab vedotin received augICE; however, all patients in the intention-to-treat population were assessed for the primary outcome, which was the proportion of patients who were PET-negative after brentuximab vedotin alone or brentuximab vedotin followed by augICE. This study is registered with ClinicalTrials.gov, number NCT01508312, and is no longer accruing patients. FINDINGS Between Jan 5, 2012, and Oct 4, 2013, we enrolled 46 patients. One patient was deemed ineligible, and not evaluable, before treatment initiation owing to having nodular, lymphocyte-predominant Hodgkins lymphoma and thus 45 patients received treatment. After brentuximab vedotin, 12 patients (27%, 95% CI 13-40) were PET-negative and proceeded to HDT/ASCT. 33 (73%, 95% CI 60-86) patients were PET-positive after brentuximab vedotin; one PET-positive patient withdrew consent, therefore 32 PET-positive patients received augICE, 22 (69%, 95% CI 53-85) of whom were PET-negative. Overall, 34 patients (76%, 95% CI 62-89) achieved PET-negativity. All 44 patients who completed treatment as per protocol proceeded to receive HDT/ASCT. Brentuximab vedotin was well tolerated and associated with few grade 3-4 adverse events including hyperglycaemia (two [4%] patients, grade 3), nausea (one [2%], grade 3), hypoglycaemia (one [2%], grade 3 and one [2%], grade 4), and hypocalcaemia (one [2%], grade 3 and one [2%], grade 4). INTERPRETATION PET-adapted sequential salvage therapy with brentuximab vedotin followed by augICE resulted in a high proportion of patients with relapsed or refractory Hodgkins lymphoma achieving PET-negativity, and therefore could optimise the chance of cure after HDT/ASCT. FUNDING Seattle Genetics.

Incidence rates of the major leukemia subtypes among U.S. Hispanics, Blacks, and non-Hispanic Whites

While leukemia rates are thought to be lower in South and Central America, no study has systematically investigated incidence rates of the leukemia subtypes among Hispanics in the U.S. This was a retrospective cohort study, using data from the Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute, 1992 – 2001, to compare leukemia incidence rates as a function of race and ethnicity. It was found that in adults, Hispanics had lower incidence rates for each of the major types of leukemia as compared to non-Hispanic Whites: For AML, elderly Whites had an incidence rate ratio (IRR) of 1.61 in comparison to Hispanics (p < 0.001) and 1.27 in comparison to Blacks (p < 0.001); for CML, the IRR among the elderly was 1.42 that of Hispanics (p < 0.001) and 1.22 that of Blacks (p = 0.003); and for CLL, the IRR was 2.31 times that of Hispanics (p < 0.001) and 1.48 times that of Blacks (p < 0.001). In ALL, however, Hispanics aged 0 – 19 had a significantly higher incidence rate than Whites and Blacks, with an IRR of 1.32 compared to Whites (p < 0.001), and 2.62 compared to Blacks (p < 0.001). In AML, CML, and CLL, among people age 65 or older, white non-Hispanics have higher incidence rates than Blacks, and Blacks have higher incidence rates than Hispanics. Childhood ALL incidence rates are highest among Hispanics, and lowest among Blacks.

Ofatumumab in combination with ICE or DHAP chemotherapy in relapsed or refractory intermediate grade B-cell lymphoma

Standard treatment of transplant-eligible patients with relapsed diffuse large B-cell lymphoma (DLBCL) consists of rituximab and platinum-based chemotherapy, either ifosfamide, carboplatin, and etoposide (ICE) or dexamethasone, cytarabine, and cisplatin (DHAP), with autologous transplant consolidation for those with chemosensitive disease. Nonetheless, outcomes are suboptimal for patients failing rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). We performed a multi-center phase II trial investigating the safety and efficacy of ofatumumab, a monoclonal antibody against CD20, combined with ICE or DHAP second-line therapy in patients with relapsed or refractory DLBCL, grade 3b follicular lymphoma, or transformed follicular lymphoma. Sixty-one patients were treated with either ofatumumab-ICE (35) or ofatumumab-DHAP (26). The overall response rate (ORR) was 61%, and the complete response (CR) rate was 37%. In patients with 2 or 3 adverse risk factors according to the second-line, age-adjusted, international prognostic index, the ORR was 59% and CR 31%, and in patients with early-relapsing or primary refractory disease, the ORR was 55% and CR 30%. Toxicity was largely hematologic, and stem cell mobilization was successful in 43 of 45 patients. Substitution of ofatumumab for rituximab in standard second-line regimens following failure of R-CHOP is a promising approach. This trial was registered at www.clinicaltrials.gov as NCT00823719.

Overview of Lymphoma Diagnosis and Management

The malignant lymphomas, including both Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL), represent a diverse group of diseases that arise from a clonal proliferation of lymphocytes. Each of the more than 30 unique types of lymphoma is a disease with a distinct natural history. This biologic heterogeneity gives rise to marked differences among the lymphomas with respect to epidemiology, pathologic characteristics, clinical presentation, and optimal management. This article emphasizes the principles of diagnosis, including appropriate pathologic evaluation and staging considerations, and focuses on the clinical presentation, staging, and optimal management strategies for the most common types of lymphoma.

Prognostic value of FDG-PET prior to autologous stem cell transplantation for relapsed and refractory diffuse large B-cell lymphoma

High-dose chemotherapy (HDT) plus autologous stem cell transplantation (ASCT) is the standard of care for chemosensitive relapsed and refractory diffuse large B-cell lymphoma (rel/ref DLBCL). Interim restaging with functional imaging by positron emission tomography using (18)F-deoxyglucose (FDG-PET) has not been established after salvage chemotherapy (ST) and before HDT-ASCT by modern criteria. Herein, we evaluated 129 patients with rel/ref DLBCL proceeding to HDT-ASCT, with ST response assessment by FDG-PET according to the contemporary Deauville 5-point scale. At 3 years, patients achieving a Deauville response of 1 to 3 to ST experienced superior progression-free survival (PFS) and overall survival (OS) rates of 77% and 86%, respectively, compared with patients achieving Deauville 4 (49% and 54%, respectively) (P < .001). No other pre-HDT-ASCT risk factors significantly impacted PFS or OS. Despite achieving remission to ST, patients with Deauville 4 should be the focus of risk-adapted investigational therapies.

Expert second-opinion pathology review of lymphoma in the era of the World Health Organization classification

BACKGROUND The World Health Organization (WHO) classification of hematologic malignancies, published in 2000, was designed to improve diagnostic accuracy by incorporating the latest in scientific understanding. The impact of the WHO classification on the frequency of diagnostic discrepancy in lymphoma is unknown. METHODS We reviewed all second-opinion pathology of lymphoma at our National Cancer Institute-designated Comprehensive Cancer Center (NCI-CCC) from January to June 2001 and from January to June 2006. Discrepancies between submitted and second-opinion diagnoses were scored based upon an a priori grading schema. RESULTS Major diagnostic revision was rendered in 65 of 365 cases (17.8%) in 2001 and 58 of 354 (16.4%) in 2006 (P=NS). Including cases reviewed and revised beforehand at another NCI-CCC, rates of major diagnostic revision were 21.4% and 18.6%, respectively (P=NS). Discrepancy rates varied by diagnosis, from Hodgkin lymphoma (10%) to Burkitts lymphoma (75%). No association was seen for age, gender, race/ethnicity, biopsy type, or nature of referring center. CONCLUSIONS Clinically meaningful diagnostic revision occurs frequently with expert pathology review for a diagnosis of lymphoma. Despite the WHO classification, rates of diagnostic revision at our institution in 2001 and 2006 did not differ significantly. Given the potential harm from misdiagnosis, expert hematopathology review should be considered the standard of care.BACKGROUND The World Health Organization (WHO) classification of hematologic malignancies, published in 2000, was designed to improve diagnostic accuracy by incorporating the latest in scientific understanding. The impact of the WHO classification on the frequency of diagnostic discrepancy in lymphoma is unknown. METHODS We reviewed all second-opinion pathology of lymphoma at our National Cancer Institute-designated Comprehensive Cancer Center (NCI-CCC) from January to June 2001 and from January to June 2006. Discrepancies between submitted and second-opinion diagnoses were scored based upon an a priori grading schema. RESULTS Major diagnostic revision was rendered in 65 of 365 cases (17.8%) in 2001 and 58 of 354 (16.4%) in 2006 (P=NS). Including cases reviewed and revised beforehand at another NCI-CCC, rates of major diagnostic revision were 21.4% and 18.6%, respectively (P=NS). Discrepancy rates varied by diagnosis, from Hodgkin lymphoma (10%) to Burkitts lymphoma (75%). No association was seen for age, gender, race/ethnicity, biopsy type, or nature of referring center. CONCLUSIONS Clinically meaningful diagnostic revision occurs frequently with expert pathology review for a diagnosis of lymphoma. Despite the WHO classification, rates of diagnostic revision at our institution in 2001 and 2006 did not differ significantly. Given the potential harm from misdiagnosis, expert hematopathology review should be considered the standard of care.

Imaging for Staging and Response Assessment in Lymphoma

Lymphoma comprises a heterogeneous group of diseases; remarkable advances have been made in diagnosis and treatment. Diagnostic imaging provides important information for staging and response assessment in patients with lymphoma. Over the years, staging systems have been refined, and dedicated criteria have been developed for evaluating response to therapy with both computed tomography (CT) and fluorine-18 fluorodeoxyglucose positron emission tomography (PET)/CT. The most recent system proposed for staging and response assessment, known as the Lugano classification, applies to both Hodgkin and non-Hodgkin lymphoma. The use of standardized criteria for staging and response assessment is important for making accurate treatment decisions and for determining the direction of further research. This review provides an overview of the updated CT and PET response criteria to familiarize the radiologist with the most important and clinically relevant aspects of lymphoma imaging. It also provides a short clinical update on lymphoma and the associated spectrum of imaging findings.