Contact Days Associated With Cancer Treatments in the CCTG LY.12 Trial.

BACKGROUND: When cancer treatments have similar oncologic outcomes, the number of days with in-person healthcare contact (""contact days'') can help contextualize expected time use with each treatment. We assessed contact days in a completed randomized clinical trial. PATIENTS AND METHODS: We conducted a secondary analysis of the CCTG LY.12 RCT that evaluated 2-3 cycles of gemcitabine, dexamethasone, and cisplatin (GDP) vs. dexamethasone, cytarabine, and cisplatin (DHAP) in 619 patients with relapsed/refractory lymphoma prior to stem cell transplant. Primary analyses reported similar response rates and survival. We calculated patient-level "contact days" by analyzing trial forms. The study period was from assignment to progression or transplant. Days without healthcare contact were considered "home days''. We compared measures of contact days across arms. RESULTS: The study period was longer in the GDP arm (median 50, vs. 47 days, P = .007). Contact days were comparable in both arms (median 18 vs 19, P = 0.79), but home days were higher in the GDP arm (median 33 vs 28, P < .001). The proportion of contact days was lower in the GDP arm (34%, vs. 38%, P = .009). The GDP arm experienced more contact days related to planned outpatient chemotherapy (median, 10 vs. 8 days), but the DHAP arm experienced many more inpatient contact days (median, 11 vs. 0 days). CONCLUSIONS: Measures of time use, such as contact days, can be extracted from RCTs. In LY.12, despite comparable oncologic outcomes, GDP was associated with fewer contact days. Such information can guide decision-making for patients with hematological cancers, who already face significant healthcare contact.

Health-related quality of life in early-stage Hodgkin lymphoma: a longitudinal analysis of the ABVD arm in the randomized controlled trial HD.6.

Early-stage Hodgkin lymphoma has become one of the most curable hematologic malignancies. Depending upon the disease location, possible toxicities, and patient preference, chemotherapy alone with ABVD remains an accepted treatment modality for this disease. There remains a paucity of data regarding the longitudinal trajectory of health-related quality of life (HRQoL) in patients treated for HL. The impact of disease and treatment on HRQoL is increasingly important to understand as the number of long-term survivors increases. We report the longitudinal HRQoL using data prospectively collected from diagnosis up to 10 years post-treatment in the ABVD arm of the HD.6 randomized controlled trial for early-stage HL patients (N=169). We analyzed HRQoL using the EORTC QLQ-C30 collected at baseline, 3 months, 6 months, and 12 months after completion of chemotherapy and yearly up to year 10. Clinically and statistically significant improvements were noted for specific domains including emotional (3 months post-treatment), social (12 months post-treatment) and financial functioning (2 years post-treatment), and the specific symptom of fatigue (6 months post-treatment) during the follow-up period. To our knowledge, this is the first prospective, longitudinal analysis of HRQoL specifically among patients with early-stage HL treated with ABVD therapy alone. Although improvements were noted, sustained clinically and statistically significant improvements were noted only in select symptoms emphasizing the need to better understand and optimize HRQoL among this patient group.

Evaluating the Indirect Costs of Care Associated with Salvage Chemotherapy for Relapsed and Refractory Aggressive-Histology Lymphoma: A Subset Analysis of the Canadian Cancer Trials Group (CCTG) LY.12 Clinical Trial.

We conducted an analysis of indirect costs alongside the LY.12 randomized trial in patients with relapsed or refractory (R/R) aggressive non-Hodgkin lymphoma (NHL). Lost productivity data for Canadian patients and caregivers in the trial were collected at baseline and with each chemotherapy cycle pre-transplant, using an adapted Lost Productivity questionnaire. Mean per patient indirect costs were CAD 2999 for patients in the GDP arm and CAD 3400 in the DHAP arm. A substantial majority was not working or had to reduce their workload during this treatment time. Salvage chemotherapy for R/R aggressive NHL is associated with significant indirect costs to patients and their caregivers.

A Canadian Prospective Study of Linkage of Randomized Clinical Trial to Cancer and Mortality Registry Data.

In a prospective study, we sought to determine acceptability of linkage of administrative and clinical trial data among Canadian patients and Research Ethics Boards (REBs). The goal is to develop a more harmonized approach to data, with potential to improve clinical trial conduct through enhanced data quality collected at reduced cost and inconvenience for patients. On completion of the original LY.12 randomized clinical trial in lymphoma (NCT00078949), participants were invited to enrol in the Long-term Innovative Follow-up Extension (LIFE) component. Those consenting to do so provided comprehensive identifying information to facilitate linkage with their administrative data. We prospectively designed a global assessment of this innovative approach to clinical trial follow-up including rates of REB approval and patient consent. The pre-specified benchmark for patient acceptability was 80%. Of 16 REBs who reviewed the research protocol, 14 (89%) provided approval; two in Quebec declined due to small patient numbers. Of 140 patients invited to participate, 115 (82%, 95% CI 76 to 88%) from across 9 Canadian provinces provided consent and their full name, date of birth, health insurance number and postal code to facilitate linkage with their administrative data for long-term follow-up. Linkage of clinical trial and administrative data is feasible and acceptable. Further collaborative work including many stakeholders is required to develop an optimized secure approach to research. A more coordinated national approach to health data could facilitate more rapid testing and identification of new effective treatments across multiple jurisdictions and diseases from diabetes to COVID-19.

The conditional survival analysis of relapsed DLBCL after autologous transplant: a subgroup analysis of LY.12 and CORAL.

The conditional survival of patients after frontline therapy for diffuse large B-cell lymphoma (DLBCL) approaches that of the general population once patients have survived disease free for 2 years. We sought to determine the conditional survival of patients among patients with relapsed de novo DLBCL successfully undergoing an autologous stem-cell transplant (ASCT) after first relapse. A total of 478 patients with de novo DLBCL, relapsed after 1 treatment from the Collaborative Trial in Relapsed Aggressive Lymphoma (CORAL) and LY.12, were included. Patients were followed prospectively after ASCT for a median of 5.3 and 8.2 years, respectively. Individual patient data were analyzed for event-free survival (EFS) and overall survival. Standardized mortality ratios (SMRs) were estimated using French and Canadian life tables. The EFS estimates declined with each year of follow-up after ASCT and were 50.1% (95% confidence interval [CI]: 43.7% to 56.3%) and 43.4% (95% CI: 36.7% to 49.9%) at 5 years in CORAL and LY.12, respectively. The rate of death stabilized once patients achieved at least 4 years of EFS. Compared with the age- and sex-matched population, the SMR was significantly higher until 5 years after ASCT, when values were no longer statistically significant. Patients undergoing ASCT for relapsed DLBCL continue to have a higher rate of death at least until they have survived event free for 5 years. These observations can help to determine endpoints for future clinical trials in this population and for patient counseling. This trial was registered at www.clinicaltrials.gov as #NCT00078949.

Salvage chemotherapy and autologous stem cell transplantation for peripheral T-cell lymphoma: a subset analysis of the Canadian Cancer Trials Group LY.12 randomized phase 3 study.

Peripheral T-cell lymphoma (PTCL) is a rare, heterogeneous malignancy. Of the 619 patients with relapsed and refractory (R/R) aggressive lymphoma enrolled in the Canadian Cancer Trials Group LY.12 phase 3 trial, 59 (9.5%) had PTCL. Among these, 81% had advanced stage disease, 41% had an International Prognostic Score ≥3, and 41% were refractory to primary therapy. Within the PTCL cohort, the overall response rate after two cycles of salvage chemotherapy was 36%; no difference was observed between dexamethasone, cytarabine, cisplatin (10/30, 33%), and gemcitabine, cisplatin, dexamethasone (11/29, 38%) therapy. At one year, event-free survival (EFS) was 16% and overall survival (OS) was 28%. For PTCL patients, who received autologous stem cell transplant, two-year EFS and OS were 21% and 42%, respectively. Patients with PTCL had inferior OS (HR 0.49, p < .0001) and EFS (HR 0.53, p < .0001) compared to B-cell lymphoma. Outcomes for patients with R/R PTCL are poor with currently available therapies.

Effect of the addition of rituximab to salvage chemotherapy prior to autologous stem cell transplant in aggressive CD20+ lymphoma: a cohort comparison from the NCIC Clinical Trials Group Study LY.12.

The impact of the addition of rituximab to salvage chemotherapy prior to autologous stem cell transplant (ASCT) was evaluated in a retrospective subgroup analysis of NCIC CTG LY.12. Among 414 patients who relapsed following R-CHOP, 96 received salvage chemotherapy alone [R - cohort]; and 318 received rituximab with chemotherapy [R + cohort] following a protocol amendment. The R-cohort had a higher proportion of patients with PS ≥2 and relapse <1 year after R-CHOP. The response rate (45.6% vs. 25.0%, p = 0.0003), CR/CRu (15.7% vs. 4.2%, p = 0.003) and transplantation rate (51.9% vs. 31.3%, p = 0.0004) was higher in the R + cohort. Event-free (27% vs. 22%, p = 0.0954) and overall survival at four years (43% vs. 31%; p = 0.045) were greater in the R + cohort when the patients with best response SD/PD to R-CHOP were excluded. Addition of rituximab to salvage therapy before ASCT appears to improve the response rate, transplantation rate, and overall survival in patients with CD20+ lymphoma who responded to R-CHOP.

Salvage chemotherapy and autologous stem cell transplantation for transformed indolent lymphoma: a subset analysis of NCIC CTG LY12.

The treatment of transformed indolent lymphoma (TRIL) often includes salvage chemotherapy (SC) and autologous stem cell transplant (ASCT). NCIC CTG LY12 is a randomized phase 3 trial comparing gemcitabine, dexamethasone, and cisplatin (GDP) with dexamethasone, cytarabine, and cisplatin (DHAP) before ASCT. This analysis compares the results of SC and ASCT for TRIL with de novo diffuse large B-cell lymphoma (DLBCL). Six-hundred nineteen patients with relapsed/refractory aggressive non-Hodgkin lymphoma were randomized to GDP or DHAP; 87 patients (14%) had TRIL and 429 (69%) had DLBCL. The response rate to SC was 47% in TRIL and 45% in DL (P = .81). Transplantation rates were similar: TRIL 53% and DL 52% (P = 1.0). With a median follow-up of 53 months, 4 year overall survival was 39% for TRIL and 41% for DL (P = .78); 4 year event-free survival (EFS) was 27% for TRIL and 27% for DL (P = .83). Post-ASCT, 4-year EFS was 45% for TRIL and 46% for DL. Histology (TRIL or DL) was not a predictor of any outcome in multivariate models. Patients with relapsed or refractory TRIL and DLBCL have similar outcomes with SC and ASCT; this therapy should be considered the standard of care for patients with TRIL who have received prior systemic chemotherapy. NCIC CTG LY12 is registered at ClinicalTrials.gov as #NCT00078949.

Randomized comparison of gemcitabine, dexamethasone, and cisplatin versus dexamethasone, cytarabine, and cisplatin chemotherapy before autologous stem-cell transplantation for relapsed and refractory aggressive lymphomas: NCIC-CTG LY.12.

PURPOSE: For patients with relapsed or refractory aggressive lymphoma, we hypothesized that gemcitabine-based therapy before autologous stem-cell transplantation (ASCT) is as effective as and less toxic than standard treatment. PATIENTS AND METHODS: We randomly assigned 619 patients with relapsed/refractory aggressive lymphoma to treatment with gemcitabine, dexamethasone, and cisplatin (GDP) or to dexamethasone, cytarabine, and cisplatin (DHAP). Patients with B-cell lymphoma also received rituximab. Responding patients proceeded to stem-cell collection and ASCT. Coprimary end points were response rate after two treatment cycles and transplantation rate. The noninferiority margin for the response rate to GDP relative to DHAP was set at 10%. Secondary end points included event-free and overall survival, treatment toxicity, and quality of life. RESULTS: For the intention-to-treat population, the response rate with GDP was 45.2%; with DHAP the response rate was 44.0% (95% CI for difference, -9.0% to 6.7%), meeting protocol-defined criteria for noninferiority of GDP (P = .005). Similar results were obtained in a per-protocol analysis. The transplantation rates were 52.1% with GDP and 49.3% with DHAP (P = .44). At a median follow-up of 53 months, no differences were detected in event-free survival (HR, 0.99; stratified log-rank P = .95) or overall survival (HR, 1.03; P = .78) between GDP and DHAP. Treatment with GDP was associated with less toxicity (P < .001) and need for hospitalization (P < .001), and preserved quality of life (P = .04). CONCLUSION: For patients with relapsed or refractory aggressive lymphoma, in comparison with DHAP, treatment with GDP is associated with a noninferior response rate, similar transplantation rate, event-free survival, and overall survival, less toxicity and hospitalization, and superior quality of life.

ABVD alone versus radiation-based therapy in limited-stage Hodgkin's lymphoma.

BACKGROUND: Chemotherapy plus radiation treatment is effective in controlling stage IA or IIA nonbulky Hodgkin's lymphoma in 90% of patients but is associated with late treatment-related deaths. Chemotherapy alone may improve survival because it is associated with fewer late deaths. METHODS: We randomly assigned 405 patients with previously untreated stage IA or IIA nonbulky Hodgkin's lymphoma to treatment with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) alone or to treatment with subtotal nodal radiation therapy, with or without ABVD therapy. Patients in the ABVD-only group, both those with a favorable risk profile and those with an unfavorable risk profile, received four to six cycles of ABVD. Among those assigned to subtotal nodal radiation therapy, patients who had a favorable risk profile received subtotal nodal radiation therapy alone and patients with an unfavorable risk profile received two cycles of ABVD plus subtotal nodal radiation therapy. The primary end point was 12-year overall survival. RESULTS: The median length of follow-up was 11.3 years. At 12 years, the rate of overall survival was 94% among those receiving ABVD alone, as compared with 87% among those receiving subtotal nodal radiation therapy (hazard ratio for death with ABVD alone, 0.50; 95% confidence interval [CI], 0.25 to 0.99; P=0.04); the rates of freedom from disease progression were 87% and 92% in the two groups, respectively (hazard ratio for disease progression, 1.91; 95% CI, 0.99 to 3.69; P=0.05); and the rates of event-free survival were 85% and 80%, respectively (hazard ratio for event, 0.88; 95% CI, 0.54 to 1.43; P=0.60). Among the patients randomly assigned to ABVD alone, 6 patients died from Hodgkin's lymphoma or an early treatment complication and 6 died from another cause; among those receiving radiation therapy, 4 deaths were related to Hodgkin's lymphoma or early toxic effects from the treatment and 20 were related to another cause. CONCLUSIONS: Among patients with Hodgkin's lymphoma, ABVD therapy alone, as compared with treatment that included subtotal nodal radiation therapy, was associated with a higher rate of overall survival owing to a lower rate of death from other causes. (Funded by the Canadian Cancer Society and the National Cancer Institute; HD.6 ClinicalTrials.gov number, NCT00002561.).

Bortezomib ADDED to R-CVP is safe and effective for previously untreated advanced-stage follicular lymphoma: a phase II study by the National Cancer Institute of Canada Clinical Trials Group.

PURPOSE: Bortezomib has demonstrated promising activity in patients with follicular lymphoma (FL). This is the first study to evaluate the safety and efficacy of bortezomib added to rituximab, cyclophosphamide, vincristine, and prednisone (R-CVP) in previously untreated advanced-stage FL. PATIENTS AND METHODS: This is a phase II multicenter trial adding bortezomib (1.3 mg/m(2) days 1 and 8) to standard-dose R-CVP (BR-CVP) for up to eight cycles in patients with newly diagnosed stage III/IV FL requiring therapy. Two co-primary end points, complete response rate (complete response [CR]/CR unconfirmed [CRu]) and incidence of grade 3 or 4 neurotoxicity, were assessed. RESULTS: Between December 2006 and March 2009, 94 patients were treated with BR-CVP. Median patient age was 57 years (range, 29 to 84 years), and the majority had a high (47%) or intermediate (43%) Follicular Lymphoma International Prognostic Index score. BR-CVP was extremely well tolerated, with 90% of patients completing the intended eight cycles. No patients developed grade 4 neurotoxicity, and only five of 94 patients (5%; 95% CI, 0.8% to 9.9%) developed grade 3 neurotoxicity, which was largely reversible. On the basis of an intention-to-treat analysis, 46 of 94 patients (49%; 95% CI, 38.8% to 59.0%) achieved a CR/CRu, and 32 of 94 patients (34%) achieved a partial response, for an overall response rate of 83% (95% CI, 75.4% to 90.6%). CONCLUSION: The addition of bortezomib to standard-dose R-CVP for advanced-stage FL is feasible and well tolerated with minimal additional toxicity. The complete response rate in this high-risk population compares favorably to historical results of patients receiving R-CVP. Given these results, a phase III trial comparing BR-CVP with R-CVP is planned.

Phase II study of vandetanib or placebo in small-cell lung cancer patients after complete or partial response to induction chemotherapy with or without radiation therapy: National Cancer Institute of Canada Clinical Trials Group Study BR.20.

PURPOSE: This double-blind randomized phase II trial examined whether vandetanib, an inhibitor of vascular endothelial and epidermal growth factor receptors, could prolong progression-free survival in responding patients with small-cell lung cancer. PATIENTS AND METHODS: Eligible patients with complete response (CR) or partial response (PR) to combination chemotherapy (+/- thoracic or prophylactic cranial radiation) received oral vandetanib 300 mg/d or matched placebo. With 100 patients and 77 events, the study had 80% power to detect an improvement in median progression-free survival from 4 to 6.5 months (one-sided, 10%-level test). RESULTS: Between May 2003 and March 2006, 107 patients were accrued; 46 had limited disease and 61 extensive disease. There were fewer patients with a performance status of 0 (n = 11 v 20), and fewer had CR to initial therapy (n = 4 v 8) in the vandetanib arm. Vandetanib patients had more toxicity and required more dose modifications for gastrointestinal toxicity and rash. Asymptomatic Corrected QT interval (QTC) prolongation was observed in eight vandetanib patients. Median progression-free survival for vandetanib and placebo was 2.7 and 2.8 months, respectively (hazard ratio [HR], 1.01; 80% CI, 0.75 to 1.36; one-sided P = .51). Overall survival for vandetanib was 10.6 versus 11.9 months for placebo (HR, 1.43; 80% CI, 1.00 to 2.05; one-sided P = 0.9). In planned subgroup analyses, a significant interaction was noted (P = .01): limited-stage vandetanib patients had longer overall survival (HR, 0.45; one-sided P = .07) and extensive-stage vandetanib patients shorter survival compared with placebo (HR, 2.27; one-sided P = .996). CONCLUSION: Vandetanib failed to demonstrate efficacy as maintenance therapy for small-cell lung cancer.

A randomised comparison of melphalan with prednisone or dexamethasone as induction therapy and dexamethasone or observation as maintenance therapy in multiple myeloma: NCIC CTG MY.7.

The effectiveness of melphalan plus dexamethasone (M-Dex) with melphalan plus prednisone (MP) as induction therapy and dexamethasone with observation as maintenance therapy was compared in 585 older patients with multiple myeloma. Randomization to the M-Dex arm was stopped as a result of an analysis performed which met a predetermined event-related criterion. Of 466 patients randomised to MP or M-Dex, no differences were detected in the respective median progression-free survivals (PFS) [1.8 vs. 1.9 years; Hazard Ratio (HR) = 0.88, 95% CI 0.72-1.07; P = 0.2] or overall survivals (OS) (2.5 vs. 2.7 years; HR = 0.91, 95% CI 0.74-1.11; P = 0.3). Of the initial 585 patients, 292 remained evaluable for maintenance therapy. Patients randomised to maintenance dexamethasone had a superior median PFS (2.8 years vs. 2.1 years; HR = 0.61, 95% CI 0.47-0.79; P = 0.0002). No difference in median OS was detected (4.1 years vs. 3.8 years; HR = 0.88, 95% CI 0.65-1.18; P = 0.4). The maintenance therapy results were robust when analysed by using two additional methodologies. Dexamethasone did not improve clinical outcome when combined with melphalan during induction; maintenance dexamethasone improved PFS, but this did not translate into a detectable survival advantage.

Randomized comparison of ABVD chemotherapy with a strategy that includes radiation therapy in patients with limited-stage Hodgkin's lymphoma: National Cancer Institute of Canada Clinical Trials Group and the Eastern Cooperative Oncology Group.

PURPOSE: We report results of a randomized trial comparing ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) chemotherapy alone with treatment that includes radiation therapy in patients with limited-stage Hodgkin's lymphoma. PATIENTS AND METHODS: Patients with nonbulky clinical stage I to IIA Hodgkin's lymphoma were stratified into favorable and unfavorable risk cohorts. Patients allocated to radiation-containing therapy received subtotal nodal radiation if favorable risk or combined-modality therapy if unfavorable risk. Patients allocated to ABVD received four to six treatment cycles. RESULTS: We evaluated 399 patients. Median follow-up is 4.2 years. In comparison with ABVD alone, 5-year freedom from disease progression is superior in patients allocated to radiation therapy (P = .006; 93% v 87%); no differences in event-free survival (P = .06; 88% v 86%) or overall survival (P = .4; 94% v 96%) were detected. In a subset analyses comparing patients stratified into the unfavorable cohort, freedom from disease progression was superior in patients allocated to combined-modality treatment (P = .004; 95% v 88%); no difference in overall survival was detected (P = .3; 92% v 95%). Of 15 deaths observed, nine were attributed to causes other than Hodgkin's lymphoma or acute treatment-related toxicity. CONCLUSION: In patients with limited-stage Hodgkin's lymphoma, no difference in overall survival was detected between patients randomly assigned to receive treatment that includes radiation therapy or ABVD alone. Although 5-year freedom from disease progression was superior in patients receiving radiation therapy, this advantage is offset by deaths due to causes other than progressive Hodgkin's lymphoma or acute treatment-related toxicity.