Reaching beyond maximum grade: progress and future directions for modernising the assessment and reporting of adverse events in haematological malignancies.

Remarkable improvements in outcomes for many haematological malignancies have been driven primarily by a proliferation of novel therapeutics over the past two decades. Targeted agents, immune and cellular therapies, and combination regimens have adverse event profiles distinct from conventional finite cytotoxic chemotherapies. In 2018, a Commission comprising patient advocates, clinicians, clinical investigators, regulators, biostatisticians, and pharmacists representing a broad range of academic and clinical cancer expertise examined issues of adverse event evaluation in the context of both newer and existing therapies for haematological cancers. The Commission proposed immediate actions and long-term solutions in the current processes in adverse event assessment, patient-reported outcomes in haematological malignancies, toxicities in cellular therapies, long-term toxicity and survivorship in haematological malignancies, issues in regulatory approval from an international perspective, and toxicity reporting in haematological malignancies and the real-world setting. In this follow-up report, the Commission describes progress that has been made in these areas since the initial report.

Beyond maximum grade: modernising the assessment and reporting of adverse events in haematological malignancies.

Tremendous progress in treatment and outcomes has been achieved across the whole range of haematological malignancies in the past two decades. Although cure rates for aggressive malignancies have increased, nowhere has progress been more impactful than in the management of typically incurable forms of haematological cancer. Population-based data have shown that 5-year survival for patients with chronic myelogenous and chronic lymphocytic leukaemia, indolent B-cell lymphomas, and multiple myeloma has improved markedly. This improvement is a result of substantial changes in disease management strategies in these malignancies. Several haematological malignancies are now chronic diseases that are treated with continuously administered therapies that have unique side-effects over time. In this Commission, an international panel of clinicians, clinical investigators, methodologists, regulators, and patient advocates representing a broad range of academic and clinical cancer expertise examine adverse events in haematological malignancies. The issues pertaining to assessment of adverse events examined here are relevant to a range of malignancies and have been, to date, underexplored in the context of haematology. The aim of this Commission is to improve toxicity assessment in clinical trials in haematological malignancies by critically examining the current process of adverse event assessment, highlighting the need to incorporate patient-reported outcomes, addressing issues unique to stem-cell transplantation and survivorship, appraising challenges in regulatory approval, and evaluating toxicity in real-world patients. We have identified a range of priority issues in these areas and defined potential solutions to challenges associated with adverse event assessment in the current treatment landscape of haematological malignancies.

Preexisting Cardiovascular Risk and Subsequent Heart Failure Among Non-Hodgkin Lymphoma Survivors.

Purpose The use of anthracycline chemotherapy is associated with heart failure (HF) among survivors of non-Hodgkin lymphoma (NHL). We aimed to understand the contribution of preexisting cardiovascular risk factors to HF risk among NHL survivors. Methods Using Danish registries, we identified adults diagnosed with aggressive NHL from 2000 to 2010 and sex- and age-matched general-population controls. We assessed HF from 9 months after diagnosis through 2012. We used Cox regression analysis to assess differences in risk for HF between survivors and general population controls. Among survivors only, preexisting cardiovascular factors (hypertension, dyslipidemia, and diabetes) and preexisting cardiovascular disease were ascertained. We used multivariable Cox regression to model the association of preexisting cardiovascular conditions on subsequent HF. Results Among 2,508 survivors of NHL and 7,399 controls, there was a 42% increased risk of HF among survivors compared with general population controls (hazard ratio [HR], 1.42; 95% CI, 1.07 to 1.88). Among survivors (median age at diagnosis, 62 years; 56% male), 115 were diagnosed with HF during follow-up (median years of follow-up, 2.5). Before NHL diagnosis, 39% had ≥ 1 cardiovascular risk factor; 92% of survivors were treated with anthracycline-containing regimens. In multivariable analysis, intrinsic heart disease diagnosed before lymphoma was associated with increased risk of HF (HR, 2.71; 95% CI, 1.15 to 6.36), whereas preexisting vascular disease had no association with HF ( P > .05). Survivors with cardiovascular risk factors had an increased risk of HF compared with those with none (for 1 v 0 cardiovascular risk factors: HR, 1.63; 95% CI, 1.07 to 2.47; for ≥ 2 v 0 cardiovascular risk factors: HR, 2.86; 95% CI, 1.56 to 5.23; joint P < .01). Conclusion In a large, population-based cohort of NHL survivors, preexisting cardiovascular conditions were associated with increased risk of HF. Preventive approaches should take baseline cardiovascular health into account.

A Comprehensive Assessment of Toxicities in Patients with Central Nervous System Lymphoma Undergoing Autologous Stem Cell Transplantation Using Thiotepa, Busulfan, and Cyclophosphamide Conditioning.

High-dose therapy and autologous stem cell transplantation (ASCT) with thiotepa, busulfan, and cyclophosphamide (TBC) conditioning has emerged as an effective postinduction treatment strategy for patients with primary central nervous system lymphoma (PCNSL) or secondary central nervous system lymphoma (SCNSL), but it is associated with considerable toxicity and transplantation-related mortality (TRM) in the modern era. Forty-three adult patients with chemosensitive PCNSL or SCNSL underwent TBC-conditioned ASCT between 2006 and 2015. Twenty-eight of these patients received pharmacokinetically (PK)-targeted busulfan dosing. The median number of clinically relevant individual grade ≥3 nonhematologic toxicities per patient was 5. We found no association between pretransplantation patient characteristics and the presence of more than 5 grade ≥3 nonhematologic toxicities. Patients with elevated first-dose busulfan area under the curve values did not experience more toxicity. Paradoxically, patients treated with more than 2 regimens before undergoing ASCT had lower first-dose busulfan AUC values. With a median follow-up among survivors of 20 months, 1-year progression-free survival (PFS) and overall survival (OS) from the time of ASCT were 83% and 87%, respectively. Although this study reaffirms the favorable PFS and OS associated with TBC-conditioned ASCT for PCNSL or SCNSL, this treatment strategy carries a large toxicity burden.

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.

Management of colorectal cancer in elderly patients: focus on the cost of chemotherapy.

The treatment of colorectal cancer has evolved dramatically over the last 15 years. Advances in surgery, radiotherapy and chemotherapy have enabled oncologists to cure more patients and offer improved quality of life to patients not amenable to cure. Specific knowledge of colorectal cancer care of the elderly, while lagging behind the treatment of younger patients, is beginning to emerge. Informed by recent trials, the approach towards elderly patients is shifting towards more aggressive treatment and multimodal therapy. Surgeons are operating on the elderly with greater frequency, less operative mortality and greater success; 5-year survival following potentially curative surgery has risen from 50% to 67%.Research of adjunctive therapy for colorectal cancer is enrolling more elderly patients, and with this has come an understanding of the role of chemotherapeutic agents in the treatment of the elderly, used individually and within multi-drug regimens. This research offers insight into how the elderly respond to chemotherapy, informing clinicians on anticipated benefits and toxicities of treatment. Fluorouracil-based regimens, which have long been the standard adjuvant chemotherapy, have been shown to offer benefits to the elderly compared with those not receiving adjuvant chemotherapy (71% versus 64% 5-year survival), and to cause similar toxicities as seen in younger patients. The role of novel chemotherapeutic agents in the treatment of elderly patients with colorectal cancer is also emerging, with studies finding that irinotecan, in combination with a fluorouracil-based regimen, can offer a further survival benefit of over 2 months compared with fluorouracil alone. While newer agents such as capecitabine, oxaliplatin, raltitrexed and tegafur/uracil (UFT) have been focused upon by clinical researchers, data on their use in the elderly remain unconvincing. Not only are we approaching a clearer understanding of the effectiveness of cancer care among the elderly, but research is also beginning to identify the cost effectiveness of both standard and emerging chemotherapeutic agents. Cost effectiveness of fluorouracil-based regimens, depending on delivery strategy, use of modulating agents and stage of cancer vary from US dollars 2000 per quality-adjusted life-year (QALY) to US dollars 20200 per QALY (1992 values). Irinotecan therapy has not been fully investigated from the perspective of cost effectiveness; the figure of US dollars 10000 per QALY (1998 values) for irinotecan monotherapy over fluorouracil regimens is likely an underestimate, while cost analysis of irinotecan and fluorouracil combination therapy has not yet been reported. Our understanding of cost effectiveness of other novel agents has lagged behind; further research on these agents is needed. Nonetheless, as the effects of these novel agents upon both outcomes and costs continue to be defined, both curative and palliative treatment of colorectal cancer in the elderly patient will become more sophisticated and effective.