Andrea K. Ng

American Society of Clinical Oncology Clinical Evidence Review on the Ongoing Care of Adult Cancer Survivors: Cardiac and Pulmonary Late Effects

PURPOSE To review the evidence on the incidence of long-term cardiac or pulmonary toxicity secondary to chemotherapy, radiotherapy, or trastuzumab in symptomatic and asymptomatic cancer survivors. METHODS An American Society of Clinical Oncology Panel reviewed pertinent information from the literature through February 2006. RESULTS Few studies directly addressing the benefits of screening for long-term cardiac or pulmonary toxicity in asymptomatic cancer survivors who received chemotherapy, radiotherapy, or trastuzumab were identified. The reviewed literature included primarily retrospective and cross-sectional studies describing the incidence of cardiac and pulmonary late effects. Anatomic and/or functional abnormalities have been associated with use of all currently available anthracyclines and their derivatives. Trastuzumab-related cardiac dysfunction rarely causes death, and in most cases is reversible with improvement in cardiac function on drug discontinuation and/or treatment with cardiac medications. The estimated aggregate incidence of radiation-induced cardiac disease is 10% to 30% by 5 to 10 years post-treatment, although the incidence may be lower with modern techniques. Radiation pneumonitis is reported in 5% to 15% of lung cancer patients receiving definitive external-beam radiation therapy. A minority of patients may develop progressive pulmonary fibrosis; late complications include cor pulmonale and respiratory failure. Bleomycin-induced pneumonitis is an acute rather than late effect of treatment. Late pulmonary complications in bone marrow or stem cell transplantation patients who develop interstitial pneumonitis include idiopathic pneumonia syndrome and bronchiolitis obliterans. CONCLUSION An increased incidence of cardiac and/or pulmonary dysfunction is observed in cancer survivors. Research is needed to identify high-risk patients, and to determine the optimal screening strategies and subsequent treatment.

Long-Term Survival and Competing Causes of Death in Patients With Early-Stage Hodgkin’s Disease Treated at Age 50 or Younger

PURPOSE To analyze the long-term survival and the pattern and timing of excess mortality in patients with early-stage Hodgkins disease. PATIENTS AND METHODS Between 1969 and 1997, 1,080 patients age 50 or younger were treated for clinical stage IA to IIB Hodgkins disease. Overall survival was determined, and prognostic factors were assessed. Relative risk and absolute excess risk (AR) of mortality were calculated for the entire cohort and by prognostic groups (on the basis of B symptoms, mediastinal status, and number of sites, modified from the European Organization for Research and Treatment of Cancer). RESULTS The median follow-up was 12 years. The 15- and 20-year Kaplan-Meier survival estimates were 84% and 78%, respectively. Cox proportional hazards models showed that number of involved sites (P =.006), mediastinal status (P =.02), and histology (P =.02) were independent predictors of death from all causes. The AR of mortality in patients with a favorable prognosis increased over time, whereas for those with an unfavorable prognosis, the AR peaked in the first 5 years, predominantly from Hodgkins disease. The relative risk of mortality from all causes, causes other than Hodgkins disease, second tumors, and cardiac disease remained significantly elevated more than 20 years after treatment. CONCLUSION Patients treated for early-stage Hodgkins disease have a sustained excess mortality risk despite good control of the disease. Treatment reduction efforts in patients with early-stage, favorable-prognosis disease should continue, but for patients with an unfavorable prognosis, modified treatment may not be advisable. The excess mortality noted beyond two decades underscores the importance of long-term follow-up care in patients treated for Hodgkins disease.

Modern Radiation Therapy for Hodgkin Lymphoma: Field and Dose Guidelines From the International Lymphoma Radiation Oncology Group (ILROG)

Radiation therapy (RT) is the most effective single modality for local control of Hodgkin lymphoma (HL) and an important component of therapy for many patients. These guidelines have been developed to address the use of RT in HL in the modern era of combined modality treatment. The role of reduced volumes and doses is addressed, integrating modern imaging with 3-dimensional (3D) planning and advanced techniques of treatment delivery. The previously applied extended field (EF) and original involved field (IF) techniques, which treated larger volumes based on nodal stations, have now been replaced by the use of limited volumes, based solely on detectable nodal (and extranodal extension) involvement at presentation, using contrast-enhanced computed tomography, positron emission tomography/computed tomography, magnetic resonance imaging, or a combination of these techniques. The International Commission on Radiation Units and Measurements concepts of gross tumor volume, clinical target volume, internal target volume, and planning target volume are used for defining the targeted volumes. Newer treatment techniques, including intensity modulated radiation therapy, breath-hold, image guided radiation therapy, and 4-dimensional imaging, should be implemented when their use is expected to decrease significantly the risk for normal tissue damage while still achieving the primary goal of local tumor control. The highly conformal involved node radiation therapy (INRT), recently introduced for patients for whom optimal imaging is available, is explained. A new concept, involved site radiation therapy (ISRT), is introduced as the standard conformal therapy for the scenario, commonly encountered, wherein optimal imaging is not available. There is increasing evidence that RT doses used in the past are higher than necessary for disease control in this era of combined modality therapy. The use of INRT and of lower doses in early-stage HL is supported by available data. Although the use of ISRT has not yet been validated in a formal study, it is more conservative than INRT, accounting for suboptimal information and appropriately designed for safe local disease control. The goal of modern smaller field radiation therapy is to reduce both treatment volume and treatment dose while maintaining efficacy and minimizing acute and late sequelae. This review is a consensus of the International Lymphoma Radiation Oncology Group (ILROG) Steering Committee regarding the modern approach to RT in the treatment of HL, outlining a new concept of ISRT in which reduced treatment volumes are planned for the effective control of involved sites of HL. Nodal and extranodal non-Hodgkin lymphomas (NHL) are covered separately by ILROG guidelines.

Psychological Distress in Long-term Survivors of Adult-Onset Cancer: Results From a National Survey

BACKGROUND As advances in cancer screening and treatment increase the number of long-term cancer survivors, it is important to understand the long-term psychological sequelae of the cancer experience. METHODS The 4636 respondents who identified themselves as survivors of adult-onset cancer of 5 years or more and 122 220 respondents who were never diagnosed as having cancer were identified in the 2002 to 2006 National Health Interview Survey. The primary outcome in this population-based study was serious psychological distress (SPD) defined as a K6 scale (a validated screening tool for mental illness) score of 13 or more. RESULTS Among survivors, the median age at diagnosis was 50 years, the age at interview was 66 years, and the time since diagnosis was 12 years. The prevalence of SPD was significantly higher among long-term cancer survivors than among respondents who were never diagnosed as having cancer (5.6% vs 3.0%; P < .001). After adjustment for clinical and sociodemographic variables (age, sex, race, relationship status, educational attainment, insurance status, comorbidities, smoking history, and ability to perform instrumental activities of daily living), survivors remained significantly more likely to experience SPD (adjusted odds ratio, 1.4; 95% confidence interval, 1.2-1.7). After adjustment for other clinical and sociodemographic variables, long-term survivors who were younger, were unmarried, had less than a high school education, were uninsured, had more comorbidities, or had difficulty performing instrumental activities of daily living were more likely to experience SPD. CONCLUSIONS Long-term survivors of adult-onset cancer are at increased risk for psychological distress. This study identifies several clinical and sociodemographic factors associated with SPD that may help target high-risk survivors for psychological screening and support.

Clinically significant cardiac disease in patients with Hodgkin lymphoma treated with mediastinal irradiation

This study assessed the cumulative incidence of clinically significant cardiac disease in 1279 Hodgkin lymphoma patients treated with mediastinal irradiation and quantified the standard incidence ratios (SIRs) and absolute excess risks of cardiac procedures compared with a normal matched population. Cox regression analysis was used to explore factors associated with cardiac complications. Poisson regression analysis of SIRs was used to estimate the excess risk of cardiac interventions from mediastinal irradiation. After a median follow-up of 14.7 years, 187 patients experienced 636 cardiac events and 89 patients required a cardiac procedure. 5-, 10-, 15-, and 20-year cumulative incidence rates of cardiac events were 2.2%, 4.5%, 9.6%, and 16%. SIRs for cardiac procedures were increased for coronary artery bypass graft (3.19), percutaneous intervention (1.55), implantable cardioverter defibrillator or pacemaker placement (1.9), valve surgery (9.19), and pericardial surgery (12.91). Absolute excess risks were 18.2, 19.3, 9.4, 14.1, and 4.7 per 10 000 person-years, respectively. Older age at diagnosis and male sex were predictors for cardiac events. However, younger age at diagnosis was associated with excess risk specifically from radiation therapy compared with the general population. These results may help guideline development for both the types and timing of cardiac surveillance in survivors of Hodgkin lymphoma.

Second Malignant Neoplasms and Cardiovascular Disease Following Radiotherapy

Second malignant neoplasms (SMNs) and cardiovascular disease (CVD) are among the most serious and life-threatening late adverse effects experienced by the growing number of cancer survivors worldwide and are due in part to radiotherapy. The National Council on Radiation Protection and Measurements (NCRP) convened an expert scientific committee to critically and comprehensively review associations between radiotherapy and SMNs and CVD, taking into account radiobiology; genomics; treatment (ie, radiotherapy with or without chemotherapy and other therapies); type of radiation; and quantitative considerations (ie, dose-response relationships). Major conclusions of the NCRP include: 1) the relevance of older technologies for current risk assessment when organ-specific absorbed dose and the appropriate relative biological effectiveness are taken into account and 2) the identification of critical research needs with regard to newer radiation modalities, dose-response relationships, and genetic susceptibility. Recommendation for research priorities and infrastructural requirements include 1) long-term large-scale follow-up of extant cancer survivors and prospectively treated patients to characterize risks of SMNs and CVD in terms of radiation dose and type; 2) biological sample collection to integrate epidemiological studies with molecular and genetic evaluations; 3) investigation of interactions between radiotherapy and other potential confounding factors, such as age, sex, race, tobacco and alcohol use, dietary intake, energy balance, and other cofactors, as well as genetic susceptibility; 4) focusing on adolescent and young adult cancer survivors, given the sparse research in this population; and 5) construction of comprehensive risk prediction models for SMNs and CVD to permit the development of follow-up guidelines and prevention and intervention strategies.

FDG-PET is Superior to Gallium Scintigraphy in Staging and More Sensitive in the Follow-up of Patients with de novo Hodgkin Lymphoma: A Blinded Comparison

Accurate staging of Hodgkin lymphoma (HD) allows for minimization of therapy and reduction of long-term toxicities. The present study prospectively compares FDG-PET with gallium/SPECT scintigraphy at time of diagnosis and in follow-up of 36 patients with HD. Prior to therapy, whole body FDG-PET and gallium/SPECT were performed. Follow-up scans were obtained after 3 cycles of chemotherapy (n = 22), and at the end of chemotherapy (n = 32). Two nuclear medicine physicians independently interpreted scans in blinded and random order and a consensus was obtained. Baseline scans revealed a greater number of supradiaphragmatic disease sites detected by PET, and 5 patients had splenic involvement on PET not noted by gallium (P = 0.05); 3 patients were upstaged on PET. Midway through therapy, 5 patients had positive PET (4 of whom relapsed), and 3 had positive gallium (1 relapsed). At conclusion of chemotherapy, 8 patients had a positive PET (4 relapsed) and 3 had a positive gallium (2 relapsed). In conclusion, diagnostic PET and gallium are largely concordant, with the exception of unique detection of splenic disease by PET. However, more patients have persistently positive PET at the end of chemotherapy compared with gallium (P = 0.04), although only half of these patients have relapsed.

Modern Radiation Therapy for Nodal Non-Hodgkin Lymphoma—Target Definition and Dose Guidelines From the International Lymphoma Radiation Oncology Group

Radiation therapy (RT) is the most effective single modality for local control of non-Hodgkin lymphoma (NHL) and is an important component of therapy for many patients. Many of the historic concepts of dose and volume have recently been challenged by the advent of modern imaging and RT planning tools. The International Lymphoma Radiation Oncology Group (ILROG) has developed these guidelines after multinational meetings and analysis of available evidence. The guidelines represent an agreed consensus view of the ILROG steering committee on the use of RT in NHL in the modern era. The roles of reduced volume and reduced doses are addressed, integrating modern imaging with 3-dimensional planning and advanced techniques of RT delivery. In the modern era, in which combined-modality treatment with systemic therapy is appropriate, the previously applied extended-field and involved-field RT techniques that targeted nodal regions have now been replaced by limiting the RT to smaller volumes based solely on detectable nodal involvement at presentation. A new concept, involved-site RT, defines the clinical target volume. For indolent NHL, often treated with RT alone, larger fields should be considered. Newer treatment techniques, including intensity modulated RT, breath holding, image guided RT, and 4-dimensional imaging, should be implemented, and their use is expected to decrease significantly the risk for normal tissue damage while still achieving the primary goal of local tumor control.

Second Malignant Neoplasms: Assessment and Strategies for Risk Reduction

Improvements in early detection, supportive care, and treatment have resulted in an increasing number of cancer survivors, with a current 5-year relative survival rate for all cancers combined of approximately 66.1%. For some patients, these survival advances have been offset by the long-term late effects of cancer and its treatment, with second malignant neoplasms (SMNs) comprising one of the most potentially life-threatening sequelae. The number of patients with SMNs is growing, with new SMNs now representing about one in six of all cancers reported to the National Cancer Institutes Surveillance, Epidemiology, and End Results (SEER) Program. SMNs reflect not only the late effects of therapy but also the influence of shared etiologic factors (in particular, tobacco and excessive alcohol intake), genetic susceptibility, environmental exposures, host effects, and combinations of factors, including gene-environment interactions. For selected SMNs, risk is also modified by age at exposure and attained age. SMNs can be categorized into three major groups according to the predominant etiologic factor(s): (1) treatment-related, (2) syndromic, and (3) those due to shared etiologic exposures, although the nonexclusivity of these groups should be underscored. Here we provide an overview of SMNs in survivors of adult-onset cancer, summarizing the current, albeit limited, clinical evidence with regard to screening and prevention, with a focus on the provision of guidance for health care providers. The growing number of patients with second (and higher-order) cancers mandates that we also further probe etiologic influences and genetic variants that heighten risk, and that we better define high-risk groups for targeted preventive and interventional clinical strategies.

Therapeutic Guidelines for the Treatment of Bone Metastasis: A Report from the American College of Radiology Appropriateness Criteria Expert Panel on Radiation Oncology

Bone metastases remain a therapeutic challenge because of the diversity of the problems they cause, the relative paucity of data regarding their treatment, and the necessity for management by a multidisciplinary palliative care team. The American College of Radiology convened an Appropriateness Criteria Expert Panel on Radiation Oncology for the treatment of bone metastasis to create representative clinical case scenarios and then rank the appropriate use of treatment modalities as well as the most reasonable radiotherapy dose schema and treatment planning methods. Here we present both the resulting Appropriateness Criteria and the rationale for making these decisions. The treatment recommendations are placed within the larger framework of the role of radiation in palliative care by discussing the efficiency of palliative radiotherapy schedules, cost effectiveness issues, and the need for additional research regarding the proper multidisciplinary care of patients with symptomatic bone metastasis.