The successful integration of clinical trials into pediatric oncology has led to steady improvement in the 5-year survival rate for children diagnosed with Hodgkin lymphoma (HL). It is estimated that >95% of children newly diagnosed with HL will become long-term survivors. Despite these successes, survival can come at a cost. Historically, long-term survivors of HL have a high risk of late-occurring adverse health effects and increased risk of nonrelapse mortality compared with the general population. The recognition of late-occurring events paired with the decades of life remaining for children cured of HL have made paramount the need to develop effective treatments that minimize the risk of late toxicity. Toward this goal, multiple, dose-intense, risk- and response-based regimens that use lower cumulative doses of chemotherapy and radiation have been developed. Appropriate frontline treatment selection requires a level of familiarity with the efficacy, acute toxicity, convenience, and late effects of treatments that may be impractical for providers who infrequently treat children with HL. There is an increasing need for guideline developers to begin to merge considerations from both frontline treatment and survivorship guidelines into practical documents that integrate potential long-term health risks. Herein, we take the first steps toward doing so by aligning cumulative treatment exposures, anticipated risks of late toxicity, and suggested surveillance recommendations for NCCN-endorsed Pediatric HL Guidelines. Future studies that integrate simulation modeling will strengthen this integrated approach and allow for opportunities to incorporate regimen-specific risks, health-related quality of life, and cost-effectiveness into decision tools to optimize HL therapy.
Matthew J. Ehrhardt, Jamie E. Flerlage, Saro H. Armenian, Sharon M. Castellino, David C. Hodgson, and Melissa M. Hudson
Jamie E. Flerlage, Susan M. Hiniker, Saro Armenian, Ellen C. Benya, Adam J. Bobbey, Vivian Chang, Stacy Cooper, Don W. Coulter, Branko Cuglievan, Bradford S. Hoppe, Leidy Isenalumhe, Kara Kelly, Leslie Kersun, Adam J. Lamble, Nicole A. Larrier, Jeffrey Magee, Kwadwo Oduro, Martha Pacheco, Anita P. Price, Kenneth B. Roberts, Christine M. Smith, Aliyah R. Sohani, Erin M. Trovillion, Emily Walling, Ana C. Xavier, Jennifer L. Burns, and Mallory Campbell
Hodgkin lymphoma (HL) is a highly curable form of cancer, and current treatment regimens are focused on improving treatment efficacy while decreasing the risk of late effects of treatment. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for pediatric HL provide recommendations on the workup, diagnostic evaluation, and treatment of classic HL, including principles of pathology, imaging, staging, systemic therapy, and radiation therapy. This portion of the NCCN Guidelines focuses on the management of pediatric classic HL in the upfront and relapsed/refractory settings.
Chongkai Wang and Marwan Fakih
Dual HER2-targeted therapy has been associated with clinical responses and prolonged progression-free survival and overall survival in RAS-wild type HER2-amplified colorectal cancer (CRC). However, no clinical benefits have been reported in patients with CRC with HER2 mutations. Activated HER2 mutations have been largely deemed resistant to trastuzumab and to dual HER2 targeting. This report describes a patient with metastatic CRC with concurrent HER2 amplification and a HER2 S310F mutation, which is an active mutation located in the extracellular dimerization domain of HER2. Treatment with trastuzumab + lapatinib resulted in an excellent response that lasted for 10 months. Upon disease progression, treatment with the antibody–drug conjugate trastuzumab–deruxtecan resulted in a short-lived response. This is the first case report of successful HER2 targeting in metastatic CRC with concurrent HER2 amplification and a HER2 S310F mutation.
Featured Updates to the NCCN Guidelines
Amye Tevaarwerk, Crystal S. Denlinger, Tara Sanft, Shannon M. Ansbaugh, Saro Armenian, K. Scott Baker, Gregory Broderick, Andrew Day, Wendy Demark-Wahnefried, Kristin Dickinson, Debra L. Friedman, Patricia Ganz, Mindy Goldman, Norah Lynn Henry, Christine Hill-Kayser, Melissa Hudson, Nazanin Khakpour, Divya Koura, Allison L. McDonough, Michelle Melisko, Kathi Mooney, Halle C.F. Moore, Natalie Moryl, Javid J. Moslehi, Tracey O’Connor, Linda Overholser, Electra D. Paskett, Chirayu Patel, Lindsay Peterson, William Pirl, M. Alma Rodriguez, Kathryn J. Ruddy, Lidia Schapira, Lillie Shockney, Sophia Smith, Karen L. Syrjala, Phyllis Zee, Nicole R. McMillian, and Deborah A. Freedman-Cass
The NCCN Guidelines for Survivorship are intended to help healthcare professionals working with cancer survivors to ensure that each survivor’s complex and varied needs are addressed. The Guidelines provide screening, evaluation, and treatment recommendations for consequences of adult-onset cancer and its treatment; recommendations to help promote healthful lifestyle behaviors, weight management, and immunizations in survivors; and a framework for care coordination. This article summarizes the recommendations regarding employment and return to work for cancer survivors that were added in the 2021 version of the NCCN Guidelines.
Nathan J. Moore, Megan Othus, Anna B. Halpern, Nicholas P. Howard, Linyi Tang, Kyle E. Bastys, Mary-Elizabeth M. Percival, Paul C. Hendrie, Garrett A. Hartley, Verna L. Welch, Elihu H. Estey, and Roland B. Walter
Background: Early hospital discharge (EHD) after intensive acute myeloid leukemia (AML) induction chemotherapy has become routine at the University of Washington/Seattle Cancer Care Alliance over the past several years. We assessed the financial implications of EHD over the first 4 years after its broad adoption for patients with AML and other high-grade myeloid neoplasms undergoing AML-like induction chemotherapy. Patients and Methods: We retrospectively compared charges between 189 patients with EHD who received all postinduction inpatient/outpatient care within our care system between August 2014 and July 2018 and 139 medically matched control patients who remained hospitalized for logistical reasons. Charges from the day of initial discharge (patients with EHD) or end of chemotherapy (control patients) until blood count recovery, additional chemotherapy or care transition, hospital discharge (for control patients only), an elapse of 42 days, or death were extracted from financial databases and separated into categories: facility/provider, emergency department, transfusions, laboratory, imaging, pharmacy, and miscellaneous. Results: Combined charges averaged $4,157/day (range, $905–$13,119/day) for patients with EHD versus $9,248/day (range, $4,363–$48,522/day) for control patients (P<.001). The EHD cohort had lower mean facility/provider, transfusion, laboratory, and pharmacy charges but not imaging or miscellaneous charges. During readmissions, there was no statistically significant difference in daily inpatient charges between the EHD and control cohorts. After multivariable adjustment, average charges were $3,837/day lower for patients with EHD (P<.001). Conclusions: Together with previous data from our center showing that EHD is safe and associated with reduced healthcare resource utilization, this study further supports this care approach for AML and other high-grade myeloid neoplasms if infrastructure is available to enable close outpatient follow-up.
Naomi R.M. Schwartz, Lynn M. Matrisian, Eva E. Shrader, Ziding Feng, Suresh Chari, and Joshua A. Roth
Background: There are no established methods for pancreatic cancer (PAC) screening, but the NCI and the Pancreatic Cancer Action Network (PanCAN) are investigating risk-based screening strategies in patients with new-onset diabetes (NOD), a group with elevated PAC risk. Preliminary estimates of the cost-effectiveness of these strategies can provide insights about potential value and inform supplemental data collection. Using data from the Enriching New-Onset Diabetes for Pancreatic Cancer (END-PAC) risk model validation study, we assessed the potential value of CT screening for PAC in those determined to be at elevated risk, as is being done in a planned PanCAN Early Detection Initiative trial. Methods: We created an integrated decision tree and Markov state-transition model to assess the cost-effectiveness of PAC screening in patients aged ≥50 years with NOD using CT imaging versus no screening. PAC prevalence, sensitivity, and specificity were derived from the END-PAC validation study. PAC stage distribution in the no-screening strategy and PAC survival were derived from the SEER program. Background mortality for patients with diabetes, screening and cancer care expenditure, and health state utilities were derived from the literature. Life-years (LYs), quality-adjusted LYs (QALYs), and costs were tracked over a lifetime horizon and discounted at 3% per year. Results are presented in 2020 US dollars, and we took a limited US healthcare perspective. Results: In the base case, screening resulted in 0.0055 more LYs, 0.0045 more QALYs, and $293 in additional expenditures for a cost per QALY gained of $65,076. In probabilistic analyses, screening resulted in a cost per QALY gained of <$50,000 and <$100,000 in 34% and 99% of simulations, respectively. In the threshold analysis, >25% of screen-detected PAC cases needed to be resectable for the cost per QALY gained with screening to be <$100,000. Conclusions: We found that risk-based PAC screening in patients with NOD is likely to be cost-effective in the United States if even a modest fraction (>25%) of screen-detected patients with PAC are resectable. Future studies should reassess the value of this intervention once clinical trial data become available.
Cynthia Villarreal-Garza, Fernanda Mesa-Chavez, Alejandra Plata de la Mora, Melina Miaja-Avila, Marisol Garcia-Garcia, Alan Fonseca, Sylvia de la Rosa-Pacheco, Marlid Cruz-Ramos, Manuel Rolando García Garza, Alejandro Mohar, and Enrique Bargallo-Rocha
Background: Despite the risk of treatment-related infertility, implementation of fertility-preservation (FP) strategies among young patients with breast cancer is often suboptimal in resource-constrained settings such as Mexico. The “Joven & Fuerte: Program for Young Women With Breast Cancer” strives to enhance patient access to supportive care services, including FP measures through alliances with assisted-reproduction units and procurement of coverage of some of these strategies. This study describes patients from Joven & Fuerte who have preserved fertility, and assesses which characteristics were associated with the likelihood of undergoing FP. Methods: Women aged ≤40 years with recently diagnosed breast cancer were prospectively accrued. Sociodemographic and clinicopathologic data were collected from patient-reported and provider-recorded information at diagnosis and 1-year follow-up. Descriptive statistics, chi-square test, and simple logistic regression were used to compare patients who preserved fertility with those who did not. Results: In total, 447 patients were included, among which 53 (12%) preserved fertility, representing 38% of the 140 women who desired future biologic children. Oocyte/embryo cryopreservation was the most frequently used method for FP (59%), followed by temporary ovarian suppression with gonadotropin-releasing hormone agonists (GnRHa) during chemotherapy (26%), and use of both GnRHa and oocyte/embryo cryopreservation (15%). Younger age, higher educational level, being employed, having private healthcare insurance, and having one or no children were associated with a significantly higher likelihood of preserving fertility. Conclusions: By facilitating referral and seeking funds and special discounts for underserved patients, supportive care programs for young women with breast cancer can play a crucial role on enhancing access to oncofertility services that would otherwise be prohibitive because of their high costs, particularly in resource-constrained settings. For these efforts to be successful and widely applied in the long term, sustained and extended governmental coverage of FP options for this young group is warranted.
Changyu Shen, Enrico G. Ferro, Huiping Xu, Daniel B. Kramer, Rushad Patell, and Dhruv S. Kazi
Background: Statistical testing in phase III clinical trials is subject to chance errors, which can lead to false conclusions with substantial clinical and economic consequences for patients and society. Methods: We collected summary data for the primary endpoints of overall survival (OS) and progression-related survival (PRS) (eg, time to other type of event) for industry-sponsored, randomized, phase III superiority oncology trials from 2008 through 2017. Using an empirical Bayes methodology, we estimated the number of false-positive and false-negative errors in these trials and the errors under alternative P value thresholds and/or sample sizes. Results: We analyzed 187 OS and 216 PRS endpoints from 362 trials. Among 56 OS endpoints that achieved statistical significance, the true efficacy of experimental therapies failed to reach the projected effect size in 33 cases (58.4% false-positives). Among 131 OS endpoints that did not achieve statistical significance, the true efficacy of experimental therapies reached the projected effect size in 1 case (0.9% false-negatives). For PRS endpoints, there were 34 (24.5%) false-positives and 3 (4.2%) false-negatives. Applying an alternative P value threshold and/or sample size could reduce false-positive errors and slightly increase false-negative errors. Conclusions: Current statistical approaches detect almost all truly effective oncologic therapies studied in phase III trials, but they generate many false-positives. Adjusting testing procedures in phase III trials is numerically favorable but practically infeasible. The root of the problem is the large number of ineffective therapies being studied in phase III trials. Innovative strategies are needed to efficiently identify which new therapies merit phase III testing.