Cancer prevention, screening, and early detection play an integral role in cancer incidence and outcomes. It is estimated that 30% to 50% of cancers worldwide are preventable, and it is well established that early detection of many cancers is associated with improved treatment outcomes. A recent NCCN Policy Summit: Reducing the Cancer Burden Through Prevention and Early Detection brought together healthcare providers, payers, policymakers, patient advocates, industry representatives, and technology representatives to explore challenges, triumphs, and outstanding questions surrounding current practices. Keynotes were delivered by Dr. Lisa Richardson, Director of the Division of Cancer Prevention and Control within the CDC, and Dr. Danielle Carnival, White House Cancer Moonshot Coordinator. Dr. Richardson focused on the field of public health, translating its utility in preventing and diagnosing cancer in the United States, while Dr. Carnival discussed ambitious goals by the Cancer Moonshot in reducing the cancer burden. Panelists highlighted characteristics of high-impact prevention and early detection programs, including how genetic testing has impacted this space. Existing programs are often challenged due to limitations in data, as well as financial, structural, and social barriers to motivating individuals to act on recommendations. Despite these barriers, we can learn from highly successful programs and should apply proven attributes, such as community engagement, more broadly.
NCCN Policy Summit: Reducing the Cancer Burden Through Prevention and Early Detection
Lindsey Bandini, Alyssa Schatz, Victoria Hood, Nikia Clark, Michael J. Hall, and Robert W. Carlson
Principles of Surgical Management of Peritoneal Mesothelioma
Jessica A. Steadman and Travis E. Grotz
Malignant peritoneal mesothelioma (MPeM) is a rare malignancy and represents 5% to 30% of malignant mesothelioma cases. The primary curative therapy for MPeM is radical cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC), with the strongest predictor of long-term survival being complete cytoreduction. There is a paucity of high-quality evidence available to guide management in MPeM; however, NCCN Guidelines for the management of MPeM were updated this year. In well-selected patients, 5-year overall survival exceeds 65%, but achieving optimal results requires careful preoperative evaluation and expert surgical management. Preoperative patient selection includes histology review and staging with cross-sectional imaging. Ideal candidates for curative intent surgery are those with epithelioid MPeM, a low peritoneal cancer index, and a good performance status. Contraindications to curative intent surgery include the sarcomatoid MPeM, distant metastases, extensive nodal metastases, and extensive small bowel serosal or mesentery involvement not amenable to complete cytoreduction. Those with biphasic histology, bicavitary disease, and metastatic lymphadenopathy may be considered for surgery following response to neoadjuvant therapy. CRS involves resection of all peritoneal disease, the extent of which varies case by case. Key aspects involve careful evaluation of all peritoneal surfaces, complete parietal peritonectomy and omentectomy, and evaluating suspicious abdominal lymph node basins. Once maximum cytoreduction is achieved, HIPEC is performed using a platinum-based perfusate. Postoperative protocols are recommended to optimize recovery and mitigate HIPEC-specific complications, namely chemotherapy-mediated nephrotoxicity and bone marrow suppression.
Real-World Impact of Prophylactic Growth Factor Use on Timing of Febrile Neutropenia and Infection After High-Risk Chemotherapy
Douglas W. Blayney, Nicole M. Kuderer, Alice Kate Cummings Joyner, John Jarvis, Dominic Nunag, Jasmine Wells, Lan Huang, Ramon Monhanlal, and Gary H. Lyman
Background: Prophylactic growth-factor therapy with granulocyte colony-stimulating factor (G-CSF) reduces the risk of febrile neutropenia (FN) in patients with breast cancer initiating myelosuppressive chemotherapy. However, little is known about the protective benefit early in the chemotherapy cycle. Methods: To assess the relationship between G-CSF prophylaxis and incidence of FN/infection in week 1 versus beyond week 1 of the first chemotherapy cycle, a retrospective study was conducted using Medicare claims from 2005 through 2020 among patients with breast cancer initiating high-risk chemotherapy. Two cohorts were compared based on G-CSF prophylaxis within 3 days following chemotherapy initiation. The primary outcome was FN or infection, defined as hospitalization with neutropenia, fever, or infection diagnosis. Secondary outcomes were a stricter definition of FN and infection-related hospitalization. Unadjusted and regression-adjusted proportions of patients experiencing each outcome during week 1 versus beyond week 1 of the first chemotherapy cycle were compared. Results: Of 78,810 patients meeting all inclusion criteria (>98% female; mean age, 69 years), 79% initiated TC (docetaxel/cyclophosphamide), 14% TCH (docetaxel/carboplatin/trastuzumab), and 7% TAC (docetaxel/doxorubicin/cyclophosphamide). Among patients receiving G-CSF (74%), incidence of first-cycle FN/infection was lower compared with patients not receiving G-CSF (overall, 6% vs 13%; TAC, 12% vs 19%; TC, 6% vs 12%; TCH, 5% vs 15%). However, patients who received G-CSF were generally more likely to experience FN/infection in week 1 (adjusted odds ratio [aOR], 1.24 for all; 1.73 for TAC; 1.35 for TC; and 0.76 for TCH). Results were similar for strictly defined FN (overall aOR, 1.29 for week 1 and 0.12 for beyond week 1) and infection-related hospitalization (overall aOR, 1.33 for week 1 and 0.27 for beyond week 1). Conclusions: Overall, the rates of chemotherapy-related FN and infection in week 1 of the first chemotherapy cycle are similar for patients receiving and not receiving G-CSF, suggesting continued risk in week 1 despite prophylactic G-CSF.
Rechallenge With Switching Immune Checkpoint Inhibitors Following Autoimmune Myocarditis in a Patient With Lynch Syndrome
Cody Eslinger, Daniel Walden, Timothy Barry, Shimoli Shah, Niloy Jewel Samadder, and Tanios S. Bekaii-Saab
Immune checkpoint inhibitors (ICIs) induce profound benefits in cancer patients with mismatch repair gene mutations or high levels of microsatellite instability. Herein, we present a case of a patient with history of Muir-Torre/Lynch syndrome and metastatic gastric adenocarcinoma in the presence of an MSH2 gene mutation. The patient was initially treated with a PD-1 inhibitor, pembrolizumab, but developed grade 4 myocarditis requiring treatment with infliximab and a prolonged steroid taper. Following discontinuation of pembrolizumab, surveillance testing showed no radiographic or endoscopic evidence of progression for 7 months, until biopsy results from a repeat upper endoscopy indicated local disease recurrence. The patient was subsequently rechallenged with another PD-1 inhibitor, nivolumab, at a 50% dose reduction without recurrent adverse events and eventually achieved a complete response after 13 cycles. This case highlights the relative importance of considering careful rechallenge with ICI therapy in patients with microsatellite instability–high malignancies and a high risk of severe adverse events.
Treatment and Survival Among Patients With Colorectal Cancer in Sub-Saharan Africa: A Multicentric Population-Based Follow-Up Study
Lucia Hämmerl, Nikolaus C.S. Mezger, Tobias P. Seraphin, Walburga Yvonne Joko-Fru, Mirko Griesel, Jana Feuchtner, Franck Gnahatin, Freddy Houéhanou Rodrigue Gnangnon, Nathan Okerosi, Phoebe Mary Amulen, Rolf Hansen, Margaret Ziona Borok, Carla Carrilho, Brahima Mallé, Clausina Ahoui Apendi, Nathan G. Buziba, Edom Seife, Biying Liu, Rafael Mikolajczyk, Donald M. Parkin, Eva J. Kantelhardt, and Ahmedin Jemal
Background: The burden of colorectal cancer (CRC) is increasing in Sub-Saharan Africa (SSA). However, little is known about CRC treatment and survival in the region. Methods: A random sample of 653 patients with CRC diagnosed from 2011 to 2015 was obtained from 11 population-based cancer registries in SSA. Information on clinical characteristics, treatment, and/or vital status was obtained from medical records in treating hospitals for 356 (54%) of the patients (“traced cohort”). Concordance of CRC treatment with NCCN Harmonized Guidelines for SSA was assessed. A Cox proportional hazards model was used to examine the association between survival and human development index (HDI). Results: Of the 356 traced patients with CRC, 51.7% were male, 52.8% were from countries with a low HDI, 55.1% had colon cancer, and 73.6% were diagnosed with nonmetastatic (M0) disease. Among the patients with M0 disease, however, only 3.1% received guideline-concordant treatment, 20.6% received treatment with minor deviations, 31.7% received treatment with major deviations, and 35.1% received no treatment. The risk of death in patients who received no cancer-directed therapy was 3.49 (95% CI, 1.83–6.66) times higher than in patients who received standard treatment or treatment with minor deviations. Similarly, the risk of death in patients from countries with a low HDI was 1.67 (95% CI, 1.07–2.62) times higher than in those from countries with a medium HDI. Overall survival at 1 and 3 years was 70.9% (95% CI, 65.5%–76.3%) and 45.3% (95% CI, 38.9%–51.7%), respectively. Conclusions: Fewer than 1 in 20 patients diagnosed with potentially curable CRC received standard of care in SSA, reinforcing the need to improve healthcare infrastructure, including the oncology and surgical workforce.
Understanding Cancer Risk—Genes Matter!
BRAF/MEK Inhibition as a Bridge to Immunotherapy for Symptomatic BRAF V600 Melanoma Brain Metastases: A Case Series
Jacob Strelnikov, Alice Zhou, Omar Butt, Michael Ansstas, and George Ansstas
Targeted and immune therapies have changed the paradigm of treatment for patients with metastatic melanoma. Treatment of patients with symptomatic melanoma brain metastases, however, is complicated by the frequent use of immune suppression for the management of vasogenic edema and the urgency in addressing disease burden. Use of BRAF/MEK inhibitors in patients with a corresponding BRAF V600 mutation often results in rapid response but is hindered by high rates of disease relapse and progression. Immunotherapy has higher durability of response, but the rate of response is slower and responses can be significantly diminished for patients on concurrent steroid therapy. Considering this gap in evidence-based guidance for optimal adjuvant therapy sequence in immunosuppressed patients with BRAF V600–mutant melanoma brain metastases, we report on 4 cases utilizing BRAF/MEK inhibitors as a bridging therapy for brain metastases management before initiation of immune checkpoint inhibitor therapy. Future prospective studies will be required to determine the optimal treatment sequencing for patients in this population with high unmet medical need.
Hormone Receptor–Positive Breast Cancer Sensitive to Pembrolizumab: Evidence of the Pathogenicity of the MLH1 Variant 1835del3
Henry G. Kaplan, Jeffrey R. Whiteaker, Brianna Nelson, Richard G. Ivey, Travis D. Lorentzen, Uliana Voytovich, Lei Zhao, David J. Corwin, Robert Resta, and Amanda G. Paulovich
A woman with estrogen/progesterone receptor–positive, ERBB2-negative metastatic breast cancer developed progressive disease despite treatment with multiple hormonal and chemotherapeutic modalities. She carried a germline variant of MLH1 (1835del3), also known as c.1835_1837del and v612del, the pathogenicity of which has not been conclusively determined. MLH1 staining was not seen on immunohistochemical staining of her tumor tissue. The patient experienced a >5-year dramatic response to 4 doses of pembrolizumab. Family studies revealed multiple other relatives with the MLH1 1835del3 variant, as well as multiple relatives with colon cancer. The one relative with colon cancer who underwent genetic testing demonstrated the same variant. Laboratory studies revealed that the patient’s tumor showed loss of heterozygosity (LOH) in the MLH1 region, high levels of microsatellite instability, and a high tumor mutational burden. LOH in the MLH1 region, along with the remarkable clinical response to pembrolizumab treatment and the presence of the same MLH1 variant in affected relatives, supports the hypothesis that the MLH1 1835del3 variant is pathogenic. Given the patient’s family history, this likely represents an uncommon presentation of Lynch syndrome. Physicians should be alert to evaluate patients for targetable genetic variants even in unlikely clinical situations such as the one described here.
Molecular Classification Improves Therapeutic Options for Infants and Young Children With Medulloblastoma
Aditi Bagchi, Sandeep K. Dhanda, Paige Dunphy, Edgar Sioson, and Giles W. Robinson
Medulloblastoma in infants and young children is a major challenge to treat because craniospinal irradiation (CSI), a cornerstone of therapy for older children, is disproportionately damaging to very young children. As a result, trials have attempted to delay, omit, and replace this therapy. Although success has been limited, the approach has not been a complete failure. In fact, this approach has cured a significant number of children with medulloblastoma. However, many children have endured intensive regimens of chemotherapy only to experience relapse and undergo salvage treatment with CSI, often at higher doses and with worse morbidity than they would have initially experienced. Recent advancements in molecular diagnostics have proven that response to therapy is biologically driven. Medulloblastoma in infants and young children is divided into 2 molecular groups: Sonic Hedgehog (SHH) and group 3 (G3). Both are chemotherapy-sensitive, but only the SHH medulloblastomas are reliably cured with chemotherapy alone. Moreover, SHH can be molecularly parsed into 2 groups: SHH-1 and SHH-2, with SHH-2 showing higher cure rates with less intensive chemotherapy and SHH-1 requiring more intensive regimens. G3 medulloblastoma, on the other hand, has a near universal relapse rate after chemotherapy-only regimens. This predictability represents a significant breakthrough and affords oncologists the ability to properly risk-stratify therapy in such a way that the most curative and least toxic therapy is selected. This review examines the treatment of medulloblastoma in infants and young children, discusses the molecular advancements, and proposes how to use this information to structure the future management of this disease.