The KEYNOTE-522 study is a practice-changing phase III randomized study that demonstrated that the addition of pembrolizumab to polychemotherapy improves outcomes in patients with high-risk early-stage triple-negative breast cancer (TNBC). This regimen is highly efficacious with unprecedented pathologic complete response (pCR) rates, and clinically meaningful improvements in event-free survival (EFS). However, the combination is also associated with significant high-grade treatment-related toxicity. The backbone regimen deviated from common practice, including the addition of carboplatin, lack of dose dense anthracyclines, and adjuvant capecitabine for residual disease, thus brining important questions regarding real-world translation of these results. This brief report practically addresses some of the most relevant questions physicians and patients face in optimizing care using the best available evidence.
Cesar A. Santa-Maria, Maureen O’Donnell, Raquel Nunes, Jean L. Wright, and Vered Stearns
Featured Updates to the NCCN Guidelines
Douglas E. Wood, Ella A. Kazerooni, Denise Aberle, Abigail Berman, Lisa M. Brown, Georgie A. Eapen, David S. Ettinger, J. Scott Ferguson, Lifang Hou, Dipen Kadaria, Donald Klippenstein, Rohit Kumar, Rudy P. Lackner, Lorriana E. Leard, Inga T. Lennes, Ann N.C. Leung, Peter Mazzone, Robert E. Merritt, David E. Midthun, Mark Onaitis, Sudhakar Pipavath, Christie Pratt, Varun Puri, Dan Raz, Chakravarthy Reddy, Mary E. Reid, Kim L. Sandler, Jacob Sands, Matthew B. Schabath, Jamie L. Studts, Lynn Tanoue, Betty C. Tong, William D. Travis, Benjamin Wei, Kenneth Westover, Stephen C. Yang, Beth McCullough, and Miranda Hughes
The NCCN Guidelines for Lung Cancer Screening recommend criteria for selecting individuals for screening and provide recommendations for evaluation and follow-up of lung nodules found during initial and subsequent screening. These NCCN Guidelines Insights focus on recent updates to the NCCN Guidelines for Lung Cancer Screening.
Quisette P. Janssen, Jacob L. van Dam, Laura R. Prakash, Deesje Doppenberg, Christopher H. Crane, Casper H.J. van Eijck, Susannah G. Ellsworth, William R. Jarnagin, Eileen M. O’Reilly, Alessandro Paniccia, Marsha Reyngold, Marc G. Besselink, Matthew H.G. Katz, Ching-Wei D. Tzeng, Amer H. Zureikat, Bas Groot Koerkamp, Alice C. Wei, and for the Trans-Atlantic Pancreatic Surgery (TAPS) Consortium
Background: The value of neoadjuvant radiotherapy (RT) after 5-fluorouracil with leucovorin, oxaliplatin, and irinotecan, with or without dose modifications [(m)FOLFIRINOX], for patients with borderline resectable (BR) pancreatic ductal adenocarcinoma (PDAC) is uncertain. Methods: We conducted an international retrospective cohort study including consecutive patients with BR PDAC who received (m)FOLFIRINOX as initial treatment (2012–2019) from the Trans-Atlantic Pancreatic Surgery Consortium. Because the decision to administer RT is made after chemotherapy, patients with metastases or deterioration after (m)FOLFIRINOX or a performance score ≥2 were excluded. Patients who received RT after (m)FOLFIRINOX were matched 1:1 by nearest neighbor propensity scores with patients who did not receive RT. Propensity scores were calculated using sex, age (≤70 vs >70 years), WHO performance score (0 vs 1), tumor size (0–20 vs 21–40 vs >40 mm), tumor location (head/uncinate vs body/tail), number of cycles (1–4 vs 5–8 vs >8), and baseline CA 19-9 level (≤500 vs >500 U/mL). Primary outcome was overall survival (OS) from diagnosis. Results: Of 531 patients who received neoadjuvant (m)FOLFIRINOX for BR PDAC, 424 met inclusion criteria and 300 (70.8%) were propensity score–matched. After matching, median OS was 26.2 months (95% CI, 24.0–38.4) with RT versus 32.8 months (95% CI, 25.3–42.0) without RT (P=.71). RT was associated with a lower resection rate (55.3% vs 72.7%; P=.002). In patients who underwent a resection, RT was associated with a comparable margin-negative resection rate (>1 mm) (70.6% vs 64.8%; P=.51), more node-negative disease (57.3% vs 37.6%; P=.01), and more major pathologic response with <5% tumor viability (24.7% vs 8.3%; P=.006). The OS associated with conventional and stereotactic body RT approaches was similar (median OS, 25.7 vs 26.0 months; P=.92). Conclusions: In patients with BR PDAC, neoadjuvant RT following (m)FOLFIRINOX was associated with more node-negative disease and better pathologic response in patients who underwent resection, yet no difference in OS was found. Routine use of RT cannot be recommended based on these data.
Yujiao Sun, Adam Hendrix, Benyam Muluneh, and Sachiko Ozawa
Background: Since prices of imatinib (Gleevec) remain high, patients on oral chemotherapy are looking for alternative methods to access this life-saving medication. We assessed the accessibility of imatinib through online pharmacies and analyzed each website for medication safety, price, and marketing tactics. Methods: We searched the term “buy imatinib online” using 4 commonly used internet search engines (Google, Bing, Yahoo!, and DuckDuckGo) and screened web pages displayed in the first 10 pages. Websites were included if they were published in English, sold imatinib, were free to access, and offered shipping in the United States. Websites were classified using LegitScript’s categorization as “certified,” “unclassified,” “unapproved,” or “rogue.” We analyzed information on websites’ patient safety characteristics, marketing techniques, pricing, domain registration information, and IP addresses. Results: Of the 44 online pharmacies identified, only 3 (7%) were certified, and the remainder were classified as rogue (52%; n=23), unapproved (30%; n=13), or unclassified (11%; n=5). Thirteen online pharmacies (30%; 9 rogue, 4 unclassified) sold imatinib without a prescription. Nearly one-quarter (n=10) of online pharmacies selling imatinib did not include drug-related warnings on their websites, and nearly half (n=21) did not limit the purchasable quantity. More than three-quarters (n=34) of online pharmacies selling imatinib did not offer pharmacist consultations, even though nearly all websites extended offers to speak with sales associates (91%; n=40). Most online pharmacies selling imatinib claimed price discounts (95%; n=42), but fewer provided bulk discounts (23%; n=10) or coupons (34%; n=15). One-third of rogue pharmacies selling imatinib (n=7) claimed to be registered or accredited on their websites. Conclusions: The lack of safety measures taken by illegitimate online pharmacies endangers patient safety because they allow patients to purchase imatinib without appropriate evaluation for response, drug interactions, and adverse effects. Healthcare providers need to be aware of this practice and should assure patient access to imatinib through safe and legitimate pharmacies.
Matthew Perez, Caitlin C. Murphy, Sandi L. Pruitt, Sawsan Rashdan, Asal Rahimi, and David E. Gerber
Background: Many individuals with cancer have survived a prior cancer and for this reason may have been excluded from clinical trials. Recent NCI guidance recommends including these individuals, especially when the risk of the prior malignancy interfering with either safety or efficacy endpoints is very low. Using breast cancer as an example, we determined the potential effect this policy change may have on clinical trial accrual. Patients and Methods: We reviewed protocols of NCI-sponsored breast cancer clinical trials activated in 1991 through 2016. We quantified prevalence of prior cancer-related exclusion criteria and assessed the association with trial characteristics using Fisher’s exact tests. Using SEER data, we estimated the prevalence and timing of prior primary (nonbreast) cancer diagnoses among patients with breast cancer. Results: Among 87 clinical trials (total target enrollment, 137,253 patients), 77% excluded individuals with prior cancer, most commonly (79%) within the preceding 5 years. Among trials with radiographic response or toxicity endpoints, 69% excluded prior cancer. In SEER data, the prevalence of a prior (nonbreast) cancer diagnosis ranged from 5.7% to 7.7%, depending on breast cancer stage, of which 39% occurred within 5 years of the incident breast cancer. For trials excluding prior cancer, the estimated proportion of patients excluded for this reason ranged from 1.3% to 5.8%, with the estimated number of excluded patients ranging from 1 to 288. Conclusions: More than three-fourths of NCI-sponsored breast cancer clinical trials exclude patients with prior cancer, including almost 70% of trials with response or toxicity endpoints. Given that >5% of patients with breast cancer have a history of prior cancer, in large phase III trials this practice may exclude hundreds of patients. Following recent NCI eligibility guidance, the inclusion of patients with prior cancer on breast cancer trials may have a meaningful impact on accrual.
Neil J. Shah, Michael R. Cook, Tianmin Wu, Shaked Lev-Ari, Matthew J. Blackburn, Michael T. Serzan, Adil Alaoui, Jaeil Ahn, and Michael B. Atkins
Background: Immune-related adverse events (irAEs) often require treatment with high-dose systemic steroids (SS) and other immunosuppressive agents (ISAs). NCCN Guidelines recommend prophylactic antibiotics for Pneumocystis jirovecii pneumonia (PJP) for patients receiving prolonged SS/ISAs. However, there is a paucity of evidence regarding the incidence of opportunistic infections (OIs) and non-OIs and the role of prophylactic antibiotics in patients on SS/ISAs for irAEs. Methods: A retrospective analysis was conducted of patients treated using immune checkpoint inhibitor (ICI) therapy at 5 MedStar Health hospitals from January 2011 to April 2018. OIs were defined per the Infectious Diseases Society of America guidelines for the prevention and treatment of OIs in patients with HIV. The study cohort included patients who received ≥20 mg daily of a prednisone equivalent for ≥4 weeks to manage irAEs. Results: The study cohort identified 112 (15%) of 758 total patients treated using ICIs. Baseline characteristics included the following: median age was 64 years, 74% (n=82) of patients were White, 89% (n=100) had an ECOG performance status ≤1, 61% (n=68) had melanoma, 19% (n=21) had non–small cell lung cancer, 45% (n=50) were treated using an anti–PD-(L)1 ICI, and 33% (n=37) were treated using an anti–PD-1/anti–CTLA-4 combination. The median starting SS dose was 100 mg of a prednisone equivalent, and 25% of patients required additional ISAs, with infliximab (n=15) and mycophenolate mofetil (n=9) being the most common. We found that 20% (n=22) of patients developed any infection, including 7% (n=8) with OIs (oral candidiasis [n=4], nondisseminated varicella zoster infection [n=2], PJP [n=1], and Listeria monocytogenes endophthalmitis [n=1]) and 13% (n=14) with non-OIs (most common: Clostridium difficile and pneumonia [n=5 each]). PJP prophylaxis with sulfamethoxazole/trimethoprim was given to 13% (n=14) patients, of whom 43% (n=6) developed OIs/non-OIs. Conclusions: Our study highlights the fundamental issues for patients on ICI therapy who require SS/ISAs for irAEs: the degree of immunosuppression and the relative risk of OI. We noted a low incidence of OIs overall and breakthrough infections despite PJP prophylaxis. We question whether PJP prophylaxis is efficacious or necessary. Prospective trials are required to answer these questions.
Lauren B. Banks and Sandra P. D’Angelo
Soft tissue sarcomas (STS) are a subset of sarcoma, a rare group of heterogeneous malignancies of mesenchymal origin. Current standard of care involves surgical resection with systemic chemotherapy used to treat high-risk localized and metastatic disease. Though classically thought to be immunologically quiet tumors, STS interact with the immune system, undergoing immunoediting that alters tumor immunogenicity and the tumor microenvironment. Recent advances with immune checkpoint inhibition have led to clinical trials exploring the efficacy of immunotherapy in treating STS. Results from these trials point to histologic subtype–specific clinical activity of immune checkpoint blockade. In addition, combinatorial strategies adding immune checkpoint inhibition to local or systemic therapies for STS have further increased their efficacy. Targeted immunotherapies using engineered T-cell receptor–based approaches also show increasing promise as treatment options for some patients with STS. Adoptive transfer of autologous T cells targeting NY-ESO-1 and MAGE-A4 have high response rates in sarcomas expressing these antigens, although recurrence is often seen in responding patients. Future work must focus on identifying primary and acquired mechanisms of resistance to these therapies, and extend T-cell receptor discovery to other tumor-associated antigens.
Kilian E. Salerno and Elizabeth H. Baldini
Retroperitoneal sarcoma comprises a small subset of all soft tissue sarcoma and includes various histopathologic subtypes, each with unique patterns of behavior and differential risks for local recurrence and hematogenous metastatic spread. The primary treatment modality is surgery, although even with complete macroscopic resection, recurrence is common. The rationale for the addition of radiotherapy to resection is to improve local control; however, the use of radiation therapy for retroperitoneal sarcoma is controversial, and existing data are suboptimal to guide management. Treatment decisions should be determined with multidisciplinary input and shared decision-making. When used in selected patients, radiation therapy should be delivered preoperatively; postoperative treatment is not recommended.
Margaret von Mehren, John M. Kane, Mark Agulnik, Marilyn M. Bui, Janai Carr-Ascher, Edwin Choy, Mary Connelly, Sarah Dry, Kristen N. Ganjoo, Ricardo J. Gonzalez, Ashley Holder, Jade Homsi, Vicki Keedy, Ciara M. Kelly, Edward Kim, David Liebner, Martin McCarter, Sean V. McGarry, Nathan W. Mesko, Christian Meyer, Alberto S. Pappo, Amanda M. Parkes, Ivy A. Petersen, Seth M. Pollack, Matthew Poppe, Richard F. Riedel, Scott Schuetze, Jacob Shabason, Jason K. Sicklick, Matthew B. Spraker, Melissa Zimel, Lisa E. Hang, Hema Sundar, and Mary Anne Bergman
Soft tissue sarcomas (STS) are rare malignancies of mesenchymal cell origin that display a heterogenous mix of clinical and pathologic characteristics. STS can develop from fat, muscle, nerves, blood vessels, and other connective tissues. The evaluation and treatment of patients with STS requires a multidisciplinary team with demonstrated expertise in the management of these tumors. The complete NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Soft Tissue Sarcoma provide recommendations for the diagnosis, evaluation, and treatment of extremity/superficial trunk/head and neck STS, as well as retroperitoneal/intra-abdominal STS, desmoid tumors, and rhabdomyosarcoma. This portion of the NCCN Guidelines discusses general principles for the diagnosis and treatment of retroperitoneal/intra-abdominal STS, outlines treatment recommendations, and reviews the evidence to support the guidelines recommendations.