Colon Cancer, Version 3.2024, NCCN Clinical Practice Guidelines in Oncology.

Colorectal cancer (CRC) is the fourth most frequently diagnosed cancer and the second leading cause of cancer death in the United States. Management of disseminated metastatic CRC involves various active drugs, either in combination or as single agents. The choice of therapy is based on consideration of the goals of therapy, the type and timing of prior therapy, the mutational profile of the tumor, and the differing toxicity profiles of the constituent drugs. This manuscript summarizes the data supporting the systemic therapy options recommended for metastatic CRC in the NCCN Guidelines for Colon Cancer.

Anal Carcinoma, Version 2.2023, NCCN Clinical Practice Guidelines in Oncology.

This discussion summarizes the NCCN Clinical Practice Guidelines for managing squamous cell anal carcinoma, which represents the most common histologic form of the disease. A multidisciplinary approach including physicians from gastroenterology, medical oncology, surgical oncology, radiation oncology, and radiology is necessary. Primary treatment of perianal cancer and anal canal cancer are similar and include chemoradiation in most cases. Follow-up clinical evaluations are recommended for all patients with anal carcinoma because additional curative-intent treatment is possible. Biopsy-proven evidence of locally recurrent or persistent disease after primary treatment may require surgical treatment. Systemic therapy is generally recommended for extrapelvic metastatic disease. Recent updates to the NCCN Guidelines for Anal Carcinoma include staging classification updates based on the 9th edition of the AJCC Staging System and updates to the systemic therapy recommendations based on new data that better define optimal treatment of patients with metastatic anal carcinoma.

Rectal Cancer, Version 2.2022, NCCN Clinical Practice Guidelines in Oncology.

This selection from the NCCN Guidelines for Rectal Cancer focuses on management of malignant polyps and resectable nonmetastatic rectal cancer because important updates have been made to these guidelines. These recent updates include redrawing the algorithms for stage II and III disease to reflect new data supporting the increasingly prominent role of total neoadjuvant therapy, expanded recommendations for short-course radiation therapy techniques, and new recommendations for a "watch-and-wait" nonoperative management technique for patients with cancer that shows a complete response to neoadjuvant therapy. The complete version of the NCCN Guidelines for Rectal Cancer, available online at NCCN.org, covers additional topics including risk assessment, pathology and staging, management of metastatic disease, posttreatment surveillance, treatment of recurrent disease, and survivorship.

Publication Bias in Gastrointestinal Oncology Trials Performed over the Past Decade.

BACKGROUND: Randomized controlled trials (RCTs) are the gold standard for evidence-based practice, but their development and implementation is resource intensive. We aimed to describe modern RCTs in gastrointestinal (GI) cancer and identify predictors of successful accrual and publication. MATERIALS AND METHODS: ClinicalTrials.gov was queried for phase III GI cancer RCTs opened between 2010 and 2019 and divided into two cohorts: past and recruiting. Past trials were analyzed for predictors of successful accrual and the subset with ≥3 years follow-up were analyzed for predictors of publication. Univariate and multivariable (MVA) logistic regression were used to identify covariates associated with complete accrual and publication status. RESULTS: A total of 533 GI RCTs were opened from 2010 to 2019, 244 of which are still recruiting. In the "past" trials cohort (235/533) MVA, Asian continent of enrollment was a predictor for successful accrual, whereas trials with prolonged enrollment (duration longer than median of 960 days) trended to failed accrual. Predictors for publication on MVA included international enrollment and accrual completion. Sponsorship was not associated with accrual or publication. Notably, 33% of past trials remain unpublished, and 60% of trials that were closed early remain unpublished. CONCLUSION: Accrual rate and the primary continent of enrollment drive both trial completion and publication in GI oncology. Accrual must be streamlined to enhance the impact of RCTs on clinical management. A large portion of trials remain unpublished, underscoring the need to encourage dissemination of all trials to, at a minimum, inform future trial design. IMPLICATIONS FOR PRACTICE: Two-thirds of gastrointestinal (GI) oncology phase III randomized controlled trials successfully accrue; however, one third of these trials are unpublished and more than half of trials that close early are unpublished. The strongest predictors for publication are successful accrual and international collaborations. Initiatives to optimize the trial enrollment process need to be explored to maximize the potential for trials to engender progress in clinical practice. Moreover, this study identified a significant publication bias in the realm of GI oncology, and the field should promote reporting of all trials in order to better inform future trial questions and design.

Colon Cancer, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology.

This selection from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Colon Cancer focuses on systemic therapy options for the treatment of metastatic colorectal cancer (mCRC), because important updates have recently been made to this section. These updates include recommendations for first-line use of checkpoint inhibitors for mCRC, that is deficient mismatch repair/microsatellite instability-high, recommendations related to the use of biosimilars, and expanded recommendations for biomarker testing. The systemic therapy recommendations now include targeted therapy options for patients with mCRC that is HER2-amplified, or BRAF V600E mutation-positive. Treatment and management of nonmetastatic or resectable/ablatable metastatic disease are discussed in the complete version of the NCCN Guidelines for Colon Cancer available at NCCN.org. Additional topics covered in the complete version include risk assessment, staging, pathology, posttreatment surveillance, and survivorship.

AIDS-Related Kaposi Sarcoma, Version 2.2019, NCCN Clinical Practice Guidelines in Oncology.

As treatment of HIV has improved, people living with HIV (PLWH) have experienced a decreased risk of AIDS and AIDS-defining cancers (non-Hodgkin's lymphoma, Kaposi sarcoma, and cervical cancer), but the risk of Kaposi sarcoma in PLWH is still elevated about 500-fold compared with the general population in the United States. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for AIDS-Related Kaposi Sarcoma provide diagnosis, treatment, and surveillance recommendations for PLWH who develop limited cutaneous Kaposi sarcoma and for those with advanced cutaneous, oral, visceral, or nodal disease.

Esophageal and Esophagogastric Junction Cancers, Version 2.2019, NCCN Clinical Practice Guidelines in Oncology.

Esophageal cancer is the sixth leading cause of cancer-related deaths worldwide. Squamous cell carcinoma is the most common histology in Eastern Europe and Asia, and adenocarcinoma is most common in North America and Western Europe. Surgery is a major component of treatment of locally advanced resectable esophageal and esophagogastric junction (EGJ) cancer, and randomized trials have shown that the addition of preoperative chemoradiation or perioperative chemotherapy to surgery significantly improves survival. Targeted therapies including trastuzumab, ramucirumab, and pembrolizumab have produced encouraging results in the treatment of patients with advanced or metastatic disease. Multidisciplinary team management is essential for all patients with esophageal and EGJ cancers. This selection from the NCCN Guidelines for Esophageal and Esophagogastric Junction Cancers focuses on recommendations for the management of locally advanced and metastatic adenocarcinoma of the esophagus and EGJ.

Cancer in People Living With HIV, Version 1.2018, NCCN Clinical Practice Guidelines in Oncology.

People living with HIV (PLWH) are diagnosed with cancer at an increased rate over the general population and generally have a higher mortality due to delayed diagnoses, advanced cancer stage, comorbidities, immunosuppression, and cancer treatment disparities. Lack of guidelines and provider education has led to substandard cancer care being offered to PLWH. To fill that gap, the NCCN Guidelines for Cancer in PLWH were developed; they provide treatment recommendations for PLWH who develop non-small cell lung cancer, anal cancer, Hodgkin lymphoma, and cervical cancer. In addition, the NCCN Guidelines outline advice regarding HIV management during cancer therapy; drug-drug interactions between antiretroviral treatments and cancer therapies; and workup, radiation therapy, surgical management, and supportive care in PLWH who have cancer.

Predictors of Nonadherence to NCCN Guideline Recommendations for the Management of Stage I Anal Canal Cancer.

Background: Definitive chemoradiotherapy (CRT) is recommended by the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Anal Carcinoma for all patients with stage I anal canal cancer. Because these patients were not well represented in clinical trials establishing CRT as standard therapy, it is unclear whether NCCN recommendations are being closely followed for stage I disease. This study identified factors that predict for NCCN Guideline-concordant versus NCCN Guideline-discordant care. Methods: Using the National Cancer Data Base, we identified patients diagnosed with anal canal carcinoma from 2004 to 2012 who received concurrent CRT (radiotherapy [RT] 45.0-59.4 Gy with multiagent chemotherapy), RT alone (45.0-59.4 Gy), or surgical procedure alone (local tumor destruction, tumor excision, or abdominoperineal resection). Demographic and clinicopathologic factors were analyzed using the chi-square test and logistic regression modeling. Results: A total of 1,082 patients with histologically confirmed stage I anal cancer were identified, among whom 665 (61.5%) received CRT, 52 (4.8%) received RT alone, and 365 (33.7%) received only a surgical procedure. Primary analyses were restricted to patients receiving CRT or excision alone, as these were most common. Multivariable analysis identified factors independently associated with reduced odds of CRT receipt: low versus intermediate/high tumor grade (adjusted odds ratio [AOR], 0.21; 95% CI, 0.14-0.29; P<.001), tumor size <1 cm vs 1 to 2 cm (AOR, 0.24; 95% CI, 0.17-0.35; P<.001), age ≥70 versus 50 to 69 years (AOR, 0.36; 95% CI, 0.24-0.54; P<.001), male sex (AOR, 0.63; 95% CI, 0.45-0.90; P=.009), and treatment at an academic versus a non-academic facility (AOR, 0.58; 95% CI, 0.41-0.81; P=.002). Conclusions: Despite the NCCN recommendation of CRT for stage I anal cancer, at least one-third of patients appear to be receiving guideline-discordant management. Excision alone is more common for patients who are elderly, are male, have small or low-grade tumors, or were evaluated at academic facilities.

Gastric Cancer, Version 3.2016, NCCN Clinical Practice Guidelines in Oncology.

Gastric cancer is the fifth most frequently diagnosed cancer and the third leading cause of death from cancer in the world. Several advances have been made in the staging procedures, imaging techniques, and treatment approaches. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Gastric Cancer provide an evidence- and consensus-based treatment approach for the management of patients with gastric cancer. This manuscript discusses the recommendations outlined in the NCCN Guidelines for staging, assessment of HER2 overexpression, systemic therapy for locally advanced or metastatic disease, and best supportive care for the prevention and management of symptoms due to advanced disease.

Addition of radiotherapy to adjuvant chemotherapy is associated with improved overall survival in resected pancreatic adenocarcinoma: An analysis of the National Cancer Data Base.

BACKGROUND: The optimal treatment for resected pancreatic cancer is controversial because direct comparisons of adjuvant chemotherapy (CT) alone and chemotherapy and radiotherapy (CRT) are limited. This study assessed outcomes of CT versus CRT in a national cohort to provide a modern estimate of comparative effectiveness. METHODS: Patients with pT1-3N0-1M0 pancreatic adenocarcinoma after pancreatectomy were identified in the National Cancer Data Base. Overall survival (OS) was compared for CT and CRT groups with Cox regression and propensity score matching. Subset analyses by clinicopathologic characteristics were performed. RESULTS: This study identified 6165 patients treated with CT (n = 2334 or 38%) or CRT (n = 3831 or 62%). Most were classified as pT3 (72%), pN1 (67%), and status-post R0 resection (84%). For CRT patients, the median radiotherapy dose was 50.4 Gy. Compared with CT, CRT was associated with improved OS in a univariate analysis (median, 20.0 vs 22.3 months; at 5 years, 16.5% vs 19.6%; P < .001) and a multivariate analysis (hazard ratio [HR], 0.893; 95% confidence interval [CI], 0.837-0.953; P = .001). CRT remained associated with improved OS after propensity score matching (HR, 0.851; 95% CI, 0.793-0.913; P < .001). Subset analyses showed that CRT was associated with improved OS among patients with pT3 (HR, 0.892; 95% CI, 0.828-0.962; P = .003) or pN1 disease (HR, 0.856; 95% CI, 0.793-0.924; P < .001) and both R0 resection (HR, 0.901; 95% CI, 0.839-0.969; P = .005) and R1 resection (HR, 0.842; 95% CI, 0.722-0.983; P = .030). CONCLUSIONS: CRT was independently associated with improved OS after the resection of pancreatic adenocarcinoma in a large national cohort and particularly among patients with R1 resection and pN1 disease. Well-designed randomized comparisons of CRT and CT are urgently needed.

Locally advanced unresectable pancreatic cancer.

Twenty-five percent of patients with pancreatic cancer present with locally advanced disease that is unresectable, and the treatment strategy for these patients is controversial, with options including chemotherapy alone, concurrent chemoradiation, or induction chemotherapy followed by chemoradiation. Abstracts presented at the 2014 American Society of Clinical Oncology (ASCO) Annual Meeting (#4001, #4126, and #4024) addressed local control, quality of life, and prognostic factors associated with current regimens of induction chemotherapy and subsequent chemoradiation.

Perioperative Modified FOLFIRINOX for Resectable Pancreatic Cancer: A Nonrandomized Controlled Trial.

Importance: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignant tumor, and durable disease control is rare with the current standard of care, even for patients who undergo surgical resection. Objective: To assess whether neoadjuvant modified 5-fluorouracil, leucovorin, oxaliplatin, and irinotecan (mFOLFIRINOX) leads to early control of micrometastasis and improves survival. Design, Setting, and Participants: This open-label, single-arm, phase 2 nonrandomized controlled trial for resectable PDAC was conducted at the Yale Smilow Cancer Hospital from April 3, 2014, to August 16, 2021. Pancreatic protocol computed tomography was performed at diagnosis to assess surgical candidacy. Data were analyzed from January to July 2023. Interventions: Patients received 6 cycles of neoadjuvant mFOLFIRINOX before surgery and 6 cycles of adjuvant mFOLFIRINOX. Whole blood was collected and processed to stored plasma for analysis of circulating tumor DNA (ctDNA) levels. Tumors were evaluated for treatment response and keratin 17 (K17) expression. Main Outcomes and Measures: The primary end point was 12-month progression-free survival (PFS) rate. Additional end points included overall survival (OS), ctDNA level, tumor molecular features, and K17 tumor levels. Survival curves were summarized using Kaplan-Meier estimator. Results: Of 46 patients who received mFOLFIRINOX, 31 (67%) were male, and the median (range) age was 65 (46-80) years. A total of 37 (80%) completed 6 preoperative cycles and 33 (72%) underwent surgery. A total of 27 patients (59%) underwent resection per protocol (25 with R0 disease and 2 with R1 disease); metastatic or unresectable disease was identified in 6 patients during exploration. Ten patients underwent surgery off protocol. The 12-month PFS was 67% (90% CI, 56.9-100); the median PFS and OS were 16.6 months (95% CI, 13.3-40.6) and 37.2 months (95% CI, 17.5-not reached), respectively. Baseline ctDNA levels were detected in 16 of 22 patients (73%) and in 3 of 17 (18%) after 6 cycles of mFOLFIRINOX. Those with detectable ctDNA levels 4 weeks postresection had worse PFS (hazard ratio [HR], 34.0; 95% CI, 2.6-4758.6; P = .006) and OS (HR, 11.7; 95% CI, 1.5-129.9; P = .02) compared with those with undetectable levels. Patients with high K17 expression had nonsignificantly worse PFS (HR, 2.7; 95% CI, 0.7-10.9; P = .09) and OS (HR, 3.2; 95% CI, 0.8-13.6; P = .07). Conclusions and Relevance: This nonrandomized controlled trial met its primary end point, and perioperative mFOLFIRINOX warrants further evaluation in randomized clinical trials. Postoperative ctDNA positivity was strongly associated with recurrence. K17 and ctDNA are promising biomarkers that require additional validation in future prospective studies. Trial Registration: ClinicalTrials.gov Identifier: NCT02047474.

Quantitative DNA Repair Biomarkers and Immune Profiling for Temozolomide and Olaparib in Metastatic Colorectal Cancer.

Purpose: O6-methylguanine DNA methyltransferase (MGMT)-silenced tumors reveal sensitivity to temozolomide (TMZ), which may be enhanced by PARP inhibitors. Approximately 40% of colorectal cancer has MGMT silencing and we aimed to measure antitumoral and immunomodulatory effects from TMZ and olaparib in colorectal cancer. Experimental Design: Patients with advanced colorectal cancer were screened for MGMT promoter hypermethylation using methylation-specific PCR of archival tumor. Eligible patients received TMZ 75 mg/m2 days 1-7 with olaparib 150 mg twice daily every 21 days. Pretreatment tumor biopsies were collected for whole-exome sequencing (WES), and multiplex quantitative immunofluorescence (QIF) of MGMT protein expression and immune markers. Results: MGMT promoter hypermethylation was detected in 18/51 (35%) patients, 9 received study treatment with no objective responses, 5/9 had stable disease (SD) and 4/9 had progressive disease as best response. Three patients had clinical benefit: carcinoembryonic antigen reduction, radiographic tumor regression, and prolonged SD. MGMT expression by multiplex QIF revealed prominent tumor MGMT protein from 6/9 patients without benefit, while MGMT protein was lower in 3/9 with benefit. Moreover, benefitting patients had higher baseline CD8+ tumor-infiltrating lymphocytes. WES revealed 8/9 patients with MAP kinase variants (7 KRAS and 1 ERBB2). Flow cytometry identified peripheral expansion of effector T cells. Conclusions: Our results indicate discordance between MGMT promoter hypermethylation and MGMT protein expression. Antitumor activity seen in patients with low MGMT protein expression, supports MGMT protein as a predictor of alkylator sensitivity. Increased CD8+ TILs and peripheral activated T cells, suggest a role for immunostimulatory combinations. Significance: TMZ and PARP inhibitors synergize in vitro and in vivo in tumors with MGMT silencing. Up to 40% of colorectal cancer is MGMT promoter hypermethylated, and we investigated whether TMZ and olaparib are effective in this population. We also measured MGMT by QIF and observed efficacy only in patients with low MGMT, suggesting quantitative MGMT biomarkers more accurately predict benefit to alkylator combinations.

Pre-operative chemoradiotherapy with or without induction chemotherapy for operable locally-advanced esophageal cancer.

Background: For patients with operable locally advanced esophageal carcinoma (LA-EC), we hypothesized that pre-operative induction chemotherapy followed by chemoradiotherapy (IC-CRT) would improve progression-free survival (PFS) and overall survival (OS) when compared to chemoradiotherapy (CRT). Methods: This was a single institution retrospective cohort study including patients with LA-EC who received preoperative-intent IC-CRT vs. CRT between 2013-2019. The Kaplan-Meier method was used to estimate OS and PFS. Cox proportional hazards regression was used to assess for variables associated with survival. The impact of treatment group on pathologic response was assessed by chi-square. Results: Ninty-five patients were included for analysis (IC-CRT n=59; CRT n=36) and the median follow-up was 37.7 months (IQR: 16.8-56.1). There was no difference in median PFS or OS for IC-CRT or CRT, 22 months (95% CI: 12-59) vs. 32 months (95% CI: 10-57) (P=0.64) and 39 months (95% CI: 23-not reached) vs. 56.5 months (95% CI: 38-not reached) (P=0.36), respectively. Amongst the subset of patients with adenocarcinoma histology, there was no difference in median PFS or OS, nor was there when analyses were further restricted to those who received ≥3 cycles of induction 5-fluorouracil and platinum, or for those who underwent esophagectomy. Pathologic complete response occurred in 45% vs. 29% (P=0.24) and N-stage regression occurred in 72% vs. 58% (P=0.28) of patients in the IC-CRT and CRT cohorts, respectively. Distant metastasis occurred in 44% of patients in each treatment cohort. Conclusions: For patients with LA-EC, preoperative-intent IC-CRT was not associated with improved PFS or OS when compared with CRT.

Utilization and Outcomes of Radiation in Stage IV Esophageal Cancer.

Introduction: For patients with stage IV esophageal cancer, esophageal radiation may be used selectively for local control and palliation. We aimed to understand patterns of radiation administration among patients with stage IV esophageal cancer and any potential survival associations. Methods: In this retrospective cohort study, the National Cancer Database was queried for patients with metastatic stage IV esophageal cancer diagnosed between 2016 and 2019. Patterns of radiation use were identified. Survival was determined through Kaplan-Meier analysis of propensity score-matched pairs of patients who did and did not receive radiotherapy and time-to-event models. Results: Overall, 12,088 patients with stage IV esophageal cancer were identified, including 32.7% who received esophageal radiation. The median age was 65 (interquartile range [IQR]: 58-73) years, and 82.6% were male. Among the irradiated patients, the median total radiation dose was 35 (IQR: 30-50) Gy administered in a median of 14 (IQR: 10-25) fractions given in 22 (IQR: 14-39) days. Overall, esophageal radiation was not associated with better survival (log-rank p = 0.41). When stratified by radiation dose, a survival advantage (over no radiation) was found in the 1144 patients (29% of the irradiated patients) who received 45 to 59.9 Gy (time ratio = 1.28, 95% confidence interval: 1.20-1.37, p < 0.001) and the 88 patients (2.2%) who received 60 to 80 Gy (time ratio = 1.37, 95% confidence interval: 1.11-1.69, p = 0.003). Conclusions: One-third of the patients with metastatic stage IV esophageal cancer in the National Cancer Database received esophageal radiation. Most received a radiation dose that, although consistent with palliative regimens, was not associated with a survival advantage. Further study is warranted to understand the indications for radiation in stage IV esophageal cancer and potentially reevaluate the most appropriate radiation dose for palliation.

Radiation Therapy for Patients with Advanced Renal Cell Carcinoma.

Stereotactic radiosurgery and stereotactic body radiation therapy (SBRT) have led to a resurgence of the use of radiotherapy in the management of advanced renal cell carcinoma (RCC). These techniques provide excellent local control and palliation of metastatic sites of disease with minimal toxicity. Additionally, SBRT to the primary tumor may be efficacious and well tolerated in select patients that are not surgical candidates. Emerging data suggest that SBRT may potentiate the immune response, and current and future study will evaluate if SBRT can improve survival outcomes in patients with metastatic RCC.

A Single-Institution Experience of Induction 5-Fluorouracil, Leucovorin, Irinotecan, and Oxaliplatin Followed by Surgery Versus Consolidative Radiation for Borderline and Locally Advanced Unresectable Pancreatic Cancer.

OBJECTIVES: In the 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) era, the benefit of surgery versus definitive radiation for borderline resectable (BR) and locally advanced (LA) unresectable pancreatic ductal adenocarcinoma (PDAC) is not well defined. Our primary objective was to identify the survival impact of surgery for BR and LA unresectable PDAC treated with induction FOLFIRINOX. METHODS: We performed a single-center retrospective review of BR and LA PDAC treated with FOLFIRINOX from 2010 to 2018. The overall survival of surgery and consolidative radiotherapy was estimated in the Kaplan-Meier method and compared via the log-rank test. Subgroup analyses were conducted for BR and LA patients. RESULTS: We identified 101 BR and LA PDAC patients treated with induction FOLFIRINOX (41 surgeries and 60 consolidative radiotherapies). Surgery patients were 68.3% (28/41) BR and 31.7% (13/41) LA, whereas consolidative radiotherapy patients were 30% (18/60) BR and 70% (42/60) LA. The R0 resection rate was 100%, and 46.3% (19/41) received preoperative radiation. Median overall survival of surgery versus consolidative radiotherapy was 42.3 versus 19.6 months, respectively (P < 0.001). On multivariate analysis, surgery associated with improved survival. CONCLUSIONS: Surgery after induction FOLFIRINOX is feasible and has a clinically meaningful survival benefit in BR and LA PDAC.

An Update to Changing Patterns of Anal Carcinoma in the United States.

OBJECTIVES: Approximately 8,300 new cases of anal carcinoma will be diagnosed in the United States in 2019. Anal squamous cell carcinoma (SCC) accounts for about 70% of all anal cancers. As cancer prevention and treatments have evolved over time, medical management of human immunodeficiency virus has improved, and sexual behaviors have changed, anal carcinoma incidence rates (IRs) may have also changed. METHODS: The 9 oldest Surveillance, Epidemiology, and End Results registries were used to identify and determine IR of carcinoma in situ (CIS) and invasive SCC for 9757 patients below 65 years diagnosed with anal SCC/CIS from 1973 to 2014. Joinpoint regression models identified time points at which incidence trends changed. RESULTS: The incidence of CIS decreased since 2010 (age-adjusted IR annual percent change [APC]: -5.65, 95% CI: -10.0 to -1.1), especially for men (APC: -8.30, 95% CI: -12.6 to -3.8). In contrast, the incidence of SCC increased since 2007 (APC: 2.59, 95% CI: 0.1-5.2). During 2010-2014, men were more likely to present with CIS (incidence rate ratio [IRR]: 3.234, 95% CI: 3.000-3.489) but less likely to present with localized (IRR: 0.827, 95% CI: 0.754-0.906), regional (IRR: 0.603, 95% CI: 0.537-0.676), and distant SCC (IRR: 0.751, 95% CI: 0.615-0.915) compared with women. CONCLUSIONS: The previously observed rise in anal SCC/CIS incidence slowed in 2010, largely due to a decline in CIS rates. Patients were more likely to present with CIS than SCC at any stage. Future studies are necessary to determine if this decline in CIS precedes a decline in invasive SCC.