Chemoradiation (CRT) is used to treat anal carcinomas which, for most patients with loco-regional disease, results in a cure but is associated with acute and chronic complications impairing quality of life (QoL). Patients with metastatic disease or recurrence are likely to experience additional QoL concerns. This paper identifies the QoL issues of these patients and determines whether the EORTC QLQ-ANL27 (QLQ-ANL27), a measure of QoL of patients treated with CRT for anal cancer used alongside the core EORTC QLQ-C30 (QLQ-C30), is suitable or needs adapting.

A systematic review was conducted of studies published between 2014 and 2024 reporting QoL of patients with metastatic or recurrent/persistent anal cancer or follow-up data of patients treated with CRT for anal cancer.

This review included 23 papers, only three focused exclusively on metastatic and/or recurrent anal cancer. Most of the 53 reported symptoms related to bowel, urinary, and sexual functioning, with 60% covered by the QLQ-ANL27 or the QLQ-C30. Issues not captured include, for example, neuropathy, hair loss, musculoskeletal problems, urinary incontinence, and embarrassment.

There is a paucity of research looking specifically at QoL outcomes of patients with metastatic or recurrent anal cancer. Whilst the QLQ-ANL27 captures most QoL issues affecting these patients, it might require adapting to improve its sensitivity.

Anal squamous cell carcinoma (ASCC) is a rare malignancy with an increasing incidence. Primary chemoradiotherapy (CRT) is the standard-of-care treatment for patients with localized ASCC. In the metastatic setting, trials testing immune-checkpoint inhibitor monotherapy have demonstrated outcomes similar to those of patients receiving chemotherapy. Conversely, adding the anti-PD-1 antibody retifanlimab to chemotherapy in patients with recurrent or metastatic ASCC has been shown to significantly improve outcomes. Despite considerable efforts to develop personalized therapy, treatment guidance and prognosis remain reliant on baseline clinical characteristics. An improved understanding of the molecular characteristics of ASCC has provided insights into the mechanisms that mediate tumour progression and response to CRT. For example, human papillomavirus (HPV) infection is known to have an aetiological role in most ASCCs and can modulate cellular responses to CRT via several distinct mechanisms. In this Review, we summarize emerging advances in the molecular and therapeutic landscape of ASCC, including the implementation of biomarkers for treatment guidance and translation into new therapeutic approaches, with HPV infection constituting a global determinant of both tumour biology and clinical outcome. We also discuss the rationale for combining immune-checkpoint inhibitors with CRT in patients with HPV+ tumours.

Perianal fistulizing Crohn's disease (PFCD)-associated anorectal and fistula cancers are rare but often devastating diagnoses. However, given the low incidence and consequent lack of data and clinical trials in the field, there is little to no guidance on screening and management of these cancers. To inform clinical practice, we developed consensus guidelines on PFCD-associated anorectal and fistula cancers by multidisciplinary experts from the international TOpClass consortium.

We conducted a systematic review by standard methodology, using the Newcastle-Ottawa Scale quality assessment tool. We subsequently developed consensus statements using a Delphi consensus approach.

Of 561 articles identified, 110 were eligible, and 76 articles were included. The overall quality of evidence was low. The TOpClass consortium reached consensus on 6 structured statements addressing screening, risk assessment, and management of PFCD-associated anorectal and fistula cancers. Patients with long-standing (>10 years) PFCD should be considered at small but increased risk of developing perianal cancer, including squamous cell carcinoma of the anus and anorectal carcinoma. Risk factors for squamous cell carcinoma of the anus, notably human papilloma virus, should be considered. New, refractory, or progressive perianal symptoms should prompt evaluation for fistula cancer. There was no consensus on timing or frequency of screening in patients with asymptomatic perianal fistula. Multiple modalities may be required for diagnosis, including an examination under anesthesia with biopsy. Multidisciplinary team efforts were deemed central to the management of fistula cancers.

Inflammatory bowel disease clinicians should be aware of the risk of PFCD-associated anorectal and fistula cancers in all patients with PFCD. The TOpClass consortium consensus statements outlined herein offer guidance in managing this challenging scenario.

Anti-PD-L1 antibodies are associated with responses in <25% of patients with metastatic human papillomavirus-associated malignancies. VEGF signaling causes immune evasion and immune suppression within the tumor. We evaluated the anti-PD-L1 antibody atezolizumab and anti-VEGF antibody bevacizumab for patients with unresectable, advanced anal cancer.

For this phase II study, participants with previously treated, immunotherapy-naïve anal cancer received atezolizumab (1,200 mg) and bevacizumab (15 mg/kg) intravenously every 21 days. Responses were evaluated every 9 weeks (RECIST version 1.1). The primary endpoint was the best radiographic response. Median survival was estimated by Kaplan-Meier and compared for selected biomarkers (including paired pre- and on-treatment biopsies) using a log-rank test.

Among 20 participants, the overall response rate was 11% [95% confidence interval (CI): 1.2-32]. Median progression-free survival and overall survival were 4.1 months (95% CI, 2.6-not assessable) and 11.6 months (95% CI, 9.5-20), respectively. One grade 5 bevacizumab-related bowel perforation occurred. Analyses of 16 paired biopsies linked increases in IFN-γ (P = 0.03) and inflammatory response (P = 0.02) gene expression signatures with prolonged progression-free survival, as did increases in CD3+CD8+PD1+ (P = 0.02) cells and decreases in CD3+FoxP3+ cells (P = 0.04) from 10 paired biopsies with multiplex immunofluorescence. A subgroup of anal cancers characterized by the SBS31 "prior-platinum" signature demonstrated shorter median overall survival (HR, 6.3; 95% CI, 1.2-32; P = 0.01).

Atezolizumab and bevacizumab demonstrate activity similar to anti-PD-1 antibodies alone for unresectable anal cancer. Our translational data identify undescribed chromosomal and transcriptomic biomarkers associated with survival for metastatic anal cancer. These correlative findings warrant confirmation and further validation in larger, prospective immunotherapy trials for advanced anal cancer.

Anal cancer is a rare diagnosis, but incidence has been increasing over the past decade. Anal cancer is associated with the human papilloma virus (HPV), specifically the high-risk subtypes of 16 and 18. In addition, the precursor lesion for anal cancer is high-grade squamous intraepithelial lesions (HSILs) and its treatment and surveillance has been emphasized over the last 5 years. The current standard of care for anal cancer includes the Nigro protocol, concurrent chemoradiation, typically radiation with systemic mitomycin and 5-fluorouracil (5-FU). The protocol's efficacy laid the foundation for sphincter preservation and non-operative management. This review will detail the essential clinical trials in the treatment and surveillance of premalignant lesions and anal squamous cell cancer, including alterations in radiation dosing, systemic chemotherapy, and immunotherapy over the last several decades.

Human papillomavirus (HPV)-related lower genital cancers, including cervical cancer, anal squamous cell carcinoma (SCC), vaginal cancer, vulvar cancer, and penile cancer, pose a significant health burden, with approximately 45,000 new cases diagnosed annually. Current effective treatment modalities include chemoradiotherapy, systemic chemotherapy, and immune checkpoint inhibitors (ICIs). The tumor microenvironment in HPV-related cancers is characterized by immune evasion mechanisms, including the modulation of immune checkpoints such as PD-L1/PD-1. HPV oncoproteins E5, E6, and E7 play crucial roles in this process, altering the expression of immune inhibitory molecules and the recruitment of immune cells. ICIs, such as programmed cell death protein 1 (PD-1) inhibitors, have shown efficacy in enhancing the immune response against HPV-associated tumors by blocking proteins that allow cancer cells to evade immune surveillance. Recent studies have demonstrated that HPV-positive tumors exhibit a more favorable response to ICI-based therapies compared to HPV-negative tumors. The integration of ICIs into treatment regimens for HPV-related cancers has been supported by several clinical trials. The inclusion of ICIs in the treatment approach for HPV-related lower genital cancers presents a promising opportunity for improving patient outcomes. Ongoing research and clinical trials are advancing our understanding of the immune microenvironment and the therapeutic potential of immunotherapy for these cancers.

Patients who experience progression of advanced human papillomavirus (HPV)-associated cancers and who have previously received first-line systemic treatment have a poor prognosis and limited therapeutic options.

To assess the clinical activity of the combination of the HPV type 16 therapeutic vaccine PDS0101, the tumor-targeting interleukin 12 antibody-drug conjugate PDS01ADC, and the bifunctional anti-programmed cell death ligand 1 (PD-L1)/transforming growth factor β (TGF-β) bintrafusp alfa in advanced HPV-associated cancers.

This nonrandomized clinical trial was phase 1/2 and investigator initiated, and was conducted at a single US cancer research center between June 2020 and July 2022. Patients with advanced or metastatic HPV-associated cancers were eligible, including patients who were both immune checkpoint blockade (ICB) naive and ICB resistant. The cutoff date for data analysis was May 13, 2024.

Patients received 1 mL of PDS0101 subcutaneously every 4 weeks for 6 doses then every 12 weeks for 2 additional doses, PDS01ADC, 16.8 µg/kg, subcutaneously every 4 weeks or PDS01ADC, 8 µg/kg, subcutaneously every 2 weeks, and bintrafusp alfa, 1200 mg, intravenously every 2 weeks.

Objective response rate (ORR) by Response Evaluation Criteria in Solid Tumors version 1.1 in ICB-naive patients.

Of the 50 eligible patients, 26 (52%) were men and the median age was 56 years (range, 28-80 years). The median (IQR) follow-up was 37.7 (30.6-42.0) months. Fourteen patients (28%) were ICB naive, with an ORR of 35.7% (95% CI, 12.8%-64.9%), and median overall survival (OS) 42.4 months (95% CI, 8.3 months-not estimable); in ICB-resistant patients, the ORR was 16.7% (6 of 36 patients; 95% CI, 6.4%-32.8%) and median OS was 15.8 months (95% CI, 9.0-21.3 months). Among patients with HPV-16-positive tumors (37 patients [74%]), in the ICB-naive group (8 patients [21.6%]) the ORR was 62.5% (95% CI, 24.5%-91.5%) and a median OS measure was not reached. Grade 3 and 4 treatment-related adverse events occurred in 26 of 50 patients (52%). There were no treatment-related deaths.

In this trial, the combination of PDS0101, PDS01ADC, and bintrafusp alfa showed an acceptable safety profile and promising antitumor activity and improved OS in patients with HPV-16-positive cancers, in both ICB-naive and ICB-resistant patients, warranting further evaluation of the combination of PDS0101 and PDS01ADC with simultaneous PD-L1/TGF-β inhibition in these populations.

ClinicalTrials.gov Identifier: NCT04287868.

This first-in-human phase 1 study (NCT04432597) evaluated the safety and recommended phase 2 dose (RP2D) of PRGN-2009, a gorilla adenoviral-vector targeting oncoproteins E6, E7 (human papillomavirus (HPV)16/18) and E5 (HPV16), as monotherapy (Arm 1A) and combined with the bifunctional TGF-β "trap"/anti-PD-L1 fusion protein bintrafusp alfa (BA; Arm 1B), in patients with recurrent/metastatic HPV-associated cancer.

Patients with ≥ 1 prior treatment (immunotherapy allowed) received PRGN-2009 (1 × 1011 particle units or 5 × 1011 particle units, subcutaneously) every 2 weeks for 3 doses, then every 4 weeks (Arm 1A), or PRGN-2009 (RP2D, schedule per Arm 1A) and BA (1200 mg, intravenously) every 2 weeks (Arm 1B). Primary endpoints were safety and RP2D of PRGN-2009; secondary objectives included overall response rate (ORR) and overall survival (OS).

Seventeen patients were treated. In Arm 1A (n = 6) there were no dose limiting toxicities or grade 3/4 treatment-related adverse events (TRAEs), 5 × 1011 PU was selected as RP2D, no responses were observed, and median OS (mOS) was 7.4 months (95% CI 2.9-26.8). In Arm 1B (n = 11), grade 3/4 TRAEs occurred in 27% of patients, ORR was 20% for all patients (22% in checkpoint-resistant patients), and mOS was 24.6 months (95% CI 9.6-not reached). Multifunctional HPV-specific T cells were increased or induced de novo in 80% of patients and not impacted by anti-vector antibodies. Higher serum IL-8 at baseline associated with shorter OS.

PRGN-2009 was well tolerated, and immune responses were observed to PRGN-2009. Encouraging anti-tumor activity and OS were noted in the combination with BA arm, consisting mainly of checkpoint-resistant patients. Trial Registration ClinicalTrials.gov Identifier: NCT04432597.

Background/Objectives: Anal cancer is a rare malignancy with limited treatment options. Immune checkpoint inhibitors have shown benefits in some patients with metastatic disease, but predictive factors for immunotherapy response remain undefined. This study retrospectively evaluated clinical and pathological features associated with survival outcomes in metastatic anal cancer treated with immunotherapy. Methods: Data from 105 patients with metastatic anal cancer were analyzed. Kaplan-Meier analysis was used to estimate progression-free survival (PFS) and overall survival (OS), with subgroup comparisons utilizing the Mantel-Cox test. Associations between survival and clinicopathologic features were assessed with Fisher's exact test. Results: Of the patients, 69 (65.7%) received immunotherapy during the first three treatment lines. With a median follow-up of 23.2 months, the median PFS for first-, second-, and third-line systemic therapies was 7.2, 3.7, and 4.7 months, respectively (χ2 = 14.2; p < 0.001). In the treatment-refractory setting, median PFS was similar for immunotherapy and chemotherapy: 3.6 months (95% CI, 2.3-4.9) vs. 4.4 months (95% CI, 3.8-5.0), respectively (HR 0.89, 95% CI 0.60-1.3; p = 0.52). Among patients treated with immunotherapy, patients with lymph node-only metastases had significantly prolonged PFS compared to patients with visceral organ involvement (11.3 vs. 3.1 months; HR 0.49, 95% CI 0.21-0.74; p = 0.03). Conclusions: Patients with lymph node-only metastatic anal cancer experienced significantly prolonged PFS with immunotherapy relative to those with involvement of other distant organs, highlighting a distinct subgroup of patients who may benefit from immunotherapy. We also contextualize PFS outcomes across treatment lines for metastatic anal cancer, which can be applied towards the design of future immunotherapy clinical trials.

Metastatic anal squamous cell carcinoma (SCC) carries a poor prognosis and the evidence base for surgical resection of metastases remains limited. The aim of this study was to establish the survival outcomes for patients undergoing metastasectomy for anal SCC.

A systematic review was performed using the MEDLINE®, Embase®, Cochrane and PubMed® databases. Studies were considered for inclusion in the review if they involved patients aged >18 years with a diagnosis of stage IV anal SCC who underwent metastasectomy for liver and/or lung metastases. The primary outcome measure was overall survival. Secondary outcome measures were disease free survival, early morbidity according to the Clavien-Dindo classification and quality of life, measured using a validated scoring tool. Risk of bias was assessed with the ROBINS-I (Risk Of Bias In Non-randomised Studies - of Interventions) tool.

There were 10 studies with a total of 98 patients. There was heterogeneity in results reporting, with recurrence free survival the most reported outcome. For all studies reporting on liver metastasectomy, the one-year overall survival rate was 87%. In studies with adequate follow-up reported, the three and five-year overall survival rates were 53% and 38% respectively. Only one study reported on lung metastasectomy patients; the overall median survival was 24 months. None of the studies reported on quality of life measures. The ROBINS-I tool identified a critical risk of bias in six studies, a serious risk in one study and a moderate risk in three studies.

The evidence base for metastasectomy in metastatic anal SCC is limited. Further information is required to inform future treatment methods and use of a standardised outcomes reporting method is needed to support this.

Human papillomavirus (HPV)-driven cancers include head and neck squamous cell carcinoma and cervical cancer and represent approximately 5% of all cancer cases worldwide. Standard-of-care chemotherapy, radiotherapy, and immune checkpoint inhibitors (ICIs) are associated with adverse effects and limited responses in patients with HPV-driven cancers. The integration of targeted therapies with ICIs may improve outcomes. In a previous study, we demonstrated that Aurora kinase A (AURKA, Aurora A) inhibitors lead to apoptosis of human HPV-positive cancer cells in vitro and in vivo. Here, we explored the potential of Aurora A inhibition to enhance response to ICIs in immune-competent preclinical models of HPV-driven cancers.

We assessed the induction of apoptosis, DNA damage, and immunogenic cell death (ICD) in response to treatment with the Aurora A inhibitor alisertib in vitro and antitumor efficacy of alisertib as a monotherapy and in combination with ICIs that inhibit programmed cell death protein-1 (PD-1) or cytotoxic T-lymphocyte associated protein 4 (CTLA-4) in murine HPV-positive immune-competent tumor models. In each treatment group, we determined the tumor growth kinetics and long-term survival and assessed the tumor immune microenvironment using polychromatic flow cytometry.

Aurora A inhibition induced apoptosis, DNA damage, and ICD in vitro in multiple human and murine HPV-positive cancer cell lines. Importantly, Aurora A inhibition induced selective apoptotic depletion of myeloid-derived suppressor cells (MDSCs). In vivo experiments demonstrated that the combination of alisertib with ICIs, specifically anti-CTLA4, resulted in improved survival outcomes by altering the tumor immune microenvironment. This combination enhanced CD8 T-cell infiltration and decreased the frequencies of MDSCs, whereas neither alisertib nor ICIs (anti-PD-1/anti-CTLA-4) alone showed such effects.

Our study establishes the potential of Aurora A inhibition to sensitize HPV-positive tumors to ICIs, specifically anti-CTLA-4 treatment. This combination strategy resulted in enhanced antitumor efficacy, driven by systemic and intratumoral increases in CD8 T-cell responses and reduced immunosuppressive cell populations, specifically MDSCs. These findings offer insights into the synergistic effects of Aurora A inhibition and ICIs and argue for further investigation and optimization of this combination approach in HPV-driven cancers.

Dual inhibition of cytotoxic T-lymphocyte associated protein 4 (CTLA-4) and programmed death ligand 1 (PD-L1) has been shown to be an effective treatment strategy in many cancers. We sought to determine the objective response rate of combination durvalumab (D) plus tremelimumab (TM) in parallel cohorts of patients with carefully selected rare cancer types in which these agents had not previously been evaluated in phase II trials and for which there was clinical or biological rationale for dual immune checkpoint inhibitor therapy to be active.

We designed a multi-centre, non-blinded, open-label phase II basket trial with each of the following 8 rare cancers considered a separate phase II trial: salivary carcinoma, carcinoma of unknown primary (CUP) with tumour infiltrating lymphocytes and/or expressing PD-L1, mucosal melanoma, acral melanoma, osteosarcoma, undifferentiated pleomorphic sarcoma, clear cell carcinoma of the ovary (CCCO) or squamous cell carcinoma of the anal canal (SCCA). The primary objective was to evaluate the response rate of the combination of D and TM, and the secondary objectives were to evaluate the tolerability and safety of D and TM combination. Eligible patients had advanced, metastatic or recurrent, or unresectable cancer with no known life-prolonging treatment option, age ≥16 years, ECOG performance status 0 or 1. Patients received D (1500 mg IV) + TM (75 mg IV) on Day 1 q4 weeks for 4 cycles followed by D q4 weeks until disease progression. This trial is registered with ClinicalTrials.gov, NCT02879162.

From December 14th, 2016, to August 14, 2019, 140 patients enrolled into seven cohorts. The rare melanoma cohorts were closed due to lack of accrual. Of the 140 patients enrolled, 138 were eligible, 138 were evaluable for toxicity and 128 (91%) were evaluable for response. Durable responses were noted in all cohorts except for osteosarcoma. The overall response rate for eligible patients was 16% (95% CI: 10-23%). The response rates in each cancer cohort were undifferentiated pleomorphic sarcoma 15% (n = 3/20; 95% CI 3-38%), salivary carcinoma 20% (n = 4/20; 95% CI: 6-44%), CUP 17% (n = 3/18; 95% CI 4-41%), SCCA 10% (n = 2/20; 95% CI 12-32%) and CCCO 21% (n = 8/39; 95% CI 9-37%). Grade 3/4 adverse events were rare, where 4 patients experienced grade 4 related events and39 patients experienced grade 3 events.

Durvalumab + tremelimumab treatment resulted in meaningful responses in salivary carcinoma and CCCO and deserves further exploration in front-line studies.

AstraZeneca and Canadian Cancer Society.

Metastatic squamous cell carcinoma of the anal canal is a rare presentation that is suspected in patients with risk factors such as known primary anal cancer, human papillomavirus/human immunodeficiency virus, immunosuppression, smoking, and receptive anal intercourse. Patients may present with metastasis at the index presentation of anal cancer or metastases may occur following the chemoradiation of the primary tumor. Treatment is focused on systemic therapy with chemotherapy, with the consideration of immunotherapy as second-line therapy. Predictive biomarkers may be able to personalize treatment in the future. Clinical trials of different chemotherapy and immunotherapy combinations are active to improve current management.

The current standard of care for anal squamous cell carcinoma (ASCC) is definitive concurrent chemoradiotherapy (CRT). However, about a third of patients may experience treatment failure. Recently, immunotherapy has emerged as a novel strategy for metastatic ASCC patients. We evaluated the efficacy and safety of surgery, CRT alone, and CRT with immunotherapy (CRT-I) in 100 nonmetastatic ASCC patients, treated from April 2012 through May 2023, by determining survival outcomes and acute adverse events. The median (range) follow-up was 30.7 (7.6 to 134.9) months. The study cohort 3-year overall survival (OS), progression-free survival (PFS), distant metastasis-free survival (DMFS), and locoregional recurrence-free survival (LRFS) rates were 80.7 %, 62.2 %, 71.1 %, and 67.6 %, respectively. The Surgery group had significantly lower rates than the CRT and CRT-I groups for 3-year PFS (33.1% vs. 65.2% vs. 92.9 %, P < 0.001), DMFS (46.7% vs. 74.6% vs. 92.9 %, P = 0.002) and LRFS (37.0% vs. 73.3% vs. 92.9 %, P < 0.001), respectively. All patients receiving CRT-I were alive at last follow-up. Of 100 patients, 26 (26.0 %) experienced severe (≥ grade 3) acute toxicity. Of 24 patients receiving CRT-I, 8 (33.3 %) had severe acute toxicity. Using immunohistochemistry, peritumoural stromal infiltration by CD8+ T cells was significantly higher after CRT-I compared to before CRT-I and to after CRT alone. The addition of immunotherapy to CRT may be an effective first-line treatment option with favourable survival outcomes and acceptable toxicity for patients with ASCC. A prospective, randomized trial assessing the efficacy of CRT combined with a PD-1 inhibitor in patients with locally advanced ASCC is in progress.

This review assesses the burden of human papillomavirus (HPV)-related cancers in Bosnia and Herzegovina (BH), aiming to inform strategies for prevention and early detection. Despite the availability of highly effective HPV vaccines and screening programs, HPV-related cancers remain a significant public health burden worldwide. We conducted a comprehensive search of PubMed and GLOBOCAN to identify all available data on HPV prevalence/genotype and HPV-related malignancies in BH, including information on HPV vaccination and cervical cancer screening. A comprehensive literature search revealed limited data on HPV prevalence and HPV-related cancers, as well as the absence of a national HPV vaccination or cervical cancer screening program in BH. In the largest study with available data from BH, HPV prevalence was 43% among women undergoing routine gynecologic exams. HPV-16 was identified as the most common cause of cervical cancer. The HPV prevalence was 50% in head and neck cancer, with HPV-18 being the most prevalent subtype. HPV was detected in 80% of patients with colorectal cancer, and HPV-16 was the most common subtype. Conclusions. HPV-related cancers, particularly cervical cancer, represent a significant public health problem in BH. Implementation of a national HPV vaccination program, along with organized cervical cancer screening is essential to reduce HPV-related morbidity and mortality. Addressing systemic challenges, such as establishing a comprehensive cancer registry, is essential for effective HPV prevention and control. Raising public awareness about HPV infection, its consequences, and the importance of prevention is essential for vaccine acceptance and promoting healthy behaviors. By investing in HPV prevention, BH can significantly improve the health and well-being of its population, particularly women.

The influence of human immunodeficiency virus (HIV) infection on clinical outcomes in patients receiving (chemo)radiation therapy (RT) for squamous cell carcinoma of the anus (SCCA) is debated. The objective of this study was to compare efficacy and safety according to HIV status in patients with SCCA treated with C/RT.

Between January 2015 and April 2020, 488 patients with a known HIV status (17.6% HIV+) were treated with radiation therapy for SCCA and included in the FFCD-ANABASE multicentric prospective cohort. Clinical outcomes including overall survival (OS), locoregional recurrence-free survival, colostomy-free survival, response rate at 4 to 6 months, cancer-specific survival, relapse-free survival, and severe acute and late toxicity were compared between HIV+ and HIV- patients.

The median follow-up was 35.8 months. HIV+ patients were younger (P < .01) and predominantly male (P < .01). Intensity modulated radiation therapy was performed in 80.7% of patients, and 80.9% received concurrent chemotherapy. A higher proportion of HIV+ patients received induction chemotherapy compared with HIV- patients. No statistically significant difference in overall treatment time or severe acute and late toxicities was found between HIV+ and HIV- patients. In univariate analyses, OS (HR = 2.1 [CI 95% 1.2;3.5], P = .007), locoregional recurrence-free survival (HR = 1.7 [1.1;2.7], P = .02), and colostomy-free survival (HR = 1.7 [1.1;2.6], P = .01) were significantly shorter in HIV+ patients than in HIV- patients. Response rate, cancer-specific survival, and relapse-free survival were not significantly different. The recurrence site was significantly different according to HIV status. In the multivariate analysis, prognostic factors for OS were a World Health Organization performance status of ≥1 for the whole population, as well as HIV+ status for the subgroup of women.

HIV+ patients treated with chemo-RT for SCCA have poorer clinical outcomes, especially women. No difference was found in toxicity according to HIV status with intensity modulated radiation therapy technique.

Anal canal squamous cell carcinoma (SCC) is a relatively uncommon neoplasia, and it is mostly a local-regional cancer, of low metastatic potential (only 15%), resulting in cure in most cases treated with definitive chemoradiation. On the other hand, its incidence has been steadily increasing over the last decades, which makes it an important public health problem. In an effort to provide surgeons and oncologists who treat patients with anal cancer with the most updated information based on the best scientific evidence, the Brazilian Society of Surgical Oncology (SBCO) has produced the present guideline for the management of anal canal SCC, focused on the main topics related to daily clinical practice.

The SBCO developed the present guidelines to provide recommendations on the main topics related to the management of anal canal squamous cell carcinoma (SCC) based on current scientific evidence.

Between October 2022 and January 2023, 14 experts met to develop the guidelines for the management of anal canal cancer. A total of 30 relevant topics were distributed among the participants. The methodological quality of a final list with 121 sources was evaluated, all the evidence was examined and revised, and the management guidelines were formulated by the 14-expert committee. To reach a final consensus, all the topics were reviewed in a meeting that was attended by all the experts.

The proposed guidelines contained 30 topics considered to be highly relevant in the management of anal canal cancer, covering subjects related to screening recommendations, preventive measures, tests required for diagnosing and staging, treatment strategies, response assessment after chemoradiotherapy, surgical technique-related aspects, and follow-up recommendations. In addition, screening and response assessment algorithms, and a checklist were proposed to summarize the important information and offer an updated tool to assist surgeons and oncologists who treat anal canal cancer and in providing the best care to their patients.

These guidelines summarize recommendations based on the most current scientific evidence on relevant aspects of anal canal cancer management and are a practical guide to help surgeons and oncologists who treat anal canal cancer make the best therapeutic decisions.

The past few decades have witnessed the rise of immunotherapy for Gastrointestinal (GI) tract cancers. The role of immune checkpoint inhibitors (ICIs), particularly programmed death protein 1 (PD-1) and PD ligand-1 antibodies, has become increasingly pivotal in the treatment of advanced and perioperative GI tract cancers. Currently, anti-PD-1 plus chemotherapy is considered as first-line regimen for unselected advanced gastric/gastroesophageal junction adenocarcinoma (G/GEJC), mismatch repair deficient (dMMR)/microsatellite instability-high (MSI-H) colorectal cancer (CRC), and advanced esophageal cancer (EC). In addition, the encouraging performance of claudin18.2-redirected chimeric antigen receptor T-cell (CAR-T) therapy in later-line GI tract cancers brings new hope for cell therapy in solid tumour treatment. Nevertheless, immunotherapy for GI tumour remains yet precise, and researchers are dedicated to further maximising and optimising the efficacy. This review summarises the important research, latest progress, and future directions of immunotherapy for GI tract cancers including EC, G/GEJC, and CRC.

Early-onset colorectal cancer (EOCRC) is associated with a poorer prognosis relative to late-onset colorectal cancer (LOCRC), and its incidence has witnessed a gradual escalation in recent years. This necessitates a comprehensive examination of the underlying pathogenesis and the identification of therapeutic targets specific to EOCRC patients. The present study aimed to delineate the distinct molecular landscape of EOCRC by juxtaposing it with that of LOCRC.

A total of 11 344 colorectal cancer patients, diagnosed between 2003 and 2022, were enrolled in this study, comprising 578 EOCRC cases and 10 766 LOCRC cases. Next-generation sequencing technology was employed to assess the tumor-related mutation and tumor mutation burden (TMB) in these patients. PD-L1 expression was quantified using immunohistochemistry. Microsatellite instability (MSI) was determined via capillary electrophoresis (2B3D NCI Panel).

Upon comparing LOCRC with EOCRC patients, the latter group demonstrated a tendency towards advanced TNM stage, lower tumor differentiation, and less favorable histological types. Among LOCRC patients, those with MSI-H status were found to have an earlier TNM stage compared to those with MSI-L/MSS status. Significantly, the incidence of MSI-H was notably higher in EOCRC (10.2%) compared to LOCRC (2.2%). Mutations in the 7-gene panel (ARID1A, FANCI, CASP8, DGFRA, DPYD, TSHR, and PRKCI) were more prevalent in LOCRC. Within the EOCRC cohort, patients with the MSI-H subtype displayed an earlier TNM stage but concurrently exhibited poorer tissue differentiation and a higher frequency of mucinous adenocarcinoma. Among EOCRC patients, FBXW7, FAT1, ATM, ARID1A, and KMT2B mutations were significantly enriched in the MSI-H subgroup. A comparative analysis of MSI-H patients revealed heightened mutation frequencies of FGFBR2, PBRM1, RNF43, LRP1B, FBXW7, ATM, and ARID1A in the EOCRC group. Furthermore, EOCRC patients demonstrated a higher overall TMB, particularly in the MSI-H subtype. PD-L1 expression was elevated in EOCRC and positively associated with MSI status.

This study revealed a significantly higher MSI-H distribution rate in EOCRC, and EOCRC exhibits a distinct mutational signature coupled with higher PD-L1 expression. These findings hold promise in guiding personalized therapeutic strategies for improved disease management in EOCRC patients.

Concurrent chemoradiotherapy (CCRT) is the standard treatment for locoregional anal squamous cell carcinoma (ASCC) in western countries. However, there have been few reports on the clinical outcomes of CCRT in Japan. This study aimed to evaluate the clinical outcomes of CCRT, prognostic factors, and the clinical impact of programmed cell death-ligand 1 (PD-L1) expression of ASCC in Japan.

Patients with locoregional ASCC were enrolled between 2007 and 2017. All patients received CCRT consisting of ≥ 45 Gy of radiation, 5-fluorouracil, and mitomycin C. Disease-free survival (DFS), overall survival (OS), and adverse events (AEs) were estimated. Expression of p16 and PD-L1 were assessed by immunohistochemical staining (IHC).

This study included 36 patients, of whom 30 (83.3%) were female. Among the participants, 32 (88.9%) achieved complete clinical remission, while six (16.7%) experienced recurrence. The five-year DFS and five-year OS were 72.2% and 84.7%, respectively. Grades ≥ 3 serious AEs included neutropenia in 10 (27.7%) and perianal dermatitis in eight (22.2%). In a univariate analysis, male sex, lymph node metastasis, and large tumor size were significantly associated with worse outcome. In a multivariate analysis, tumor size was an independent factor associated with short DFS. Of the 30 patients whose biopsy specimens were available for IHC, 29 (96.7%) were positive for p16, and 13 (43.3%) were positive for PD-L1. However, PD-L1 expression did not show any clinical impact.

The comparative etiology, clinical outcomes, and prognostic factors of CCRT observed in Japanese patients with locoregional ASCC were consistent with western data.

Squamous cell carcinoma of the anus (SCCA) is an HPV-associated malignancy that has limited treatment options. Immunotherapy has expanded these options and here we review current and emerging immunotherapeutic approaches.

Multiple studies of single-agent anti-PD1/PD-L1 immunotherapy have demonstrated a modest response rate of approximately 10% to 15%. While a minority of patients (~5%) with SCCA experience durable complete responses, most advanced SCCAs are resistant to anti-PD1/PD-L1 monotherapy. Given the need for more broadly effective immunotherapies, novel strategies, such as adaptive cell therapies and therapeutic vaccination, are being explored. To reduce the recurrence risk of localized high-risk SCCA, strategies combining immunotherapy with chemoradiation are also being investigated. While a small subset of patients with SCCA have prolonged responses to PD1-directed immunotherapy, the majority do not derive clinical benefit, and new immunotherapeutic strategies are needed. Better understanding of the immune microenvironment and predictive biomarkers could accelerate therapeutic advances.

Multiple common cancers benefit from immunotherapy; however, less is known about efficacy in rare tumors. We report the results of the adrenocortical carcinoma cohort of NCI/SWOG S1609 Dual Anti-CTLA-4 and Anti-PD-1 blockade in Rare Tumors.

A prospective, phase 2 clinical trial of ipilimumab plus nivolumab was conducted by the SWOG Early Therapeutics and Rare Cancers Committee for multiple rare tumor cohorts across >1,000 National Clinical Trial Network sites.

21 eligible patients were registered. Median age was 53 years (range 26-69); 16 (76%) were women.

Ipilimumab 1 mg/kg intravenously every 6 weeks with nivolumab 240 mg intravenously every 2 weeks was administered until disease progression, symptomatic deterioration, treatment delay for any reason >56 days, unacceptable or immune-related toxicity with inability to decrease prednisone to <10 mg daily, or per patient request.

The primary endpoint was the overall response rate (ORR) (RECIST V.1.1). Secondary endpoints include clinical benefit rate (CBR) (includes stable disease (SD)>6 months), progression-free survival (PFS), overall survival (OS), and toxicity. Immune-related outcomes included immune ORR (iORR), immune CBR (iCBR), and immune PFS (iPFS). A two-stage design was used assuming: null=5% alternative=30%, n=6 in the first stage, 16 max, one-sided alpha=13%.

The median number of prior therapy lines was 2 (range: 1-9). 3 of 21 patients attained confirmed partial response (PR) (ORR=14%). In addition, one patient had an unconfirmed PR; one, stable disease (SD)>6 months; one, immune-related RECIST (iRECIST) PR (iPR); and one patient attained iSD>6 months: clinical benefit rate (response or SD>6 months)=5/21 (24%), iORR=4/21 (19%), iCBR=7/21 (33%). The 6-month PFS was 24%; 6-month iPFS, 33%. The PFS for patients (N=7) with iRECIST clinical benefit were 57, 52, 18, 15, 13, 7, and 7 months. The 6-month OS was 76%; the median OS, was 15.8 months. The most common toxicities were fatigue (62%) and rash (38%), and the most common grade 3/4 immune-related adverse events were hepatic dysfunction (9.5%) and adrenal insufficiency (9.5%). Treatment-related adverse events leading to discontinuation of therapy in four patients (21%). There were no grade 5 adverse events.

Ipilimumab plus nivolumab is active in refractory metastatic adrenocortical cancer meeting the primary endpoint of the study, with a 19% iORR and 33% iCBR (includes SD/iSD>6 months) and with the longest PFS/iPFS of 52 and 57 months.

NCT02834013 (registered 15 July, 2016; https://clinicaltrials.gov/ct2/show/NCT02834013).

With a significant global impact, treatment of gastrointestinal (GI) cancers still presents with challenges, despite current multimodality approaches in advanced stages. Clinical trials are expanding for checkpoint inhibition (ICI) combined with radiation therapy (RT). This review intends to offer a comprehensive image of the current data regarding the effectiveness of this association, and to reflect on possible directions to further optimize the results.

Several early phase studies demonstrated encouraging potential. However, translating preclinical outcomes to clinical settings proves challenging, especially in immunologically "cold" environments. GI cancers exhibit heterogeneity, requiring tailored approaches based on disease stage and patient characteristics. Current results, though promising, lack the power of evidence to influence the general practice.

Finding biomarkers for identifying or converting resistant cancers is essential for maximizing responses, moreover in this context strategic RT parameters need to be carefully considered. Our review emphasizes the significance of having a thorough grasp of how immunology, tumour biology, and treatment settings interact in order to propose novel research avenues and efficient GI cancer therapy.

Background: The present meta-analysis was performed to evaluate the prognostic and clinicopathological significance of PD-L1 in anal cancer (AC). Methods: Hazard ratios (HRs) and 95% CIs regarding overall survival (OS) and progression-free survival (PFS) were calculated based on PD-L1 levels. Results: According to the combined data, PD-L1 showed no significant relationship with OS (HR = 0.76; 95% CI = 0.35-1.67; p = 0.502) or PFS (HR = 0.88; 95% CI = 0.35-2.33; p = 0.789) in patients with AC. Based on subgroup analysis, PD-L1 overexpression significantly predicted prolonged OS (HR = 0.38; 95% CI = 0.17-0.84; p = 0.017) in tumor node metastasis stages I-III and inferior PFS (HR = 2.73; 95% CI = 1.32-5.65; p = 0.007) in patients with stage I-IV AC. Conclusion: PD-L1 level assessed by immunohistochemistry did not significantly predict survival outcomes in AC cases.

A rapid increase in the incidence of anal squamous cell carcinoma (SCC) was reported in several countries over the past decades. This study assessed trends in epidemiology and primary treatment over a 32-year period (1990-2021) using the Netherlands Cancer Registry. The study population included 4273 patients, 44.2% male and 55.8% female (median age 63 years). The age-standardised incidence rate (European Standardised Rate, ESR) increased from 0.5 to 1.6 per 100,000, which entailed an average annual percentage change (AAPC) of 5.0% (95% confidence interval [CI]: 4.5%-5.8%). While incidence among females increased continuously over the total period (AAPC 4.9%; 95%CI: 4.4%-5.6%), to 1.8 per 100,000 ESR in 2021, incidence among males increased until 2016 (annual percentage change [APC] of 6.3%; 95%CI: 5.6%-10.7%), after which it seemed to stabilise (APC -2.1%; 95%CI: -16.8%-4.5%). Significant trends were also observed in distribution of age, tumour stage and primary treatment modalities. Five-year relative survival (RS) was estimated using the Pohar-Perme estimator, and this improved from 56.1% in 1990-1997 (95%CI: 49.3%-62.4%) to 67.9% in 2014-2021 (95%CI: 64.7%-70.9%), but remained poor for stage IV disease. Evaluation through a multivariable Poisson regression model demonstrated diagnosis in the most recent period to be independently associated with better RS, in addition to female sex, younger age, early disease stage and any treatment. In conclusion, the rising incidence of anal SCC seems to decline in males, but not in females, and advances in diagnostics and therapeutic management have likely contributed to improved prognosis.

Squamous cell carcinoma of unknown primary origin in the pelvis is rare. We report a case of a 64-year-old woman with a large osteolytic squamous cell carcinoma of unknown primary origin in the pelvis that presented with p16 expression. The patient presented with leg pain and swelling and was admitted to our hospital. Computed tomography scans of the pelvis revealed a large osteolytic tumor. A computed tomography-guided needle biopsy was performed, and pathological examination revealed neoplastic cells with metastatic squamous cell carcinoma presenting with p16 expression. Despite a whole-body examination, tumor origin remained undetected. The patient was treated for this metastatic squamous cell carcinoma of unknown primary using palliative radiotherapy for hip pain and nivolumab. Remarkable reduction in the tumor marker levels and tumor size were obtained after therapy. Finally, partial remission and progression-free survival for more than 7 months were achieved. In conclusion, we experienced a rare case with a large p16-positive squamous cell carcinoma of unknown primary in pelvis, which responded well to radiotherapy and nivolumab.

The modified docetaxel, cisplatin, and fluorouracil (mDCF) regimen has shown efficacy and safety as first-line treatment for advanced squamous cell carcinoma of the anus, making it a standard regimen. Inhibitors of programmed cell death protein 1 and its ligand, such as pembrolizumab, nivolumab, retifanlimab, avelumab, and atezolizumab, have shown some antitumour activity as monotherapy in advanced squamous cell carcinoma of the anus that is refractory to chemotherapy. This phase 2 study evaluated the combination of mDCF and atezolizumab as first-line treatment in advanced squamous cell carcinoma of the anus.

In this randomised, open-label, non-comparative, phase 2 study, participants from 21 centres (academic, private, and community hospitals and cancer research centres) across France with chemo-naive, metastatic, or unresectable locally advanced recurrent squamous cell carcinoma of the anus, aged 18 years or older, and with an Eastern Cooperative Oncology Group performance status of 0 or 1, were randomly allocated (2:1) to receive either atezolizumab (800 mg intravenously every 2 weeks up to 1 year) plus mDCF (eight cycles of 40 mg per m2 docetaxel and 40 mg per m2 cisplatin on day 1 and 1200 mg per m2 per day of fluorouracil for 2 days, every 2 weeks intravenously; group A) or mDCF alone (group B). Randomisation was done centrally using a minimisation technique and was stratified by age (<65 years vs ≥65 years) and disease status. The primary endpoint was investigator-assessed 12-month progression-free survival in the modified intention-to-treat population in group A (35% for the null hypothesis and 50% for the alternative hypothesis). This trial is registered with ClinicalTrials.gov, NCT03519295, and is closed to new participants.

97 evaluable participants (64 in group A and 33 in group B) were enrolled between July 3, 2018, and Aug 19, 2020. The median follow-up was 26·5 months (95% CI 24·8-28·4). The median age of participants was 64·1 years (IQR 56·2-71·6), and 71 (73%) were female. 12-month progression-free survival was 45% (90% CI 35-55) in group A and 43% (29-58) in group B. In participants with a PD-L1 combined positive score of 5 or greater, 12-month progression-free survival was 70% (95% CI 47-100) in group A and 40% (19-85) in group B (interaction p=0·051) Both groups showed high compliance. Adverse events of grade 3 or higher were observed in 39 (61%) participants in group A and 14 (42%) in group B. The most common grade 3-4 adverse events were neutropenia (nine [14%] participants in group A vs five [15%] in group B), anaemia (nine [14%] vs one [3%]), fatigue (three [5%] vs four [12%]), and diarrhoea (seven [11%] vs one [3%]). Serious adverse events occurred in 16 (25%) participants in group A and four (12%) in group B, and these were mDCF-related in seven (11%) participants in group A and four (12%) in group B. Atezolizumab-related serious adverse events occurred in nine (14%) participants in group A, including grade 2 infusion-related reaction in three (5%), grade 3 infection in two (3%), and grade 2 colitis, grade 3 acute kidney injury, grade 3 sarcoidosis, and a grade 4 platelet count decrease each in one participant (2%). There were no treatment-related deaths.

Despite a higher incidence of adverse events, combining atezolizumab with mDCF is feasible, with similar dose intensity in both groups, although the primary efficacy endpoint was not met. The predictive value of a PD-L1 combined positive score of 5 or greater now needs to be confirmed in future studies.

GERCOR, Roche.

Gliomas constitute a diverse and complex array of tumors within the central nervous system (CNS), characterized by a wide range of prognostic outcomes and responses to therapeutic interventions. This literature review endeavors to conduct a thorough investigation of gliomas, with a particular emphasis on glioblastoma (GBM), beginning with their classification and epidemiological characteristics, evaluating their relative importance within the CNS tumor spectrum. We examine the immunological context of gliomas, unveiling the intricate immune environment and its ramifications for disease progression and therapeutic strategies. Moreover, we accentuate critical developments in understanding tumor behavior, focusing on recent research breakthroughs in treatment responses and the elucidation of cellular signaling pathways. Analyzing the most novel transcriptomic studies, we investigate the variations in gene expression patterns in glioma cells, assessing the prognostic and therapeutic implications of these genetic alterations. Furthermore, the role of epigenetic modifications in the pathogenesis of gliomas is underscored, suggesting that such changes are fundamental to tumor evolution and possible therapeutic advancements. In the end, this comparative oncological analysis situates GBM within the wider context of neoplasms, delineating both distinct and shared characteristics with other types of tumors.

Patients with paraneoplastic syndromes (PNS) are excluded from clinical trials involving immune checkpoint inhibitors (ICIs) due to safety concerns. Moreover, real-world data on efficacy and safety is scarce.

In this retrospective study, data were collected on patients with PNS and solid tumors receiving ICI between 2015 and 2022 at nine institutions. Patients were classified into: Cohort 1 (pre-existing PNS before ICI initiation), cohort 2 (PNS during ICI treatment), and cohort 3 (PNS after ICI discontinuation). Patients with metastatic non-small cell lung cancer (NSCLC) (mNSCLC) from cohort 1 were matched to patients who were PNS-free at each institution up to a 1:3 ratio for age, sex, type of ICI, use of concurrent chemotherapy, and number of lines of systemic therapy prior to ICI initiation. Kaplan-Meier method was used to assess overall survival (OS) and time-to-next treatment (TTNT).

Among 109 patients with PNS treated with ICIs, median age at ICI initiation was 67 years (IQR: 58-74). The most represented cancer type was NSCLC (n=39, 36%). In cohort 1 (n=55), PNS exacerbations occurred in 16 (29%) patients with median time to exacerbation after ICI of 1.1 months (IQR: 0.7-3.3). Exacerbation or de novo PNS prompted temporary/permanent interruption of ICIs in 14 (13%) patients. For cohort 2 (n=16), median time between ICI initiation and de novo PNS was 1.2 months (IQR: 0.4-3.5). Treatment-related adverse events (trAEs) occurred in 43 (39%) patients. Grade ≥3 trAEs occurred in 18 (17%) patients. PNS-directed immunosuppressive therapy was required in 55 (50%) patients. We matched 18 patients with mNSCLC and PNS (cohort 1) to 40 without PNS, treated with ICIs. There was no significant difference in OS or TTNT between patients with mNSCLC with and without PNS, although a trend was seen towards worse outcomes in patients with PNS. TrAEs occurred in 6/18 (33%) and 14/40 (35%), respectively. Grade ≥3 trAEs occurred in 4 (22%) patients with PNS and 7 (18%) patients without PNS.

Exacerbations of pre-existing PNS occurred in 29% of patients treated with ICIs and both exacerbations and de novo PNS occur early in the ICI course. TrAE from ICIs were similar between patients with and without PNS. Our data suggest that pre-existing PNS should not preclude consideration of ICI therapy although patients may not derive the same clinical benefit compared with patients without PNS.

Metastatic gastrointestinal cancer is not an uncommon situation, especially for pancreatic, gastric, and colorectal cancers. In this setting, few data are available on the impact of the treatment of the primary tumour. Oligometastatic disease is associated with longer survival in comparison with more advanced disease. Metastasis-directed therapy, such as stereotactic body radiotherapy, seems related to better outcomes, but the level of evidence is low. In most tumour locations, prospective data are very scarce and inclusion in ongoing trials is strongly recommended.