Colostomy-free Survival Research Articles

Clinical outcomes, patterns of failure, and salvage therapies of a large modern cohort of patients with anal squamous cell carcinoma treated with definitive-intent IMRT

PurposePatterns of failure and salvage therapy options for patients with anal squamous cell carcinoma (ASCC) who recur after definitive-intent intensity-modulated radiotherapy (IMRT) with concurrent chemotherapy are not well described. Patients and MethodsWe identified consecutive patients with ASCC treated with definitive-intent IMRT between July 2005 and December 2019. Relevant patient and tumor parameters, disease outcomes (locoregional failure (LRF), distant failure (DF), progression-free survival (PFS), colostomy-free survival (CFS), and overall survival (OS)), patterns of failure, and salvage therapies were collected. Failures were analyzed by competing risks methods, whereas survival endpoints were estimated by Kaplan-Meier method. Univariate and multivariate analyses were performed. Landmark analyses were conducted by considering whether patients had LRF within 12 months from completing IMRT. Results375 patients were identified with a median follow-up of 6 years. Stage breakdown was 15%, 23%, and 62% for AJCC stage 0-I, II, and III, respectively. Six-year rates of LRF, DF, PFS, CFS, and OS were 12%, 13%, 73%, 76%, and 80%, respectively. Disease recurred in 74 patients. Among the 45 patients with LRF, 39 (87%) failed within the anorectum, with 25 anal canal, 6 anal margin, and 8 rectal recurrences. Only 4 (9%) patients had isolated nodal failure. Patients experiencing LRF had worse six-year OS than patients without LRF (44% versus 86%, P<0.0001). Approximately 30% of patients who underwent salvage therapy were alive ten years after recurrence, compared with none of the patients who were managed with chemotherapy alone or best supportive care. ConclusionsThis large ASCC cohort managed with definitive-intent IMRT demonstrated excellent rates of locoregional control and survival. Isolated regional nodal failures were uncommon, whereas the majority of LRFs occurred within the anorectum, despite dose escalation by tumor stage. We observed poor outcomes for patients experiencing locoregional disease recurrence, even after aggressive salvage treatment.

A systematic review on the role of interventional radiotherapy for treatment of anal squamous cell cancer: multimodal and multidisciplinary therapeutic approach.

Aim was to compare the efficacy of interventional radiotherapy (IRT) boost vs. external beam radiotherapy (EBRT) boost after chemoradiation (CCRT) in patients with anal cancer (AC). The P.I.C.O. framework was: in patients with AC [P], is IRT boost [I] superior to EBRT boost [C] in terms of local control (LC), cancer specific survival (CSS), overall survival (OS), distant meta-static free Survival (DMFS), colostomy free survival (CFS) and toxicity [O]? 651 patients were analyzed. The median 5-year locoregional control rates was 87.8% in the IRT boost group versus 72.8% in the EBRT boost group. The 5-year cancer-specific survival rate was 91% in the IRT boost group versus 78% in the EBRT boost group. 5-years overall survival was 74.6% in IRT boost versus 67.7% in the EBRT boost. 5-years disease metastasis-free survival rate was 92.9% in IRT boost group vs. 85.6% for the EBRT boost group. Cancer-free survival rate was 76.8% in the IRT group vs. 63.1% in the EBRT boost group. Acute toxicity above grade 2 was less common in the IRT boost group while chronic toxicity was similar between both groups. IRT boost after CCRT could lead to better outcomes than EBRT boost in treating AC.

Treatment of Stages I-III Squamous Cell Anal Cancer: A Comparative Effectiveness Systematic Review.

To assess the effectiveness and harms of initial treatment strategies for stages I-III anal squamous cell cancer (SCC). We searched Medline®, Embase®, and CENTRAL®, between January 1, 2000- March 2024, for randomized controlled trials and nonrandomized studies of interventions comparing initial treatment strategies. Individual study risk of bias (RoB) and overall strength of evidence (SOE) were evaluated for a prespecified outcome list using standardized methods. We identified 33 eligible studies and extracted data. Six were deemed low/moderate RoB. Compared with radiotherapy (RT) alone, chemoradiotherapy (CRT) with 5-fluorouracil (FU) and mitomycin C (MMC) probably shows a benefit in locoregional failure (LRF), disease-specific (DSS), and colostomy-free survival (CFS) (moderate SOE) yet may result in greater overall and acute hematologic toxicity, with no difference in late harms (low SOE). CRT with 5FU+MMC may show a benefit in LRF, DSS, and CFS rates compared with 5FU alone (low SOE). CRT with 5FU+cisplatin vs 5FU+MMC probably results in no differences in several effectiveness outcomes or overall acute or late harms, and probably increases hematologic toxicity with MMC (moderate SOE). Compared with CRT using capecitabine+MMC, CRT with capecitabine+MMC+paclitaxel may improve OS, DSS, and CFS, yet cause more acute harms (low SOE). Evidence was insufficient for remaining comparisons. CRT with 5FU+MMC or 5FU+cisplatin is likely more effective yet incurs greater acute hematologic toxicity than RT alone or single-agent CRT. Adding paclitaxel to capecitabine+MMC may increase treatment efficacy and toxicity. Evidence is insufficient comparing post-treatment surveillance strategies and patient-reported outcomes, highlighting research opportunities.

Prognostic Value of 18F-FDG PET/CT Assessment After Radiotherapy of Squamous Cell Carcinoma of the Anus in Patients from the National Multicentric Cohort FFCD-ANABASE.

This study aimed to evaluate the prognostic value of 18F-FDG PET/CT qualitative assessment in terms of recurrence-free survival (RFS), colostomy-free survival (CFS), and overall survival (OS) after radiation therapy (RT) of squamous cell carcinoma of the anus (SCCA). Secondary objectives were to evaluate the prognostic value of baseline and posttherapeutic quantitative 18F-FDG PET/CT parameters in terms of RFS, CFS, and OS. Methods: We included all consecutive patients from the French multicentric cohort FFCD-ANABASE who had undergone 18F-FDG PET/CT at baseline and 4-6 mo after RT or chemoradiotherapy for a localized SCCA. Qualitative assessments separated patients with complete metabolic response (CMR) and non-CMR. Quantitative parameters were measured on baseline and posttreatment 18F-FDG PET/CT. RFS, CFS, and OS were analyzed using the Kaplan-Meier method. Associations among qualitative assessments, quantitative parameters, and RFS, CFS, and OS were analyzed using univariate and multivariate Cox regression. Results: Among 1,015 patients treated between January 2015 and April 2020, 388 patients (300 women and 88 men) from 36 centers had undergone 18F-FDG PET/CT at diagnosis and after treatment. The median age was 65 y (range, 32-90 y); 147 patients (37.9%) had an early-stage tumor and 241 patients (62.1%) had a locally advanced-stage tumor; 59 patients (15.2%) received RT, and 329 (84.8%) received chemoradiotherapy. The median follow-up was 35.5 mo (95% CI, 32.8-36.6 mo). Patients with CMR had better 3-y RFS, CFS, and OS, at 84.2% (95% CI, 77.8%-88.9%), 84.7% (95% CI, 77.2%-89.3%), and 88.6% (95% CI, 82.5%-92.7%), respectively, than did non-CMR patients, at 42.1% (95% CI, 33.4%-50.6%), 47.9% (95% CI, 38.1%-56.8%), and 63.5 (95% CI, 53.2%-72.1%), respectively (P < 0.0001). Quantitative parameters were available for 154 patients from 3 centers. The following parameters were statistically significantly associated with 3-y RFS: baseline SUVmax (primitive tumor [T]) (hazard ratio [HR], 1.05 [95% CI, 1.01-1.1; P = 0.018]), SUVpeak (T) (HR, 1.09 [95% CI, 1.02-1.15; P = 0.007]), MTV 41% (T) (HR, 1.02 [95% CI, 1-1.03; P = 0.023]), MTV 41% (lymph node [N]) (HR, 1.06 [95% CI, 1.03-1.1; P < 0.001]), MTV 41% (T + N) (HR, 1.02 [95% CI, 1-1.03; P = 0.005]), and posttreatment SUVmax (HR, 1.21 [95% CI, 1.09-1.34; P < 0.001]). Conclusion: Treatment response assessed by 18F-FDG PET/CT after RT for SCCA has a significant prognostic value.18F-FDG PET/CT could be useful for adapting follow-up, especially for patients with locally advanced-stage tumors. Quantitative parameters could permit identification of patients with a worse prognosis but should be evaluated in further trials.

Chemoradiotherapy versus radiotherapy alone in the management of early-stage anal squamous cell carcinoma: A comparative analysis of the French cohort FFCD-ANABASE

IntroductionEarly-stage anal squamous cell carcinomas (ASCC) are usually treated with chemoradiotherapy (CRT), with good outcomes. Radiotherapy (RT) alone might be sufficient while reducing toxicity. MethodsPatients included in the French prospective FFCD-ANABASE and treated for T1–2N0 ASCC between 2015/01 and 2020/04 were divided into CRT and RT groups. Clinical outcomes and toxicity were reported. Propensity score matching was conducted for 105 pairs of patients. Results440 patients were analyzed: 261 (59.3 %) in the CRT group and 179 (40.7 %) in the RT group. The median follow-up was 35.7 months. Patients receiving CRT were younger, had better Performance Status (PS) and larger tumors. No statistical difference was observed for 3-year Disease-free survival (85.3 % vs 83 %, p = 0.28), Overall survival (89.6 % vs 94.8 %, p = 0.69) and Colostomy-free survival (84.5 % vs 87.2 %, p = 0.84) between CRT and RT groups, respectively. Propensity score-matched analysis confirmed these findings. Treatment interruptions were significantly more frequent in the CRT group (36.3 % vs 21.9 %, p = 0.0013), resulting in an Overall Treatment Time (OTT) extended by 7 days. Grade 3 CTCAE v4.0 toxicities were more prevalent in the CRT group (46 % vs 19 %, p < 0.001). ConclusionAdding chemotherapy to radiotherapy did not significantly improve outcomes for T1–2N0 ASCC in our study, but increased toxicity and OTT.

Efficacy and Toxicity of (Chemo)Radiation Therapy in HIV+ Patients with Squamous Cell Anal Cancer, a Subgroup Analysis of the National Multicenter Cohort FFCD-ANABASE

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.

Cisplatin and capecitabine as definitive chemoradiation for squamous cell carcinoma of the anal canal (SCCAC): A prospective cohort.

e15503 Background: SCCAC is a rare disease. The standard of care treatment with curative intent is chemoradiation (CRT) with mitomycin (MMC) or cisplatin (CDDP) plus infusional 5-Fluoracil (5-FU). Capecitabine may replace 5-FU in MMC doublet. However, MMC and infusional pumps are frequently unavailable in underdeveloped countries. CCDP and capecitabine are widely available, but there is no prospective data about the feasibility and efficacy of this combination in a definitive SCCAC CRT setting. Methods: A Prospective cohort study aimed to evaluate the safety and efficacy of treatment with chemoradiation with CDDP 60mg/m2 D1 and D29 plus Capecitabine 825mg/m2 BID in a population without MMC and infusional pump access. Eligible patients (pts) had T2-4, N0-3, and M0 disease candidates for a full curative CRT regimen. The study data were prospectively collected using REDCap. The primary endpoint was the response by RECIST v.1.1 at 24 weeks(w). The secondary endpoints included toxicity by CTCAE v.5.0, adherence, PFS, and OS. Results: We enrolled 40 consecutive pts between Aug/2019-Dec/2022 in a tertiary cancer center in Brazil. The median age was 61y, the majority were stage III (n = 31, 77.5%) and ECOG 1 (n = 20, 50%). HIV+ serology was observed in 11 pts (27,5%). All patients received CRT, with a median dose of 54Gy in the primary tumor and 45Gy in the elective nodes. At 8w, 35% (n = 14) had a complete response (CR), 50% (n = 20) partial response (PR), and 2.5% (n = 1) progressive disease (PD). At 6 months, CR was observed in 55% (n = 22), PR in 22.5% (n = 9), and PD in 10% (n = 4). 11 pts had disease recurrence, and six died. 1y OS was 94.7% (IC95%: 80.7- 98.6%), and 1y PFS was 75.3% (IC95%:57.8 - 86.3%). Colostomy-free survival at one year was 89.6% (IC95%: 74.7 - 95.9%). Median PFS and OS were not reached with a 2-year median follow-up. Regarding toxicities, radiodermatitis was observed in 94% (n = 36), nausea in 90% (n = 36), and diarrhea in 65% (n = 26). Any grade 3/4 toxicity was present in 27.5% (n = 11), being the majority of radiodermatitis. Four older pts (average age 73y) had definitive suspension of treatment due to toxicity, 06 pts were hospitalized because of a skin infection, and one died due to treatment toxicity. Conclusions: Definitive chemoradiotherapy with cisplatin and capecitabine is feasible; however, older populations require extra attention to early toxicities management.

Long-term outcomes of definitive radiation with volumetric modulated arc therapy and concurrent chemotherapy for squamous cell carcinoma of the anus in a regional Australian cancer centre.

Concurrent chemoradiotherapy is the standard of care in the curative intent treatment of squamous cell carcinoma (SCC) of the anus. Volumetric arc therapy (VMAT) is a highly conformal radiation therapy technique that has been implemented to reduce toxicity for these patients. However, there are few reports evaluating the long-term outcomes of VMAT. Thus, we evaluated the survival and toxicity outcomes of anal cancer patients treated in our regional cancer centre undergoing curative intent chemoradiotherapy using VMAT and following the Australian EviQ guidelines. All consecutive patients treated with the VMAT technique for curative-intent definitive chemoradiotherapy for anal SCC at our institution from 2013 until 2022 were retrospectively reviewed for survival and toxicity outcomes. Kaplan-Meier estimates of locoregional control, distant metastasis-free survival, disease-free survival, anal cancer-specific survival and overall survival were obtained. In total, 44 patients were analysed. The median follow-up was 48.9 months (Range 7.8-107). 97.7% of patients completed the prescribed radiation therapy and 88.6% chemotherapy. Five patients (11.4%) recurred. Four (9.1%) had isolated local failures, and one (2.3%) had an isolated distant failure. There were no regional nodal failures. The Kaplan-Meier estimates for locoregional control, distant metastasis-free survival, disease-free survival, anal cancer-specific survival and overall survival were 90.3%, 97.7%, 88.1%, 97.1% and 87% at 3 years, and 90.3%, 97.7%, 88.1%, 93.0% and 72.3% at 5 years, respectively. Acute grade 3 genitourinary (GU), gastrointestinal (GI) and skin toxicities occurred in 2.2%, 6.8% and 13.6% of patients, respectively. There were no acute grade 4 toxicities. Late grade 2 GU and GI toxicities occurred in 6.8% and 11.3% of patients, respectively. There were no late grade 3 or 4 toxicities or treatment-related deaths. The 5 -year colostomy-free survival rate was 86.4%. Outcomes for anal SCC after definitive chemoradiotherapy using VMAT in our regional cancer centre results in low rates of grade 3/4 toxicity, high rates of organ preservation and excellent survival outcomes.

Simultaneous Integrated Boost (SIB) Versus Sequential Boost in Anal Cancer Patients: A Single-Center Experience.

Concurrent chemoradiation is the standard of care for the treatment of anal cancer. Radiation can be delivered by sequential or simultaneous integrated boost (SIB) approach. The present study was conducted to compare the treatment outcomes and toxicity profile of patients with anal cancer treated with sequential boost and SIB approach. A single-institution retrospective analysis of patients with squamous cell carcinoma of the anal canal treated between 2019 and 2022 with radical chemoradiation was performed. The sequential boost schedule consisted of 45Gy in 25 fractions (1.8Gy daily) to the gross tumor, nodes, and elective nodal volume, followed by a 9Gy in five fractions boost to the gross disease. Patients receiving SIB were treated as per RTOG 0529 protocol. In both the groups, patients were treated with volumetric modulated arc therapy (VMAT). The two groups were compared in terms of overall survival (OS), colostomy-free survival (CFS), relapse-free survival (RFS), and acute toxicity profile. p-values < 0.05 were considered statistically significant. The patient and disease characteristics in both treatment arms were comparable. The only difference was a significantly longer overall treatment time of ≥ 50days in the sequential arm (77.8% vs 43.8%, p = 0.04). The median follow-up was 18months. The 2-year CFS was 80% in sequential vs 87.5% at 2years for the SIB arm, 2-year OS 83.3% vs 58.6%, and 2-year RFS was 38.9% vs 41.7%, respectively. A total of 14 (77.8%) in sequential and 8 (50%) in the SIB arm had disease relapse. On univariate analysis, the involved pelvic lymph node significantly affected OS (HR 10.45, p = 0.03) while inguinal lymph node involvement adversely affected RFS (HR 6.16, p = 0.02). The most common acute toxicity was radiation-induced dermatitis, 15 (83.4%; 5 grade II, 10 grade III) in sequential vs 7 (43.8%; 3 each grade II and III) in the SIB group followed by hematological (61.1% vs 68.75%). However, the incidence of overall acute toxicities was significantly less in the SIB arm (p = 0.006). Our study showed that concurrent chemoradiation with the SIB-VMAT approach is well tolerated in patients of anal carcinoma and resulted in lesser treatment interruptions and comparable outcomes as compared to the sequential approach. Our results warrant further evaluation in a prospective study.

Management of non-metastatic anal cancer in the elderly: ancillary study of the French multicenter prospective cohort FFCD-ANABASE.

Standard care for non-metastatic squamous cell carcinoma of the anus (SCCA) is chemoradiotherapy, data about elderly patients are scarce. All consecutive patients treated for non-metastatic SCCA from the French multicenter FFCD-ANABASE cohort were included. Two groups were defined according to age: elderly (≥75 years) and non-elderly (<75). Of 1015 patients, 202 (19.9%) were included in the elderly group; median follow-up was 35.5 months. Among the elderly, there were more women (p = 0.015); frailer patients (p < 0.001), fewer smokers (p < 0.001) and fewer HIV-infected (p < 0.001) than in the non-elderly group. Concomitant chemotherapy and inguinal irradiation were less frequent (p < 0.001 and p = 0.04). In the elderly group; 3-year overall survival (OS), recurrence-free survival (RFS) and colostomy-free survival (CFS) were 82.9%, 72.4% and 78.0%, respectively; complete response rate at 4-6 months was 70.3%. There were no differences between groups for all outcomes and toxicity. In multivariate analyses for the elderly, PS ≥ 2 and locally-advanced tumors were significantly associated with poor OS (HR = 3.4 and HR = 2.80), RFS (HR = 2.4 and HR = 3.1) and CFS (HR = 3.8 and HR = 3.0); and treatment interruption with poor RFS (HR = 1.9). In the FFCD-ANABASE cohort, age did not influence tumor and tolerance outcomes of non-metastatic SCCA. Optimal curative treatment should be offered to elderly patients.

High-tailored Anal Canal Radiotherapy (HIT-ART): Outcomes of a 10-Year Single Center Clinical Experience.

The current standard for anal cancer treatment is essentially a 'one size fits all' approach where the dose of radiotherapy is similar whether the tumor is very small or very large. Trials are ongoing to evaluate dose de-escalation or escalation in localized disease depending on tumor size. The aim of the study was to assess results of a personalized approach involving dose stratification by stage and boost dose adjusted according to tumor early response. We retrospectively reviewed squamous cell anal cancer (SCAC) patients treated between 2011 and 2021 by long-course intensity-modulated radiotherapy (IMRT) and concomitant chemotherapy (CT); a sequential boost could be administered by IMRT or interventional radiotherapy (IRT) to obtain a total equivalent dose in 2 Gy (EQD2) of 54-60 Gy. We analyzed 110 patients (61% T3-4 stage, 71% node-positive). A total of 68.2% of patients received a sequential boost, mainly by IRT; median total EQD2 to primary site was 59.3 Gy. Acute ≥G3 toxicity rate was 36.4%. Median follow-up (FUP) was 35.4 months. A total of 83% of patients achieved clinical complete response (cCR); locoregional recurrence (LRR) occurred in 20.9% and distant metastases in 6.4% of cases. A total of 12.7% patients underwent salvage surgery. A total of 25.5% of patients reported ≥G2 and 4.5% ≥G3 late toxicity. The estimated 3-year overall survival, disease-free survival and colostomy-free survival were 92%, 72% and 84% respectively; 3-year-LRR was 22%. Nodal stage was associated with poorer cCR probability and higher LRR (p<0.05). Our results on a large cohort of patients with locally advanced SCAC and long FUP time confirmed the efficacy of IMRT; high local control and manageable toxicity also suggest IRT as a promising method in treatment personalization.

Real-World Experience of Intensity Modulated Radiation Therapy and Concurrent Chemotherapy for Anal Cancer with Long-Term Follow up and Clinical Outcomes

The standard treatment for epidermoid anal cancer (AC) is concurrent chemoradiation (CRT). Here we present real world evidence of the safety and outcomes of AC patients managed by IMRT and concurrent chemotherapy at a single academic cancer center. We retrospectively reviewed the outcomes of 180 AC patients treated with definitive CRT between 2011 and 2018. Patients were managed according to a prospectively designed protocol of IMRT with radiation dose escalated according to tumor stage: 50.4, 55.8 and 63 Gy for T1, T2 and T3/T4 disease respectively, and 36 Gy for elective nodal RT. Involved nodes were given the same dose based on T category. Concurrent chemotherapy consisted of two cycles of mitomycin C (MMC, 12 mg/m2) and 5-fluorouracil (5FU, 1000 mg/m2/day x 4 days) given on week 1 and 5. There was no planned treatment break. Univariate and multivariate analysis for outcomes were performed using Cox proportional hazard method and likelihood ratio statistics. Overall survival (OS) disease free (DFS), colostomy-free survival (CFS) and local failure rates (LFR) were described by Kaplan-Meier methods. There were 128 female and 52 male patients with a median age of 64 (IQR 55-74). The median size of the primary was 4.0 cm (0.6-11.0 cm). There were 18 T1, 91 T2, 38 T3 and 33 T4 lesions; 50.6% (91/180) of the patients had N0 disease. Thirteen (7.2%) did not receive concurrent chemotherapy, and 16 (8.9%) failed to complete treatment as planned. Forty-three (23.9%) patients had a treatment gap >5 (6-33) days. Eighteen of 147 (12%) with T1-3 disease failed locally, LF was observed in 13/33 (39%) T4 lesions (P = 0.0002). The 5-year OS, DFS, CFS and LFR were 85.1%, 75.6%, 87.6% and 15.5% respectively. On multivariate analysis, increasing age and N+ disease were significant for worse OS, and increasing size of the primary tumor was the only significant factor for worse DFS, CFS and LFR. Grade ≥3 acute toxicities were observed in 42.8% of patients, with grade ≥3 neutropenia and febrile neutropenia observed in 18.9% and 13.9% of patients respectively. Six patients (3.3%) died of acute toxicities. Thirteen (7%) patients experienced grade ≥3 late toxicities. Size of the primary appears to be the most important determinant of outcome following standard CRT using IMRT for AC. Despite IMRT, almost 1 in 4 patients required a treatment break, and over 40% experienced grade ≥3 acute toxicities including neutropenia and febrile neutropenia. Future studies with RT dose escalation or de-escalation, stratifying patients based on tumor size, HPV status and molecular markers are necessary to improve outcomes and decrease treatment related toxicity.

Capecitabine/Mitomycin versus 5-Fluorouracil/Mitomycin in Combination with Simultaneous Integrated Boost Intensity-Modulated Radiation Therapy for Anal Cancer.

Since EXTRA, a non-randomized phase II trial with 31 patients, explored the use of capecitabine, mitomycin and radiation therapy (RT) in the treatment of localized squamous cell carcinoma of the anal canal (SCCAC), this treatment has been considered as an acceptable alternative to infusional 5-FU. However, the differences in efficacy between capecitabine and 5-FU in chemoradiation therapy (CRT) with simultaneous integrated boost (SIB) radiation therapy (SIB-IMRT) for local SCCAC are not well documented. Patients included in this prospective monocentric cohort study were treated with SIB-RapidArc (a unique RT method treatment for all patients: identical technique, volume and constraints for at-risk organs), mitomycin C and 5-FU each day of RT for 7 weeks (group 1) or capecitabine each day of RT (group 2). Patients treated between July 2009 and August 2017 (group 1) and between November 2012 and April 2018 (group 2) for local SCCAC T2-4 classified as N, M0 or T, N1-3, M0 were included. Primary endpoints were progression-free survival (PFS) and acute toxicities. Results: One hundred forty-seven patients were included, 91 in group 1 and 56 in group 2. The two groups were statistically comparable in terms of sex, Eastern Cooperative Oncology Group Performance Status (ECOG PS) and TNM. With a median duration of follow-up of 53.5 months, the PFS rate at 3 years was 80% for group 1 and 75% for group 2 (p = 0.32). The 3-year colostomy-free survival rate was 92% for group 1 and 85% for group 2 (p = 0.11). The rate of patients with at least one grade 3 or higher acute toxicity was 35.5% in group 1 and 21.4% in group 2 (p = 0.10), with a trend of fewer acute toxicities with capecitabine. Conclusion: Capecitabine/mitomycin in combination with SIB RapidArc radiation therapy for anal cancer seems as effective as 5-FU-based chemotherapy and is well tolerated with minimal toxicity.

Capecitabine/cisplatin combined with concurrent intensity-modulated radiation therapy: a feasible therapeutic strategy for anal squamous cell carcinoma.

To evaluate the efficacy and safety of capecitabine/cisplatin (XP) combined with intensity-modulated radiation therapy (IMRT) in patients with non-metastatic anal squamous cell carcinoma (ASCC). All patients with ASCC who received radical concurrent chemoradiotherapy in the past 8years were screened. Patients who received XP or mitomycin/5-fluorouracil (MF) were selected and analyzed retrospectively. ASCC is an uncommon cancer, there were 36 patients were included in our study. The XP group and MF group included 18 patients each. The clinical complete response (cCR) rates in the XP group and the MF group were 94.4% and 88.9%, respectively (P = 1). The 2-year local control (LC), disease-free survival (DFS), and colostomy-free survival (CFS) rates were higher in the XP group than in the MF group (100% vs 93.3%, P = 0.32). Hematologic toxicities, especially grade ≥ 3 leukopenia (11.1% vs 44.4%, P = 0.06) and neutropenia (5.6% vs 61.1%, P = 0.001), were lower in the XP group than MF group. As a result of fewer side effects, fewer patients in the XP group demanded the dose reduction of chemotherapy (11.1% vs 50%, P = 0.03) and radiation interruption (55.6% vs 77.8%, P = 0.289). Delayed radiotherapy was shorter in the XP group (2.5 vs 6.5days, P = 0.042) than in the MF group. The XP regimen was as effective as the MF regimen in non-metastatic ASCC. Compared with the standard MF regimen, XP combined with IMRT showed higher treatment completion and lower toxicities. It could be considered a feasible alternative for patients with non-metastatic ASCC.

Panitumumab in combination with chemoradiotherapy for the treatment of locally-advanced anal canal carcinoma: Results of the FFCD 0904 phase II trial

Background and purposeStandard treatment of squamous cell carcinoma of the anus (SCCA)is 5-fluorouracil (5FU) and mitomycin C (MMC) based chemoradiotherapy (CRT). This phase II study (EudraCT: 2011–005436-26) assessed the tolerance and complete response (CR) rate at 8 weeks of panitumumab (Pmab) combined with MMC-5FU-based CRT. MethodsPatients with locally advanced tumors without metastases (T2 > 3 cm, T3-T4, or N + whatever T stage) were treated with IMRT up to 65 Gy and concomitant CT according to the doses defined by a previous phase I study (MMC: 10 mg/m2; 5FU: 400 mg/m2; Pmab: 3 mg/kg). The expected CR rate was 80%. ResultsForty-five patients (male: 9, female: 36; median age: 60.1 [41.5–81]) were enrolled in 15 French centers. The most common related grade 3–4 toxicities observed were digestive (51.1%), hematologic (lymphopenia: 73.4%; neutropenia: 11.1%), radiation dermatitis (13.3%), and asthenia (11.1%) with RT interruption in 14 patients. One patient died because of mesenteric ischemia during the CRT, possibly related to treatment. In ITT analysis, the CR rate at 8 weeks after CRT was 66.7% [90%CI: 53.4–78.2]. Median follow-up was 43.6 months [IC 95%: 38.61–47.01]. Overall survival, recurrence-free and colostomy-free survival at 3 years were 80% [95%CI: 65.1–89], 62.2% [IC95%: 46.5–74.6] and 68.8 % [IC95%: 53.1–80.2] respectively. ConclusionPanitumumab in combination with CRT for locally advanced SCCA failed to meet the expected CR rate and exhibited a poor tolerance. Furthermore, late RFS, CFS, and OS did not suggest any outcome improvement to justify further clinical trials.ClinicalTrials.gov identifier: NCT01581840.

Anal carcinoma: A retrospective analysis in a Mexican cohort.

e15502 Background: Anal carcinoma is a rare neoplasm, representing &lt; 1% of all neoplasms with rising incidence and mortality. More than 90% of cases are linked with high-risk human papillomavirus (HPV). Other factors such as HIV status, smoking and socioeconomic disparity may have important roles. Few data are available on the Mexican population. Methods: Retrospective analysis of patients with pathology-confirmed anal carcinoma treated at an Oncology Reference Center in North-East Mexico from 2010 to 2020. Using descriptive statistics, we report clinical and pathological features, time from symptom onset to diagnosis and treatment, as well as response and recurrence rate. Results: Forty-one patients were included in the final analysis. The mean age at diagnosis was 61.4 +/- 13.8 years and 58.5% were women. Smoking history was identified in 17 patients (41.5%). 9.8% were HIV-positive, however 63.4% of all patients had unknown status at cancer diagnosis. Mean duration of symptoms to diagnosis was 344 days (range 4-1435 days) and the median interval from symptom onset to registration for oncology consultation was 424 days (range 28-1695 days). Patients attended a median of 3 (range 1 to 7) previous clinical consultations before being referred to our center. It is noteworthy that 44% of patients had hemorrhoidal disease history. Squamous cell carcinoma was the most common histological subtype with 93% of all cases, arising from the anal canal in 78% of cases, while 22% corresponded to perianal cancer. Regarding the clinical stage at presentation, 2.4% of patients had localized disease, while 95% had regional spread and 2.4% presented with distant metastases at diagnosis. Treatment intent was curative in 85.4%. Treatment modalities included radiotherapy (97%), surgery (7%), chemotherapy (88%). Concurrent chemoradiotherapy was received by 85%. Most patients were treated with a total dose between 45 and 60 Gy to the tumor volume. Radiotherapy delays due to toxicity occurred in 31.7% of cases, these unplanned treatment interruptions correlated negatively with response rate (p &lt; 0.001). The chemotherapy regimen used was 5-fluorouracil (5-FU) with mitomycin C (MMC) in 29%, capecitabine monotherapy in 31.7%, 5-FU with cisplatin in 12.5%, capecitabine with MMC in 5%, and capecitabine with cisplatin in 5%. Among patients treated with curative-intent, 46% had a complete response and 37% had a partial response. Relapse occurred in 10 cases (24%), the majority being local relapses (54%). Distant relapse occurred in 15% of all cases. The median disease-free interval (DFI) was 32.5 months (range 0-252 mo). Colostomy rate was 29%, the median colostomy-free survival (CFS) was 10 months (range 3-15 mo). The comparative analysis between MMC-based chemotherapy and chemo without MMC did not show difference in response rate, recurrence, DFS and CFS. Conclusions: Due to its rarity and complex management patients with anal carcinoma should be treated at experienced centers.

Atezolizumab plus tiragolumab in combination with chemoradiotherapy in localized squamous cell carcinoma of the anal canal: TIRANUS (GEMCAD-2103) trial.

TPS3624 Background: Radical chemoradiotherapy (CRT) is the standard of care in patients with localized anal squamous cell carcinoma; however, around 30% of patients do not achieve a complete clinical response (CCR) and require savage surgery. Approximately 84% of anal carcinoma is associated with high risk types of human papilloma virus (HPV), primarily HPV 16 that generates high frequencies of tumor-infiltrating lymphocytes and inflammatory responses that have been linked with upregulation of PD-L1 (up to 74% of patients with squamous cell anal cancer). Additionally, poliovirus receptor (PVR) expression has been described in several squamous cell carcinomas, and has been correlated with PD-L1 expression and poorer prognosis, suggesting dual inhibition of PVR and PD-L1 as a potential mechanism of overcome the resistance to immune checkpoint monotherapy. Moreover, CRT induces the generation of tumor-neoantigens and could act in synergy with immunotherapy in this setting. The trial hypothesizes that the addition of atezolizumab (anti-PD-L1) and tiragolumab (anti-TIGIT) to chemoradiotherapy may lead to enhanced and more durable responses. Methods: TIRANUS is a Phase II, single-arm, open-label, non-randomized, multicenter clinical trial of atezolizumab and tiragolumab in concomitance with standard CRT as definitive therapy in treatment-naïve, localized squamous cell carcinoma of the anal canal. Patients receive atezolizumab (1200mg) plus tiragolumab (600 mg) for 2 cycles (Q3W) in concomitance with the 6 weeks of CRT (cisplatin: 60 mg/m² on days 1 and 29; 5-FU: 1000 mg/m² per day on days 1-4 and 29-32; radiotherapy: 1.8 Gy per day / total dose 54 Gy). After the concomitant phase, patients receive atezolizumab (1200mg) and tiragolumab (600 mg) Q3W for 6 additional cycles (consolidation phase). The primary endpoint is CCR rate, defined as the percentage of patients who achieve radiological complete response (CR), disappearance of all lesions according to RECIST 1.1 criteria (locally assessed) and no presence of residual disease assessed by biopsy at the end of consolidation phase (week 26). Secondary endpoints include Locoregional failure rate (LFR), Disease-free survival (DFS), Colostomy-free survival (CFS), Overall survival (OS), quality of life, safety and the determination of immune biomarkers potentially predictors of response in blood and tumor samples. Using a precision analysis by Clopper-Pearson method (asymptotic 95% confidence interval) and an expected CCR rate of 85%, a total of 45 evaluable patients are needed to obtain a precision estimation of ±10.4%. Accrual started in February 2023. EudraCT: 2021-005887-24 Clinical Trial identifier: NCT05201612. Clinical trial information: NCT05661188 .

Intensity-modulated radiotherapy and cisplatin-based chemotherapy for anal cancer: long-term outcomes at a single institution.

To evaluate oncological outcomes and late toxicities in a retrospective series of patients with locally-extended anal squamous cell carcinoma (ASCC), treated with curative Intensity Modulated Radiotherapy (IMRT) and chemotherapy. ASCC patients who underwent chemo-radiotherapy with IMRT from 2010 to 2020 were included. Oncological outcomes were assessed in terms of overall survival (OS), disease-free survival (DFS), colostomy-free survival (CFS) and event-free survival (EFS). Late toxicity was detected according to CTCAE v.5.0 and RTOG late radiation morbidity scoring system. Ninety-five patients were included. Most patients (83%) received chemotherapy with oral Fluoropyrimidine plus Cisplatin. The median follow-up was 5.5years. The OS was 85.2%, 82.1% and 79.3% at 3, 5 and 8years, respectively. The DFS was 73.1%, 70%, and 65.3% at 3, 5 and 8years, respectively; 3, 5 and 8years CFS was 86.2%, 84.3% and 84.3%, respectively. The EFS was 71%, 67.9% and 63.1%, at 3, 5 and 8years, respectively. On univariable analysis, a statistically significant lower OS was found for patients with T3-T4 stage (HR = 4.58, p = 0.005) and overall treatment time (OTT) ≥ 47days (HR = 3.37, p = 0.038). A statistically significant lower DFS was reported for patients with T3-T4 stage (HR = 2.72, p = 0.008) and Serum Squamous Cell Carcinoma Antigen (SCC) value post-RT > 1.5 (HR = 2.90, p = 0.038.). Ten severe late toxicity (≥ G3) events were reported in 8 patients (8.6%). Our data confirm IMRT concomitant with a Cisplatin-based chemotherapy as an effective treatment of ASCC, ensuring acceptable long-term toxicities and good oncological outcomes.

The impact of brachytherapy boost for anal canal cancers in the era of de-escalation treatments

PURPOSETo analyze clinical outcomes of high-dose-rate (HDR) interstitial brachytherapy boost (ISBT) after external beam radiation therapy (EBRT) or chemoradiotherapy (CRT) for the treatment of anal canal cancers (ACC). METHODS AND MATERIALSA total of 78 patients with ACC were treated at our institution by ISBT. Local Control (LC), disease-free survival (DFS), overall survival (OS), colostomy-free survival (CFS) and toxicity rates were analyzed. RESULTSWith a median followup (FU) of 59.8 months (95% CI [55.8–64.2]), six (7.7%) local recurrences with 2 patients (2.6%) having persistent disease at 3 months were observed. The 5-year rate of LC for the entire population was 92% [83–96%]. The 5-year DFS rate was 86% [76–93%]. The 5-year OS was 96% [88–99%]. In the univariate analysis, chemotherapy was significantly associated with morbidity grade ≥2. Late digestive toxicity grade ≥3 was reported in 8.9% patients, 1 patient underwent colostomy due to toxicity. The 5-year CFS rate was 88% [79–94%]. CONCLUSIONSHDR interstitial brachytherapy boost provide excellent rates of tumor control and colostomy-free survival with a favorable profile of GI toxicity. Continence in anal cancer survivors is a challenge and the boost technique must be discussed in a multidisciplinary approach as part of de-escalation treatments.

Impact of dose escalation on colostomy-free survival and treatment outcome in squamous cell anal carcinoma

PurposePrimary radiochemotherapy (RCT) constitutes the standard of care for early- and advanced-stage anal carcinoma. This retrospective study investigates the impact of dose escalation on colostomy-free survival (CFS), overall survival (OS), locoregional control (LRC), progression-free survival (PFS), and acute and late toxicities in patients with squamous cell anal cancer.MethodsConsidered were the outcomes of 87 patients with anal cancer treated with radiation/RCT between May 2004 and January 2020 at our institution. Toxicities were evaluated according to the Common Terminology Criteria for Adverse Events (CTCAE version 5.0).ResultsThe 87 patients received treatment with a median boost of 63 Gy to the primary tumor. With a median follow-up of 32 months, the 3‑year CFS, OS, LRC, and PFS were 79.5%, 71.4%, 83.9%, and 78.5%, respectively. Tumor relapse occurred in 13 patients (14.9%). Dose escalation to > 63 Gy (maximum 66.6 Gy) to the primary tumor in 38/87 patients revealed a nonsignificant trend for improved 3‑year CFS (82.4% vs. 97%, P = 0.092), a significantly improved CFS for T2/T3 tumors (72.6% vs. 100%, P = 0.008), and a significantly improved 3‑year PFS for T1/T2 tumors (76.7% vs. 100%, P = 0.035). While acute toxicities did not differ, dose escalation > 63 Gy led to a higher rate of chronic skin toxicities (43.8% vs. 69%, P = 0.042). Treatment with intensity-modulated radiotherapy (IMRT) showed a significant improvement in 3‑year OS (75.4% vs. 53.8%, P = 0.048). In multivariate analysis, significant improvements for T1/T2 tumors (CFS, OS, LRC, PFS), G1/2 tumors (PFS), and IMRT (OS) were shown. The nonsignificant trend for CFS improvement with dose escalation > 63 Gy was also apparent in multivariate analysis (P = 0.067).ConclusionDose escalation > 63 Gy (maximum 66.6 Gy) may improve CFS and PFS for certain subgroups, with a concomitant increase in chronic skin toxicities. Modern IMRT seems to be associated with an improvement in OS.