Squamous Cell Carcinoma Of The Anal Canal Research Articles

Definitive Intensity-Modulated Radiation Therapy For Anal Squamous Cell Carcinoma: Outcomes And Toxicities From A Large Single Institution Experience

To describe outcomes and toxicities of a large single institution cohort of patients with anal squamous cell carcinoma (SCC) treated with intensity-modulated radiation therapy (IMRT). Patients treated with definitive intent IMRT for anal SCC at our institution from 2005 to 2018 were identified. Actuarial control and survival rates for locoregional control (LRC), freedom from distant metastasis (FDM) and disease-free (DFS), colostomy-free (CFS), and overall (OS) survival were calculated by the Kaplan-Meier method. Acute and late toxicities were assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. Three hundred thirty-two consecutive patients with a median follow-up of 36 months were treated with definitive intent IMRT for anal SCC from 2005 to 2018 at a single institution. The cohort included 243 (73%) women and 89 (27%) men with median age of 60 years with 49 (15%) stage I, 78 (24%) stage II, and 205 (62%) stage III disease. Median dose to the primary tumor was 50, 54, and 56 Gy for stage I, stage II, and stage III disease, respectively. Of the 158 patients tested for HPV, 87% were positive for either p16, HPV, or both by immunostaining and/or in-situ hybridization. 327 (99%) patients received concurrent chemotherapy largely consisting of mitomycin in combination with fluoropyrimidine (N = 316; 97%). The actuarial 3-year LRC, FDM, DFS, CFS, and OS rates were 87%, 88%, 77%, 82%, and 88%, respectively. Patients who developed a locoregional recurrence had worse FDM (57% vs. 92%, p<0.001), CFS (16% vs. 91%, p<0.001) and OS (53% vs. 92%, p<0.001) at 3 years as compared to patients without locoregional recurrence. Of the 37 patients with locoregional recurrent disease, 25 (68%) underwent salvage surgery, which resulted in no difference in FDM (57% vs. 62%, p = 0.463) but improved OS (62% vs. 39%, p = 0.016) as compared to patients with locally recurrent disease managed non-operatively. In comparison to patients without locoregional recurrence, surgical salvage patients had significantly worse FDM (64% vs. 92%, p<0.001) and OS (62% vs. 92%, p<0.001). Grade 3+ acute toxicity included dermatitis (11%), proctitis (2%), diarrhea (2%), fatigue (2%), nausea (1%), oral mucositis (<1%), and cystitis (<1%). Late grade 2+ toxicity rate was 12%. IMRT provides excellent clinical outcomes for patients with SCC of the anal canal with manageable acute and acceptable rates of late toxicity. Patients with locoregional recurrence had worse overall survival. While, surgical salvage was effective in approximately 70% of patients with locoregional recurrence, these patients remained at higher risk for distant metastatic disease and death. Upfront locoregional control correlates with long term survival in patients with anal SCC.

Definitive Intent Locoregional IMRT In Oligometastatic Anal Squamous Cell Carcinoma

The role of locoregional intensity modulated radiation therapy (IMRT) in patients with metastatic anal squamous cell carcinoma (SCC) remains undefined. There is growing evidence of the potential benefit of local therapy even in the setting of oligometastatic disease to prevent the morbidity of uncontrolled pelvic disease. We queried an institutional database of 358 consecutive patients with SCC of the anal canal treated with definitive intent pelvic IMRT from 2005 to 2018 to identify patients with de novo metastatic disease. Locoregional control (LRC), progression-free survival (PFS), and overall survival (OS) were computed using the Kaplan-Meier method. Acute and late toxicities were assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. Twenty-five patients with a median follow-up of 26 months including 19 (76%) women and 6 (24%) men with a median age of 60 years comprised the evaluable cohort. Eight (32%) patients had a solitary metastasis, 10 (40%) had two metastatic lesions, 2 (8%) had three metastatic lesions, 5 (20%) had four or more metastatic lesions. Non-regional lymph nodes were the most common site of metastatic disease (N = 16, 49%) followed by liver (N = 10, 30%), lung (N = 4, 12%), and others (N = 3, 9%). Sixteen patients had HPV related disease and 3 patients were HIV+. The median dose to the primary tumor was 56Gy (range, 50-58Gy) in a median of 28 fractions (range, 25-29) over a median of 39 elapsed days (range, 35-55). Twelve (48%) patients received induction chemotherapy and all patients received concurrent chemotherapy predominately mitomycin and capecitabine based. Twenty-one (84%) patients had metastatic-directed ablative therapy which included radiation (N = 20, 80%) and IR-ablation (N = 1, 4%). No patients underwent metastasectomy or received additional chemotherapy, targeted therapy, or immunotherapy prior to progression of disease. The 3-year LRC was 81%, PFS was 27%, and OS was 53%. In comparing patients with non-regional lymph node involvement to patients with visceral organ involvement there was no significant difference in LRC (86% vs. 79%, p = 0.950) but a trend for improved PFS (71% vs. 18%, p = 0.069) and OS (86% vs. 49%, p = 0.365). Grade 3+ acute toxicity included dermatitis (12%), proctitis (4%), and diarrhea (4%). Late grade 2+ toxicity rate was 12%. Definitive intent pelvic IMRT provides excellent locoregional control in patients with oligometastatic anal SCC. Local and extended regional nodal radiation is important to prevent the significant morbidity of uncontrollable pelvic disease given durable PFS and OS in patients with oligometastatic anal SCC.

P-54 BISQUIT: A randomized phase II study of the administration of prebiotics and probiotics during definitive treatment with chemotherapy-radiotherapy for patients with squamous cell carcinoma of the anal canal

The standard treatment for patients (pts) with localized squamous cell carcinoma of the anal canal (SCCAC) is chemoradiation (ChRT). Yet nearly 30% of patients do not respond or will recur and have to undergo salvage anorectal amputation. SCCAC is mostly a virus-associated tumor and thus potentially immunogenic. In fact, immune checkpoint inhibitors seem promising in trials of metastatic SCCAC. Recently, studies have shown that the composition of the intestinal microbiota influences the onset of colorectal cancer and response to immunotherapy in some solid tumors, and the replacement of the intestinal

P-240 Anal cancer treatment: Major reduction of acute toxicity with an approach using 4-fractions-per-week

The purpose of our study was to report the long-term excellent outcome in patients with squamous cell carcinoma of the anal canal (SCCA), who were treated with definitive chemo-radiotherapy (CRT) using an innovative approach of 4-fraction-per-week and conventional 3D radiotherapy technique. Twenty-four patients who received definitive chemo-radiotherapy from January 2013 to December 2018 were included in this study. All patients received 5-fluorouracil with mitomycin C as this has been our institutional practice. No patients received cisplatin. All 24 patients were treated with conventional radiotherapy technique. The median dose was 5400 cGy (range = 5220-5580 cGy). Median follow-up was 36 months. All 24 patients were treated using a modified regimen of 5 fractions only for the first week, followed by 4 fractions per week thereafter (Fridays off starting the second week of treatment with no planned break). For a few patients receiving the highest dose of 5580 cGy in 31 fractions, this was equivalent to 7.5 weeks or 51 days. Acute skin toxicity was: grade I: 21 patients (88%), grade II: 3 patients (12%), with no grade III or IV skin toxicity. Acute hematologic toxicity: grade I: 16 patients (66%), grade II: 7 patients (29%), with no grade III or IV hematologic toxicity. Acute GI toxicity: grade I: 14 patients (58%), no grade II, III or IV GI toxicity. All patients completed treatment as prescribed. Treatment compliance was 100%. No patients required hospitalization from side effects of chemo-radiotherapy treatment. This innovative approach of 4-fraction-per-week using conventional 3D radiotherapy technique was initially conceived to reduce skin toxicity. Interestingly, in addition to a significant reduction of acute skin toxicity, hematologic, and GI toxicity was also greatly reduced, with virtually no need for treatment breaks, and yielded excellent local-regional control and overall survival when compared with known randomized RTOG studies. This innovative approach of 4-fraction-per-week deserves further study by individual investigators and/or appropriate clinical trials.

P-341 Capecitabine/mitomycin versus 5-fluorouracil/mitomycin in combination with simultaneous integrated boost-intensity modulated radiation therapy for anal cancer

Within the past decade, several studies have tested capecitabin as a substitute for 5-FU in the treatment of localised squamous cell carcinoma of the anal canal (SCCAC) and reported similar clinical response rates, making capecitabin an acceptable and more convenient alternative to infusional 5-FU. However, the differences in efficacy between capecitabine and 5-FU in CRT with simultaneous integrated boost-intensity modulated radiation therapy (SIB-IMRT) for locally SCCAC are not documented. We performed this retrospective study to compare the response of capecitabine and 5-FU in survival and toxicity terms in patients with locally SCCAC treated with concurrent SIB-IMRT.

Prospective study of biomarkers in squamous cell carcinoma of the anal canal (SCCAC) and their influence on treatment outcomes: Five-year long-term results.

4053 Background: Chemoradiation (CRT) is a curative treatment for SCCAC. However, some patients (pts) present primary CRT resistance. As a rare tumor, there is a lack of prospective studies of prognostic factors in this setting. Methods: This prospective cohort study was aimed to evaluate predictive biomarkers (Ki-67, PD-L1, Human papillomavirus (HPV), HIV status, and tumor DNA mutations) in SCCAC. We published the 6 months (m) response rate (RR) of this cohort showing that HIV- were 5.7 times more likely to achieve response 6m post CRT (OR 5.72, CI 95% 2.5-13.0, P &lt; 0.001). Now we report the long-term follow-up results of 5-year progression-free survival (PFS) and overall survival (OS). Eligible pts had T2-4/N0-3/M0 disease and were candidates to standard CRT. DNA mutations were analyzed by next-generation sequencing (NGS). HPV positivity was tested by PapilloCheck Test. KI-67 and PD-L1 were evaluated by immunohistochemistry. Results: 78 pts were recruited from Jan/2011 to Dec/2015. 75 were evaluable for PFS and OS. The median age was 57 years; 49 (65%) were stage III, and 9 (12%) were HIV+. HPV was evaluated in 67 and found in 47 (70.1%); HPV16 was the most common. PD-L1 was tested in 61; 10 (16.4%) had positive expression &gt; 1%. Ki-67 was performed in 65, with a median of 50% (range 1-90%). The median follow up is 66m. 5-year PFS and OS rates were 63.3% (95% CI 51.2-73.2%) and 76.4% (95% CI 64.8-84.6%), respectively. In a multivariate analysis, age (HR 1.06, P = 0.022, IC 95% 1.01-1.11) and absence of complete response at 6m (HR 3.36, P = 0.007, IC 95% 1.39-8.09) was associated with inferior OS. The OS rate was 62.5% in HIV+ group (95% CI 22.9-86%) in comparison with 78% (95% CI 65.7-86.3%) among HIV- pts, although this difference was not statistically significant (P = 0.400). A tendency to inferior OS was observed among pts with p53 codon 72 polymorphism (HR 2.83, P = 0.181, 95% CI 0.61-13.02). Other tumor mutations, HPV, Ki-67 expression, and PD-L1 expression, were not associated with PFS and OS. Conclusions: HIV- pts were 5.7 times more likely to achieve response 6m post CRT. The absence of complete response at 6m was the main factor associated with poor 5-year OS. New strategies of follow up and complementary treatment should be studied in late responders and HIV+ pts to ensure the success of curative treatment. Clinical trial information: 36211 .

Disease-Free Survival and Time to Complete Response After Definitive Chemoradiotherapy for Squamous-Cell Carcinoma of the Anus According to HIV Infection

BackgroundThe standard treatment for localized squamous-cell carcinoma of the anal canal is definitive chemoradiotherapy. A meta-analysis of published studies conducted by our group showed significantly lower rates of disease-free survival (DFS) and overall survival at 3 years among HIV-positive patients. We aimed to compare detailed treatment outcomes between the groups of HIV-positive and -negative patients. Patients and MethodsWe performed a retrospective multicenter study of a comparative cohort of consecutive patients with histologic diagnosis of localized squamous-cell carcinoma of the anal canal who received definitive chemoradiotherapy. Patients’ characteristics and outcomes were compared according to HIV status. The primary end points were time to complete response (CR) and DFS time. ResultsFrom June 2001 to September 2018, a total of 185 patients were included; 43 (30.2%) were HIV positive and 142 (69.8%) were HIV negative. The overall CR rates were 67.4% and 91.5% for HIV-positive and -negative patients, respectively (P < .001). The median follow-up was 47.8 months and the median time to experience CR was 7.8 months (95% confidence interval [CI], 5.7-10.5) for HIV-positive versus 4.89 months (95% CI, 4.54-5.25) for HIV-negative (P < .001) patients. The median DFS times were 79.7 months (95% CI, 56.8-102.6) and 127.9 months (95% CI, 112.6-143.2) for HIV-positive and -negative patients, respectively (P = .02). There was a trend toward greater grade 3/4 toxicity in the HIV-positive group. ConclusionHIV-positive patients take longer to experience CR and present worse DFS. These findings have clinical implications because waiting longer to define CR among these patients may prevent unnecessary anorectal amputations.

Long-term follow-up experience in anal canal cancer treated with Intensity-Modulated Radiation Therapy: Clinical outcomes, patterns of relapse and predictors of failure

Background and purposeTo assess the long-term outcomes of patients with squamous cell carcinoma of the anal canal (SCCAC) treated with Intensity-Modulated Radiation Therapy (IMRT). Material and methodsFrom 2007 to 2015, 193 patients were treated by IMRT for SCCAC. Radiotherapy delivered 45 Gy in 1.8 Gy daily-fractions to the primary tumor and elective nodal areas, immediately followed by a boost of 14.4–20 Gy to the primary tumor and involved nodes. Concurrent chemotherapy with 5-FU-mitomycin (MMC) or cisplatin was added for locally advanced tumors. Survivals were estimated by Kaplan–Meier method. Locoregional (LR) relapses were precisely assessed. Prognostic factors were evaluated by uni- and multivariate analyses. Late toxicity was scored according to the Common Toxicity Criteria for Adverse Events v4.0. ResultsMedian follow-up was 70 months (range, 1–131). Forty-nine men (25%) and 144 women (75%) were analyzed. Median age was 62 years. Tumor stages were I, II, III and IV in 7%, 24%, 63% and 6% of cases, respectively. Chemotherapy was delivered in 167 patients (87%), mainly MMC (80%). Five-year OS, DFS, CFS and LR control rates were 74%, 68%, 66% and 85%, respectively. Forty-one patients (21%) had a relapse: 22 were LR, mostly in-field (68%). Predictors for LR failure were exclusive radiotherapy, chemotherapy lacking MMC and treatment breaks >3 days. Overall late toxicity ≥grade 2 occurred in 43% of patients, with 24% grade 3 and one case of grade 4 (hematuria). ConclusionCRT with IMRT assures excellent local control in locally advanced SCCAC with manageable long-term toxicity. Multicentric prospective trials are required to reinforce those results.

A prospective, multi-centre trial of multi-parametric MRI as a biomarker in anal carcinoma

Background and purposeTo investigate the role of multi-parametric magnetic resonance imaging (MP-MRI) as a biomarker for squamous cell carcinoma of the anal canal (SCCAC). Materials and methodsFrom January 2013 to January 2017, 25 patients with non-metastatic SCCAC were enrolled in a multi-centre prospective clinical trial, of whom 20 completed protocol treatment. MP-MRIs, incorporating diffusion weighted magnetic resonance imaging (DW-MRI) and dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) sequences, were performed before (baseline), during the second and fourth weeks of chemo-radiotherapy (CRT), and 8 weeks following treatment completion. Histogram analysis of multi-parametric maps generated maximum, mean, median, minimum, skewness, kurtosis, and standard deviation metrics. Exact logistic regression and ROC AUC analyses were performed for each metric at every timepoint. An elastic net LASSO logistic regression was also performed using all measures at each timepoint. ResultsWith a median follow up of 17.1 months, 3/20 patients had a local recurrence, and 5/20 had any recurrence. Several apparent diffusion coefficient (ADC) metrics extracted from DW-MRIs correlated with local recurrence and demonstrated excellent discrimination: baseline skewness (p = 0.04, ROC AUC 0.90) and standard deviation (SD) (p = 0.02, ROC AUC 0.90), week 2 skewness (p = 0.02, ROC AUC 0.91) and SD (p = 0.01, ROC AUC 0.94), week 4 kurtosis (p = 0.01, AUC 0.92) and SD (p = 0.01, ROC AUC 0.96). Changes in minimum ADC between baseline and week 2 (p = 0.02, ROC AUC 0.94) and baseline and week 4 (p = 0.02, ROC AUC 0.94) were prognostic for local recurrence. For prediction of any recurrence, ADC minimum (p = 0.02, ROC AUC 0.87) and SD (p = 0.01, ROC AUC 0.85) at baseline, and ADC maximum (p = 0.03, ROC AUC 0.77) and SD (p = 0.02, ROC AUC 0.81) at week 4 were significant. On LASSO logistic regression, ADC minimum and SD at baseline were retained for any recurrence. The only significant finding for DCE-MRI was a correlation of k-trans min at the second follow-up with local recurrence (p = 0.05, AUC 0.84). ConclusionSeveral ADC parameters at various time points correlate with recurrence suggesting DW-MRI is a potential biomarker for SCCAC.

660TiP - BISQUIT: A randomized phase II study of the administration of prebiotics and probiotics during definitive treatment with chemotherapy-radiotherapy for patients with squamous cell carcinoma of the anal canal

BackgroundThe standard treatment for patients (pts) with localized squamous cell carcinoma of the anal canal (SCCAC) is chemoradiation (ChRT). Yet nearly 30% of patients are not cured and undergo salvage anorectal amputation. SCCAC is mostly a virus-associated tumor and thus potentially immunogenic. In fact, immune checkpoint inhibitors are promising in trials of metastatic SCCAC. Recently, studies have shown that the composition of the intestinal microbiota influences response to immunotherapy in some solid tumors, and the replacement of the intestinal "carcinogenic" by a protective microbiota has led to investigations with prebiotics and probiotics (PreProbiotics). Yet, there are no studies on the use of these agents in SCCAC. Thus we are conducting a randomized phase II study to test the efficacy of PreProbiotics during definitive ChRT aiming to improve the cure rate of pts with localized SCCAC. Trial designRandomized open label parallel phase II trial, where eligible pts will be randomized 1:1 to receive PreProbiotics starting one week prior to ChRT and throughout treatment until response evaluation at 6 to 8 weeks post ChRT or conventional ChRT. Eligible pts are ≥ 18 years, with histologically confirmed SCCAC, localized disease (≥ T2N0M0), indication to start definitive ChRT; HIV seropositive pts are eligible. Pts with active infection requiring antibiotics will be excluded. Primary endpoint: complete clinical and radiological response (CR) at 6 to 8 weeks post ChRT. Secondary endpoints: CR at 6 months, progression free survival, colostomy-free survival, metabolic response measured by 18-FDG PET-CT (baseline and at 6-8 weeks), toxicity, incidence of HPV in tumor tissues. All pts will have the following biological samples collected for correlative studies at baseline, 6-8 weeks and 6 months post ChRT: blood samples for circulating tumor DNA, inflammatory cytokines, anal/rectal swabs and feces to evaluate microbiota. Sample size assumptions: the H0 is CR at week 6 - 8 of 70% and H1, 90%; with a type I error of 10%, power of 80% and attrition rate of 10%, the final sample size is 75 patients. Clinical trial identificationNCT03870607. Legal entity responsible for the studyRachel Riechelmann. FundingAC Camargo Cancer Center. DisclosureAll authors have declared no conflicts of interest.

2659 A Rare Occurrence: Anal Squamous Cell Carcinoma With Metastasis to Duodenum Causing Duodenal Stricture and Gastric Outlet Obstruction

INTRODUCTION: Squamous cell carcinoma (SCC) of the anal canal is a rare entity encompassing only 2–4 percent of all colon, rectal, and anal cancers. SCC of the anal canal tends to be loco-regional and in the event of rare metastasis, most common sites of secondary seedlings are liver and lung. To our knowledge, metastatic spread from primary anal SCC to small bowel has been reported only once before. We report a rare case of SCC of anal canal with duodenal metastases in a 49-year-old female. CASE DESCRIPTION/METHODS: A 49-years-old female with 8-month history of anal SCC Stage IIIA, status post chemo-radiation therapy and loop ileostomy creation, was seen for complaints of vague abdominal pain, nausea, vomiting, and anorexia. Physical examination was significant for mild periumbilical tenderness. Computed tomography (CT) of the abdomen and pelvis with contrast revealed distended stomach with food contents and distended proximal duodenum. Esophagogastroduodenoscopy (EGD) showed moderate gastritis with duodenal edema resulting in narrowing of the second portion of the duodenum. An upper gastrointestinal series revealed distended stomach with air-fluid level and marked narrowing at the junction of the distal descending and transverse duodenum with "U-shaped" appearance and normal appearing jejunum. Colonoscopy via the stoma revealed normal colon proximal to diverting colostomy, normal terminal ileum, narrowed and scarred rectal vault. Biopsy from the duodenal stricture revealed duodenal mucosa with scattered malignant cells and malignant cell clusters within lymphatic spaces. Immunohistological staining demonstrated malignant cells positive for CK7, p16, p63 and negative for CK20, CDX2, GATA-3, CA19.9, TTF-1, Napsin A and PAX-8 favoring a metastatic anal SCC. DISCUSSION: Primary rectal squamous cell carcinomas (SCC) are very rare tumors. Additionally, either primary or metastatic SCC of the gastrointestinal tract is extremely rare with very few cases reported in the literature. In our case, the patient with established 8-month history of anal SCC stage IIIA, status post chemotherapy, radiation, and status post loop ileostomy creation presented with a rare duodenal metastasis, which has only been reported once before. The possibility of primary SCC of the small bowel was excluded with duodenal stricture biopsy showing scattered malignant cells and malignant cell clusters within lymphatic spaces and positive immunohistological staining favoring a metastatic lesion.

Anal Cancer Treatment: Significant Reduction of Acute Toxicity Using 4-Fraction-per-Week Approach

The purpose of this study was to compare outcomes in patients with squamous cell carcinoma of the anal canal (SCCA) who were treated with definitive chemo-radiotherapy (CRT) using an alternative approach of 4-fraction-per-week conventional 3D radiotherapy technique. Twenty patients who received definitive chemo-radiotherapy from January 2013 to December 2017 were included in this study. All 20 patients received 5-fluorouracil with mitomycin C (n = 20) as this is our institutional practice, no patients received cisplatin. All 20 patients were treated with conventional radiotherapy technique. The median dose was 5400 cGy (range 5220-5580 cGy). Median follow-up was 24 months. All 20 patients were treated using a modified regimen of 5 fractions only for the first week, followed by 4 fractions per week thereafter (Fridays off starting second week of treatment with no planned break). For the highest dose of 5580 cGy in 31 fractions, this is equivalent to 7.5 weeks or 51 days. Acute skin toxicity was: grade I: 18 patients (90%), grade II: 2 patients (10%), with no grade III or IV skin toxicity. Acute hematologic toxicity: grade I: 14 patients (70%), grade II: 6 patients (30%), with no grade III or IV hematologic toxicity. Acute GI toxicity: grade I: 12 patients (60%), no grade II, III, or IV skin toxicity. No patients required hospitalization from side effects of chemo-radiotherapy treatment. All patients completed treatment as prescribed. Treatment compliance was 100%. The 2-year overall survival in this study is 100%. Since this study was conceived for the purpose of reducing skin toxicity, we were pleasantly surprised to also discover that by having Fridays off, the hematologic and GI toxicity profile was mostly minor in nature and was easily manageable. This innovative approach of 4-fraction-per-week using conventional 3D radiotherapy technique was associated with significantly less acute toxicity (skin, hematologic, and GI), with virtually no need for treatment breaks, and yielded excellent loco-regional control, overall survival when compared with known randomized studies. The acute toxicity profile using this regimen of 4-fraction-per-week 3D conformal technique is better than those reported by similar IMRT studies. This innovative approach of 4-fraction-per-week 3D conformal technique deserves further study by individual investigators or by appropriate clinical trials.

Anal squamous cell carcinoma with metastasis to duodenum causing duodenal stricture and gastric outlet obstruction

Squamous cell carcinoma (SCC) of the anal canal is a rare entity encompassing only 2-4 percent of all colon, rectal, and anal cancers. SCC of the anal canal tends to be loco-regional, and in the event of distant metastasis, a most common site of spread is to liver and lung. We report an unusual case of SCC of the anal canal with duodenal metastases in a 49-year-old female who had presented with symptoms of abdominal pain, nausea, and vomiting eight months after the primary diagnosis of SCC of the anal canal. Esophagogastroduodenoscopy (EGD) revealed duodenal stricture with subsequent biopsy revealing duodenal mucosa with scattered malignant cell clusters within lymphatic spaces, consistent with metastatic carcinoma. Immunohistological staining demonstrated malignant cells positive for CK7, p16, p63 favoring a metastatic SCC.

Dose-finding and single-arm confirmatory study of definitive chemoradiotherapy (dCRT) with S-1/mitomycin-C (MMC) in patients (pts) with clinical (c) stage II/III squamous cell carcinoma of the anal canal (SCCA): JCOG0903.

686 Background: dCRT with 5-FU/MMC is a standard treatment for cStage II/III SCCA. S-1 is an oral fluoropyrimidine and has a greater effect on radiosensitivity. We conducted this trial of dCRT with S-1/MMC to determine the recommended dose (RD) of S-1 in phase I part (P I) and to evaluate the efficacy and safety in phase II part (P II) for cStage II/III SCCA. When the primary endpoint in P II part is proven to be satisfactory, we can regard this combined treatment as the new standard treatment. Methods: Eligibility criteria included histologically proven SCCA, cStage II/III (UICC 6th), PS 0-1, and age 20-80 years. dCRT consisted of MMC (10 mg/m2 on days 1, 29) and S-1 (60 mg/m2/d in level 0 and 80 mg/m2/d in level 1 on days 1-14, 29-42) with concurrent 3-dimensional RT of 59.4 Gy/33fr. The P I adopted the 3+3 cohort design. The primary endpoint of P II was proportion of 3-year event-free survival (% 3-year-EFS). The sample size was 65 in the P II, with one-sided alpha of 5% and power of 80%, threshold and expected % 3-year EFS as 60% and 75%. Results: From Feb/2010 to Mar/2015, 69 pts (3 in level 0 and 66 [7 in P I and 59 in P II] in level 1) were enrolled. Pts’s backgrounds for level 1 were as follows: M/F, 12/54; Age, median 64 (range 33-80); cStage II/IIIA/IIIB, 29/9/28. Three in level 1 were ineligible and 63 eligible assigned to level 1 were included in efficacy analysis. In the P I, considering the details of DLTs, RD of S-1 was determined as 80 mg/m2/d. In the 63 eligible of level 1, %3-year EFS was 65.0% (90% CI 54.1-73.9%). % 3-year OS, PFS, and colostomy-free survival were 87.3% (95% CI 76.2-93.4%), 85.7% (74.3-92.3%), and 76.2% (63.7-84.9%), respectively. The complete response rate was 81% on central review. Among 65 pts receiving level 1 dCRT, common grade 3 or 4 acute toxicities were leukopenia (63.1%), neutropenia (40%), diarrhea (20%), radiation dermatitis (15.4%), and febrile neutropenia (3.1%). Only 6 (9.2%) showed grade 3 late toxicities. No treatment-related deaths were observed. Conclusions: Although dCRT with S-1/MMC showed acceptable toxicities and favorable 3-year survival, this study did not meet its primary endpoint. Clinical trial information: UMIN000003237.

LBA21 - InterAACT: A multicentre open label randomised phase II advanced anal cancer trial of cisplatin (CDDP) plus 5-fluorouracil (5-FU) vs carboplatin (C) plus weekly paclitaxel (P) in patients (pts) with inoperable locally recurrent (ILR) or metastatic treatment naïve disease - An International Rare Cancers Initiative (IRCI) trial

Whilst advanced squamous cell carcinoma of the anal canal (SCCA) is a rare disease incidence has risen by 2%/year for the past decade. There is no consensus on management of these pts who generally have a poor overall survival (OS) and to date no randomised trial has been completed. The combination of fluoropyrimidine /platinum agents is often considered standard 1st line therapy whilst taxanes have shown activity. We conducted a randomised phase II study to establish a standard of care.

Phase II study of panitumumab, 5-fluorouracil, mitomycin-c and radiotherapy treatment in patients with non-metastatic squamous cell carcinoma of the anal canal: safety and efficacy results (VITAL study)—GEMCAD 09-02.

3566Background: More than 80% of squamous cell carcinoma of the anal canal (SCCAC) express epidermal growth factor receptor protein (EGFR). VITAL was a phase II, multicentre, single arm study, whic...

Extended-Field Chemoradiation Therapy for Definitive Treatment of Anal Canal Squamous Cell Carcinoma Involving the Para-Aortic Lymph Nodes

To report cancer control rates and adverse events (AEs) of curative-intent, extended-field chemoradiation therapy administered to patients with squamous cell carcinoma (SCC) of the anal canal presenting with distant metastasis limited to the para-aortic (PA) lymph nodes. This was a retrospective review of patients with SCC of the anal canal metastatic to the PA lymph nodes at initial diagnosis who were treated with curative-intent, extended-field chemoradiation therapy between September 2002 and February 2016 at two tertiary care centers. Outcomes assessed included treatment-related AEs (Common Terminology Criteria for Adverse Events, version 4.0), disease control (cumulative incidence estimates), and survival (Kaplan-Meier estimates). Thirty patients were included. Involved and elective PA nodes were treated to median doses of 51Gy (range 45-57.6) and 45Gy (range 30.6-50.4) in 29 fractions (range 17-32). All patients received one of these concomitant regimens: 6 weekly cycles of cisplatin with 5-fluoruracil/capecitabine (5-FU) (n=22), 2 cycles of mitomycin-C with 5-FU (n=7), or daily capecitabine (n=1). After a median follow-up period of 3.1years, 18 patients (60%) remained alive and 17 patients were without evidence of anal cancer after definite and salvage treatments. Overall and disease-free survival at 3years was 67% (95% CI 49%-89%) and 42% (95% CI 25%-69%). Fifteen (50%) patients experienced a recurrence at a median of 0.9year (range 0.5-3.5years). The predominant site of recurrence was distant metastases, with a 3-year cumulative incidence of 50% (95% CI 20%-68%). There was no acute grade 5 AE. Grade 3 to 4 gastrointestinal, dermatologic, and hematologic AEs occurred in 30%, 27%, and 20% of patients respectively. Extended-field chemoradiation therapy is a potentially curative treatment option for patients presenting with SCC of the anal canal with metastases limited to the PA lymph nodes.

HPV positive, wild type TP53, and p16 overexpression correlate with the absence of residual tumors after chemoradiotherapy in anal squamous cell carcinoma

BackgroundAnal residual tumors are consensually identified within six months of chemoradiotherapy and represent a persistent lesion that may have prognostic value for overall survival. The aim of this study was to evaluate the association of HPV and HIV status, p16 expression level and TP53 mutations with the absence of residual tumors (local response) in Squamous Cell Carcinoma (SCC) of the anal canal after chemoradiotherapy.MethodsWe performed a study on 78 patients with SCC of the anal canal who submitted to chemoradiotherapy and were followed for a six-month period to identify the absence or presence of residual tumors. HPV DNA was identified by polymerase chain reaction and direct sequencing, HIV RNA was detected by TaqMan amplification, p16 expression was detected by western blotting, and the mutational analysis of TP53 was performed by direct sequencing; additionally, samples carrying mutations underwent fluorescent in sit hybridization. The evaluation of the tumor response to treatment was conducted six months after the conclusion of chemoradiotherapy. The following classifications were used to evaluate the outcomes: a) no response (presence of residual tumor) and b) complete response (absence of residual tumor).ResultsThe significant variables associated with the absence of residual tumors were HPV positive, p16 overexpressed, wild-type TP53, female gender, and stages I and II. Only the presence of HPV was independently correlated with the clinical response; this variable increased the chances of a response within six months by 31-fold.ConclusionsThe presence of HPV in tumor cells was correlated with the absence of a residual tumor. This correlation is valuable and can direct future therapeutic approaches in the anal canal.

Treatment of squamous cell carcinoma of the anal canal: A new strategies with anti-EGFR therapy and immunotherapy.

The incidence of squamous cell carcinoma of the anal canal (SCAC) is increasing in both sexes but the standard treatment remains that of 20 years ago. However, interesting data have recently emerged on the use of anti-epidermal growth factor receptor (EGFR) agents and immunotherapy in advanced disease. Thus, new avenues of research are opening up that will hopefully lead to more effective therapeutic strategies. We provide an overview of the latest studies published on this tumor and discuss the possible future therapeutic options for combination therapy, anti-EGFR treatment and radiotherapy.

Evolving prevalence and incidence trends of SCC of the anal canal: A SEER study.

583 Background: The incidence of squamous cell carcinoma of the anal canal (SCCA) has been rising in the last three decades. With changing patient demographics and behaviors, the trends in prevalence and incidence of the disease have changed in recent years. Methods: The Surveillance, Epidemiology, and End Results (SEER) data set from 2000 to 2014 was analyzed for trends in prevalence and incidence of SCCA and for associated demographic and tumor characteristics including stage (localized vs. regional vs. distant disease), age (20-34, 35-49, 50-64, &gt; 65 years), and race/ethnicity (White, Black, American Indian/American Natives (AI/AN), American Pacific Islanders (API)). Results: 16,540 patients with SCCA were identified in the SEER database within the study period. The prevalence rate of SCCA was 0.01% (of 2000 standard U.S population), and the age-adjusted incidence rate of SCCA was 1.3/100,000. Prevalence and incidence was highest in patients age 50-64 and in the black population. Trend analysis of incidence demonstrated that while incidence rate continued to increase from 2000 to 2014, the average annual percentage change (APC) of incidence decreased from 4.80 before 2009 to 1.44 after. Patient population was divided into two groups: 2000-2008, with incidence of 1.6/100,000 and 2009-2014, with incidence of 2.1/100,000 (RR = 1.29, 95%CI = 1.25-1.33, p &lt; 0.001). Incidence in the 2009-2014 group increased compared to the 2000-2008 group among all staged SCCA, patients 50 years of age and older (RR = 1.41, p &lt; 0.001 and RR = 1.37, p &lt; 0.001 for age groups 50-64 and &gt; 65, respectively), and black (RR = 1.33, p &lt; 0.001) and white (RR = 1.32, p &lt; 0.001) race/ethnicity groups. APC in the 2009-2014 group decreased in all staged SCCA, increased in patients age 20-34, and decreased in all racial groups except AI/AN. Conclusions: There is a higher incidence and prevalence of SCCA in patients 50 years or older and in those of black ethnicity. Incidence of SCCA has increased in the US from 2000-2014, but the average APC in incidence has been decreasing except for in young patients and in those of AI/AN ethnicity. Awareness of disease prevalence and the pattern of change in incidence rate is important in the effort of disease prevention.