Advanced Anal Carcinoma Research Articles

Very pronounced bowel sparing during radiation therapy for anal carcinoma using a natural spacer (Myoma) – a case report

BackgroundUsing dose-painted intensity-modulated radiation therapy, specific dose volume constraints or implantation of tissue expanders prior to radiotherapy are validated options for reducing radiation dose on the bowel and therefore minimizing acute gastrointestinal toxicity during chemoradiation for anorectal malignancies. We describe the rare case of a female patient with a locally advanced anal carcinoma where a large myomatous uterus served as a natural spacer to protect the bowel during radiation therapy.Case presentationInitially the patient presented with anal pain, proctoscopy followed by an excisional biopsy confirmed the diagnosis of a squamous cell carcinoma of the anus. Imaging examination showed a locally advanced tumor and in addition a large uterus with typical leiomyomas up to 11.5 cm in diameter. The patient underwent chemoradiation; because of the large leiomyomas there was almost no dose burden for the small intestine and therefore practically no gastrointestinal toxicity.ConclusionAs we know, this report describes the situation that a large myomatous uterus served as a natural spacer during radiation therapy in a way that is unique to date.

Analysis of definitive chemo-radiation outcomes in anal cancer: insights from a tertiary cancer center in the MENA Region.

Outcomes of chemo-radiation (CRT) for anal cancer in Middle East and North Africa (MENA) are scarce. We aim to report treatment outcomes for anal cancer treated at tertiary cancer center, with a particular focus on patients managed with non-oncological surgery prior definitive CRT. We conducted a retrospective review of patients diagnosed with locally advanced anal carcinoma, who underwent definitive CRT King Hussein Cancer Center, from January 2007 till January 2020. Patient demographics and disease characteristics were extracted, and a univariate chi-squared test was employed to assess the impact of chemotherapy type, HPV status, and pre-treatment non-oncological surgery on outcomes, including complete remission (CR), disease-free survival (DFS), and overall survival (OS). Kaplan-Meier tests were employed to analyze the obtained survival data. Among the 34 initially identified patients, 30 were eligible, 24 (80%) achieved CR. Notably, 20 out of 21 HPV positive patients achieved CR, versus 1 out 4 HPV-negative achieved CR, p=0.006The 5-years OS for HPV-positive patients was 89% compared with 25% for HPV-negative, p=0001. There was no statistical significant difference in patients outcomes as regard type of chemotherapy, radiation technique and non-oncologic resection prior to CRT. Herein, we reported the first series of anal cancer from our region. CRT had yielded an oncologic outcome comparable with series in the literature. HPV-positive patients demonstrated better results. Moreover, we found non-oncologic resection prior to CRT did not seem to impact the outcomes. Further studies are warranted to overcome the limitations of our study.

Prognostic role of HPV integration status and molecular profile in advanced anal carcinoma: An ancillary study to the epitopes-HPV02 trial.

Squamous Cell Carcinoma of the Anal canal (SCCA) is a rare disease associated with a Human Papillomavirus (HPV) infection in most cases, predominantly the HPV16 genotype. About 15% of SCCA are diagnosed in metastatic stage and some will relapse after initial chemoradiotherapy (CRT). Treatment of patients by Docetaxel, Cisplatin and 5-fluorouracil (DCF) has been recently shown to improve their complete remission and progression-free survival. The aim of this retrospective study was to explore the impact of HPV infection, HPV DNA integration, TERT promoter mutational status and somatic mutations of oncogenes on both progression-free (PFS) and overall survivals (OS) of patients treated by DCF. Samples obtained from 49 patients included in the Epitopes-HPV02 clinical trial, diagnosed with metastatic or non-resectable local recurrent SCCA treated by DCF, were used for analyses. Median PFS and OS were not associated with HPV status. Patients with episomal HPV had an improved PFS compared with SCCA patients with integrated HPV genome (p=0.07). TERT promoter mutations were rarely observed and did not specifically distribute in a subset of SCCA and did not impact DCF efficacy. Among the 42 genes investigated, few gene alterations were observed, and were in majority amplifications (68.4%), but none were significantly correlated to PFS. As no biomarker is significantly associated with patients’ survival, it prompts us to include every patient failing CRT or with metastatic disease in DCF strategy.

Anti-PD-1 for pretreated advanced anal carcinoma: which patients will benefit?

In The Lancet Gastroenterology & Hepatology, Aurélien Marabelle and colleagues1 report the efficacy and safety of pembrolizumab in the anal squamous cell carcinoma cohort of the non-randomised, multicohort, multicentre, phase 2 KEYNOTE-158 study. The results are promising, showing durable antitumour activity with pembrolizumab monotherapy in a subset of patients, with objective responses observed in 12 (11%, 95% CI 6 to 18) of 112 patients and a median duration of response not being reached (range 6·0+ to 33·9+ months) after a long median follow-up (34·7 months [IQR 32·5 to 36·4]).

Trigger-Based Adaptive Planning to Reduce Bowel Dose in Patients Receiving Radiotherapy for Anal Cancer

<h3>Purpose/Objective(s)</h3> Standard of care for locally advanced anal carcinoma is definitive chemoradiation with IMRT. Currently, target and organ-at-risk (OAR) volumes are created using a pre-treatment CT-simulation scan. However, during the course of radiotherapy, there is often change in the size and/or position of the tumor and surrounding normal structures. Therefore, we hypothesize that the implementation of an adaptive radiation therapy treatment protocol in anal cancer may reduce radiation dose to critical surrounding normal structures, such as the bowel, through the use of anatomy-adapted replanning. <h3>Materials/Methods</h3> Retrospective daily adaptive CTs were created for 4 patients (54 Gy, 30 fraction VMAT) in an oncology imaging informatics system using the Adaptive Calculation and Tracking for Offline Plan Review (ACTOR) toolkit. Each adaptive CT was created by deformable image registration (dir) of the planning CT to the daily CBCT. The structure sets from the planning CT were deformed onto each adaptive CT and ultimately corrected and revised by two qualified radiation oncologists. The adaptive CTs were transferred to a treatment planning system for recalculation. The original treatment plan was recalculated on each fraction adaptive CT to establish the real dose received during treatment. A two-sample t-test was used to compare the average real dose received dosimetric values to the values obtained on trigger-based adaptive planning. <h3>Results</h3> Using dose prescriptions for target volumes and normal tissue dose constraints as defined in RTOG 0529 (Kachnic et al 2013), normal bowel dose metrics, including bowel V45 < 20cc, were tracked as possible triggers for adaptation. Using bowel V45 > 20cc as trigger 1, there was a significant reduction in bowel V45 for each patient (table), with an average reduction in bowel V45 of 86.7% (<i>P</i> = 0.0001) across all patients. Adapting only the 5 fractions with the highest values for bowel V45 (trigger 2), we also found a significant reduction for each patient (table), with an average reduction of 20.8 % (<i>P</i> = 0.0011) across all patients. <h3>Conclusion</h3> Our study demonstrated that triggered adaptive re-planning using bowel V45 > 20cc could likely achieve reductions in normal tissue dose. Adaptive planning during radiation treatment of anal cancer may therefore be beneficial for reduction of treatment-related GI toxicity. These results can help inform a future randomized trial of adaptive therapy vs. standard planning.

Treatment algorithm and prognostic factors for patients with stage I–III carcinoma of the anal canal: a 20-year multicenter study

Despite a growing incidence in developed countries and a recent improved understanding of its pathogenesis, anal cancer management has not evolved over the past decades and drug combination used as first-line regimen still largely depends on clinician preferences. Aiming at paving the way for precision medicine, a large cohort of 372 HIV-negative patients diagnosed over a 20-year time period with locally advanced anal carcinoma was collected and carefully characterized at the clinical, demographic, histopathologic, immunologic, and virologic levels. Both the prognostic relevance of each clinicopathological parameter and the efficacy of different concurrent chemoradiation strategies were determined. Overall, the incidence of anal cancer peaked during the sixth decade (mean: 63.4) and females outnumbered males (ratio: 2.51). After completion of treatment, 95 (25.5%) patients experienced progression of persistent disease or local/distant recurrence and 102 (27.4%) died during the follow-up period (median: 53.8 months). Importantly, uni-multivariate analyses indicated that both negative HPV/p16ink4a status and aberrant p53 expression were far better predictors for reduced progression-free survival than traditional risk factors such as tumor size and nodal status. As for overall survival, the significant influences of age at diagnosis, p16ink4a status, cTNM classification as well as both CD3+ and CD4+ T-cell infiltrations within tumor microenvironment were highlighted. Cisplatin-based chemoradiotherapy was superior to both radiotherapy alone and other concurrent chemoradiation therapies in the treatment of HPV-positive tumors. Regarding their HPV-uninfected counterparts, frequent relapses were observed, whatever the treatment regimen administered. Taken together, our findings reveal that current anal cancer management and treatment have reached their limits. A dualistic classification according to HPV/p53 status should be considered with implications for therapy personalization and optimization.

Randomized phase II trial of avelumab alone or with cetuximab for unresectable, locally advanced or metastatic squamous cell anal carcinoma progressed to at least one line of treatment: The CARACAS study.

4051 Background: Advanced squamous cell anal carcinoma (advSCAC) is a rare disease with poor prognosis. No standard therapies beyond first line are currently available, yet a promising activity was documented for the anti-EGFR cetuximab (CET) and for anti-PD-1 agents in previous retrospective case series and phase I-II studies, respectively. In experimental models combination of EGFR and PD-L1 blockade was synergistic as PD-L1 blockade led to NK cells activation enhancing cetuximab ADCC. In this trial we aimed to evaluate safety and activity of the anti-PD-L1 avelumab (AVE) alone or in combination with CET in pretreated advSCAC. Methods: This was an open-label, prospective, multicenter randomized phase 2 trial (NCT03944252). Patients (pts) with advSCAC progressed after at least 1 line of treatment were randomized 1:1 to receive either AVE 10 mg/kg (arm A) or AVE + CET 500 mg/sqm (arm B) as bi-weekly regimens. A Simon’s two-stage Mini-Max design was used. The null hypothesis of a true response rate 5% was tested against the one-sided alternative of a true response rate 20% in each arm. Setting type I error at 0.05 and power at 80%, 30 pts per arm had to be randomized. No formal comparison between the two arms was planned. Primary endpoint was overall response rate (ORR); secondary endpoints were Progression-Free Survival (PFS), Overall Survival (OS) and safety. Results: Sixty pts were enrolled, 30 in each arm. All baseline characteristics were well balanced between the two arms. Median age was 63 years; M/F was 19/41; 12 out of 30 pts in each arm had distant metastases; 7 in arm A and 10 in arm B received &gt; 1 previous lines of treatment. At a median follow up of 8.7 months, 3 out of 30 pts in each arm obtained PR (ORR 10%); SD was observed in 12 pts in arm A (40%) and 14 in arm B (47%). Disease control rate was thus 50% in arm A and 57% in arm B. Duration of disease control was 6.1 (95%CI 3.7–11.0) and 6.1 (95%CI 4.1–9.6) months in arm A and B, respectively. Median PFS was 2.1 (95%CI 1.8–4.0) in arm A and 3.9 months (95%CI 2.1–5.6) in arm B. Grade 3-4 adverse events were 13.3% in arm A and 33.3% in arm B: anemia 10% vs 13.3%, fatigue 0 vs 6.7%, skin toxicity 0 vs 6.7%. Treatment interruption due to AE occurred in 3 pts, 1 in arm A and 2 in arm B. Translational analyses will be performed on tissue and blood samples for exploratory purpose. Conclusions: The CARACAS trial was the first clinical study to test dual EGFR and PD-L1 blockade in advSCAC. Both AVE monotherapy and AVE-CET showed promising activity with manageable safety profile. Clinical trial information: NCT03944252 .

Cetuximab + Avelumab or Avelumab Alone for Unresectable, Locally Advanced or Metastatic Squamous Cell Anal Carcinoma (SCCAC) Progressed After at Least One Line of Systemic Treatment (CARACAS)

Cetuximab + Avelumab or Avelumab Alone for Unresectable, Locally Advanced or Metastatic Squamous Cell Anal Carcinoma (SCCAC) Progressed After at Least One Line of Systemic Treatment (CARACAS)

Clinical Validity of HPV Circulating Tumor DNA in Advanced Anal Carcinoma: An Ancillary Study to the Epitopes-HPV02 Trial.

Human papillomavirus (HPV) is found in 90% of squamous cell carcinomas of the anal canal (SCCA). We investigated the clinical validity of HPV circulating tumor DNA (ctDNA) detection in patients enrolled in the Epitopes-HPV02 trial that demonstrated the efficacy of docetaxel, cisplatin, and 5-FU as first-line chemotherapy in advanced SCCA. According to the protocol, serum samples were collected before chemotherapy and on completion of chemotherapy. HPV16 ctDNA was quantified by droplet digital PCR (ddPCR) and correlated with prospectively registered patient characteristics and outcomes. A landmark was set at the time of chemotherapy completion for postchemotherapy progression-free survival (PFS) analyses. Among 57 patients with HPV16-related advanced SCCA, HPV ctDNA was detected in 91.1% (95% confidence interval, 81.1-96.2) of baseline samples. Baseline HPV ctDNA levels were not associated with any patient characteristics; baseline ctDNA level below the cutoff obtained by AUC (area under the curve) was associated with a longer PFS (HR = 2.1; P = 0.04). Among the 36 patients who completed 5 months of chemotherapy, residual HPV ctDNA was detected after chemotherapy in 38.9% of patients. Residual HPV ctDNA detected at chemotherapy completion was associated with shorter postchemotherapy PFS (median PFS 3.4 months vs. not reached; HR = 5.5; P < 0.001) and a reduction of 1-year overall survival rate (OR = 7.0; P = 0.02). This prospective study in advanced SCCA demonstrated a significant prognostic impact of HPV ctDNA level before first-line chemotherapy and HPV ctDNA negativity after chemotherapy completion. With a limited cost and short turnaround, this assay is a promising tool to optimize the therapeutic management of SCCA.See related commentary by Morris, p. 2030.

Alternative chemoradiotherapy to treat locally advanced (LA) anal carcinoma (AC) in patients (pts) with mutations in thymidylate synthase (TYMS) and dihydropyrimidine dehydrogenase (DPYD) genes: A case series.

605 Background: 5-FU and mitomycin-C (MMC) with radiotherapy (RT) remain an established treatment for pts with LA (T2-4, N0-1, M0 or T1-4, N2-3, M0) AC. Genetic mutations in 2 major metabolizing enzymes for 5-FU; DPYD and TYMS have been associated with clinical response and toxicity. However their place in treatment of AC remains undetermined. Methods: We retrospectively reviewed 21 pts with LA AC treated between 2012 - 2018. All pts were treated with 5-FU 1,000mg/m2/day continuous IV infusion 1–4 and 29–32, MMC 10mg/m2 IV bolus Days 1 and 29 plus RT. Acute toxicity was recorded and discussed during weekly multidisciplinary meetings. The worst grade was scored from start of treatment until 30 days after the last fraction of radiotherapy according to the NCI-CTCAE, v4.03. Tumor response was evaluated by DRE and palpation of inguinal nodes during treatment, at the end of treatment, and radiological imaging 4–6 weeks after completion of treatment. Pts who developed ≥3 toxicities were tested for DPYD and TYMS genes (2 major polymorphisms has been associated with altered TYMS: polymorphic 28bp tandem repeat polymorphism in 5’-untranslated region (5’UTR) into TYMS sequence enhancer region (TSER) and TYMS 1494del, is a 6-base pair (bp) deletion polymorphism in 3’-UTR. Results: 6/21 ptsdeveloped severe toxicities (Caucasians; 5 females, 1 male; age range: 42 -68 yrs) consisting of grade ≥3 pancytopenia, neutropenia, thrombocytopenia, mucositis, nausea, rash and nephritis. The most common genetic mutations found in these pts included TYMS 2RG/3RC (2), 3RG/3RC (1), 2R/2R (2), TYMS 3 ' UTR del/Ins (2) and DPYD c.2864A&gt;T heterozygous (1). Treatment was changed in 2 pts to MMC 10 mg/m2 Day 1 and 29 with cisplatin 25 mg/m2/week plus RT. These 2 pts reached pCR at 70 days and other 4 pts at 140 days. Conclusions: Molecular testing for DPYD and TYMS genes can allow us to identify pts who are most likely to respond or face severe toxicity to 5-FU. Combining radiation with MMC and cisplatin in pts with LA AC is feasible and EORTC is currently comparing this combination with MMC/5-FU in a large phase III trial.

94P - HPV circulating tumor DNA as predictive biomarker of sustained response to chemotherapy in advanced anal carcinoma

94P - HPV circulating tumor DNA as predictive biomarker of sustained response to chemotherapy in advanced anal carcinoma

Safety and antitumor activity of the anti-PD-1 antibody pembrolizumab in patients with recurrent carcinoma of the anal canal

BackgroundSafety and efficacy of pembrolizumab, a humanized programmed death 1 monoclonal antibody, was assessed in KEYNOTE-028, a multicohort, phase Ib trial for patients with programmed death ligand 1 (PD-L1)-positive advanced solid tumors. We report results for the cohort of patients with advanced anal carcinoma.Patients and methodsPatients with PD-L1-positive tumors (≥1%) received intravenous pembrolizumab 10 mg/kg once every 2 weeks for up to 2 years or until confirmed progression or unacceptable toxicity. Response was assessed every 8 weeks for the first 6 months and every 12 weeks thereafter per Response Evaluation Criteria In Solid Tumors, version 1.1. Primary endpoints were safety and overall response rate per investigator review. Secondary endpoints included progression-free survival, overall survival, and response duration. Data cutoff date was 1 July 2015.ResultsOf the 43 patients with advanced anal carcinoma evaluable for PD-L1 expression, 32 (74%) had PD-L1-positive tumors as assessed with the 22C3 prototype assay, of whom 25 were enrolled between April and September 2014. Sixteen patients (64%) experienced treatment-related adverse events; the most common ones were diarrhea and fatigue in four patients (16%) each and nausea in three patients (12%). There were no treatment-related deaths or discontinuations as of the data cutoff date. Among the 24 patients with squamous cell carcinoma histology, four had confirmed partial response, for an overall response rate of 17% [95% confidence interval (CI), 5%–37%) and 10 (42%) had confirmed stable disease, for a disease control rate of 58%. One additional patient with non-squamous histology had confirmed stable disease.ConclusionIn this population of patients with PD-L1-positive advanced squamous cell anal carcinoma, pembrolizumab demonstrated a manageable safety profile and encouraging antitumor activity. These data support further study of pembrolizumab for this patient population.ClinicalTrials.govNCT02054806.

Chemoradiotherapy with capecitabine for locally advanced anal carcinoma: an alternative treatment option.

Background:Capecitabine is an established treatment alternative to intravenous 5-fluorouracil (5-FU) for patients with rectal cancer receiving chemoradiotherapy. Its place in the treatment of locally advanced anal carcinoma (AC), however, remains undetermined. We investigated whether capecitabine is as effective as 5-FU in the treatment of patients with locally advanced AC.Methods:One hundred and five patients with squamous cell AC stage T2-4 (T2>4 cm), N0-1, M0 or T1-4, N2-3, M0, were included in this retrospective study. Forty-seven patients were treated with continuous 5-FU (750 mg m−2) on days 1–5 and 29–33, mitomycin C (MMC, 10 mg m−2) on day 1, and radiotherapy; 58 patients were treated with capecitabine (825 mg m−2 b.i.d. on weekdays), MMC (10 mg m−2) on day 1, and radiotherapy. The primary end points of the study were: clinical complete response rate, locoregional control (LRC) and overall survival (OS). Secondary end points were: colostomy-free survival (CFS), toxicity and associations of genetic polymorphisms (GSTT1, GSTM1, GSTP1 and TYMS) with outcome and toxicity.Results:Clinical complete response was achieved in 41/46 patients (89.1%) with 5-FU and in 52/58 patients (89.7%) with capecitabine. Three-year LRC was 76% and 79% (P=0.690, log-rank test), 3-year OS was 78% and 86% (P=0.364, log-rank test) and CFS was 65% and 79% (P=0.115, log-rank test) for 5-FU and capecitabine, respectively. GSTT1 and TYMS genotypes were associated with severe (grade 3–4) toxicity.Conclusions:Capecitabine combined with MMC and radiotherapy was equally effective as 5-FU-based chemoradiotherapy. This study shows that capecitabine can be used as an acceptable alternative to 5-FU for the treatment of AC.

Curiethérapie du canal anal

Low dose-rate brachytherapy as a boost after concomitant chemoradiation therapy is a standard of care for locally advanced anal carcinoma, providing a rigorous selection taking into account the initial staging and tumor response to external beam radiotherapy. Local control is likely to be superior when the boost is performed with brachytherapy than with external beam radiotherapy. The several steps of the brachytherapy procedure are described. The standard treatment scheme is a concomitant chemoradiation therapy, including 45Gy (1,8Gy×5) pelvic external beam radiotherapy and two courses of 5-fluorouracil and mitomycin-C, followed by a 15Gy brachytherapy boost with a gap limited to 2 to 3weeks. Higher irradiation dose for the most advanced cases has not yet demonstrated a therapeutic gain in terms of colostomy free survival. Exclusive brachytherapy for in-situ carcinoma or invasive carcinoma less than 10mm is not recommended due to a high risk of local recurrence. Pulsed dose rate brachytherapy is an alternative to low dose rate brachytherapy (iridium wires) providing the respect of the recommended dose rate (0.5 to 1Gy/hour). High dose rate brachytherapy is still under evaluation.

Simultaneous Integrated Boost–Intensity Modulated Radiation Therapy With Concomitant Capecitabine and Mitomycin C for Locally Advanced Anal Carcinoma: A Phase 1 Study

Newer radiation techniques, and the application of continuous 5-FU exposure during radiation therapy using oral capecitabine may improve the treatment of anal cancer. This phase 1, dose-finding study assessed the feasibility and efficacy of simultaneous integrated boost-intensity modulated radiation therapy (SIB-IMRT) with concomitant capecitabine and mitomycin C in locally advanced anal cancer, including pharmacokinetic and pharmacogenetic analyses. Patients with locally advanced anal carcinoma were treated with SIB-IMRT in 33 daily fractions of 1.8 Gy to the primary tumor and macroscopically involved lymph nodes and 33 fractions of 1.5 Gy electively to the bilateral iliac and inguinal lymph node areas. Patients received a sequential radiation boost dose of 3 × 1.8 Gy on macroscopic residual tumor if this was still present in week 5 of treatment. Mitomycin C 10 mg/m(2) (maximum 15 mg) was administered intravenously on day 1, and capecitabine was given orally in a dose-escalated fashion (500-825 mg/m(2) b.i.d.) on irradiation days, until dose-limiting toxicity emerged in ≥2 of maximally 6 patients. An additional 8 patients were treated at the maximum tolerated dose (MTD). A total of 18 patients were included. The MTD of capecitabine was determined to be 825 mg/m(2) b.i.d. The predominant acute grade ≥3 toxicities included radiation dermatitis (50%), fatigue (22%), and pain (6%). Fifteen patients (83% [95%-CI: 66%-101%]) achieved a complete response, and 3 (17%) patients a partial response. With a median follow-up of 28 months, none of the complete responders, and 2 partial responders had relapsed. SIB-IMRT with concomitant single dose mitomycin C and capecitabine 825 mg/m(2) b.i.d. on irradiation days resulted in an acceptable safety profile, and proved to be a tolerable and effective treatment regimen for locally advanced anal cancer.

Bloqueio neurolítico subaracnoideo em paciente com dor oncológica refratária: relato de caso

JUSTIFICATIVA E OBJETIVOS: O uso de bloqueio neurolítico subaracnoideo no controle de dor tem diminuído nos últimos anos devido à introdução de novas técnicas, mas ainda tem importância no controle de dor oncológica refratária. O objetivo deste estudo foi apresentar um caso de dor oncológica, em que esta técnica foi utilizada para controle da dor. RELATO DO CASO: Paciente do sexo masculino, 45 anos, diagnosticado com carcinoma espinocelular de canal anal localmente avançado e lesão ulcerada em região perineal com presença de fístula retovesical e infecção local. O paciente apresentava dor intensa com escala verbal numérica (EVN) =10 e recebia tratamento farmacológico com doses altas de opioide e adjuvantes sem boa resposta. Foi realizado bloqueio neurolítico subaracnoideo com fenol a 5% e após realização do bloqueio houve melhora significativa do quadro doloroso, tendo paciente referindo alívio de 80% após 20 minutos do procedimento. A melhora permaneceu até o 21º dia após bloqueio quando o paciente foi a óbito devido complicações infecciosas. CONCLUSÃO: O caso ilustrou o uso do bloqueio subaracnoideo com fenol a 5% para controle de dor oncológica. Conclui-se que para casos selecionados, onde a expectativa de vida é limitada, esta técnica pode ser empregada com sucesso.

P-0148 A Radiotherapy Planning Study Comparing Helical Tomotherapy with Conformal Radiotherapy for the Treatment of Node Positive Advanced Anal Carcinoma

ABSTRACT Introduction Within the UK ACT II trial, 3 year DFS for advanced anal cancer (T3/4) is still only 66%, with approximately half of these patients getting isolated locoregional recurrence. Standard treatment is also associated with significant acute perineal morbidity. IMRT offers an opportunity to intensify treatment and reduce normal tissue toxicity. A radiotherapy planning study was carried out comparing conformal radiotherapy (CRT) with intensity modulated radiotherapy (IMRT) using helical tomotherapy (HT), to quantify the potential advantage for the treatment of node positive advanced anal squamous cell carcinoma (SCC). Methods Six patients with node positive (Stage 3) SCC of the anal canal treated in our department were identified and their CT data sets used to generate CRT (as per the ACT II protocol) and two sets of IMRT plans (see table). Comparisons were made of the dose volume histograms (DVHs) for the planning target volumes (PTVs) and organs at risk (OARs) for the three different plans. Comparisons were also made for treatment in the supine and prone positions. Three patients had CT data sets in the prone position and three patients had CT scans in the supine position. Results Target coverage of the primary tumour and involved nodes was improved with both types of IMRT plans compared to CRT plans. This study demonstrated a significant improvement in the DVHs for external genitalia using IMRT plans. The mean dose was reduced from 50.1Gy for CRT, to 35.1Gy and 36.3Gy for SDIMRT and HDIMRT respectively. Maximal skin doses were also substantially reduced with IMRT. Doses to small bowel were higher with SDIMRT and HDIMRT than CRT, due to dose escalation to involved and elective nodes (V30Gy 44.7%, 45.5% and 23.7% respectively), but were still within acceptable limits ( Conclusion IMRT plans achieve a better conformal dose to the tumour and involved nodes whilst improving sparing of surrounding normal tissues, in particular external genitalia and skin, thus limiting acute debilitating toxicities. We are also able to dose escalate to the tumour and nodes with no increase in dose to OARs. Thus, dose escalation is feasible for high risk anal cancer with the aim of improving cure. Table 1 .

P-0145 Anal Canal Carcinoma – Radiotherapy and Combined Chemotherapy with Mitomycin-C and 5-Fluorouracil Continuous Infusion – A Single Portuguese Institution Experience

ABSTRACT Introduction Anal canal squamous cell carcinoma is an uncommon malignancy, accounting for a small percentage (4%) of all cancers of the lower intestinal tract. Concurrent chemoradiation with 5-fluorouracil (5-FU) and mitomycin-C (MMC) is the standard of care. Due to acute and long term treatment related toxicities, a split radiotherapy course was the norm. Developments in radiation technique with three-dimensional planning and conformal treatment decreased toxicity, allowing for a shortened 6 weeks treatment time with no planned treatment break. The concurrent use of chemotherapy is also responsible for treatment toxicity. The best way to combine chemotherapy with the shortened radiotherapy is still subject to debate. Along with MMC, a continuous infusion of 5-FU for the hole duration of radiotherapy could reduce the toxicity, maintaining the effectiveness of the treatment. We aim to describe a single institution experience in advanced anal carcinoma combined treatment with radiation and MMC with continuous infusion of 5-FU. Methods Retrospective analysis of all anal cancer patients treated at our institution with the chemoradiation regimen of MMC (10mg/m2 in the beginning of the first and the last week of radiotherapy) and 5-FU (200mg/m2/day continuously for the whole duration). Radiotherapy doses were 45 Gy plus a 9 Gy boost. Endpoints were response, toxicity, colostomy-free rate, relapse and survival. Results From 2007-2011, 29 patients (pts) were included (20 women and 9 men), median age 67 years (35-82) and median follow-up time 25 months (1-58). Tumor location: canal – 28, margin – 1. Histology: squamous cell carcinoma – 25, basaloid carcinoma – 4. Stage groups: I – 4, II – 13, IIIA – 1, IIIB – 11. Median duration of chemoradiotherapy (CMT) was 57 days. Tumor response: complete response – 23, partial response – 1, progression – 5. Among 28 pts who completed CMT, 14 pts (50%) presented with recurrence (local – 5, distant – 9) at a median time of 7 months after CMT ending. Local relapse was treated with salvage surgery in 3 cases and palliative colostomy in 2. Distant metastasis locations were bone – 3, lung, liver and lymph node – 2 each, skin – 1. Four pts received chemotherapy and 1 had a local resection of a single lesion. 6 pts died (related to cancer – 5, AIDS – 1) at a median time of 15 months. Acute grade III/IV toxicities were present in 12 pts (perineal skin reaction – 10, haematological – 4, diarrhoea – 1, mucositis – 1) and 3 pts had severe late toxicity (vaginal and canal anal stenosis). Conclusion In our results continuous infusion of 5-FU during radiotherapy in the treatment of anal carcinoma was associated with complete remission in 82.1% of patients with acceptable toxicity (42.8% of acute and 10.7% of late severe events). The response data is comparable to our previous experience, but there is a high rate of early recurrence that warrants further analysis and suggests that continuous infusion might not be the best 5-FU regimen to combine with radiation in anal canal cancer.

Development of new drug strategies in infrequent digestive tumors: esophageal, biliary tract, and anal cancers

In the last years, interesting advances have been reported in the treatment of infrequent digestive tumors. The increasing development of new targeted therapies in human cancer has also impacted in these rare gastrointestinal malignancies providing a wide range of possibilities in the design of future clinical trials. The inhibition of angiogenesis and the blockage of the epidermal growth factor receptor pathway have provided the most interesting activity in recently reported studies for esophageal and biliary tract carcinomas. Additionally, several targeted therapies have been developed to target the main kinase proteins of the most important pathways of these malignancies. The results of the biggest phase III trial in locally advanced anal carcinoma have been recently published. Finally, the inhibition of epidermal growth factor receptor has also showed promising activity in anal carcinomas. Recent advances in the knowledge of molecular mechanism of carcinogenesis have led to meaningful changes in the management of gastrointestinal cancers. Although the major advances in targeted therapy have been introduced in the treatment of colorectal cancer, new interesting approaches have been reported in less frequent gastrointestinal tumors such as esophageal, biliary tract, and anal canal carcinoma opening a new hope in the treatment of these rare tumors in the molecular targeted therapy era.

Combining Cisplatin and Mitomycin with Radiotherapy in Anal Carcinoma

The European Organization for Research and Treatment of Cancer (EORTC) phase II study No. 22953 demonstrated the feasibility of reducing the overall treatment time of chemoradiation, delivering mitomycin C twice rather than once and fluorouracil during the whole treatment. We tested the feasibility of chemoradiation in anal carcinoma with mitomycin and cisplatin in a phase II study. Twenty-one patients with locally advanced anal carcinoma (15 women, 6 men) were treated. The first sequence of radiotherapy consisted of 36 Gy over four weeks. After a gap interval of 16 days, a second sequence of radiotherapy was given, delivering 23.4 Gy over 2.5 weeks. Mitomycin C was delivered at 10 mg/m(2) day 1 of each sequence and cisplatin was delivered at 25 mg/m(2)/week of each sequence. The compliance rates for the first sequence with radiation, mitomycinm, and cispaltin (dose and timing) were 100 percent. The median duration gap was 16 days (14-30 days). The compliance rates for the second sequence with radiation, mitomycin, and cisplatin (dose and timing) were 100, 76.2, and 85.7 percent, respectively. Grade > or = 2 acute toxicities of 62, 29, 25, and 5 percent were observed for skin, diarrhea, hematologic, and renal toxicities, respectively. Nineteen patients were in complete response (90.5 percent). Combining radiation with mitomycin and cisplatin in patients with locally advanced anal cancer is feasible. The results are promising. The EORTC is currently comparing this combination with mitomycin and 5-fluorouracil in a large phase II-III trial.