BACKGROUND AND PURPOSE:

Definitive chemoradiation is the standard management for anal squamous cell carcinoma (ASCC); more conformal pelvic radiotherapy using intensity modulated radiotherapy (IMRT) minimizes toxicity but may increase locoregional recurrences (LRR). We compared IMRT and conventional radiotherapy (CRT) outcomes in ASCC patients.

MATERIAL AND METHODS:

We retrospectively reviewed records of 223 ASCC patients treated at Memorial Sloan-Kettering Cancer Center from 1991 to 2010. Forty-five patients received IMRT and 178 CRT. We determined locoregional recurrence-free survival (LRFS), distant metastases-free survival (DMFS), and overall survival (OS) for each radiation modality. A propensity score analysis was performed using potentially confounding variables. Locoregional and distant patterns of failure for CRT and IMRT were compared.

RESULTS:

Patients treated with IMRT had significantly higher N stage (P<.01), and were less likely to be treated with induction chemotherapy (P=.01). The 2-year LRFS, DMFS, and OS were 87%, 86%, and 93%, respectively, for IMRT; and 82%, 88%, 90%, respectively, for CRT; with no significant difference in outcomes by univariate analysis or in a propensity score analysis adjusted for disparity between the groups.

CONCLUSIONS:

This large, single-institution experience of definitive chemoradiation for ASCC using CRT vs. IMRT demonstrates that outcomes are not compromised by more conformal radiotherapy. In the absence of prospective, multi-institutional, randomized trials of IMRT in ASCC, these retrospective data, using methods to minimize bias, can help to establish the role of IMRT in the definitive therapy of ASCC.

Management of anal cancer is a challenge. The goal of treatment is to eradicate tumor without sacrificing the anal sphincters. The idea of organ preservation emerged following the discovery of a high complete response rate from preoperative combined chemoradiation (CRT) prior to abdominoperineal resection.CRT is widely accepted as the standard therapy for treating anal squamous cell cancer. The combination of external beam radiotherapy with interstitial brachytherapy increases the dose to the tumor volume and decreases dose to normal tissues. The current goal is to avoid colostomy, and surgery has become a salvage or secondary therapy. In this article, we review the non-surgical management of anal cancer with special emphasis on CRT, role of intensity modulated radiation therapy and brachytherapy.

BACKGROUND:

This study sought to determine the feasibility and recommended phase 2 dose (RP2D) of the combination of cetuximab with chemoradiotherapy based on 5-fluorouracil (5-FU) and cisplatin (CP) in locally advanced anal canal carcinoma.

METHODS:

Cetuximab was administered on days 1, 8, 15, 29, 36, 43, and 50 (400 mg/m(2) initial dose, then 250 mg/m(2) /week) concurrent with total dose radiation of 55 to 59 Gy, both starting on day 1. Escalating doses of 5-FU (96-hour infusion) and CP (2-hour infusion), both on days 1 and 29, were administered according to the following design: starting dose level (0) 5-FU/CP = 800/60 mg/m(2) /day and up to dose level (+2) 5-FU/CP = 1000/80 mg/m(2) /day.

RESULTS:

Dose-limiting toxicity (DLT) events (uncontrolled diarrhea or febrile neutropenia) occurred in 3 of 14 assessable patients receiving escalated dose of 5-FU/CP, with 1 in dose level (0) and 2 in dose level (+2). The RP2D was 5-FU/CP = 800/80 mg/m(2) /day. Because of unexpected non-DLT treatment-related grade 3 (G3) adverse events (AEs) such as thrombosis/embolism, syncope, and infection occurring in ≥ 20% of patients, a safety expansion cohort with an additional 9 patients was investigated with the RP2D. The most frequent G3/G4 AEs evaluated in 23 patients were radiation dermatitis (12 patients), diarrhea (10 patients), thrombosis/embolism (6 patients), and infection (5 patients). The study was closed due to these severe AEs, although no G5 AEs occurred. Twenty of 21 patients (95%) achieved pathological complete response at primary tumor. With a median follow-up of 43.4 months, the 3-year locoregional control rate was 64.2%.

CONCLUSIONS:

Cetuximab could not be integrated with chemoradiotherapy-cisplatin-based therapy due to the high toxicity rate. However, efficacy is encouraging and further investigation of an epidermal growth factor receptor-targeted agent (other than cetuximab) concurrent with chemoradiation should be pursued. Cancer 2013. © 2013 American Cancer Society.

PURPOSE:

To report on chronic adverse events (CAE) and quality of life (QOL) after radiochemotherapy (RCT) in patients with anal cancer (AC).

PATIENTS AND METHODS:

Of 83 patients who had received RCT at our department between 1988 and 2011, 51 accepted the invitation to participate in this QOL study. CAE were evaluated using the Common Terminology Criteria for Adverse Events (CTCAE) v. 4.0 and QOL was assessed with the Functional Assessment of Cancer Therapy-Colorectal (FACT-C) questionnaire.

RESULTS:

CAE could be evaluated in 49 patients. There was a tendency toward a higher rate of grade 3 CAE in female patients, i.e. 18 out of 37 (49 %) vs. 2 out of 12 (17 %) male patients (p = 0.089). The most common grade 3 CAE were dyspareunia and vaginal symptoms (itching, burning and dryness) in 35 and 22 % of female patients, respectively, followed by stool incontinence in 13 % of all patients (6 out of 49). Both FACT-C and CAE information were available for 42 patients, allowing evaluation of the impact of CAE on QOL. The median total FACT-C score was 110 (40-132) out of a possible maximum of 136. The absence of grade 3 CAE (115 vs. 94, p = 0.001); an interval of ≥ 67 months after the end of the treatment (111 vs. 107, p = 0.010), no stool incontinence vs. grade 3 stool incontinence (111 vs. 74, p = 0.009), higher education (114 vs. 107, p = 0.013) and no dyspareunia vs. grade 3 dyspareunia (116 vs. 93, p = 0.012) were significantly associated with a higher median FACT-C score.

CONCLUSION:

The majority of AC patients treated with RCT have acceptable overall QOL scores, which are comparable to those of the normal population. Patients with grade 3 CAE-particularly dyspareunia and fecal incontinence-have a poorer QOL compared to patients without CAE. In order to improve long-term QOL, future strategies might aim at a reduction in dose to the genitalia and more intensive patient support measures.

Historically, squamous cell carcinoma of the anal canal was treated with abdominoperineal resection. Nigro discovered that radiation therapy combined with 5-fluorouracil and mitomycin resulted in high rates of local control and colostomy-free and overall survival without surgical intervention. Recent advances include the integration of PET into staging, radiation treatment planning, disease monitoring, and the use of intensity-modulated radiation therapy. For rectal cancer, clinical trials have established the role for neoadjuvant therapy for T3-4 and/or node-positive tumor presentations. Chemotherapy and targeted agents are under study in both anal and rectal cancers to improve on the standard combinations of chemotherapy and radiation.

PURPOSE:

To evaluate the influence of elective inguinal node radiation therapy (INRT) on locoregional control (LRC) in patients with early-stage T2N0 anal cancer treated conservatively with primary RT.

METHODS AND MATERIALS:

Between 1976 and 2008, 116 patients with T2 node-negative anal cancer were treated curatively with RT alone (n=48) or by combined chemoradiation therapy (CRT) (n=68) incorporating mitomycin C and 5-fluorouracil. Sixty-four percent of the patients (n=74) received elective INRT.

RESULTS:

Over a median follow-up of 69 months (range, 4-243 months), 97 (84%) and 95 patients (82%) were locally and locoregionally controlled, respectively. Rates for 5-year actuarial local control, LRC, cancer-specific, and overall survival for the entire population were 81.7% ± 3.8%, 79.2% ± 4.1%, 91.1% ± 3.0%, and 72.1% ± 4.5%, respectively. The overall 5-year inguinal relapse-free survival was 92.3% ± 2.9%. Isolated inguinal recurrence occurred in 2 patients (4.7%) treated without INRT, whereas no groin relapse was observed in those treated with INRT. The 5-year LRC rates for patients treated with and without INRT and with RT alone versus combined CRT were 80.1% ± 5.0% versus 77.8% ± 7.0% (P=.967) and 71.0% ± 7.2% versus 85.4% ± 4.5% (P=.147), respectively. A trend toward a higher rate of grade ≥3 acute toxicity was observed in patients treated with INRT (53% vs 31%, P=.076).

CONCLUSIONS:

In cases of node-negative T2 anal cancer, the inguinal relapse rate remains relatively low with or without INRT. The role of INRT in the treatment of early-stage anal carcinoma needs to be investigated in future prospective trials.

Introduction One standard of care for advanced non-small cell lung cancer (NSCLC) is paclitaxel plus carboplatin ± bevacizumab. This two-step phase I study evaluated the feasibility of adding everolimus to paclitaxel plus carboplatin ± bevacizumab for advanced NSCLC. Methods Adults with advanced NSCLC naive to systemic therapy were enrolled. A Bayesian dose-escalation model was used to identify feasible daily or weekly everolimus doses given with paclitaxel (200 mg/m(2) q21 days) and carboplatin (AUC 6 mg/mL/min q21 days) (step 1) and paclitaxel (200 mg/m(2) q21 days), carboplatin (AUC 6 mg/mL/min q21 days), and bevacizumab (15 mg/kg q21 days) (step 2). Primary endpoint was end-of-cycle 1 dose-limiting toxicity (DLT) rate. Secondary endpoints included safety; relative dose intensities of paclitaxel, carboplatin, and bevacizumab; pharmacokinetics; and tumor response. Results Fifty-two patients were enrolled and received everolimus 5 mg/day plus carboplatin and paclitaxel (step 1 daily; n = 13); everolimus 30 mg/week plus carboplatin and paclitaxel (step 1 weekly; n = 13); everolimus 5 mg/day plus carboplatin, paclitaxel, and bevacizumab (step 2 daily; n = 13); or everolimus 30 mg/week plus carboplatin, paclitaxel, and bevacizumab (step 2 weekly; n = 13). End-of-cycle 1 DLT rate was 16.7 % (step 1 daily), 30.8 % (step 1 weekly), 30.0 % (step 2 daily), and 16.7 % (step 2 weekly). Cycle 1 DLTs were grade 3 neutropenia, anal abscess, diarrhea, and thrombocytopenia and grade 4 myalgia, cellulitis, neutropenia, febrile neutropenia, pulmonary embolism, and thrombocytopenia. The most common adverse events were neutropenia, fatigue, anemia, and thrombocytopenia. One patient (step 2 daily) experienced complete response, 10 patients partial response. Conclusions The feasible everolimus doses given with carboplatin and paclitaxel ± bevacizumab were 5 mg/day and 30 mg/week. Neither schedule was very well tolerated in this unselected NSCLC population.

Chemoradiation became the standard of care for anal cancer after the ACT I trial. However, only two-thirds of patients achieved local control, with 5-year survival of 50%; therefore, better treatments are needed. We investigated whether replacing mitomycin with cisplatin in chemoradiation improves response, and whether maintenance chemotherapy after chemoradiation improves survival.In this 2×2 factorial trial, we enrolled patients with histologically confirmed squamous-cell carcinoma of the anus without metastatic disease from 59 centres in the UK. Patients were randomly assigned to one of four groups, to receive either mitomycin (12 mg/m(2) on day 1) or cisplatin (60 mg/m(2) on days 1 and 29), with fluorouracil (1000 mg/m(2) per day on days 1-4 and 29-32) and radiotherapy (50·4 Gy in 28 daily fractions); with or without two courses of maintenance chemotherapy (fluorouracil and cisplatin at weeks 11 and 14). The random allocation was generated by computer and patients assigned by telephone. Randomisation was done by minimisation and stratified by tumour site, T and N stage, sex, age, and renal function. Neither patients nor investigators were masked to assignment. Primary endpoints were complete response at 26 weeks and acute toxic effects (for chemoradiation), and progression-free survival (for maintenance). The primary analyses were done by intention to treat. This study is registered at controlled-trials.com, number 26715889.We enrolled 940 patients: 472 were assigned to mitomycin, of whom 246 were assigned to no maintenance, 226 to maintenance; 468 were assigned to cisplatin, of whom 246 were assigned to no maintenance, 222 to maintenance. Median follow-up was 5·1 years (IQR 3·9-6·9). 391 of 432 (90·5%) patients in the mitomycin group versus 386 of 431 (89·6%) in the cisplatin group had a complete response at 26 weeks (difference -0·9%, 95% CI -4·9 to 3·1; p=0·64). Overall, toxic effects were similar in each group (334/472 [71%] for mitomycin vs 337/468 [72%] for cisplatin). The most common grade 3-4 toxic effects were skin (228/472 [48%] vs 222/468 [47%]), pain (122/472 [26%] vs 135/468 [29%]), haematological (124/472 [26%] vs 73/468 [16%]), and gastrointestinal (75/472 [16%] vs 85/468 [18%]). 3-year progression-free survival was 74% (95% CI 69-77; maintenance) versus 73% (95% CI 68-77; no maintenance; hazard ratio 0·95, 95% CI 0·75-1·21; p=0·70).The results of our trial-the largest in anal cancer to date-show that fluorouracil and mitomycin with 50·4 Gy radiotherapy in 28 daily fractions should remain standard practice in the UK.Cancer Research UK.