VITAL phase 2 study: Upfront 5‐fluorouracil, mitomycin‐C, panitumumab and radiotherapy treatment in nonmetastatic squamous cell carcinomas of the anal canal (GEMCAD 09‐02)

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Abstract

Aim

VITAL, a phase II single‐arm study, aimed to evaluate efficacy and safety of panitumumab addition to 5‐fluorouracil (5‐FU), mitomycin‐C (MMC) and radiotherapy (RT) in patients with localized squamous cell carcinoma of the anal canal (SCCAC).

Methods

Adult, treatment‐naïve SCCAC patients (Stage T2‐T4, any N, M0) and ECOG‐PS ≤2, received panitumumab (6 mg/kg, day 1 and Q2W; 8 weeks), 5‐FU (1000 mg/m ²/d, days 1‐4 and 29‐32), MMC (10 mg/m ², days 1 and 29) and RT 45 Gy (1.8 Gy/fraction) to the primary tumor and mesorectal, iliac and inguinal lymph nodes, plus 10‐15 Gy boost dose to the primary tumor and affected lymph nodes. The primary objective was disease free survival rate (DFS) at 3‐years (expected 3‐year DFS rate: 73.7 ± 12%).

Results

Fifty‐eight patients (31 women; median age: 59 years; ECOG‐PS 0‐1:98%; TNM II [29%] (T2 or T3/N0/M0)/IIIA (T1‐T3/N1/M0 or T4/N0/M0) [21%]/IIIB (T4/N1/M0 or any T/N2 or N3/M0) [47%]/nonevaluable [4%]) were included. The median follow‐up was 45 months. The 3‐year DFS rate was 61.1% (95% CI: 47.1, 72.4). The 3‐year overall survival rate was 78.4% (95% CI: 65.1, 87.1). Eighteen patients (31.0%) required a colostomy within 2 years posttreatment. Grade 3‐4 toxicities were experienced by 53 (91%) patients. Most common grade 3‐4 treatment‐related events were radiation skin injury (40%) and neutropenia (24%). No toxic deaths occurred. Improved efficacy in colostomy‐free survival and complete response rate was observed in human papilloma virus positive patients.

Conclusions

Panitumumab addition to MMC‐5FU regimen in SCCAC patients increases toxicity and does not improve patients’ outcomes. RT plus MMC‐5FU remains the standard of care for localized SCCAC patients.

Abstract

VITAL, a phase II single‐arm study, was aimed to evaluate efficacy and safety of panitumumab addition to 5‐fluorouracil (5‐FU), mitomycin‐C (MMC) and radiotherapy in patients with localized squamous cell carcinoma of the anal canal (SCCAC). The study concluded that panitumumab addition to MMC‐5FU regimen in SCCAC patients increases toxicity and does not improve patients’ outcomes.

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Most cited references 38

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Radiotherapy plus cetuximab or cisplatin in human papillomavirus-positive oropharyngeal cancer (NRG Oncology RTOG 1016): a randomised, multicentre, non-inferiority trial

Maura L. Gillison, Andy M Trotti, Jonathan Harris … (2018)

Patients with human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma have high survival when treated with radiotherapy plus cisplatin. Whether replacement of cisplatin with cetuximab-an antibody against the epidermal growth factor receptor-can preserve high survival and reduce treatment toxicity is unknown. We investigated whether cetuximab would maintain a high proportion of patient survival and reduce acute and late toxicity.

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Mitomycin or cisplatin chemoradiation with or without maintenance chemotherapy for treatment of squamous-cell carcinoma of the anus (ACT II): a randomised, phase 3, open-label, 2×2 factorial trial

Roger D James, Robert Glynne-Jones, Helen M Meadows … (2013)

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. Copyright © 2013 Elsevier Ltd. All rights reserved.

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Human papillomavirus, smoking, and sexual practices in the etiology of anal cancer.

Janet R Daling, Margaret Madeleine, Lisa Johnson … (2004)

The incidence of anal cancer has increased among both men (160%) and women (78%) from 1973 to 2000 in the U.S. The authors conducted a population-based case-control study of anal cancer to examine factors that may account for this increase. Men (n = 119 patients) and women (n = 187 patients) who were diagnosed with anal cancer between 1986 and 1998 in the Seattle area were ascertained through the local Surveillance, Epidemiology, and End Results registry. Control participants (n = 1700) were ascertained through random-digit telephone dialing. Participants were interviewed in person and provided blood samples. Archival tumor tissue was tested for human papilloma virus (HPV) DNA, and serum samples were tested for HPV type 16 (HPV-16). Overall, 88% of tumors (all histologies) in the study were found to be positive for HPV. HPV-16 was the most frequent HPV type detected (73% of all tumors), followed by HPV-18 (6.9%), regardless of gender. However, 97.7% of tumors from men who were not exclusively heterosexual contained HPV DNA. The risk of anal cancer increased among men (odds ratio [OR], 5.3; 95% confidence interval [95% CI], 2.4-12.0) and women (OR, 11.0; 95% CI, 5.5-22.1) who had > or = 15 sexual partners during their lifetime. Among men who were not exclusively heterosexual and women, receptive anal intercourse was related strongly to the risk of anal cancer (OR, 6.8 [95% CI, 1.4-33.8] and OR, 2.2 [95% CI, 1.4-3.3], respectively). Current smokers among men and women were at particularly high risk for anal cancer, independent of age and other risk factors (OR, 3.9 [95% CI, 1.9-8.0] and OR, 3.8 [95% CI, 2.4-6.2], respectively). The high proportion of tumors with detectable HPV suggests that infection with HPV is a necessary cause of anal cancer, similar to that of cervical cancer. Increases in the prevalence of exposures, such as cigarette smoking, anal intercourse, HPV infection, and the number of lifetime sexual partners, may account for the increasing incidence of anal cancer in men and women. Copyright 2004 American Cancer Society.

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Author and article information

Contributors

Jaime Feliu:

ORCID: https://orcid.org/0000-0003-4867-1420

jaime.feliu@salud.madrid.org

Journal

Journal ID (nlm-ta): Cancer Med

Journal ID (iso-abbrev): Cancer Med

Journal ID (doi): 10.1002/(ISSN)2045-7634

Journal ID (publisher-id): CAM4

Title: Cancer Medicine

Publisher: John Wiley and Sons Inc. (Hoboken )

ISSN (Electronic): 2045-7634

Publication date (Electronic): 18 December 2019

Publication date Collection: February 2020

Volume: 9

Issue: 3 ( doiID: 10.1002/cam4.v9.3 )

Pages: 1008-1016

Affiliations

[ ¹ ] Department of Medical Oncology CIBERONC Catedra UAM‐AMGEN Hospital Universitario La Paz Madrid Spain

[ ² ] Department of Medical Oncology Hospital Universitario Virgen del Rocio Sevilla Spain

[ ³ ] Department of Medical Oncology imas12 UCM CNIO CIBERONC Hospital Universitario 12 de Octubre Madrid Spain

[ ⁴ ] Department of Medical Oncology Hospital Universitari Vall d'Hebron Vall Hebron Institute of Oncology (VHIO) Barcelona Spain

[ ⁵ ] Department of Medical Oncology Hospital Althaia‐Manresa Manresa Spain

[ ⁶ ] Department of Medical Oncology Instituto de Investigacion Sanitaria de Aragon Hospital Universitario Miguel Servet Zaragoza Spain

[ ⁷ ] Department of Medical Oncology Hospital Universitario Marques de Valdecilla Santander Spain

[ ⁸ ] Department of Medical Oncology Hospital General Universitario Gregorio Maranon Madrid Spain

[ ⁹ ] Department of Medical Oncology Hospital Virgen Blanca Leon Spain

[ ¹⁰ ] Investigacion Clinica y Traslacional en Cancer Instituto de Investigaciones Biomedicas de Malaga (IBIMA) Hospitales Universitarios Regional y Virgen de la Victoria Malaga Spain

[ ¹¹ ] Department of Radiation Oncology Hospital Universitario de La Princesa Madrid Spain

[ ¹² ] Department of Radiation Oncology Hospital Clinic IDIBAPS University of Barcelona Barcelona Spain

[ ¹³ ] Department of Radiation Oncology Hospital Universitario Virgen del Rocio Sevilla Spain

[ ¹⁴ ] Department of Oncology Hospital Universitario La Paz Madrid Spain

[ ¹⁵ ] Department of Medical Oncology Hospital de la Santa Creu i Sant Pau Barcelona Spain

[ ¹⁶ ] Department of Medical Oncology Hospital Universitario Infanta Sofia Madrid Spain

[ ¹⁷ ] Department of Medical Oncology Hospital Universitario Fundacion Jimenez Diaz Madrid Spain

[ ¹⁸ ] Department of Radiation Oncology ICO Badalona Hospital Universitari Germans Trias i Pujol Badalona Spain

[ ¹⁹ ] Department of Medical Oncology Hospital Son Llatzer Palma de Mallorca Spain

[ ²⁰ ] Department of Medical Oncology Hospital Clinic Translational Genomics and Targeted Therapeutics in Solid Tumours Group IDIBAPS University of Barcelona Barcelona Spain

Author notes

[*] [* ] Correspondence

Jaime Feliu, Servicio de Oncología Médica, Hospital Universitario La Paz, Paseo de la Castellana, 261, 28046 Madrid, Spain.

Email: jaime.feliu@ 123456salud.madrid.org

Author information

Jaime Feliu https://orcid.org/0000-0003-4867-1420

Jaume Capdevila https://orcid.org/0000-0001-8017-9941

Article

Publisher ID: CAM42722

DOI: 10.1002/cam4.2722

PMC ID: 6997048

PubMed ID: 31851776

SO-VID: 6dff01e4-e347-42fe-a2fc-0e8268cc8880

License:

This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

History

Date received : 10 September 2019

Date revision received : 05 November 2019

Date accepted : 06 November 2019

Page count

Figures: 2, Tables: 3, Pages: 9, Words: 5515

Funding

Funded by: Amgen S.A.

Custom metadata

source-schema-version-number 2.0

cover-date February 2020

details-of-publishers-convertor Converter:WILEY_ML3GV2_TO_JATSPMC version:5.7.5 mode:remove_FC converted:03.02.2020

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: chemotherapy,radiotherapy,rectal cancer,target therapy

Data availability:

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: chemotherapy, radiotherapy, rectal cancer, target therapy

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VITAL phase 2 study: Upfront 5‐fluorouracil, mitomycin‐C, panitumumab and radiotherapy treatment in nonmetastatic squamous cell carcinomas of the anal canal (GEMCAD 09‐02)

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Karger: Oncology

Most cited references 38

Radiotherapy plus cetuximab or cisplatin in human papillomavirus-positive oropharyngeal cancer (NRG Oncology RTOG 1016): a randomised, multicentre, non-inferiority trial

Mitomycin or cisplatin chemoradiation with or without maintenance chemotherapy for treatment of squamous-cell carcinoma of the anus (ACT II): a randomised, phase 3, open-label, 2×2 factorial trial

Human papillomavirus, smoking, and sexual practices in the etiology of anal cancer.

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