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J Clin Oncol. 2017 March 1; 35(7): 727–733.
Published online 2016 December 12. doi:  10.1200/JCO.2016.69.1642
PMCID: PMC5455422

Cetuximab Plus Chemoradiotherapy for HIV-Associated Anal Carcinoma: A Phase II AIDS Malignancy Consortium Trial

Abstract

Purpose

Squamous cell carcinoma of the anal canal (SCCAC) is characterized by high locoregional failure (LRF) rates after definitive chemoradiation (CRT), associated with anogenital human papilloma virus, and often appears in HIV infection. Because cetuximab enhances the effect of radiation therapy in human papilloma virus–associated oropharyngeal SCC, we hypothesized that adding cetuximab to CRT would reduce LRF in SCCAC.

Methods

Forty-five patients with stage I to III SCCAC and HIV infection received CRT: 45 to 54 Gy radiation therapy to the primary tumor and regional lymph nodes plus eight once-weekly doses of concurrent cetuximab and two cycles of cisplatin and fluorouracil. The study was designed to detect at least a 50% reduction in 3-year LRF rate (one-sided α, 0.10; power, 90%), assuming a 35% LRF rate from historical data.

Results

The 3-year LRF rate was 42% (95% CI, 28% to 56%; one-sided P = .9) by binomial proportional estimate using the prespecified end point (LRF or alive without LRF and followed < 3 years), and 20% (95% CI, 10% to 37%) by Kaplan-Meier estimate in post hoc analysis using definitions and methods consistent with historical data. Three-year rates by Kaplan-Meier estimate were 72% (95% CI, 56% to 84%) for progression-free survival and 79% (95% CI, 63% to 89%) for overall survival. Grade 4 toxicity occurred in 26%, and 4% had treatment-associated deaths.

Conclusion

HIV-associated SCCAC is potentially curable with definitive CRT. Although addition of cetuximab may result in less LRF, the 20% recurrence and 26% grade 4 toxicity rates indicate the continued need for more-effective and less-toxic therapies.

INTRODUCTION

There is an approximately 60-fold increase in the risk of squamous cell carcinoma of the anal canal (SCCAC) in individuals with HIV infection compared with the general population.1 Sphincter-sparing definitive chemoradiation (CRT), including concurrent radiation plus fluorouracil (FU) and mitomycin-C or cisplatin, is potentially curative but is associated with high rates of dermatitis, GI toxicity, myelosuppression, and other toxicities.2-6 Locoregional failure (LRF) may occur in approximately 30% and is associated with significant morbidity, distant recurrence, and mortality.5 New approaches are needed to develop more effective therapies that result in improved local and systemic disease control.

SCCAC is commonly associated with human papillomavirus (HPV) infection.7-9 The HPV-associated E5 protein amplifies the mitogenic signals mediated by the epidermal growth factor receptor (EGFR),10 which is broadly expressed in epithelial cancers, including squamous cell carcinoma of the anogenital tract and oropharynx.11,12 Because the anti-EGFR antibody cetuximab prolongs survival when used in combination with radiation therapy (RT) in patients with locally advanced SCC of the oropharynx,13,14 another cancer that is typically associated with HPV infection,15-17 we hypothesized that the addition of cetuximab to CRT would improve locoregional control in patients with SCCAC. We therefore designed two trials that were concurrently conducted to determine the effectiveness of cetuximab plus CRT in patients with HIV infection (AMC045) and without HIV infection (E3205). We herein report the results of the AMC045, which is the first prospectively conducted clinical trial to our knowledge in patients with SCCAC and HIV infection, and also report the results of E3205 is a separate accompanying report.18 Both trials were single-arm phase II trials evaluating cetuximab plus the same CRT regimen of cisplatin, FU, and external beam RT.

METHODS

Eligibility Criteria

Patients were required to have histologically confirmed anal canal or perianal (anal margin) squamous cell carcinoma (or tumors of nonkeratinizing histology, such as basaloid, transitional cell, or cloacogenic histology) and stage I (excluding well-differentiated stage I anal margin cancer), II (T2N0, T3N0), IIIA, or IIIB disease. Other requirements include age 18 years or older; Eastern Cooperative Oncology Group performance status 0 to 2; no prior potentially curative surgery, RT, or chemotherapy for this malignancy; no prior pelvic radiotherapy; no other concurrent malignancies except for nonmelanomatous skin cancer; and adequate organ function. Further details are described elsewhere in the E3205 report.18

Study Objectives

The primary objective was to estimate the LRF rate at 3 years. Secondary objectives included response rate (complete and partial), progression-free survival (PFS), colostomy-free survival (CFS), overall survival (OS), quality of life (QOL), and overall toxicity. Correlative science objectives included characterizing the effect of CRT on HIV viral load, CD4 lymphocyte count, and opportunistic infection; incidence of anogenital HPV infection; and association between LRF and EGFR, phosphatidylinositol 3-kinase, and Akt gene expression (to be reported separately).

Study End Point Definitions

LRF was defined as progression/relapse of disease in the anal canal and/or regional organs and/or regional lymph nodes. PFS was defined as time from registration to progression, relapse, or death from any cause. CFS was defined as date of registration until date that colostomy was required or death from any cause. OS was defined as time from registration until death from any cause. Response was classified according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria (version 1.0) and required radiologic confirmation at least 4 weeks after initial objective response.19 Tumor assessments were made by physical examination and computerized tomography of the abdomen and pelvis at baseline, within 4 weeks of the completion of protocol treatment, every 6 months if patient was 1 to 4 years from registration, and annually thereafter. National Cancer Institute Common Adverse Events Criteria, version 3.0, was used to grade toxicity. QOL was also evaluated using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 and CR38 Colorectal Cancer Module at baseline; at weeks 5 (after cycle 1), 12 (after completion of therapy), and 26 (ie, month 6); and again at months 12, 24, and 36 after beginning therapy. Formalin-fixed paraffin-embedded tumor biopsy specimens were assessed for HPV DNA using previously described methods.20

Statistical Considerations

The study was designed to detect at least a 50% reduction in 3-year LRF rate (one-sided α, 0.10; power, 90%), the primary study end point, and assumed a 3-year LRF rate of approximately 35% on the basis of historical data, as described in an accompanying report.18 For the primary study end point definition and analysis plan, patients were classified into two groups as a binary variable, including failure (defined as LRF, or follow-up < 3 years without LRF) or no failure (alive without an LRF event and followed for at least 3 years), and evaluated by binomial proportion. PFS, CFS, and OS were estimated using the Kaplan-Meier method, with 95% CIs calculated using Greenwood’s formula. Event rates at 3 years were evaluated, because prior studies indicated that most events related to SCCAC or its treatment occurred within 3 years.2-4,5,6,21 The cutoff date for the data analysis was September 10, 2015.

Informed Consent and Regulatory Approval

The study was reviewed and approved by the Cancer Evaluation Therapy Program of the National Cancer Institute (AIDS Malignancy Consortium trial 045) and by the institutional review board at each participating institution (ClinicalTrials.gov identifier NCT00324415). All patients provided written informed consent.

Cetuximab, Chemotherapy, and RT

The treatment schema is shown in Figure 1. Criteria for treatment modifications are summarized. RT compliance was monitored by the Quality Assurance Review Center (Lincoln, RI). Concurrent RT consisted of 1.8 Gy once per day 5 days per week for a minimum of 5 weeks and was based on prechemotherapy tumor volumes (minimum, 45.0 Gy; maximum, 54.0 Gy). Intensity-modulated RT was used at the discretion of the treating physician according to the guidelines outlined in this protocol. The total dose of irradiation to the primary tumor was 45 Gy for T1 or T2 lesions or between 50.4 Gy and 54.0 Gy for T3 or T4 lesions or T2 disease with clinical evidence of residual disease after 45 Gy. The total dose to the inguinal nodes was 30.6 Gy for N0 or N1 disease or 50.4 to 54.0 Gy for N2 or N3 disease, for clinical evidence of residual disease after 45 Gy, or for any lymph node > 3 cm (see Data Supplement for additional specific details).

Fig 1.
Treatment schema. FU, fluorouracil; IV, intravenous; RT, radiation therapy.

RESULTS

Patient Characteristics

A total of 45 patients were accrued between March 21, 2007 and April 4, 2011 at eight sites. The characteristics of the study population are outlined in Table 1.22 All patients had squamous cell histology. Poor risk features included male sex in 91%, T3 lesion in 27%, and positive regional nodes in 35%. Twenty-five of 30 tumors evaluated (83%) were HPV positive.

Table 1.
Patient Characteristics

Treatment Administration and Overall Safety

Two patients withdrew after enrollment and did not receive RT but are nevertheless including in the efficacy analysis. Information regarding chemotherapy dose intensity and RT administration is summarized in Table 2. Treatment was completed as per protocol in 37 patients (82%), whereas the remaining eight patients (18%) withdrew because of an adverse event in four patients (9%) and for other reasons in four patients (9%). Dose modifications were required for cisplatin in four patients (9%), FU in four patients (9%), and cetuximab in nine patients (20%); for cetuximab, this included dose delay in five patients, reduction in two patients, and discontinuation or unknown in one patient each. RT was delivered per protocol in 68%, with minor deviations in 16% and major deviations in 16%. For the major deviations, in six patients the mesorectum was not fully contoured; in three of these patients, lymph nodes were not fully contoured as well. The remaining deviations were assigned because of difficulty in meeting normal tissue volume constraints related to small bowel and femoral heads.

Table 2.
Treatment Administered

Grade 1 to 4 adverse events are summarized in Table 3. There were also two treatment-associated deaths (grade 5 events) due to GI bleeding in one patient and wound infection leading to sepsis in another patient, both occurring within 1 month of beginning therapy. The most common grade 3 to 4 adverse events occurring in 10% or more of patients included diarrhea in 31% (31% grade 3, 0% grade 4), neutropenia in 29% (20% grade 3, 9% grade 4), dehydration in 24% (22% grade 3, 2% grade 4), infection in 23% (16% grade 3, 7% grade 4), hypokalemia in 20% (13% grade 3, 7% grade 4), thrombocytopenia in 18% (9% grade 3, 9% grade 4), anemia in 11% (7% grade 3, 4% grade 4), and nausea in 11% (11% grade 3, 0% grade 4). Four patients (8%) had opportunistic infections, and five patients (11%) had delayed grade 1 or 2 toxicities related to radiation. Opportunistic infections included oral thrush in two patients, oral thrush and pneumonia in one patient, and cerebral toxoplasmosis in one patient. Eleven patients (24%) received granulocyte colony stimulating factor for treatment or prevention of neutropenia at the discretion of the treating physician.

Table 3.
Grade 1 to 4 Adverse Events

Primary End Point: LRF at 3 Years

At 3 years, seven patients had an LRF event (16%), four patients (9%) died of causes other than anal cancer without an LRF event, and 34 surviving patients (75%) did not have an LRF event; of the 34 surviving patients without an LRF event, 22 patients (49%) were followed for ≥ 3 years, and 12 patients (27%) were followed for < 3 years. The 3-year LRF rate was 42% (95% CI, 28% to 56%; P under H0 = .9) by binomial proportional estimate using the prespecified end point (LRF or alive without LRF and followed < 3 years). The 3-year LRF rate was 20% (95% CI, 10% to 37%) by Kaplan-Meier estimate in post hoc analysis using definitions and methods consistent with historical data. The LFR was substantially higher using the former definition, because patients followed for < 3 years were considered failures (12 of 19 LRF events). LRF rates were not significantly different in the 68% of patients who had no RT deviations and the 32% who did have deviations and was not associated with LRF in multivariate logistic regression analysis that also included HIV viral load at baseline, absolute CD4 lymphocyte count at baseline, current antiretroviral treatment (yes/no), stage (I v II v IIIA-B), sex, T > 5 cm (yes/no), positive nodes (yes/no).

Secondary End Points: Objective Response and Other Clinical Outcomes

The complete response rate was 62% (95% CI, 47% to 76%) and the overall response rate was 67% (95% CI, 51% to 80%). Complete and overall response rates were not significantly associated with HIV viral load at baseline, absolute CD4 count at baseline, or disease stage. Kaplan-Meier estimates for PFS, CFS, and OS, are shown in Figures 2A to 2C. At the time of the analysis, with a median follow-up time of 56 months (range, 0 to 68 months) in surviving patients, 10 patients died (including six from anal cancer, four from other causes), 13 patients had a PFS event (including nine with disease progression [seven locoregional, two distant] and four with death from other causes), and four patients had a colostomy. Three-year rates were 72% (95% CI, 56% to 84%) for PFS, 77% (95% CI, 60% to 87%) for CFS, and 79% (95% CI, 63% to 89%) for OS. For the four patients who died of causes other than anal cancer, two deaths occurred within 1 month of beginning therapy, as previously described, and two deaths occurred after completing therapy (acute myelogenous leukemia at 25 months and cardiac failure at 25 months).

Fig 2.
Kaplan-Meier estimates of (A) progression-free survival (PFS), (B) colostomy-free survival (CFS), and (C) overall survival (OS).

QOL

Using the Quality of Life Questionnaire C30 (Fig 3; Appendix Table A1, online only), there were significant differences between baseline and subsequent time points in global health status (week 5), physical functioning (week 12), role functioning (week 12), and social functioning (week 12), reflecting an adverse but transient impact of treatment on the QOL. There were no significant changes noted in cognitive functioning. There was a significant difference in emotional functioning between baseline and month 24. With regard to symptom scales, there were significant differences between baseline and week 5 in fatigue, anorexia, and diarrhea (and also at months 6 and 24 for diarrhea). There were also differences in pain (months 6, 12, and 24), insomnia (months 12 and 24), constipation (month 12), and financial difficulties (months 6 and 12) compared with before therapy. There were no differences in nausea and vomiting or dyspnea. Using the QLQ-CR38 (Appendix Table A2, online only), there were also significant differences compared with baseline body image and sexual enjoyment (week 5), sexual functioning (month 12), and future perspective (week 2, month 12). With regard to symptom scales, there were significant differences compared with baseline with regard to micturition problems, chemotherapy adverse effects, GI symptoms (week 5), male sexual problems (week 5 and months 12, 24, and 36), and defecation problems (months 12 and 36),

Fig 3.
European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 (QLQ-C30) global score at baseline and at weeks 5 (after cycle 1), 12 (after completion of therapy), 28 (ie, month 6), and 52 after beginning therapy.

Changes in CD4 Lymphocyte Count and HIV Viral Load

Absolute CD4 counts decreased significantly from baseline (401/μL, range, 91 to 1,283) to the end of treatment (median, 153/μL; range, 27 to 662; median change, −218/μL; P < .001), but recovered after completion of therapy (median, 278/μL; range, 46 to 941; median change, +102/μL; P < .001). There were no differences in HIV viral load before and after therapy, with more than one-half having undetectable viral load. Four patients (8%; 95% CI, 3% to 21%) developed an opportunistic infection.

DISCUSSION

It is estimated that there were approximately 37 million people worldwide living with HIV/AIDS at the end of 2014,23 including approximately 1.2 million HIV-infected individuals in the United States.24 Improved antiretroviral therapy beginning in the 1990s led to substantial declines in mortality from HIV infection in the United States,25 which continues in the United States and globally.26 HIV testing is now recommended as a component of routine medical care, not just for individuals with known risk factors,27-29 including patients with cancer.30 Although improved antiretroviral therapy has also resulted in substantially fewer HIV-associated cancers such as lymphoma and Kaposi’s sarcoma, the incidence of other cancers has increased, including anal carcinoma.1 Approximately 1% of women and 28% of men with anal cancer also have HIV infection.31

We herein report the results of the first prospectively conducted trial, to our knowledge, of CRT for the treatment of SCCAC associated with HIV infection. At the time this trial was initiated, a number of retrospective case reviews involving a limited number of patients indicated that clinical outcomes were inferior and toxicity rates with CRT excessive.32-38 We chose to use cisplatin and FU as the chemotherapy regimen in combination with standard doses of RT, because substituting cisplatin for mitomycin-C was associated with less myelosuppression and comparable or improved disease control in prior trials including patients not know to have HIV infection.39-41 In addition, we added concurrent treatment with the EGFR inhibitor cetuximab because of evidence that it enhanced the effects of RT and improved local disease control in oropharyngeal SCC,13,14 which is also commonly associated with HPV infection.7,8 We therefore performed two prospective trials evaluating cetuximab plus CRT in patients with HIV infection (AMC045) and without known HIV infection (E3205).18 When the two trials are considered together, a noteworthy finding is that patients with HIV infection had similar clinical outcomes as those who did not have HIV infection, with approximately 70% being alive and recurrence free at 3 years. Treatment tolerance and the overall adverse effect profile were also similar in the two populations. These findings are consistent with population-based data indicating that although cancer-specific mortality is increased in HIV-infected individuals compared with the general population for some cancers (eg, colorectal, pancreas, larynx, lung, melanoma, and breast cancer), this is not true for anal cancer.42 Although comparison of efficacy and toxicity observed in the two studies targeting populations differing by HIV status is limited by the modest sample size and more advanced disease for the HIV-negative cohort, our findings nevertheless provide additional data suggesting that SCCAC in HIV-infected individuals may be treated with curative intent similar to immunocompetent individuals. Although treatment was associated with a transient reduction in CD4 lymphocyte counts, opportunistic infections were uncommon, HIV viral load did not change, and CD4 counts recovered after completion of CRT. Although CRT was also associated with adverse patient-reported symptoms (eg, fatigue, anorexia) and impaired QOL, most symptoms resolved after completion of therapy.

The AMC045 and E3205 trials were primarily designed to determine whether adding cetuximab reduced the rate of LRF, which occurs in approximately 30% of patients treated with CRT alone. In comparison with patients enrolled on the E3205 trial, patients with HIV infection enrolled in AMC045 were more likely to be men (reflecting known demographics for HIV infection) and more likely to have T1 disease (reflecting differing eligibility criteria). In both trials, LRF rates were approximately 20% at 3 years, indicating that LRF rates were lower than historical data using similar definitions.3,5 Although this study did not meet its prespecified primary end point, the majority of the LRF events were categorized as failures because of insufficient follow-up and not due to a truly higher LRF rate when similar definitions of LRF were used compared with historical data.

In conclusion, this is the first prospective trial, to our knowledge, of a CRT regimen in patients with HIV-associated SCCAC that demonstrates comparable efficacy, tolerance, and toxicity when compared with the same CRT regimen plus cetuximab in a concurrently conducted trial in an HIV-negative population. These finding suggest that patients with HIV-associated SCCAC should be treated with potentially curative intent with CRT in a manner similar to patients without known HIV infection. However, the 20% LRF rate and 26% grade 4 toxicity rate indicate the continued need for more-effective and less-toxic therapies.

ACKNOWLEDGMENT

We thank Sabrina Khan, MD, MPH, for her review of the manuscript.

Appendix

Table A1.

An external file that holds a picture, illustration, etc.
Object name is JCO.2016.69.1642ta1.jpg

European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 Data

Table A2.

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Object name is JCO.2016.69.1642ta2.jpg

European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire CR38 Data

Footnotes

Coordinated by the AIDS Malignancy Consortium (Ronald Mitsuyasu, MD, Chair) and supported in part by Public Health Service Grant No. UM1CA121947 and the National Cancer Institute, National Institutes of Health, and the Department of Health and Human Services. Supported by grants U10 CA029511 (QARC) and U24 CA180803 (IROC).

The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute.

Clinical trial information: NCT00324415.

See accompanying Editorial on page 699

AUTHOR CONTRIBUTIONS

Conception and design: Joseph A. Sparano, Joel Palefsky, Lisa Kachnic, Ronald Mitsuyasu

Administrative support: Joseph A. Sparano, Jeannette Y. Lee, Thomas J. Fitzgerald

Provision of study materials or patients: Joseph A. Sparano, David H. Henry, William Wachsman, Lakshmi Rajdev, David Aboulafia, Lee Ratner, Ronald Mitsuyasu

Collection and assembly of data: Joseph A. Sparano, Jeannette Y. Lee

Data analysis and interpretation: All authors

Manuscript writing: All authors

Final approval of manuscript: All authors

Accountable for all aspects of the work: All authors

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Cetuximab Plus Chemoradiotherapy for HIV-Associated Anal Carcinoma: A Phase II AIDS Malignancy Consortium Trial (AMC045)

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/site/ifc.

Joseph A. Sparano

Stock or Other Ownership: MetaStat

Consulting or Advisory Role: Genentech, Eisai, Novartis, AstraZeneca, Celgene, Prescient Therapeutics, Bayer Health Care Pharmaceuticals, Juno Therapeutics, Eli Lilly, Celldex Therapeutics

Research Funding: Merck (Inst), Deciphera Pharmaceuticals (Inst), Prescient Therapeutics (Inst), Genentech (Inst), Merrimack Pharmaceuticals (Inst), AstraZeneca/MedImmune (Inst), Tapimmune (Inst), Eisai (Inst)

Jeannette Y. Lee

Research Funding: Merck (Inst)

Joel Palefsky

Consulting or Advisory Role: Antiva Biosciences, Agenovir, Merck (Inst), Hologic (Inst)

Research Funding: Merck (Inst), Hologic (Inst), CEL-SCI (Inst)

Travel, Accommodations, Expenses: Hologic, Merck

David H. Henry

Consulting or Advisory Role: Amgen, AMAG Pharmaceuticals

Research Funding: Amgen

Travel, Accommodations, Expenses: AMAG Pharmaceuticals

William Wachsman

Consulting or Advisory Role: Celgene

Patents, Royalties, Other Intellectual Property: Inventor with patent held by UC San Diego

Lakshmi Rajdev

No relationship to disclose

David Aboulafia

No relationship to disclose

Lee Ratner

No relationship to disclose

Thomas J. Fitzgerald

No relationship to disclose

Lisa Kachnic

Honoraria: TRM Oncology

Consulting or Advisory Role: Epic Pharma, INSYS Therapeutics

Patents, Royalties, Other Intellectual Property: UpToDate

Ronald Mitsuyasu

Stock or Other Ownership: Amgen

Research Funding: Calimmune (Inst), Sangamo BioSciences (Inst)

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