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Originally published as JCO Early Release 10.1200/JCO.2008.16.2339 on May 19 2008 © 2008 American Society of Clinical Oncology. Induction Therapy for Poor-Prognosis Anal Canal Carcinoma: A Phase II Study of the Cancer and Leukemia Group B (CALGB 9281)
From the Fox Chase Cancer Center, Philadelphia, PA; Cancer and Leukemia Group B Statistical Center, Duke University Medical Center; and University of North Carolina at Chapel Hill, Durham; and Wake Forest University, Winston-Salem, NC; Doctors Medical Center, San Pablo, CA; Dartmouth-Hitchcock Medical Center, Lebanon, NH; Southern Nevada Cancer Research Foundation Community Clinical Oncology Program, Las Vegas, NV; and Dana Farber Cancer Institute, Boston, MA Corresponding author: Neal J. Meropol, MD, Fox Chase Cancer Center, 333 Cottman Ave, Philadelphia, Pa 19111; e-mail: neal.meropol{at}fccc.edu
Purpose Although most patients with anal canal cancer are cured with sphincter-preserving, nonsurgical, combined-modality therapy, those with large tumors and lymph node involvement have a poor prognosis. To establish the safety and efficacy of induction chemotherapy with infusional fluorouracil (FU) plus cisplatin followed by FU plus mitomycin C with concurrent radiation in patients with poor-prognosis squamous cell cancers of the anal canal. Methods Patients with previously untreated anal canal cancers with T3 or T4 tumors and/or extensive nodal involvement (bulky N2 or N3) received two 28-day cycles of induction treatment with infusional FU plus cisplatin followed by two 28-day cycles of FU plus mitomycin C with concurrent split-course radiation. A third cycle of FU and cisplatin with radiation boost was given to patients with persistent primary site disease or bulky N2 or N3 disease at presentation. Results Forty-five assessable patients received protocol therapy. Treatment was generally well tolerated, and gastrointestinal and hematologic toxicities were the most common. Induction chemotherapy resulted in eight complete and 21 partial responses. After induction, combined-modality, and boost therapy, 37 (82%) of 45 assessable high-risk patients achieved a complete response. After 4 years of follow-up, 68% of patients are alive, 61% are disease-free, and 50% are colostomy- and disease-free. Conclusion A combined-modality approach that includes induction treatment with FU and cisplatin followed by combined-modality therapy with FU, mitomycin C, and concurrent radiation results in long-term disease control in the majority of patients with poor-prognosis anal canal cancer.
Carcinoma of the anal canal is an uncommon malignancy; approximately 4,700 patient cases and 700 deaths are expected to occur in the United States in 2007.1 Anal canal cancer represents an initial model for the successful application of organ-sparing, combined-modality therapy for curative treatment. Although anal canal cancer was originally a surgically treated disease that required abdominoperineal resection, approximately two thirds of patients are now cured with a combination of chemotherapy and radiation with sphincter preservation.2 An accepted standard approach for patients with localized nonmetastatic disease is external-beam radiation therapy with concurrent fluorouracil (FU) and mitomycin C. However, several studies identified clinical features, such as large primary tumors and extensive regional nodal involvement, that were associated with poor prognosis and failure of the standard approach.2,3 Small series suggested that cisplatin is active against anal canal carcinomas.4,5 In an effort to confirm the clinical activity of cisplatin and to improve outcome in patients with locally advanced anal canal carcinomas, the Cancer and Leukemia Group B (CALGB) undertook a phase II study of induction cisplatin plus FU followed by radiation therapy in combination with FU plus mitomycin in patients with poor prognostic features.
Patient Eligibility Patients were at least 18 years old and had histologically confirmed anal canal carcinomas. Squamous, basosquamous, basaloid, and cloacogenic histologies were permitted. Patients with adenocarcinomas and tumors that occurred in perianal skin were excluded. All patients had clinical evidence of poor prognosis, which was defined as T3 (> 5 cm) or T4 (adjacent organ involvement) tumors with or without nodal involvement or as bulky N2 (unilateral internal iliac or inguinal nodes > 3 cm or matted) or N3 (bilateral internal iliac or inguinal, or perirectal plus internal iliac or inguinal) nodal involvement with any T stage.6 Involved nodes required biopsy confirmation. Each patient had an Eastern Cooperative Oncology Group performance status of 0 to 2 (ie, ambulatory at least half of waking hours), and good organ function. Bidimensionally measurable disease was required for inclusion. The study protocol was IRB-approved at all study sites, and informed consent was required for all patients.
Treatment Plan
There was concern that unplanned treatment breaks were otherwise necessary during concomitant chemoradiotherapy because of toxicity, so split-course radiation was chosen in an effort to standardize and minimize treatment interruptions. Therefore, radiation therapy guidelines included 30.6 Gy external irradiation in 17 fractions (  4 MV photons) to the primary tumor and to pelvic and inguinal lymph nodes with margins around presumed microscopic extension (Fig 2A) and with wires that encircled clinically positive inguinal lymph nodes; after a rest of 2-1/2 weeks, 14.4 Gy in eight fractions to the primary site (Fig 2B), which included pelvic and/or inguinal nodes if originally positive (Fig 2C). For the inguinal areas, electrons or photons could be utilized. After restaging and during weeks 17 and/or 18, patients with clinically and/or histologically positive residual disease at the primary site were treated with 9 Gy in five fractions (Fig 2B). Bulky N2 or N3 disease, or residual nodal disease, was treated concurrent with primary site treatment with 9 Gy fractions (Fig 2C). The only stipulated radiation dose modification was a decrease in the final boost dose to local residual disease to 5.4 Gy in three fractions, which was implemented for severe perianal mucositis or proctitis. Small bowel exposure was limited to 45 Gy (as assessed with the aid of bowel contrast), and the dose to the femoral heads was not to exceed 40 Gy. The radiation therapy treatment parameters were reviewed by the Quality Assurance Review Center of the National Cancer Institute Clinical Trials Program.
Toxicity was graded with the CALGB Expanded Common Toxicity Criteria (adapted from National Cancer Institute Common Toxicity Criteria; Southwest Oncology Group Toxicity Criteria; and CALGB Toxicity Grading, September 11, 1989). FU and mitomycin were reduced for a day of treatment for neutropenia (< 1,800/µL) or thrombocytopenia (< 100,000/µL). Cisplatin was reduced for moderate neurotoxicity or for creatinine 1.5 mg/dL. FU was reduced for grade 3 gastrointestinal toxicity. All therapy was held for grade 3 diarrhea during combined modality treatment and was reinitiated with dose modification of FU after resolution to grade 1. During treatment, response was assessed by physical exam monthly and by radiographic examination at 2-month intervals. After completion of treatment, patients were assessed by physical examination, laboratory studies, and chest radiographs every 3 months for 2 years and then every 6 months for an additional 2 years. Abdominal and pelvic computed tomography or magnetic resonance imaging was obtained at 6-month intervals. Patients were followed until relapse, disease progression, death, or up to 4 years after the completion of protocol therapy.
Response Criteria
Statistical Considerations
A two-stage design was used to test the bivariate null hypothesis that the APR rate as a result of treatment complications was The proportions of patients who required APR as a result of treatment complications and who achieved pCR without salvage APR were estimated by using the uniformly minimum variance unbiased estimator.8 Independent confidence intervals, adjusted for the group sequential test, were used to provide conservative estimates of the APR rate as a result of treatment complications and the rate of pCR without salvage APR.9 Disease-free survival was measured from documented complete clinical or pathologic response until recurrence or death as a result of disease. Patients who did not recur or die as a result of disease were censored at the last follow-up or survival date. Overall survival was measured from trial entry until death as a result of any cause. The Kaplan-Meier estimate was used to estimate the disease-free and overall survival curves.10 Patient registration and data collection were managed by the CALGB Statistical Center. Data quality was ensured by careful review of data by CALGB Statistical Center staff and by the study chairperson. Statistical analyses were performed by CALGB statisticians. As part of the quality assurance program of the CALGB, members of the data audit committee visited all participating institutions at least once every 3 years to review source documents. The auditors verified compliance with federal regulations and protocol requirements, including those pertaining to eligibility, treatment, adverse events, tumor response, and outcome, in a sample of protocols at each institution. On-site review of medical records was performed for 11 patients (22%) on this study.
Fifty patients were enrolled on this study between December 1992 and July 1998. Five patients were excluded from the analyses. Three were ineligible (two because inguinal nodes were not biopsied, and one whose tumor was debulked surgically before treatment), and two experienced major protocol violations (radiation therapy and chemotherapy were not administered concurrently during cycle 2 of phase 2 in one patient, and a boost was given without break and before chemotherapy, and APR occurred after negative biopsy in one patient). Demographics and patient characteristics are listed in Table 1. Thirty-five patients (78%) had T3 or T4 tumors without bulky nodal involvement, and 10 patients (22%) had bulky nodal disease.
The most common toxicities were hematologic and gastrointestinal (Table 2). During induction chemotherapy (phase 1), grade 3 to 4 stomatitis was reported in 39%, and grade 3 to 4 nausea or vomiting was reported in 22% of patients. Grade 3 to 4 lymphopenia and neutropenia were also common and occurred in 28% and 44% of patients, respectively. Combined-modality treatment (phases 2 and 3) was associated with grade 3 to 4 lymphopenia, neutropenia, and thrombocytopenia in 63%, 43%, and 40% of patients, respectively. Grade 3 to 4 infections occurred in 18% of patients overall. No patients (0 of 45 patients; adjusted 96% CI, 0.00 to 0.08) required abdominoperineal resection for the management of treatment complications from induction therapy.
Response to treatment is shown in Figure 3. One patient died during induction therapy as a result of acute respiratory distress syndrome. A second patient was not assessable for response after induction chemotherapy because of incomplete assessments and was omitted from analysis of response to induction therapy. Three patients withdrew consent for additional treatment after induction therapy. There were eight complete (18%) and 21 (48%) partial responses (n = 44) from induction chemotherapy. One patient had disease progression. Twenty-one patients ended treatment after phase 2. Eighteen completed protocol therapy, one patient had progressive disease, one patient ended because of toxicity, and one patient ended because of an unknown reason. Overall, after the entire combined-modality treatment program, 37 (82%) of 45 patients (95% CI, 0.70 to 0.93) achieved a complete response to nonsurgical therapy (two clinical response; 35 pCR). The pCR rate was 78% and had an adjusted 95% CI of 0.62 to 0.89.
All patients have been followed for at least 4 years except for one patient, who experienced a complete response but was lost to follow-up at 1.2 years. Ten patients ultimately underwent abdominoperineal resection: four for persistent disease, and six for local control of recurrence (APR rate, 23%; approximate 95% CI, 0.106 to 0.357). Eleven of 37 patients with complete response had disease recurrence after treatment, seven of which were local only. One patient experienced recurrence in the anal canal in addition to periaortic nodes, inguinal nodes, and lung. Overall, 16 patients had persistent (n = 8) or locally recurrent (n = 8) disease. One patient had liver and periaortic nodal recurrence; one patient had liver and lung recurrence; and one patient experienced recurrence only in the lung. Seven patients died as a result of recurrent (n = 3) or persistent (n = 4) anal canal cancer. No recurrences occurred beyond 3 years of enrollment. Other causes of death included acute respiratory distress syndrome during phase 1, a drug reaction caused by infection post-treatment (n = 1), cardiac events (n = 4), second primary (small-cell lung carcinoma, n = 1; prostate adenocarcinoma, n = 1), aortic aneurysm (n = 1), and hepatorenal syndrome (n = 1). The cause of death was unknown for three patients. After 4 years of follow-up, 30 (68%) of 44 assessable patients were alive, 27 (61%) were disease-free, and 22 (50%) were colostomy- and disease-free. Figure 4 shows the Kaplan-Meier plots for disease-free and overall survival.
This prospective, multicenter study was conducted to assess the clinical activity and toxicity of induction FU plus cisplatin and of subsequent combined-modality treatment with FU, mitomycin, and radiation therapy in patients with poor-prognosis anal canal carcinomas. The current standard treatment of anal canal cancer is external-beam radiation therapy with a concurrent course of FU plus mitomycin during the first and fifth weeks of therapy. This program was defined by randomized clinical trials that first demonstrated the superiority of combined-modality treatment compared with radiation therapy alone3 and subsequently showed that mitomycin improved local control and the likelihood of sphincter preservation compared with FU as the lone radiosensitizer.2 The combination of FU, mitomycin, and radiation results in disease-free and colostomy-free survival in approximately 70% of patients. However, those patients with large tumors or nodal involvement have a worse prognosis. For example, Flam et al2 reported a 10% lower post-treatment biopsy negativity rate for patients with tumors at least 5 cm in size who were treated on Radiation Therapy Oncology Group (RTOG) Protocol 8704. Bartelink et al3 reported the results of a European Organization for Research and Treatment of Cancer study, in which nodal involvement was a significant adverse prognostic factor. These findings were confirmed in a more recent presentation of RTOG Protocol 9811, in which tumor size greater than 5 cm and nodal involvement were both prognostic for disease-free and overall survival.11 On the basis of evidence of clinical activity for cisplatin plus FU in other epidermoid cancers,12,13 and of preliminary evidence of activity against anal canal cancers,4,5 the present study was undertaken in an effort to improve outcome for patients with poor prognostic features. The results of this multicenter, phase II trial demonstrate that induction therapy with cisplatin plus FU followed by concurrent FU, mitomycin, and split-course radiation therapy is tolerable and active, as 37 (82%) of 45 high-risk patients achieved a complete response. At 4 years of follow-up, 68% of patients are alive, 61% are disease-free, and 50% are colostomy- and disease-free. These favorable results contributed to the development of RTOG Protocol 9811, which compared a standard regimen of two 28-day cycles of FU and mitomycin plus concurrent radiation to an experimental approach of four 28-day cycles of FU and cisplatin plus radiation given concurrently with the last two cycles. The preliminary findings of this study indicate that the cisplatin-based arm was not superior.11 After 4 years of follow-up, the disease-free survival in the control group was 64% compared with 60% in the experimental arm. Overall survival was 77% in the control group versus 70% in the experimental arm. Only 26% of patients had tumors greater than 5 cm, and 26% had positive nodes. Given the worse prognostic features of the patients in the study we present, our results compare favorably, although such interstudy comparisons are difficult because of other potential differences in patient characteristics. It is notable that the experimental arm of RTOG 9811 did not contain mitomycin. Two design features of the current study are unique among previous cooperative group trials. First, split-course irradiation was used. The selection of this schedule was based on the investigators’ concerns about potentially greater toxicity with this aggressive approach, wich used concomitant chemotherapy with high-dose radiation therapy (as high as 54 Gy in the patients with residual primary disease and/or residual nodal disease or bulky nodal disease at presentation). It was thought that a gap of nearly 3 weeks between the larger pelvic fields initially and the smaller fields to the areas of gross disease would allow for some normal tissue repair and, thus, for potentially better tolerance of treatment. The second gap, before a final boost, if needed because of residual primary or bulky nodal disease at presentation, was necessary to allow assessment of disease at that time but was also thought to potentially help with treatment tolerance. The encouraging pCR rate in this high-risk population suggests that radiation treatment breaks, although controversial, may be an acceptable treatment strategy; whether local control would be improved with omission or abbreviation of these breaks will require further study. Secondly, the chemotherapy plan included standard FU plus mitomycin as well as induction therapy with an alternate regimen. Thus, the cisplatin-based component did not replace the standard combined-modality approach; rather, it provided an additional potentially non–cross-resistant component. Only one patient experienced disease progression during induction therapy; therefore, these data suggest that a treatment paradigm with induction therapy before definitive chemoradiotherapy may be safely employed in future studies in patients with anal canal cancer. In conclusion, the combined-modality approach described herein has manageable toxicity and results in long-term disease control in the majority of patients with poor-prognosis squamous cell carcinomas of the anal canal. Although recent data suggest that replacement of mitomycin with cisplatin is unlikely to improve patient outcomes, it is possible that providing non–cross-resistant systemic therapy as an adjunct to standard treatment may be beneficial. Furthermore, the rarity of disease progression during induction treatment raises the possibility that this approach could serve as a platform for the investigation of other systemic therapies in patients with anal canal cancers.
The authors indicated no potential conflicts of interest.
Conception and design: Neal J. Meropol, Brenda Shank, Frank Valone, Joel Tepper, Robert J. Mayer Administrative support: Neal J. Meropol, Thomas A. Colacchio, Richard M. Goldberg Provision of study materials or patients: Neal J. Meropol, Brenda Shank, Thomas A. Colacchio, John Ellerton, Frank Valone, Judy Hopkins, Joel Tepper, Robert J. Mayer Collection and assembly of data: Neal J. Meropol, Donna Niedzwiecki, Susan Budinger, Richard M. Goldberg, Robert J. Mayer Data analysis and interpretation: Neal J. Meropol, Donna Niedzwiecki, Jeannette M. Day, Richard M. Goldberg, Robert J. Mayer Manuscript writing: Neal J. Meropol, Donna Niedzwiecki, Brenda Shank, Joel Tepper, Richard M. Goldberg Final approval of manuscript: Neal J. Meropol, Donna Niedzwiecki, Brenda Shank, Thomas A. Colacchio, John Ellerton, Frank Valone, Susan Budinger, Jeannette M. Day, Judy Hopkins, Joel Tepper, Richard M. Goldberg, Robert J. Mayer
Participating institutions. Cancer and Leukemia Group B Statistical Center, Duke University Medical Center, Durham, NC: Stephen George, PhD, supported by Grant No. CA33601; Dana-Farber Cancer Institute, Boston, MA: Eric P. Winer, MD, supported by Grant No. CA32291; Dartmouth Medical School, Norris Cotton Cancer Center, Lebanon, NH: Marc S. Ernstoff, MD, supported by Grant No. CA04326; Duke University Medical Center, Durham, NC: Jeffrey Crawford, MD, supported by Grant No. CA47577; Massachusetts General Hospital, Boston, MA: Michael L. Grossbard, MD, supported by Grant No. CA12449; Mount Sinai Medical Center, Miami, FL: Rogerio Lilenbaum, MD, supported by Grant No. CA45564; Rhode Island Hospital, Providence, RI: William Sikov, MD, supported by Grant No. CA08025; Roswell Park Cancer Institute, Buffalo, NY: Ellis Levine, MD, supported by Grant No. CA02599; State University of New York Upstate Medical University, Syracuse, NY: Stephen L. Graziano, MD, supported by Grant No. CA21060; University of California at San Diego, San Diego, CA: Joanne Mortimer, MD, supported by Grant No. CA11789; University of California at San Francisco, San Francisco, CA: Alan P. Venook, MD, supported by Grant No. CA60138; University of Iowa, Iowa City, IA: Gerald Clamon, MD, supported by Grant No. CA47642; University of Maryland Greenebaum Cancer Center, Baltimore, MD: Martin Edelman, MD, supported by Grant No. CA31983; University of Minnesota, Minneapolis, MN: Bruce A Peterson, MD, supported by Grant No. CA16450; University of Missouri/Ellis Fischel Cancer Center, Columbia, MO: Michael C Perry, MD, supported by Grant No. CA12046; University of North Carolina at Chapel Hill, Chapel Hill, NC: Thomas C. Shea, MD, supported by Grant No. CA47559; University of Tennessee Memphis, Memphis, TN: Harvey B. Niell, MD, supported by Grant No. CA47555; Wake Forest University School of Medicine, Winston-Salem, NC: David D Hurd, MD, supported by Grant No. CA03927; Weill Medical College of Cornell University, New York, NY: Scott Wadler, MD, supported by Grant No. CA07968.
Patient Eligibility.
published online ahead of print at www.jco.org on May 19, 2008. Supported in part by the following grants from the National Cancer Institute to: the Cancer and Leukemia Group B (CALGB; CA31946); the CALGB Statistical Center (CA33601); Dartmouth-Hitchcock Medical Center (CA04326); Southern Nevada Cancer Research Foundation Community Clinical Oncology Program (CA35421); Wake Forest University (CA03927); University of North Carolina at Chapel Hill (CA47559); and Dana Farber Cancer Institute (CA32291). Presented in part at the 35th Annual Meeting of the American Society of Clinical Oncology, May, 15-18, 1999, Atlanta, GA, and at the NTH Second Gastrointestinal Cancers Symposium, January 27-29, 2005, Miami, FL. The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute. Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Jemal A, Siegel R, Ward E, et al: Cancer statistics, 2007. CA Cancer J Clin 57:43-66, 2007 2. Flam M, John M, Pajak TF, et al: Role of mitomycin in combination with fluorouracil and radiotherapy, and of salvage chemoradiation in the definitive nonsurgical treatment of epidermoid carcinoma of the anal canal: Results of a phase III randomized intergroup study. J Clin Oncol 14:2527-2539, 1996[Abstract] 3. Bartelink H, Roelofsen F, Eschwege F, et al: Concomitant radiotherapy and chemotherapy is superior to radiotherapy alone in the treatment of locally advanced anal cancer: Results of a phase III randomized trial of the European Organization for Research and Treatment of Cancer Radiotherapy and Gastrointestinal Cooperative Groups. J Clin Oncol 15:2040-2049, 1997 4. Flam MS, John MJ, Mowry PA, et al: Definitive combined modality therapy of carcinoma of the anus: A report of 30 cases including results of salvage therapy in patients with residual disease. Dis Colon Rectum 30:495-502, 1987[Medline] 5. Salem PA, Habboubi N, Anaissie E, et al: Effectiveness of cisplatin in the treatment of anal squamous cell carcinoma. Cancer Treat Rep 69:891-893, 1985[Medline] 6. American Joint Commission on Cancer: AJCC Cancer Staging Manual (ed 6). New York, NY, Springer, 2002 7. Conaway MR, Petroni GR: Bivariate sequential designs for phase II trials. Biometrics 51:656-664, 1995[CrossRef][Medline] 8. Jung SH, Kim KM: On the estimation of the binomial probability in multistage clinical trials. Stat Med 23:881-896, 2004[CrossRef][Medline] 9. Jennison C: Confidence intervals for a binomial parameter following a multistage test with application to MIL-STD 105D and medical trials. Technometrics 25:49-58, 1983[Medline] 10. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. Journal Am Stat Assoc 53:457-481, 1958[CrossRef] 11. Ajani JA, Winter KA, Gunderson LL, et al: Intergroup RTOG 9811: A phase III randomized study of fluorouracil (FU), mitomycin, and radiotherapy versus fluorouracil, cisplatin and radiotherapy in carcinoma of the anal canal. J Clin Oncol 24:180s, 2006 (suppl; abstr 4009) 12. Homs MY, v d Gaast A, Siersema PD, et al: Chemotherapy for metastatic carcinoma of the esophagus and gastro-esophageal junction. Oxford, United Kingdom, Cochrane Library, CD004063, 2006 13. Kim ES, Glisson BS: Treatment of metastatic head and neck cancer: Chemotherapy and novel agents. Cancer Treat Res 114:295-314, 2003[Medline] Submitted January 17, 2008; accepted March 19, 2008.
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
30% against the alternative that the APR rate as a result of treatment complications was less than 30% and the pCR rate without salvage APR was greater than 30%. Early stopping occurred at stage I if seven or more of the first 25 treated patients underwent APR as a result of treatment complications or if eight or fewer of these patients experienced pCR without salvage APR. At stage II, the treatment regimen would be considered successful if 10 or fewer of 45 patients required APR as a result of treatment complications and if 16 or more of these patients experienced pCR without salvage APR. The simulated significance level of this test was .056 (10,000 simulations). Simulated power was .85 to detect an APR rate of .15 and a pCR rate of .50.
