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Journal of Clinical Oncology, Vol 25, No 29 (October 10), 2007: pp. 4581-4586 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.12.0170 Concurrent Chemotherapy and Intensity-Modulated Radiation Therapy for Anal Canal Cancer Patients: A Multicenter Experience
From the Department of Radiation and Cellular Oncology, University of Chicago; Department of Radiation Oncology, University of Illinois at Chicago; University of Chicago Cancer Research Center, Chicago, IL; Department of Radiation Oncology, Mayo Clinic, Rochester, MN; Department of Radiation Oncology, University of California, San Diego, La Jolla, CA; and the Department of Radiation Oncology, Emory University, Atlanta, GA Address reprint requests to Joseph K. Salama, MD, Department of Radiation and Cellular Oncology, University of Chicago, 5758 S Maryland Ave, MC 9006, Chicago, IL 60637; e-mail: jsalama{at}radonc.uchicago.edu
Purpose To report a multicenter experience treating anal canal cancer patients with concurrent chemotherapy and intensity-modulated radiation therapy (IMRT). Patients and Methods From October 2000 to June 2006, 53 patients were treated with concurrent chemotherapy and IMRT for anal squamous cell carcinoma at three tertiary-care academic medical centers. Sixty-two percent were T1-2, and 67% were N0; eight patients were HIV positive. Forty-eight patients received fluorouracil (FU)/mitomycin, one received FU/cisplatin, and four received FU alone. All patients underwent computed tomography–based treatment planning with pelvic regions and inguinal nodes receiving a median of 45 Gy. Primary sites and involved nodes were boosted to a median dose of 51.5 Gy. All acute toxicity was scored according to the Common Terminology Criteria for Adverse Events, version 3.0. All late toxicity was scored using Radiation Therapy Oncology Group criteria. Results Median follow-up was 14.5 months (range, 5.2 to 102.8 months). Acute grade 3+ toxicity included 15.1% GI and 37.7% dermatologic toxicity; all acute grade 4 toxicities were hematologic; and acute grade 4 leukopenia and neutropenia occurred in 30.2% and 34.0% of patients, respectively. Treatment breaks occurred in 41.5% of patients, lasting a median of 4 days. Forty-nine patients (92.5%) had a complete response, one patient had a partial response, and three had stable disease. All HIV-positive patients achieved a complete response. Eighteen-month colostomy-free survival, overall survival, freedom from local failure, and freedom from distant failure were 83.7%, 93.4%, 83.9%, and 92.9%, respectively. Conclusion Preliminary outcomes suggest that concurrent chemotherapy and IMRT for anal canal cancers is effective and tolerated favorably compared with historical standards.
Anal cancer affects 4,010 people each year in the US.1 Traditionally, patients with anal cancer were managed surgically via an abdominoperineal resection (APR), with an expected 5-year survival of 55% to 71%.2-4 Alternatively, patients wishing for an organ-preserving approach were managed with radiotherapy (RT), resulting in 5-year overall survival (OS) of 59% to 65%.5,6 Nigro et al pioneered the use of neoadjuvant concomitant fluorouracil (FU), mitomycin (MMC), and RT for anal cancer.7 Pathologic complete responses (CRs) were found in 23 of 28 patients at the time of surgical resection.8 Based on these positive results, many institutions enacted protocols to treat anal cancer patients with concurrent FU, MMC, and RT as definitive treatment, reserving APR for incomplete response or disease recurrence.9,10 A series of randomized trials established concomitant FU, MMC, and RT as the standard of care for all stages of anal cancer.11-14 This organ-preservation strategy has resulted in 5-year OS and colostomy-free survival (CFS) rates of 50% to 78% and 61% to 76%, respectively.11-14 However, this sphincter-preserving approach is toxic; 18% of patients experienced acute grade 4 to 5 hematologic toxicity in the US Intergroup trial.13 In the United Kingdom Coordinating Committee on Cancer Research and European Organisation for Research and Treatment of Cancer trials, significant acute dermatologic toxicity occurred in 49% to 76% of patients,11,12 and acute GI toxicity was seen in 33% to 45% of patients. The recently introduced treatment of intensity-modulated radiation therapy (IMRT) is a novel approach to RT planning and delivery.15 In contrast to conventional RT, IMRT conforms radiation tightly to tumors and high-risk regions, sparing nearby critical normal tissues. This technique is widely accepted in the treatment of prostate and head and neck cancers.16 Clinical studies demonstrate reduced acute rectal toxicity and xerostomia using IMRT.17,18 In the treatment of pelvic malignancies, IMRT maintains disease control while reducing acute and chronic GI toxicity and hematologic toxicity.19 Given that IMRT has been used to decrease acute sequelae in other disease sites, we sought to determine if IMRT could be used in the setting of concurrent chemotherapy to reduce toxicity in combined-modality anal cancer therapy. To this end, we analyzed a cohort of consecutive patients treated with concurrent chemotherapy and IMRT to determine the clinical implications of this treatment.
From October 2000 to June 2006, 53 patients with anal cancer were treated with concurrent chemotherapy and IMRT at the University of Chicago (Chicago, IL), the University of Illinois at Chicago (Chicago, IL), or the Mayo Clinic (Rochester, MN). All patients were evaluated preoperatively with a complete history and physical examination; computed tomography (CT) of the chest, abdomen, and pelvis; and examination under anesthesia with biopsy. Patients were staged according to the American Joint Committee on Cancer 2006 guidelines. Forty-eight patients received two cycles of FU 1,000 mg/m2/d for 4-day cycles (days 1 to 4 and 22 to 25) and MMC 10 mg/m2 (maximum dose, 20 mg) on days 1 and 22. One patient received FU/cisplatin and four patients received FU alone. Patients with the HIV were not prescribed different chemotherapeutic regimens on the basis of HIV infection per se. All patients were monitored at least weekly for acute hematologic, dermatologic, GI, and genitourinary (GU) toxicity. All acute toxicities were scored using the Common Terminology Criteria for Adverse Events, version 3.0. Before RT delivery, all patients underwent CT-based treatment planning. Custom immobilization was created for each patient in the frog leg position (Alpha Cradle; Smithers Medical Products Inc, Hudson, OH). The body mold was indexed to the simulator table to ensure reproducible daily setup. Thereafter, 5-mm slices were obtained from the mid-lumbar spine to the mid-femur. Rectal, bladder, and occasionally intravenous contrast were used to assist in target and normal tissue definition. According to International Commission on Radiological Units 50 guidelines, target and avoidance volumes were contoured on the planning CT scan. The gross tumor volume (GTV) included the primary tumor and involved lymph nodes. The clinical target volume (CTV) included the GTV and areas at risk for potential microscopic spread, which commonly included the gross disease and a 1-cm expansion about the inguinal, femoral, external iliac, internal iliac, and common iliac vessels. A 1-cm bolus was used over the inguinal areas for elective treatment in all patients. To account for daily setup error and organ motion, the CTV was expanded to create a planning treatment volume (PTV). The usual CTV-to-PTV expansion was 1 cm. The small bowel, bladder, skin, and genitalia were contoured as avoidance structures.
Treatments for all patients were planned using commercially available software. Treatments for patients at the Mayo Clinic and the University of Illinois at Chicago were planned using Helios and Eclipse (Varian Medical Systems, Palo Alto, CA). At the University of Chicago, treatments for patients were planned using CORVUS Versions 3.0 to 4.0 (NOMOS Corp, Sewickley, PA). Typically, nine equally spaced fields (0, 40, 80, 120, 160, 200, 240, 280, and 320 degrees) were used with 6-MV photons. The planning priority was maximal PTV coverage, with small bowel, bladder, and genitalia sparing as secondary goals. IMRT target goals specified that more than 95% of the PTV receive the prescription dose, All patients were observed in radiation, medical, and surgical oncology clinics every 3 months for 2 years, then every 6 to 12 months thereafter. At each follow-up, patients underwent a complete physical examination. The anal canal was examined via anoscopy and digital rectal examination. Pathologic proof of response was performed at the treating surgeon's discretion. Clinical CR was defined as no residual tumor seen at any follow-up, partial response (PR) was defined as any residual tumor, and stable disease (SD) was defined as less than 30% response. Blood chemistries and CBCs were ordered routinely. Imaging studies were ordered only when clinical parameters suggested recurrence. All late toxicity was scored via the Radiation Therapy Oncology Group (RTOG) late radiation morbidity scoring schema. Survival end points were calculated from date of diagnosis and estimated using the method of Kaplan and Meier. CFS was defined as the time to colostomy or death. Distant metastasis–free survival was defined as the time to distant metastasis or death. Local recurrence–free survival was defined as the time to local treatment failure, with censoring for death or loss to follow-up. Univariate survival time comparisons were performed using the log-rank test. Stage grouping, HIV status, and treatment break were analyzed as dichotomous variables. Multivariate analyses were performed using Cox proportional hazards regression. Statistical analyses were performed using STATA version 9.0 (STATA Corp, College Station, TX).
Patient and Tumor Characteristics Patient and tumor characteristics are listed in Table 1. The median and mean follow-up for all patients was 14.5 months (range, 5.2 to 102.8 months) and 21.7 months, respectively. The median patient age was 55 years. Eight patients (15.1%) were HIV positive. Seventeen patients (32.1%) had clinically positive lymphadenopathy. The median radiation dose to the pelvis and the primary was 45 Gy (range, 30.6 to 45 Gy) and 51.5 Gy (range, 32 to 60.9 Gy), respectively. The median number of treatment days was 42.
Acute Toxicity Acute toxicity during concomitant chemoradiotherapy is listed in Table 2. Fifty-eight percent of patients completed treatment without any interruption. Patients were given treatment breaks for grade 4 hematologic toxicities, painful moist desquamation, or severe GI toxicity at the discretion of the treating radiation oncologist. The reasons for treatment break included GI toxicity (n = 1), dermatologic toxicity (n = 9), or hematologic toxicity (n = 12). The median time of treatment break was 4 days (range, 2 to 14 days). Of 51 patients with data available for dermatologic toxicity, 54.7% experienced acute grade 2 desquamation, and 37.7% experienced grade 3 desquamation. Acute GI toxicity was common with thirty patients (56.6%) experiencing grade 2 toxicity, and eight patients (15.1%) experiencing grade 3 toxicity.
Acute hematologic toxicity was common with this approach. Full hematologic toxicity is listed in Table 2. In total, 39.6% of patients experienced grade 4 hematologic toxicity. Acute grade 3 to 4 leukopenia, which occurred in 28 patients, was the most common hematologic toxicity. The incidence of acute grade 3 to 4 thrombocytopenia was 28.3%, and five patients (9.4%) experienced acute grade 3 anemia. Hematologic toxicity in HIV-positive patients was similar to that of the entire cohort, with six of eight patients experiencing grade 3 to 4 hematologic toxicity.
Response
Local Control
Distant Control Four patients experienced treatment failure at distant sites. The median time to distant failure was 10.9 months (range, 6.3 to 20.9 months). As listed in Table 3, the 18 months distant metastasis–free survival was 92.3% (95% CI, 77.2% to 97.5%). Distant failures were hepatic in three patients and osseous in two patients (one patient experienced treatment failure both in the liver and thoracolumbar vertebra). All patients experiencing distant failure were node negative; three were T3 and one was T2.
Survival
No significant difference in any end point could be detected between HIV-positive and HIV-negative patients. Univariate analyses did not reveal significant factors for OS, CFS, LC, or distant metastasis–free survival. On multivariate analysis, stage IIIB patients had worse CFS (hazard ratio, 4.18; 95% CI, 1.06197 to 16.41662; P = .041).
At one time, anal cancer was a disease treated only with surgery; the advent of FU/MMC-based chemoradiotherapy has altered the treatment options. With APR limited to salvage treatment, the majority of patients are spared a colostomy. However, this combined-modality approach is toxic, with many patients requiring protracted treatment interruptions. IMRT is a major advance in RT. By altering radiation intensity across a given treatment field, clinicians have a means of tightly conforming high radiation dose levels around tumors and high-risk regions, while avoiding high doses to nearby normal tissues. The use of this technique in patients with pelvic malignancies has demonstrated decreased acute and chronic GI toxicity rates.19 We initiated an IMRT-based chemoradiotherapy approach in 2000, with the goal of reducing acute toxicities associated with anal canal cancer treatment.
These data support the hypothesis that concurrent chemotherapy and IMRT can be used to treat anal cancer patients while decreasing acute dermatologic toxicity rates. In this cohort, 38% of patients experienced acute grade 3 dermatologic toxicity and none experienced grade 4. This is lower than the grade 3 or greater acute dermatologic toxicity rates seen in patients treated without a mandated break (78%), and comparable to the 34% rate experienced by patients who were mandated to take a 2-week break while enrolled onto RTOG 92-08.20 Furthermore, the dermatologic toxicity rate in our study was lower than that in patients treated with concurrent FU/MMC (48%) enrolled onto RTOG 98-11.14 This lower rate of acute grade 3 to 4 dermatologic toxicity is important, given that patients enrolled onto RTOG 92-08 with a mandatory 2-week break had a 30% 2-year colostomy rate20 compared with a 5-year colostomy rate of 10% from RTOG 98-11 in patients treated with FU/MMC without a break.14 Our cohort tolerated treatment well, with only 41.5% of patients needing a break in treatment. Of patients requiring a treatment break, 12 (57%) of 21 patients required The decreased dermatologic toxicity observed in our study is multifactorial. Advances in treatment design and planning, with three-dimensional conformal RT or IMRT, allow improved targeting and normal tissue sparing compared with traditional techniques. Previously, we reported that IMRT had the ability to decrease radiation dose delivered to the small bowel, iliac bone marrow, bladder, and genitalia in anal canal cancer patients treated with IMRT.21 When we designed treatment volumes for this patient cohort, we routinely avoided unnecessary skin irradiation in sites distant from gross disease. The radiation dose conformality of IMRT likely augments skin sparing away from areas of gross disease. Although acute GI toxicity was present in all patients, it was mild in our patient cohort. Only 15.1% experienced grade 3 GI toxicity. RTOG 98-11, using a similar toxicity-reporting criteria (Common Terminology Criteria for Adverse Events, version 2.0), reported a 34% rate of grade 3 to 4 acute GI toxicity. This low rate of acute GI toxicity is noteworthy when one considers that in our series, the average radiation dose to the pelvis was 45 Gy (higher than that delivered in the RTOG trials).13,14 These data suggest that the intentional sparing of dose to the small bowel resulted in decreased acute GI toxicity, despite a higher delivered dose to pelvic nodal regions. The level of acute hematologic toxicity in this cohort was expected given the known hematologic sequelae of concomitant FU, MMC, and pelvic RT. The rate of grade 3 to 4 acute hematologic toxicity, while significant at 58.5%, was comparable to the 60% seen in the FU/MMC arm of RTOG 98-11.14 Furthermore, most patients were treated without intentional sparing of pelvic bone marrow within the iliac crests. Previous investigations have shown that cervical and endometrial cancer patients treated with concurrent chemotherapy and pelvic IMRT had lower rates of grade 2 or higher WBC toxicity and a lower WBC nadir when compared with patients treated with chemotherapy and conventional RT.22 It is possible that if a higher priority were placed on reducing radiation dose to the bone marrow, hematologic toxicity could be reduced further. Mell et al23 have reported an association between acute hematologic toxicity and the volume of pelvic bones receiving 10 and 20 Gy in cervical cancer patients treated with concurrent cisplatin and pelvic IMRT. Preliminary investigations have demonstrated that a similar association exists in anal cancer patients treated with IMRT and concurrent chemotherapy.24 It would seem that additional reduction in acute hematologic toxicity could be achieved with reduced IMRT field sizes and intentional sparing of pelvic bone marrow.25 The CR rate of our patients (92.5%) was similar to that seen in RTOG 87-04, with a pathologic response rate of 92% in patients receiving FU/MMC and pelvic RT. Our crude colostomy rate of 10.5% was comparable to the results of the FU/MMC arms of RTOG 98-11 (10%) and RTOG 87-04 (9%).13,14 The 18-month CFS rate in this population of 83.7% is consistent with the 2-year CFS rate of RTOG 87-04 of 80%.13 These data support the conclusion that anal cancers could be treated with IMRT without compromising local control.
Currently, the RTOG is enrolling patients onto a phase II study (RTOG 0529) combining concurrent FU/MMC and IMRT. The target accrual is 59 patients, which is similar to the number of patients presented in our study. The primary goals of RTOG 0529 are to determine if the combined rate of grade In conclusion, this analysis demonstrates that concurrent chemotherapy and IMRT is associated with favorable rates of nonhematologic acute toxicity while maintaining high rates of local control and CFS.
The author(s) indicated no potential conflicts of interest.
Conception and design: Joseph K. Salama, Steven J. Chmura Provision of study materials or patients: Robert C. Miller, Ashesh B. Jani, Arno J. Mundt, Steven J. Chmura Collection and assembly of data: Joseph K. Salama, Loren K. Mell, David A. Schomas, Robert C. Miller, Kiran Devisetty, Stanley L. Liauw, Steven J. Chmura Data analysis and interpretation: Joseph K. Salama, Loren K. Mell, Kiran Devisetty, Arno J. Mundt, John C. Roeske, Stanley L. Liauw, Steven J. Chmura Manuscript writing: Joseph K. Salama, Loren K. Mell, David A. Schomas, Ashesh B. Jani, John C. Roeske, Stanley L. Liauw, Steven J. Chmura Final approval of manuscript: Joseph K. Salama, Steven J. Chmura
Supported by the University of Chicago Cancer Research Center. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. American Cancer Society: Cancer Facts & Figures 2003. http://www.cancer.org/downloads/STT/CAFF2003PWSecured.pdf 2. Boman BM, Moertel CG, O'Connell MJ, et al: Carcinoma of the anal canal: A clinical and pathologic study of 188 cases. Cancer 54:114-125, 1984[CrossRef][Medline] 3. Frost DB, Richards PC, Montague ED, et al: Epidermoid cancer of the anorectum. Cancer 53:1285-1293, 1984[CrossRef][Medline] 4. Greenall MJ, Quan SH, Urmacher C, et al: Treatment of epidermoid carcinoma of the anal canal. Surg Gynecol Obstet 161:509-517, 1985[Medline] 5. Papillon J, Montbarbon JF: Epidermoid carcinoma of the anal canal: A series of 276 cases. Dis Colon Rectum 30:324-333, 1987[Medline] 6. Salmon RJ, Fenton J, Asselain B, et al: Treatment of epidermoid anal canal cancer. Am J Surg 147:43-48, 1984[CrossRef][Medline] 7. Nigro ND, Vaitkevicius VK, Considine B Jr: Combined therapy for cancer of the anal canal: A preliminary report. Dis Colon Rectum 17:354-356, 1974[Medline] 8. Nigro ND, Seydel HG, Considine B, et al: Combined preoperative radiation and chemotherapy for squamous cell carcinoma of the anal canal. Cancer 51:1826-1829, 1983[CrossRef][Medline] 9. Allal A, Kurtz JM, Pipard G, et al: Chemoradiotherapy versus radiotherapy alone for anal cancer: A retrospective comparison. Int J Radiat Oncol Biol Phys 27:59-66, 1993[Medline] 10. Cummings BJ, Keane TJ, O'Sullivan B, et al: Epidermoid anal cancer: Treatment by radiation alone or by radiation and 5-fluorouracil with and without mitomycin C. Int J Radiat Oncol Biol Phys 21:1115-1125, 1991[Medline] 11. UKCCCR Anal Cancer Trial Working Party, UK Co-ordinating Committee on Cancer Research: Epidermoid anal cancer: Results from the UKCCCR randomised trial of radiotherapy alone versus radiotherapy, 5-fluorouracil, and mitomycin. Lancet 348:1049-1054, 1996[CrossRef][Medline] 12. 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 13. 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] 14. Gunderson LL, Winter K, Ajani J, et al: In Intergroup RTOG 98-11 phase III comparison of chemoradiation with 5-FU and mitomycin vs 5-FU and cisplatin for anal canal carcinoma: Impact on disease free survival, overall, and colostomy free survival. Presented at Annual Meeting of the American Society of Therapeutic Radiology and Oncology, 2006, Philadelphia, PA 15. Teh BS, Woo SY, Butler EB: Intensity modulated radiation therapy (IMRT): A new promising technology in radiation oncology. Oncologist 4:433-442, 1999 16. Mell LK, Roeske JC, Mundt AJ: A survey of intensity-modulated radiation therapy use in the United States. Cancer 98:204-211, 2003[CrossRef][Medline] 17. Eisbruch A, Ship JA, Dawson LA, et al: Salivary gland sparing and improved target irradiation by conformal and intensity modulated irradiation of head and neck cancer. World J Surg 27:832-837, 2003[CrossRef][Medline] 18. Zelefsky MJ, Fuks Z, Leibel SA: Intensity-modulated radiation therapy for prostate cancer. Semin Radiat Oncol 12:229-237, 2002[CrossRef][Medline] 19. Salama JK, Roeske JC, Mehta N, et al: Intensity-modulated radiation therapy in gynecologic malignancies. Curr Treat Options Oncol 5:97-108, 2004[CrossRef][Medline] 20. John M, Pajak T, Flam M, et al: Dose escalation in chemoradiation for anal cancer: Preliminary results of RTOG 92-08. Cancer J Sci Am 2:205-211, 1996[Medline] 21. Milano MT, Jani AB, Farrey KJ, et al: Intensity-modulated radiation therapy (IMRT) in the treatment of anal cancer: Toxicity and clinical outcome. Int J Radiat Oncol Biol Phys 63:354-361, 2005[CrossRef][Medline] 22. Brixey CJ, Roeske JC, Lujan AE, et al: Impact of intensity-modulated radiotherapy on acute hematologic toxicity in women with gynecologic malignancies. Int J Radiat Oncol Biol Phys 54:1388-1396, 2002[CrossRef][Medline] 23. Mell LK, Kochanski JD, Roeske JC, et al: Dosimetric predictors of acute hematologic toxicity in cervical cancer patients treated with concurrent cisplatin and intensity-modulated pelvic radiotherapy. Int J Radiat Oncol Biol Phys 66:1356-1365, 2006[Medline] 24. Mell LK, Salama JK, Roeske JC, et al: Dosimetric predictors of acute hematologic toxicity in anal cancer patients treated with concurrent chemotherapy and intensity modulated radiation therapy (IMRT). Int J Radiat Oncol Biol Phys 66:S277-S278, 2006 25. Mell LK, Aydogan B, Salama JK, et al: Bone marrow-sparing intensity-modulated radiation therapy versus conventional techniques for pelvic inguinal irradiation in anal cancer. Presented at Annual Meeting of the American Radium Society, November 5-9, 2006, Amsterdam, the Netherlands Submitted April 12, 2007; accepted July 20, 2007.
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
20% of the PTV receive more than 110% of the prescription dose, and 
54 Gy (range, 54 to 59.4 Gy). Prolongation of treatment was not associated with statistically significant worse outcome. 
