In this issue of ONCOLOGY, Dr. Czito and colleagues from Duke University School of Medicine and the University of Texas Southwestern describe the potential benefit of incorporating intensity-modulated radiation therapy (IMRT) into the combined-modality treatment of anal canal cancer. As the authors well delineate, the treatment of anal canal cancer has progressed from radical surgery to organ preservation with the use of definitive chemoradiotherapy.
Several recent studies, including the Radiation Therapy Oncology Group (RTOG) 98-11 and ACT II phase III trials, support the administration of higher radiation doses in combination with systemic therapy for the sphincter-preserving treatment of anal canal cancer.[2,3] The combination of these increased radiation doses with fluorouracil (5-FU) and mitomycin or cisplatin therapy have resulted in good local control and disease-free survival rates but have been tempered by significant morbidity, most notably acute grade 2+ hematologic, dermatologic, and gastrointestinal toxicity, as well as late toxicity including femoral head and neck fractures.[2,4,5] Such morbidity can also lead to unintended treatment breaks that may portend poorer local control and colostomy-free survival, as demonstrated in the RTOG 92-08 trial.
Potential for Reducing Toxicity
Technologic advances in linear accelerator technology and computer software have provided radiation oncologists and physicists the necessary tools to modify treatment delivery techniques in attempts to reduce such treatment-associated toxicity. Unlike two-dimensional (2D) radiation delivery, conformal radiation planning uses computer imaging to create a three-dimensional (3D) picture in order to accurately target the tumor. More recently, an advanced form of 3D planning, known as IMRT, has been implemented. This approach uses modulation of the intensity across the radiation beam to create highly conformal treatment plans. In contrast to 2D or 3D therapy, which uses multiple static fields, IMRT provides the ability to deliver differing radiation doses within a given volume, allowing dose intensification in selected areas of concern and sparing of surrounding normal tissues. Improvements in treatment-related morbidity and, in turn, patient quality of life have been described in patients with breast, head and neck, and prostate cancer treated with IMRT, as compared to 3D chemoradiation.[7-10]
As with these other malignancies, IMRT in the treatment of anal canal cancer has tremendous potential for reducing chemoradiation-related toxicities, while allowing for higher radiation doses to the gross tumor volume. With IMRT, radiation dose to the normal structures (particularly small bowel, skin, femoral heads, bladder, and external genitalia) is reduced, compared to conventional 2D and more sophisticated 3D treatment planning. In this issue, Czito et al report a 0% grade 3 and higher acute dermatologic and 9% grade 3 and higher gastrointestinal toxicity in their unpublished retrospective IMRT experience in 45 patients receiving chemoradiation for anal canal cancer. This is in striking contrast to the acute toxicity documented in RTOG 98-11: 48% grade 3+ dermatologic and 34% grade 3+ gastrointestinal toxicity. Interestingly, pelvic IMRT has not made much of an impact in reducing hematologic toxicity, but this is understandable as IMRT delivers low doses of radiation to a large volume of the pelvic bone.
Of note, the IMRT techniques and radiation doses from Czito et al were not reported in their review. However, their reported reductions in acute toxicity are in line with two other retrospective reports of IMRT use for anal canal cancer.[12,13] Moreover, the use of IMRT appears not to have compromised elective target coverage, as local-regional control in these small retrospective reports appears favorable, albeit with very limited follow-up.
Need for Accurate Targeting
Critical to the implementation of IMRT is a clear understanding and accurate targeting of the organs and nodal groups at risk for disease. IMRT demands much more detailed knowledge of target structures than the conventionally planned 2D technique. The 2D technique is based on bony landmarks and does not lend itself to customized conformal treatment planning based on an individual’s anatomy.
Target volumes for anal cancer also differ substantially from those appropriate for gynecologic or genitourinary cancer—two areas where IMRT has been employed. The most striking differences arise from the need for proper coverage of the perirectal (mesorectum) and presacral regions. While the rectum and its associated mesentery are avoidance structures for gynecologic or genitourinary malignancies, they represent the first echelon of nodal drainage for the anus.
As Czito and colleagues point out, the anal canal tumor and nodal gross tumor volume (GTV) need to be identified prior to generating clinical and planning target volumes (CTV and PTV, respectively). Accurate targeting of the treatment volumes has been shown to be essential in clinical trials involving radiotherapy in the treatment of other gastrointestinal cancers.[14,15] The same will likely prove true for the use of IMRT in anal canal cancer.
Risk of Underdosing Subclinical Disease
The recently completed RTOG 0529 study of IMRT plus 5-FU and mitomycin for anal canal carcinoma identified inadequate elective target contouring (most notably the mesorectum) in a large number of enrolled cases (personal communication, L. Kachnic, principal investigator). Because of a pretreatment rapid submission and review process, patient care was not compromised, but 75% of enrolled patients required a change in their treatment volumes prior to initiating chemoradiation. These adjustments, if left uncorrected, could lead to a much higher than expected local-regional failure rate.
Marginal misses have been reported in head and neck cancer patients treated with IMRT. With highly conformal therapy comes the risk of underdosing sites of subclinical disease. This emphasizes the learning curve in identifying the CTV in the transition from 2D therapy to IMRT, and more importantly, warrants further education in the radiation oncology community before IMRT is adapted for routine use in the treatment of anal canal cancer. As such, RTOG has posted on its website a contouring atlas to serve as a template for the definition of the elective CTVs to be used in IMRT planning for anal canal and rectal cancer trials (http://www.rtog.org/atlases/contour.html). In addition, the American Society for Therapeutic Radiology and Oncology (ASTRO) and the American Radium Society (ARS) have conducted electronic contouring courses to further educate its members on the appropriate treatment volumes for a number of different solid cancers.
The advent of advances in imaging such as positron-emission tomography–computed tomography (PET/CT), magnetic resonance imaging (MRI) and MRI spectroscopy have also improved radiation oncologists’ ability to more accurately target at-risk GTVs and predict the outcome of treatment. As Czito and colleagues note, three recent retrospective studies have reported that approximately 25% of patients with negative lymph nodes on conventional imaging were found to have PET-positive nodal metastasis.[19-21] This may have important implications for IMRT design and radiation doses, but are we ready to modify our treatment plans based on PET scanning without validation in multi-institutional prospective trials?
Advanced technologies, such as IMRT, hold great promise in the treatment of anal canal cancer. The use of IMRT in this disease has been shown in small retrospective series to markedly reduce grade 3+ dermatologic and gastrointestinal toxicity, as compared to historical cohorts employing nonconformal radiation techniques. Early clinical outcomes appear encouraging; however, further analysis of local control and late morbidity will be required to validate this approach. To this end, the long-term results of the multi-institutional RTOG 0529 trial, utilizing IMRT with robust pretreatment quality assurance, will be of paramount importance. Until these data are available and demonstrate no detriment to pelvic control when using this highly conformal technique, the routine use of IMRT for anal canal cancer should be undertaken with caution.
1. Czito B, Pepek JM, Meyer JJ, et al: Intensity-modulated radiation therapy for anal cancer. Oncology (Williston Park) 23:1082-1089, 2009:
2. Ajani JA, Winter KA, Gunderson LL, et al: Fluorouracil, mitomycin, and radiotherapy vs fluorouracil, cisplatin, and radiotherapy for carcinoma of the anal canal: A randomized controlled trial. JAMA 299:1914-1921, 2008.
3. James R, Wan S, Glynne-Jones R, et al: A randomized trial of chemoradiation using mitomycin or cisplatin, with or without maintenance cisplatin/5fu in squamous cell carcinoma of the anus (ACT II) (abstract LBA4009). J Clin Oncol 27(15S):170s, 2009.
4. 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.
5. Baxter NN, Habermann EB, Tepper JE, et al: Risk of pelvic fractures in older women following pelvic irradiation. JAMA 294:2587-2593, 2005.
6. 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.
7. Morris DE, Emami B, Mauch PM, et al: Evidence-based review of three-dimensional conformal radiotherapy for localized prostate cancer: An ASTRO outcomes initiative. Int J Radiat Oncol Biol Phys 62:3-19, 2005.
8. Donovan E, Bleakley N, Denholm E, et al: Randomised trial of standard 2D radiotherapy (RT) versus intensity modulated radiotherapy (IMRT) in patients prescribed breast radiotherapy. Radiother Oncol 82:254-264, 2007.
9. Nutting C, A’Hern R, Rogers MS, et al: First results of a phase III multi-center randomized controlled trial of intensity modulated (IMRT) versus conventional radiotherapy (RT) in head and neck cancer (PARSPORT: ISRCTN48243537; vCRUK/03/005) (abstract LBA6006). J Clin Oncol 27(15S):302s, 2009.
10. Namiki S, Ishidoya S, Ito A, et al: Five-year follow-up of health-related quality of life after intensity-modulated radiation therapy for prostate cancer. Jpn J Clin Oncol August 8, 2009 (epub ahead of print).
11. Menkarios C, Azria D, Laliberte B, et al: Optimal organ-sparing intensity-modulated radiation therapy (IMRT) regimen for the treatment of locally advanced anal canal carcinoma: a comparison of conventional and IMRT plans. Radiat Oncol 2:41, 2007.
12. 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.
13. Salama JK, Mell LK, Schomas DA, et al: Concurrent chemotherapy and intensity-modulated radiation therapy for anal canal cancer patients: A multicenter experience. J Clin Oncol 25:4581-4586, 2007.
14. Macdonald JS, Smalley SR, Benedetti J, et al: Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. N Engl J Med 345:725-730, 2001.
15. Abrams RA, Winter KA, Regine WF, et al: Correlation of RTOG 9704 (adjuvant therapy (rx) of pancreatic adenocarcinoma (pan ca) radiation therapy quality assurance scores (RTQASc) with survival (S) (abstract 4523). J Clin Oncol 25(18S):203s, 2007.
16. RTOG 0529: A phase II evaluation of dose-painted IMRT in combination with 5-fluorouracil and mitomycin-C for reduction of acute morbidity in carcinoma of the anal canal. Available at www.rtog.com. Accessed October 17, 2009.
17. Cannon DM, Lee NY: Recurrence in region of spared parotid gland after definitive intensity-modulated radiotherapy for head and neck cancer. Int J Radiat Oncol Biol Phys 70:660-665, 2008.
18. Myerson RJ, Garofalo MC, El Naqa I, et al: Elective clinical target volumes for conformal therapy in anorectal cancer: A radiation therapy oncology group consensus panel contouring atlas. Int J Radiat Oncol Biol Phys 74:824-830, 2009.
19. Trautmann TG, Zuger JH: Positron emission tomography for pretreatment staging and posttreatment evaluation in cancer of the anal canal. Mol Imaging Biol 7:309-313, 2005.
20. Cotter SE, Grigsby PW, Siegel BA, et al: FDG-PET/CT in the evaluation of anal carcinoma. Int J Radiat Oncol Biol Phys 65:720-725, 2006.
21. Winton E, Heriot AG, Ng M, et al: The impact of 18-fluorodeoxyglucose positron emission tomography on the staging, management and outcome of anal cancer. Br J Cancer 100:693-700, 2009.