Dr. Czito and colleagues provide an intriguing overview on adapting and using more technically advanced techniques to deliver radiation therapy for anal cancer patients. The paper starts with a brief history of the treatment of anal cancer, moving from abdominoperineal resection to combined-modality therapy with radiation and chemotherapy and discusses the trials showing that combined chemoradiotherapy is superior to radiation alone in terms of local control and colostomy-free survival.[1,2] Adding mitomycin to fluorouracil (5-FU) has been scrutinized for increasing toxicity but has been shown to decrease colostomy rates compared to cisplatin/5-FU or 5-FU alone.[3,4]
The purpose of intensity-modulated radiotherapy (IMRT) is to provide greater dose conformality to target volumes. In each radiation field, the photon beam is split into many “beamlets,” each providing a different intensity of radiation within the field. This can be achieved by using dynamic multileaf collimation (dMLC) in which the MLCs move while the beam is on, or with “step-and-shoot” methods in which the radiation beam is turned off while the MLCs transit to a new position. The drawback to using IMRT is that it often contributes to greater dose variation within a target volume and more widespread low-dose coverage of normal tissues, as compared to three-dimensional (3D) conformal techniques.
Toxicity and Local Control
Using chemotherapy and radiation therapy with 3D techniques, we currently achieve high local control rates for anal cancers, but most patients experience significant acute toxicity in the form of hematologic, skin, and/or gastrointestinal side effects. Severe acute toxicity during treatment can lead to unscheduled breaks in treatment, and concern has been raised that these treatment breaks could compromise local control rates. Also, larger tumors of the anal canal—otherwise shown to be associated with poorer local control—could possibly have a better response with dose escalation. The ability to deliver higher radiation doses to target volumes while sparing critical organs from high radiation dose make IMRT a promising technique in treating these tumors. There is the potential for dose escalation to larger tumors while decreasing acute toxicity and treatment breaks.
Dosimetric comparisons of 3D conformal and IMRT treatment plans have shown a lower incidence of acute GI toxicity when 450 cm3 of bowel receives less than 30 Gy. Another study of patients with anal cancer treated with IMRT yielded 2-year survival and local control rates similar to those seen in historical controls but had no treatment breaks attributed to gastrointestinal or skin toxicity and had no grade 3 or higher nonhematologic acute toxicity. Acute skin dermatitis and desquamation of the genitalia is commonly a dose-limiting acute toxicity in our experience but remarkably was not seen in the report from Duke.
A special potential application for IMRT in the treatment of patients with carcinoma of the anus arises in patients with compromised immune systems. Standard treatment with radiation and chemotherapy in this patient population appears to be more toxic acutely than in patients with intact immune function. The incidence and degree of toxicity has been linked to CD4 T-lymphocyte counts in peripheral circulating blood, especially with a cutoff < 200/µL.[8,9] In the era of highly active antiretroviral therapy this cohort of patients seems to tolerate treatment better than previous reports indicate, but acute toxicity remains high. At Indiana University, our large organ transplant program has produced a cadre of patients who develop anal cancer while on chronic medical immunosuppression. In our recent analysis of immunocompromised anal cancer patients (including patients with HIV infection and a history of organ transplantation), we found that all patients completed treatment with a median treatment break of 6 days (range: 0–28) corresponding to an overall treatment time of 34 to 79 days (median: 51 days). We also showed that more locally advanced (T3/T4) tumors had inferior local control compared to smaller tumors and that treatment time was associated with overall survival on univariate analysis. These results are similar to those found in retrospective studies of immunocompetent anal cancer patients. This adds to the evidence that potentially dose-escalating radiation to larger tumors while decreasing acute skin and GI toxicity in this patient population has important implications on the treatment tolerance and overall clinical outcomes.
Appropriate Use of IMRT
With the advent of all new technologies, however, comes the responsibility to use them appropriately. With IMRT, accurately defining target volumes becomes paramount. With increased dose conformality to target structures comes increased dose falloff outside of the structures. Thus, it becomes easier to “miss” subclinical areas of disease spread that may have been covered under more traditional 3D conformal planning techniques and treatment fields. Also, the more planning constraints prescribed, the more difficult it may be to provide adequate homogeneous coverage of the target volumes. Furthermore, there is vast variability in contouring and defining of nodal regions; as stated in Dr. Czito’s article, nearly 80% of radiation treatment plans in the Radiation Therapy Oncology Group (RTOG) 05-29 study required a change in planning volumes following pretreatment central review. This led, in part, to the development of the RTOG anorectal contouring atlas. This new atlas should provide more consistency with respect to target delineation and appropriate volumes to be covered within an IMRT or 3D conformal radiation treatment plan.
Using new technology and more modern and advanced treatment-planning techniques has advantages in radiation oncology. However, there also are potential drawbacks. While preliminary results of using IMRT to treat anal cancers appear promising and community centers may have embraced IMRT as a replacement to 3D conformal techniques, our responsibility remains to continue research to ensure that the potential for decreasing acute toxicity does not result in inferior control rates. Longer follow-up of well designed studies such as RTOG 05-29 will lend more data to the debate.
1. 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.
2. 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.
3. 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.
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. Widder J, Kastenberger R, Fercher E, et al: Radiation dose associated with local control in advanced anal cancer: Retrospective analysis of 129 patients. Radiother Oncol 87:367-375, 2008.
6. Devisetty K, Mell LK, Salama JK, et al: A multi-institutional acute gastrointestinal toxicity analysis of anal cancer patients treated with concurrent intensity-modulated radiation therapy (IMRT) and chemotherapy. Radiother Oncol August 28, 2009 (epub ahead of print).
7. 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.
8. Edelman S, Johnstone PA: Combined modality therapy for HIV-infected patients with squamous cell carcinoma of the anus: Outcomes and toxicities. Int J Radiat Oncol Biol Phys 66:206-211, 2006.
9. Hoffman R, Welton ML, Klencke B, et al: The significance of pretreatment CD4 count on the outcome and treatment tolerance of HIV-positive patients with anal cancer. Int J Radiat Oncol Biol Phys 44:127-131, 1999.
10. Barriger RB, Calley C, Cardenes H: Treatment of anal carcinoma in immune-compromised patients. Clinical and Translational Oncology. In press.
11. 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.