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Intensity-modulated radiotherapy for squamous cell carcinoma of the anal canal: Efficacy of a low daily dose to clinically negative regions

Intensity-modulated radiotherapy for squamous cell carcinoma of the anal canal: Efficacy of a low... Background: We aimed to assess outcomes of patients with anal cancer who underwent intensity-modulated radiotherapy (IMRT) and received less than 1.80 Gy/day. Methods: We retrospectively reviewed our experience using a low fractional dose (< 1.80 Gy) of IMRT to elective nodal areas for patients receiving chemoradiotherapy for anal cancer. Three-year freedom from any disease relapse and overall survival were estimated using Kaplan-Meier curves. We documented the daily dose that was delivered to clinically uninvolved regions and to areas of gross disease. Incidence of regional failures in high (≥ 1.80 Gy) and low (< 1.80 Gy) daily dose regions was assessed. Results: Thirty-four consecutive patients (median age, 59 years) received IMRT from June 2005 through January 2009. Median follow-up duration was 22 months. Twenty-eight patients had T1 or T2 disease and 6 had T3 or T4 disease. Fourteen patients had nodal metastases. Median treatment dose was 50.40 Gy (range, 48.60-57.60 Gy) in 25 to 32 fractions. The range of fractional doses to clinically negative volumes was 1.28 to 1.80 Gy. Seventeen patients (50%) received a fractional dose of less than 1.60 Gy, 13 (38%) received less than 1.50 Gy, and 9 (26%) received less than 1.40 Gy to at least a portion of the clinically negative volume. Three-year freedom from relapse was 80%, and 3-year overall survival was 87%. No patient had treatment failure in the clinically negative volume that received a low daily dose. Conclusions: Our data support using doses between 1.50 and 1.80 Gy/day to clinically uninvolved regions. Keywords: anal cancer, chemotherapy, intensity-modulated radiotherapy, squamous cell carcinoma Introduction receive different total doses while the number of fractions Fluorouracil (FU) and mitomycin C (MMC) combined remains the same. Under certain conditions, elective with radiotherapy is the standard treatment for squa- regions could receive a fractional dose as low as 1.50 Gy mous cell carcinoma arising in the anal canal (1-4). Trials per day. Historically, anal cancer has been treated with of conventional radiotherapy techniques have shown sig- doses of at least 1.80 Gy per day, with a shrinking-field nificant toxicity (1), and interest has focused on inten- technique over the course of treatment. Data on doses sity-modulated radiotherapy (IMRT) in this setting, with less than 1.80 Gy per day are lacking. At our institution, thehopeofdecreasingseveretoxicity. TheRadiation use of such lower doses in the treatment of anal cancer is Therapy Oncology Group (RTOG) has developed an common when using IMRT. This study was undertaken to review our experience of low-dose IMRT (< 1.80 Gy IMRT protocol that has been tested in a multi-institu- tional study (5). The protocol uses a daily fraction dose per day) in the treatment of anal cancer and to determine that varies according to the specific target volume. Such the rate of regional failures with this treatment regimen. a technique allows gross disease and elective areas to Methods and Materials This study was approved by the Mayo Clinic Institu- * Correspondence: miller.robert@mayo.edu 1 tional Review Board. We reviewed all patients with Department of Radiation Oncology, Mayo Clinic, 200 First St SW, Rochester, MN 55905, USA squamous cell carcinoma of the anus who received Full list of author information is available at the end of the article © 2011 Call et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Call et al. Radiation Oncology 2011, 6:134 Page 2 of 5 http://www.ro-journal.com/content/6/1/134 chemoradiotherapy with IMRT from June 2005 through Radiotherapy January 2009 at Mayo Clinic, Rochester, Minnesota. All Details of radiotherapy are shown in additional file 1 living patients authorized review of their medical record Tables 2 and 3, stratified by nodal disease status (stage in accordance with Minnesota state law. Data on patient N0 vs N+ disease). Radiation was delivered with 6-MV and tumor characteristics, details about radiotherapy, photon beams to 11 fields (n = 1) or to 9 fields (n = 33). It was common to treat the upper pelvis with a and outcomes of disease control and survival were lower dose than the lower pelvis. (Upper and lower pel- obtained from the medical record. All cancers were eval- vis volumes typically were delineated around the bottom uated (assigned a TNM stage) according to the American of the sacroiliac joints.) The treating clinician individua- Joint Committee on Cancer Staging Manual, seventh edition (6). Regional failures were recorded, along with lized gross tumor volumes, clinical target volumes, and the dose received during IMRT. Follow-up primarily con- planning target volume expansions for each patient. A sisted of a physical examination, with imaging studies simultaneous integrated boost (SIB) technique was used performed at the discretion of the supervising physician. to treat the gross tumor volume and elective areas in a Biopsies were not routinely performed if physical exami- single treatment plan (ie, applying different doses per nation findings were favorable. fraction to different target volumes). Use of low frac- tional doses of radiation was common. Doses ranged Statistical Analysis from 48.60 to 57.60 Gy (median, 50.40 Gy) in 25 to 32 The Kaplan-Meier method was used to calculate and fractions. estimate rates of overall survival and freedom from any Gross disease was treated with a daily fraction of 1.80 disease relapse. Data were analyzed using JMP software to 2.25 Gy. The gross tumor volume was commonly (version 8.0; SAS Institute, Cary, North Carolina). treated with a margin that varied according to the dis- cretion of the treating clinician but would often include Results immediately adjacent lymph node tissues. Doses to elec- Patient and Tumor Characteristics tively covered areas that were outside those margins are We identified 34 consecutively treated patients who specified in additional file 1 Tables 2 and 3. The range of doses to clinically negative volumes was received definitive IMRT and chemotherapy (FU alone 1.28 to 1.80 Gy per day. All patients received less than [n = 1] or a combination of FU and MMC [n = 33]). 1.80 Gy per fraction to some portion of the electively Patient characteristics are displayed in Table 1. Median covered volume. Seventeen patients (50%) received a age was 59 years. Twenty-eight patients (82%) had T1 fractional dose less than 1.60 Gy, 13 (38%) received less or T2 disease, and 6 (18%) had T3 or T4 disease. Four- than 1.50 Gy, and 9 (26%) received less than 1.40 Gy to teen patients (41%) had nodal disease. The median dura- tion of follow-up was 22 months. at least a portion of the clinically negative volume. Posi- tive nodes received a median fractional dose of 1.93 Gy (range, 1.80-2.25 Gy). Table 1 Patient Characteristics (N = 34) Characteristic Value Disease Control and Overall Survival The 3-year freedom from any disease relapse was 80% Age, median (range), y 59 (46-85) (Figure 1). Three patients had a local failure, one patient IMRT dose, median (range), Gy 50.40 (48.60-57.60) had a regional lymph node failure, and 4 had cancer Chemotherapy, No. recur at distant sites (one had a distal failure 3 months FU with MMC 33 after a local failure). The patient with the regional fail- FU only 1 ure had progression at a site of gross nodal disease that TNM category, No. was treated with a dose of 56.25 Gy in 25 fractions (2.25 T1 10 Gy per day). No treatment failures were observed in the T2 18 target volumes that received less than 1.80 Gy per day T3 4 (100% regional control in low-dose areas). T4 2 Three patients died during the follow-up period. One N0 20 patient died of cardiac arrest 6 months after the diagnosis N1 7 N2 3 of anal cancer; the patient was disease free at the time of death. The second patient died of sepsis associated with N3 4 metastatic anal cancer 10 months after diagnosis. The M0 34 third patient was a 79-year-old woman with a history of congestive heart failure and chronic obstructive pulmon- Abbreviations: FU, fluorouracil; IMRT, intensity- ary disease; she died after 26 months of follow-up. modulated radiotherapy; MMC, mitomycin C. Call et al. Radiation Oncology 2011, 6:134 Page 3 of 5 http://www.ro-journal.com/content/6/1/134 Radiotherapy and concurrent FU and MMC is the current standard of care and allows many patients to avoid having a colostomy. Several prospective trials on chemoradiotherapy have been performed in the study of this disease. Although there has been some variation in technique, an overview of these trials shows that they generally have used doses of at least 1.80 Gy per day. Phase 3 trials performed by the United Kingdom Coordi- nating Committee on Cancer Research (UKCCCR) and the European Organization for Research and Treatment of Cancer (EORTC) demonstrated that chemoradiother- apy with these agents was superior to radiotherapy alone in terms of local control and the ultimate need for a colostomy (2,4). In the UKCCCR trial, treatment involved Figure 1 Estimated Rate of Freedom From Any Disease Relapse a technique of opposed anterior and posterior fields to in All Patients. The rate at 3 years was 80%. treat the central axis with a dose of 45 Gy in 20 to 25 fractions over 4 to 5 weeks. Patients with less than 50% response were treated surgically, and all others were recommended to receive a boost (15 Gy in 6 fractions, by Although the cause of death was not documented in this electrons, photons, or an interstitial implant) over 2 to 3 case, she did not have evidence of recurrent cancer dur- ing the follow-up period. The remaining 31 patients were days. In the EORTC trial, initial fields (3- or 4-field tech- alive at the time of manuscript preparation, with a med- nique) were treated with 45 Gy (1.80 Gy per day) over 5 ian survival of 23 months. The estimated survival at 3 weeks. After a 6-week break, patients with a complete years was 87% for the entire group. response then received a further boost of 15 Gy, whereas those with a partial response received 20 Gy. Other trials Discussion have examined the optimal chemotherapy to be delivered IMRT for anal cancer is currently under investigation in with radiotherapy in the definitive treatment of anal can- a multi-institutional study. Using IMRT with SIB to treat cer. Continuous infusion of FU alone (1,000 mg/m per different targets with different daily doses often results in day over 96 hours, starting days 1 and 29 of radiotherapy) some areas receiving less than the conventional fractional was inferior to chemotherapy with MMC (10 mg/m on doses of radiation (ie, < 1.80 Gy). This technique has days 1 and 29) in a phase 3 trial performed by the RTOG and Eastern Cooperative Oncology Group (trial RTOG some treatment benefits. Multiple IMRT plans could be 87-04/ECOG 1289) (3). The first 45 Gy of radiotherapy used to allow no change in fractional dose during the were concomitant with the first 2 cycles of chemotherapy treatment period, but this requires additional planning and used parallel opposed fields and a daily fraction of and quality assurance and also extends the treatment 1.80 Gy. After 30.6 Gy was administered, the top field time. Increased treatment times may be associated with border was reduced from the interspace between L4 and poor disease control (7-13). Use of IMRT to deliver an L5 to the bottom of the sacroiliac joints. This field was SIB has the advantage of being able to deliver the radia- continued until a dose of 36 Gy was administerd. Finally, tion in a shorter time. However, this necessitates varying a boost field to the tumor alone was used until a total the fractional dose, and thus clinically negative areas may dose of 45 Gy was achieved. be treated with lower daily doses than what has typically If a tumor was still palpable immediately after the been administered in anal cancer clinical trials. Data on the biologic effects and clinical outcomes of such low initial 45 Gy, the patient had a boost treatment with doses are lacking. another 5.4 Gy. For patients with N1 disease, both ingu- Historically, anal cancers were treated with surgical inal regions were initially treated with a dose of 50.40 Gy therapy involving an abdominoperineal resection. Inter- at a prescription depth of 3 cm. After 4 to 6 weeks, est in improving outcomes for these patients led to the patients were assessed by a biopsy; if results were posi- discovery that these tumors responded to chemotherapy tive, they received further therapy. For patients with and radiotherapy. Such therapy, delivered in a neoadju- biopsy results showing residual primary disease, salvage vant fashion, decreased the failure rate compared with therapy consisted of 9 Gy in 5 fractions (delivered with that of surgery alone (14,15). This ultimately led to a electrons or photons) and the same regimen of FU plus primary approach of chemoradiotherapy, obviating the cisplatin (100 mg/m ) on day 2 of radiotherapy. Patients need for surgery for patients with a complete response with palpable inguinal disease after administration of 45 and negative biopsy findings (16). to 50.4 Gy received an additional 9 Gy. Call et al. Radiation Oncology 2011, 6:134 Page 4 of 5 http://www.ro-journal.com/content/6/1/134 Trial RTOG 98-11 (1) attempted to substitute cisplatin been reported (19), and the locoregional failure rate at for the MMC component of therapy. Patients were ran- 2 years was 20%. Long-term results are not yet available domized to 1 of 2 treatment arms: 1) concurrent FU, to assess the effectiveness of the approach in a multi- MMC, and radiotherapy; or 2) neoadjuvant cisplatin and institutional setting. The results presented here add to FU alone, followed by concurrent chemoradiotherapy the growing body of data supporting the use of IMRT with cisplatin and FU. The treatment arm with MMC with SIB for anal cancer. Regional control was excellent, despite the common use of low doses per fraction. and FU had a significantly reduced colostomy rate. The Limitations of our data include the retrospective nat- radiotherapy was also administered with shrinking fields; ure of this study. In addition, no standard method was after 30.6 Gy was administered, the superior border was moved down from L5 and S1 to the bottom of the sacroi- used to prescribe radiotherapy. In addition, the relatively liac joints, and a minimum of 14.4 Gy of additional radia- small size (34 patients) and short follow-up (22 months) tion was administered to the tumor (all at 1.80 Gy per in this report should be noted. It was common for day). Node-negative patients received 36 Gy to inguinal patients to receive a low fractional dose to at least a regions. Certain patients (stage T3 or T4, node positive, portion of the elective volume; however, specific dosages or N2 with residual disease) were treated with a boost of to certain volumes were individualized according to the 10 to 14 Gy at 2 Gy per fraction, for a total tumor dose judgment of each radiation oncologist. All patients in of 55 to 59 Gy. this study received concurrent chemotherapy. We do A second phase 3 trial, conducted in the United King- not know whether the same low rate of regional failure dom, examined outcomes after replacing MMC with cis- would have been observed if such radiosensitizing agents platin that was administered concurrently (no initial gap) were not used. with a radiotherapy dose of 50.4 Gy (17). This trial showed In conclusion, our results indicate that low fractional no significant improvement in complete response rate doses of radiation may be appropriate when using IMRT with concurrent cisplatin (95%) compared with MMC for squamous cell carcinoma of the anus along with con- (94%), and the need for a colostomy was similar between current chemotherapy. A daily dose between 1.50 and groups.Currently,radiotherapy delivered concurrently 1.80 Gy per day to clinically negative areas, prescribed with FU and MMC remains the standard of care for squa- according to the RTOG technique, may be appropriate in mous cell carcinoma of the anal canal. certain clinical situations. No treatment failures were The RTOG initiated a multi-institutional effort to pro- noted in the low-dose prescription volumes, despite the frequent use of fractional doses less than 1.80 Gy. spectively treat patients with IMRT-based chemora- diotherapy (RTOG 0529) (5). In this protocol, patients received IMRT with SIB to treat the elective areas and Additional material gross disease in the same number of fractions. IMRT was able to significantly reduce the grade 2+ dermatologic and Additional file 1: Tables 2 and 3 grade 3+ gastrointestinal/genitourinary events compared with the results of the RTOG 98-11 trial. Fractional doses varied by the clinical situation but were as low as 1.5 Gy Abbreviations per day to clinically negative areas. EORTC: European Organization for Research and Treatment of Cancer; FU: fluorouracil; IMRT: intensity-modulated radiotherapy; MMC: mitomycin C; Our data indicate that a low dose per fraction when RTOG: Radiation Therapy Oncology Group; SIB: simultaneous integrated treating with an SIB technique may be effective for clini- boost; UKCCCR: United Kingdom Coordinating Committee on Cancer cally negative areas. It was common to treat at least a Research portion of the elective areas with less than 1.80 Gy per Acknowledgements day. We observed only one regional failure that occurred Reprints: Robert C. Miller, MD, Department of Radiation Oncology, Mayo at the siteofa grosslypositivenodethatreceived a dose Clinic, 200 First St SW, Rochester, MN 55905 (http://miller.robert@mayo.edu). Portions of this work have been accepted for an oral presentation at the of 56.25 Gy (2.25 Gy per day). No patients in our series annual meeting of the American Radium Society (ARS), Palm Beach, Florida, had treatment failure within the elective, low-dose April 30 to May 4, 2011. volume. Kachnic et al (18) reported results from several Author details centers in Boston using an IMRT technique that com- Department of Radiation Oncology, Mayo Clinic, 200 First St SW, Rochester, monly treated elective nodal areas with doses as low as 2 MN 55905, USA. Division of Medical Oncology, Mayo Clinic, 200 First St SW, 1.5 Gy per fraction. With a median follow-up of 24 Rochester, MN 55905, USA. Division of Colon and Rectal Surgery, Mayo Clinic, 200 First St SW, Rochester, MN 55905, USA. months, these authors noted a 2-year local control rate of 95%, and only 2 of 43 patients had a pelvic recurrence. In Authors’ contributions addition, trial RTOG-0529 used a similar technique for JAC: Reviewed charts, gathered data, and drafted the manuscript. MGH: Aided in the design of the study, helped draft the manuscript. DWL: Aided treating patients by using IMRT to deliver a low daily in the design of the study, helped draft the manuscript. JFQ: Aided in the dose to elective areas. Preliminary 2-year results have Call et al. Radiation Oncology 2011, 6:134 Page 5 of 5 http://www.ro-journal.com/content/6/1/134 design of the study, helped draft the manuscript. RCM: Participated in study carcinoma of the anus (ACT II) [abstract]. J Clin Oncol 2009, 27(18S): design and coordination and helped draft the manuscript. All authors read LBA4009.. and approved the final version of this manuscript. 18. Kachnic LA, Tsai HK, Coen JJ, Blaszkowsky LS, Hartshorn K, Kwak EL, et al: Dose-painted intensity-modulated radiation therapy for anal cancer: a Conflicts of interests multi-institutional report of acute toxicity and response to therapy. Int J The authors declare that they have no competing interests. Radiat Oncol Biol Phys 2010. 19. Kachnic L, Winter K, Myerson R, Goodyear M, Willins J, Esthappan J, et al: Received: 26 April 2011 Accepted: 6 October 2011 Early efficacy results of RTOG 0529: a phase II evaluation of dose- Published: 6 October 2011 painted IMRT in combination with 5-fluorouracil and mitomycin-C for the reduction of acute morbidity in carcinoma of the anal canal [abstract]. Int J Radiat Oncol Biol Phys 2010, 78(3 Suppl 1):S55. References 1. Ajani JA, Winter KA, Gunderson LL, Pedersen J, Benson AB, Thomas CR Jr, doi:10.1186/1748-717X-6-134 et al: Fluorouracil, mitomycin, and radiotherapy vs fluorouracil, cisplatin, Cite this article as: Call et al.: Intensity-modulated radiotherapy for and radiotherapy for carcinoma of the anal canal: a randomized squamous cell carcinoma of the anal canal: Efficacy of a low daily dose controlled trial. JAMA 2008, 299(16):1914-21. to clinically negative regions. Radiation Oncology 2011 6:134. 2. Bartelink H, Roelofsen F, Eschwege F, Rougier P, Bosset JF, Gonzalez DG, 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 1997, 15(5):2040-9. 3. Flam M, John M, Pajak TF, Petrelli N, Myerson R, Doggett S, 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 1996, 14(9):2527-39. 4. 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 1996, 348(9034):1049-54. 5. Kachnic L, Winter K, Myerson R, Goodyear M, Willins J, Esthappan J, et al: 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 [abstract]. Int J Radiat Oncol Biol Phys 2009, 75(3 Suppl 1):S5. 6. Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A, editors: AJCC Cancer Staging Manual. New York: Springer;c2010. 7. Ben-Josef E, Moughan J, Ajani J, Flam M, Gunderson L, Pollock J, et al: The impact of overall treatment time on survival and local control in anal cancer patients: a pooled data analysis of RTOG trials 8704 and 9811 [abstract]. Int J Radiat Oncol Biol Phys 2009, 75(3 Suppl 1):S26-S7. 8. Constantinou EC, Daly W, Fung CY, Willett CG, Kaufman DS, DeLaney TF: Time-dose considerations in the treatment of anal cancer. Int J Radiat Oncol Biol Phys 1997, 39(3):651-7. 9. Deniaud-Alexandre E, Touboul E, Tiret E, Sezeur A, Houry S, Gallot D, et al: Results of definitive irradiation in a series of 305 epidermoid carcinomas of the anal canal. Int J Radiat Oncol Biol Phys 2003, 56(5):1259-73. 10. Graf R, Wust P, Hildebrandt B, Gogler H, Ullrich R, Herrmann R, et al: Impact of overall treatment time on local control of anal cancer treated with radiochemotherapy. Oncology 2003, 65(1):14-22. 11. Huang K, Haas-Kogan D, Weinberg V, Krieg R: Higher radiation dose with a shorter treatment duration improves outcome for locally advanced carcinoma of anal canal. World J Gastroenterol 2007, 13(6):895-900. 12. Weber DC, Kurtz JM, Allal AS: The impact of gap duration on local control in anal canal carcinoma treated by split-course radiotherapy and concomitant chemotherapy. Int J Radiat Oncol Biol Phys 2001, 50(3):675-80. 13. Widder J, Kastenberger R, Fercher E, Schmid R, Langendijk JA, Dobrowsky W, et al: Radiation dose associated with local control in Submit your next manuscript to BioMed Central advanced anal cancer: retrospective analysis of 129 patients. Radiother Oncol 2008, 87(3):367-75. and take full advantage of: 14. Nigro ND, Vaitkevicius VK, Considine B Jr: Combined therapy for cancer of the anal canal: a preliminary report. Dis Colon Rectum 1974, 17(3):354-6. • Convenient online submission 15. Nigro ND, Seydel HG, Considine B, Vaitkevicius VK, Leichman L, Kinzie JJ: • Thorough peer review Combined preoperative radiation and chemotherapy for squamous cell carcinoma of the anal canal. Cancer 1983, 51(10):1826-9. • No space constraints or color figure charges 16. Leichman L, Nigro N, Vaitkevicius VK, Considine B, Buroker T, Bradley G, • Immediate publication on acceptance et al: Cancer of the anal canal: model for preoperative adjuvant • Inclusion in PubMed, CAS, Scopus and Google Scholar combined modality therapy. Am J Med 1985, 78(2):211-5. 17. James R, Wan S, Glynne-Jones R, Sebag-Montefiore D, Kadalayil L, • Research which is freely available for redistribution Northover J, et al: A randomized trial of chemoradiation using mitomycin or cisplatin, with or without maintenance cisplatin/5FU in squamous cell Submit your manuscript at www.biomedcentral.com/submit http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Radiation Oncology Springer Journals

Intensity-modulated radiotherapy for squamous cell carcinoma of the anal canal: Efficacy of a low daily dose to clinically negative regions

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Copyright © 2011 by Call et al; licensee BioMed Central Ltd.
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Medicine & Public Health; Oncology; Radiotherapy
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Abstract

Background: We aimed to assess outcomes of patients with anal cancer who underwent intensity-modulated radiotherapy (IMRT) and received less than 1.80 Gy/day. Methods: We retrospectively reviewed our experience using a low fractional dose (< 1.80 Gy) of IMRT to elective nodal areas for patients receiving chemoradiotherapy for anal cancer. Three-year freedom from any disease relapse and overall survival were estimated using Kaplan-Meier curves. We documented the daily dose that was delivered to clinically uninvolved regions and to areas of gross disease. Incidence of regional failures in high (≥ 1.80 Gy) and low (< 1.80 Gy) daily dose regions was assessed. Results: Thirty-four consecutive patients (median age, 59 years) received IMRT from June 2005 through January 2009. Median follow-up duration was 22 months. Twenty-eight patients had T1 or T2 disease and 6 had T3 or T4 disease. Fourteen patients had nodal metastases. Median treatment dose was 50.40 Gy (range, 48.60-57.60 Gy) in 25 to 32 fractions. The range of fractional doses to clinically negative volumes was 1.28 to 1.80 Gy. Seventeen patients (50%) received a fractional dose of less than 1.60 Gy, 13 (38%) received less than 1.50 Gy, and 9 (26%) received less than 1.40 Gy to at least a portion of the clinically negative volume. Three-year freedom from relapse was 80%, and 3-year overall survival was 87%. No patient had treatment failure in the clinically negative volume that received a low daily dose. Conclusions: Our data support using doses between 1.50 and 1.80 Gy/day to clinically uninvolved regions. Keywords: anal cancer, chemotherapy, intensity-modulated radiotherapy, squamous cell carcinoma Introduction receive different total doses while the number of fractions Fluorouracil (FU) and mitomycin C (MMC) combined remains the same. Under certain conditions, elective with radiotherapy is the standard treatment for squa- regions could receive a fractional dose as low as 1.50 Gy mous cell carcinoma arising in the anal canal (1-4). Trials per day. Historically, anal cancer has been treated with of conventional radiotherapy techniques have shown sig- doses of at least 1.80 Gy per day, with a shrinking-field nificant toxicity (1), and interest has focused on inten- technique over the course of treatment. Data on doses sity-modulated radiotherapy (IMRT) in this setting, with less than 1.80 Gy per day are lacking. At our institution, thehopeofdecreasingseveretoxicity. TheRadiation use of such lower doses in the treatment of anal cancer is Therapy Oncology Group (RTOG) has developed an common when using IMRT. This study was undertaken to review our experience of low-dose IMRT (< 1.80 Gy IMRT protocol that has been tested in a multi-institu- tional study (5). The protocol uses a daily fraction dose per day) in the treatment of anal cancer and to determine that varies according to the specific target volume. Such the rate of regional failures with this treatment regimen. a technique allows gross disease and elective areas to Methods and Materials This study was approved by the Mayo Clinic Institu- * Correspondence: miller.robert@mayo.edu 1 tional Review Board. We reviewed all patients with Department of Radiation Oncology, Mayo Clinic, 200 First St SW, Rochester, MN 55905, USA squamous cell carcinoma of the anus who received Full list of author information is available at the end of the article © 2011 Call et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Call et al. Radiation Oncology 2011, 6:134 Page 2 of 5 http://www.ro-journal.com/content/6/1/134 chemoradiotherapy with IMRT from June 2005 through Radiotherapy January 2009 at Mayo Clinic, Rochester, Minnesota. All Details of radiotherapy are shown in additional file 1 living patients authorized review of their medical record Tables 2 and 3, stratified by nodal disease status (stage in accordance with Minnesota state law. Data on patient N0 vs N+ disease). Radiation was delivered with 6-MV and tumor characteristics, details about radiotherapy, photon beams to 11 fields (n = 1) or to 9 fields (n = 33). It was common to treat the upper pelvis with a and outcomes of disease control and survival were lower dose than the lower pelvis. (Upper and lower pel- obtained from the medical record. All cancers were eval- vis volumes typically were delineated around the bottom uated (assigned a TNM stage) according to the American of the sacroiliac joints.) The treating clinician individua- Joint Committee on Cancer Staging Manual, seventh edition (6). Regional failures were recorded, along with lized gross tumor volumes, clinical target volumes, and the dose received during IMRT. Follow-up primarily con- planning target volume expansions for each patient. A sisted of a physical examination, with imaging studies simultaneous integrated boost (SIB) technique was used performed at the discretion of the supervising physician. to treat the gross tumor volume and elective areas in a Biopsies were not routinely performed if physical exami- single treatment plan (ie, applying different doses per nation findings were favorable. fraction to different target volumes). Use of low frac- tional doses of radiation was common. Doses ranged Statistical Analysis from 48.60 to 57.60 Gy (median, 50.40 Gy) in 25 to 32 The Kaplan-Meier method was used to calculate and fractions. estimate rates of overall survival and freedom from any Gross disease was treated with a daily fraction of 1.80 disease relapse. Data were analyzed using JMP software to 2.25 Gy. The gross tumor volume was commonly (version 8.0; SAS Institute, Cary, North Carolina). treated with a margin that varied according to the dis- cretion of the treating clinician but would often include Results immediately adjacent lymph node tissues. Doses to elec- Patient and Tumor Characteristics tively covered areas that were outside those margins are We identified 34 consecutively treated patients who specified in additional file 1 Tables 2 and 3. The range of doses to clinically negative volumes was received definitive IMRT and chemotherapy (FU alone 1.28 to 1.80 Gy per day. All patients received less than [n = 1] or a combination of FU and MMC [n = 33]). 1.80 Gy per fraction to some portion of the electively Patient characteristics are displayed in Table 1. Median covered volume. Seventeen patients (50%) received a age was 59 years. Twenty-eight patients (82%) had T1 fractional dose less than 1.60 Gy, 13 (38%) received less or T2 disease, and 6 (18%) had T3 or T4 disease. Four- than 1.50 Gy, and 9 (26%) received less than 1.40 Gy to teen patients (41%) had nodal disease. The median dura- tion of follow-up was 22 months. at least a portion of the clinically negative volume. Posi- tive nodes received a median fractional dose of 1.93 Gy (range, 1.80-2.25 Gy). Table 1 Patient Characteristics (N = 34) Characteristic Value Disease Control and Overall Survival The 3-year freedom from any disease relapse was 80% Age, median (range), y 59 (46-85) (Figure 1). Three patients had a local failure, one patient IMRT dose, median (range), Gy 50.40 (48.60-57.60) had a regional lymph node failure, and 4 had cancer Chemotherapy, No. recur at distant sites (one had a distal failure 3 months FU with MMC 33 after a local failure). The patient with the regional fail- FU only 1 ure had progression at a site of gross nodal disease that TNM category, No. was treated with a dose of 56.25 Gy in 25 fractions (2.25 T1 10 Gy per day). No treatment failures were observed in the T2 18 target volumes that received less than 1.80 Gy per day T3 4 (100% regional control in low-dose areas). T4 2 Three patients died during the follow-up period. One N0 20 patient died of cardiac arrest 6 months after the diagnosis N1 7 N2 3 of anal cancer; the patient was disease free at the time of death. The second patient died of sepsis associated with N3 4 metastatic anal cancer 10 months after diagnosis. The M0 34 third patient was a 79-year-old woman with a history of congestive heart failure and chronic obstructive pulmon- Abbreviations: FU, fluorouracil; IMRT, intensity- ary disease; she died after 26 months of follow-up. modulated radiotherapy; MMC, mitomycin C. Call et al. Radiation Oncology 2011, 6:134 Page 3 of 5 http://www.ro-journal.com/content/6/1/134 Radiotherapy and concurrent FU and MMC is the current standard of care and allows many patients to avoid having a colostomy. Several prospective trials on chemoradiotherapy have been performed in the study of this disease. Although there has been some variation in technique, an overview of these trials shows that they generally have used doses of at least 1.80 Gy per day. Phase 3 trials performed by the United Kingdom Coordi- nating Committee on Cancer Research (UKCCCR) and the European Organization for Research and Treatment of Cancer (EORTC) demonstrated that chemoradiother- apy with these agents was superior to radiotherapy alone in terms of local control and the ultimate need for a colostomy (2,4). In the UKCCCR trial, treatment involved Figure 1 Estimated Rate of Freedom From Any Disease Relapse a technique of opposed anterior and posterior fields to in All Patients. The rate at 3 years was 80%. treat the central axis with a dose of 45 Gy in 20 to 25 fractions over 4 to 5 weeks. Patients with less than 50% response were treated surgically, and all others were recommended to receive a boost (15 Gy in 6 fractions, by Although the cause of death was not documented in this electrons, photons, or an interstitial implant) over 2 to 3 case, she did not have evidence of recurrent cancer dur- ing the follow-up period. The remaining 31 patients were days. In the EORTC trial, initial fields (3- or 4-field tech- alive at the time of manuscript preparation, with a med- nique) were treated with 45 Gy (1.80 Gy per day) over 5 ian survival of 23 months. The estimated survival at 3 weeks. After a 6-week break, patients with a complete years was 87% for the entire group. response then received a further boost of 15 Gy, whereas those with a partial response received 20 Gy. Other trials Discussion have examined the optimal chemotherapy to be delivered IMRT for anal cancer is currently under investigation in with radiotherapy in the definitive treatment of anal can- a multi-institutional study. Using IMRT with SIB to treat cer. Continuous infusion of FU alone (1,000 mg/m per different targets with different daily doses often results in day over 96 hours, starting days 1 and 29 of radiotherapy) some areas receiving less than the conventional fractional was inferior to chemotherapy with MMC (10 mg/m on doses of radiation (ie, < 1.80 Gy). This technique has days 1 and 29) in a phase 3 trial performed by the RTOG and Eastern Cooperative Oncology Group (trial RTOG some treatment benefits. Multiple IMRT plans could be 87-04/ECOG 1289) (3). The first 45 Gy of radiotherapy used to allow no change in fractional dose during the were concomitant with the first 2 cycles of chemotherapy treatment period, but this requires additional planning and used parallel opposed fields and a daily fraction of and quality assurance and also extends the treatment 1.80 Gy. After 30.6 Gy was administered, the top field time. Increased treatment times may be associated with border was reduced from the interspace between L4 and poor disease control (7-13). Use of IMRT to deliver an L5 to the bottom of the sacroiliac joints. This field was SIB has the advantage of being able to deliver the radia- continued until a dose of 36 Gy was administerd. Finally, tion in a shorter time. However, this necessitates varying a boost field to the tumor alone was used until a total the fractional dose, and thus clinically negative areas may dose of 45 Gy was achieved. be treated with lower daily doses than what has typically If a tumor was still palpable immediately after the been administered in anal cancer clinical trials. Data on the biologic effects and clinical outcomes of such low initial 45 Gy, the patient had a boost treatment with doses are lacking. another 5.4 Gy. For patients with N1 disease, both ingu- Historically, anal cancers were treated with surgical inal regions were initially treated with a dose of 50.40 Gy therapy involving an abdominoperineal resection. Inter- at a prescription depth of 3 cm. After 4 to 6 weeks, est in improving outcomes for these patients led to the patients were assessed by a biopsy; if results were posi- discovery that these tumors responded to chemotherapy tive, they received further therapy. For patients with and radiotherapy. Such therapy, delivered in a neoadju- biopsy results showing residual primary disease, salvage vant fashion, decreased the failure rate compared with therapy consisted of 9 Gy in 5 fractions (delivered with that of surgery alone (14,15). This ultimately led to a electrons or photons) and the same regimen of FU plus primary approach of chemoradiotherapy, obviating the cisplatin (100 mg/m ) on day 2 of radiotherapy. Patients need for surgery for patients with a complete response with palpable inguinal disease after administration of 45 and negative biopsy findings (16). to 50.4 Gy received an additional 9 Gy. Call et al. Radiation Oncology 2011, 6:134 Page 4 of 5 http://www.ro-journal.com/content/6/1/134 Trial RTOG 98-11 (1) attempted to substitute cisplatin been reported (19), and the locoregional failure rate at for the MMC component of therapy. Patients were ran- 2 years was 20%. Long-term results are not yet available domized to 1 of 2 treatment arms: 1) concurrent FU, to assess the effectiveness of the approach in a multi- MMC, and radiotherapy; or 2) neoadjuvant cisplatin and institutional setting. The results presented here add to FU alone, followed by concurrent chemoradiotherapy the growing body of data supporting the use of IMRT with cisplatin and FU. The treatment arm with MMC with SIB for anal cancer. Regional control was excellent, despite the common use of low doses per fraction. and FU had a significantly reduced colostomy rate. The Limitations of our data include the retrospective nat- radiotherapy was also administered with shrinking fields; ure of this study. In addition, no standard method was after 30.6 Gy was administered, the superior border was moved down from L5 and S1 to the bottom of the sacroi- used to prescribe radiotherapy. In addition, the relatively liac joints, and a minimum of 14.4 Gy of additional radia- small size (34 patients) and short follow-up (22 months) tion was administered to the tumor (all at 1.80 Gy per in this report should be noted. It was common for day). Node-negative patients received 36 Gy to inguinal patients to receive a low fractional dose to at least a regions. Certain patients (stage T3 or T4, node positive, portion of the elective volume; however, specific dosages or N2 with residual disease) were treated with a boost of to certain volumes were individualized according to the 10 to 14 Gy at 2 Gy per fraction, for a total tumor dose judgment of each radiation oncologist. All patients in of 55 to 59 Gy. this study received concurrent chemotherapy. We do A second phase 3 trial, conducted in the United King- not know whether the same low rate of regional failure dom, examined outcomes after replacing MMC with cis- would have been observed if such radiosensitizing agents platin that was administered concurrently (no initial gap) were not used. with a radiotherapy dose of 50.4 Gy (17). This trial showed In conclusion, our results indicate that low fractional no significant improvement in complete response rate doses of radiation may be appropriate when using IMRT with concurrent cisplatin (95%) compared with MMC for squamous cell carcinoma of the anus along with con- (94%), and the need for a colostomy was similar between current chemotherapy. A daily dose between 1.50 and groups.Currently,radiotherapy delivered concurrently 1.80 Gy per day to clinically negative areas, prescribed with FU and MMC remains the standard of care for squa- according to the RTOG technique, may be appropriate in mous cell carcinoma of the anal canal. certain clinical situations. No treatment failures were The RTOG initiated a multi-institutional effort to pro- noted in the low-dose prescription volumes, despite the frequent use of fractional doses less than 1.80 Gy. spectively treat patients with IMRT-based chemora- diotherapy (RTOG 0529) (5). In this protocol, patients received IMRT with SIB to treat the elective areas and Additional material gross disease in the same number of fractions. IMRT was able to significantly reduce the grade 2+ dermatologic and Additional file 1: Tables 2 and 3 grade 3+ gastrointestinal/genitourinary events compared with the results of the RTOG 98-11 trial. Fractional doses varied by the clinical situation but were as low as 1.5 Gy Abbreviations per day to clinically negative areas. EORTC: European Organization for Research and Treatment of Cancer; FU: fluorouracil; IMRT: intensity-modulated radiotherapy; MMC: mitomycin C; Our data indicate that a low dose per fraction when RTOG: Radiation Therapy Oncology Group; SIB: simultaneous integrated treating with an SIB technique may be effective for clini- boost; UKCCCR: United Kingdom Coordinating Committee on Cancer cally negative areas. It was common to treat at least a Research portion of the elective areas with less than 1.80 Gy per Acknowledgements day. We observed only one regional failure that occurred Reprints: Robert C. Miller, MD, Department of Radiation Oncology, Mayo at the siteofa grosslypositivenodethatreceived a dose Clinic, 200 First St SW, Rochester, MN 55905 (http://miller.robert@mayo.edu). Portions of this work have been accepted for an oral presentation at the of 56.25 Gy (2.25 Gy per day). No patients in our series annual meeting of the American Radium Society (ARS), Palm Beach, Florida, had treatment failure within the elective, low-dose April 30 to May 4, 2011. volume. Kachnic et al (18) reported results from several Author details centers in Boston using an IMRT technique that com- Department of Radiation Oncology, Mayo Clinic, 200 First St SW, Rochester, monly treated elective nodal areas with doses as low as 2 MN 55905, USA. Division of Medical Oncology, Mayo Clinic, 200 First St SW, 1.5 Gy per fraction. With a median follow-up of 24 Rochester, MN 55905, USA. Division of Colon and Rectal Surgery, Mayo Clinic, 200 First St SW, Rochester, MN 55905, USA. months, these authors noted a 2-year local control rate of 95%, and only 2 of 43 patients had a pelvic recurrence. In Authors’ contributions addition, trial RTOG-0529 used a similar technique for JAC: Reviewed charts, gathered data, and drafted the manuscript. MGH: Aided in the design of the study, helped draft the manuscript. DWL: Aided treating patients by using IMRT to deliver a low daily in the design of the study, helped draft the manuscript. JFQ: Aided in the dose to elective areas. Preliminary 2-year results have Call et al. Radiation Oncology 2011, 6:134 Page 5 of 5 http://www.ro-journal.com/content/6/1/134 design of the study, helped draft the manuscript. RCM: Participated in study carcinoma of the anus (ACT II) [abstract]. J Clin Oncol 2009, 27(18S): design and coordination and helped draft the manuscript. All authors read LBA4009.. and approved the final version of this manuscript. 18. Kachnic LA, Tsai HK, Coen JJ, Blaszkowsky LS, Hartshorn K, Kwak EL, et al: Dose-painted intensity-modulated radiation therapy for anal cancer: a Conflicts of interests multi-institutional report of acute toxicity and response to therapy. Int J The authors declare that they have no competing interests. Radiat Oncol Biol Phys 2010. 19. Kachnic L, Winter K, Myerson R, Goodyear M, Willins J, Esthappan J, et al: Received: 26 April 2011 Accepted: 6 October 2011 Early efficacy results of RTOG 0529: a phase II evaluation of dose- Published: 6 October 2011 painted IMRT in combination with 5-fluorouracil and mitomycin-C for the reduction of acute morbidity in carcinoma of the anal canal [abstract]. Int J Radiat Oncol Biol Phys 2010, 78(3 Suppl 1):S55. References 1. 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Flam M, John M, Pajak TF, Petrelli N, Myerson R, Doggett S, 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 1996, 14(9):2527-39. 4. 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 1996, 348(9034):1049-54. 5. Kachnic L, Winter K, Myerson R, Goodyear M, Willins J, Esthappan J, et al: 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 [abstract]. Int J Radiat Oncol Biol Phys 2009, 75(3 Suppl 1):S5. 6. 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Nigro ND, Seydel HG, Considine B, Vaitkevicius VK, Leichman L, Kinzie JJ: • Thorough peer review Combined preoperative radiation and chemotherapy for squamous cell carcinoma of the anal canal. Cancer 1983, 51(10):1826-9. • No space constraints or color figure charges 16. Leichman L, Nigro N, Vaitkevicius VK, Considine B, Buroker T, Bradley G, • Immediate publication on acceptance et al: Cancer of the anal canal: model for preoperative adjuvant • Inclusion in PubMed, CAS, Scopus and Google Scholar combined modality therapy. Am J Med 1985, 78(2):211-5. 17. James R, Wan S, Glynne-Jones R, Sebag-Montefiore D, Kadalayil L, • Research which is freely available for redistribution Northover J, et al: A randomized trial of chemoradiation using mitomycin or cisplatin, with or without maintenance cisplatin/5FU in squamous cell Submit your manuscript at www.biomedcentral.com/submit

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Radiation OncologySpringer Journals

Published: Oct 6, 2011

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