Intensity-modulated radiation therapy (IMRT) in the treatment of anal cancer: Toxicity and clinical outcome
2005; Elsevier BV; Volume: 63; Issue: 2 Linguagem: Inglês
10.1016/j.ijrobp.2005.02.030
ISSN1879-355X
AutoresMichael T. Milano, Ashesh B. Jani, Karl Farrey, Carla Rash, Ruth Heimann, Steven J. Chmura,
Tópico(s)Gastric Cancer Management and Outcomes
ResumoPurpose: To assess survival, local control, and toxicity of intensity modulated radiation therapy (IMRT) in squamous cell carcinoma of the anal canal.Methods and Materials: Seventeen patients were treated with nine-field IMRT plans. Thirteen received concurrent 5-fluorouracil and mitomycin C, whereas 1 patient received 5-fluorouracil alone. Seven patients were planned with three-dimensional anteroposterior/posterior-anterior (AP/PA) fields for dosimetric comparison to IMRT.Results: Compared with AP/PA, IMRT reduced the mean and threshold doses to small bowel, bladder, and genitalia. Treatment was well tolerated, with no Grade ≥3 acute nonhematologic toxicity. There were no treatment breaks attributable to gastrointestinal or skin toxicity. Of patients who received mitomycin C, 38% experienced Grade 4 hematologic toxicity. IMRT did not afford bone marrow sparing, possibly resulting from the clinical decision to prescribe 45 Gy to the whole pelvis in most patients, vs. the Radiation Therapy Oncology Group–recommended 30.6 Gy whole pelvic dose. Three of 17 patients, who did not achieve a complete response, proceeded to an abdominoperineal resection and colostomy. At a median follow-up of 20.3 months, there were no other local failures. Two-year overall survival, disease-free survival, and colostomy-free survival are: 91%, 65%, and 82% respectively.Conclusions: In this hypothesis-generating analysis, the acute toxicity and clinical outcome with IMRT in the treatment of anal cancer is encouraging. Compared with historical controls, local control is not compromised despite efforts to increase conformality and reduce normal structure dose. Purpose: To assess survival, local control, and toxicity of intensity modulated radiation therapy (IMRT) in squamous cell carcinoma of the anal canal. Methods and Materials: Seventeen patients were treated with nine-field IMRT plans. Thirteen received concurrent 5-fluorouracil and mitomycin C, whereas 1 patient received 5-fluorouracil alone. Seven patients were planned with three-dimensional anteroposterior/posterior-anterior (AP/PA) fields for dosimetric comparison to IMRT. Results: Compared with AP/PA, IMRT reduced the mean and threshold doses to small bowel, bladder, and genitalia. Treatment was well tolerated, with no Grade ≥3 acute nonhematologic toxicity. There were no treatment breaks attributable to gastrointestinal or skin toxicity. Of patients who received mitomycin C, 38% experienced Grade 4 hematologic toxicity. IMRT did not afford bone marrow sparing, possibly resulting from the clinical decision to prescribe 45 Gy to the whole pelvis in most patients, vs. the Radiation Therapy Oncology Group–recommended 30.6 Gy whole pelvic dose. Three of 17 patients, who did not achieve a complete response, proceeded to an abdominoperineal resection and colostomy. At a median follow-up of 20.3 months, there were no other local failures. Two-year overall survival, disease-free survival, and colostomy-free survival are: 91%, 65%, and 82% respectively. Conclusions: In this hypothesis-generating analysis, the acute toxicity and clinical outcome with IMRT in the treatment of anal cancer is encouraging. Compared with historical controls, local control is not compromised despite efforts to increase conformality and reduce normal structure dose. IntroductionThe standard of care for carcinoma of the anal canal has been evolving over the past 30 years from abdominoperineal resection, resulting in subsequent lifelong colostomy, to organ preservation therapy employing combined chemotherapy and radiation. Although chemoradiotherapy results in >70% colostomy-free survival rates, acute and late morbidity remain substantial. Acute toxicities, including proctitis, dysuria, dermatitis (especially in perineal structures), coupled to reported long-term sequelae of perineal skin atrophy, fibrosis, dyspareunia, and impotence, has prompted investigations into alternatives to both the chemotherapeutic regimen and radiation delivery techniques.Intensity-modulated radiation therapy (IMRT) is an emerging technology that allows delivery of radiation dose in a more conformal manner than conventional two- or three-dimensional radiation therapy by varying the radiation beams spatially or temporally (1Intensity Modulated Radiation Therapy Collaborative Working GroupIntensity-modulated radiotherapy Current status and issues of interest.Int J Radiat Oncol Biol Phys. 2001; 51: 880-914Abstract Full Text Full Text PDF PubMed Scopus (701) Google Scholar). The physician contours targets to treat and regions to avoid on axial computed tomography (CT) slices. In contrast to conventional radiotherapy, IMRT uses inverse planning, with the field modulation optimized by planning software. To our knowledge, there are no other published series on the use of IMRT in anal cancer. At the University of Chicago, IMRT was implemented in 1998, and results have been published in gynecologic (2Mundt A.J. Roeske J.C. Lujan A.E. et al.Initial clinical experience with intensity-modulated whole-pelvis radiation therapy in women with gynecologic malignancies.Gynecol Oncol. 2001; 82: 456-463Abstract Full Text PDF PubMed Scopus (127) Google Scholar, 3Brixey C.J. Roeske J.C. Lujan A.E. et al.Impact of intensity-modulated radiotherapy on acute hematologic toxicity in women with gynecologic malignancies.Int J Radiat Oncol Biol Phys. 2002; 54: 1388-1396Abstract Full Text Full Text PDF PubMed Scopus (199) Google Scholar, 4Mundt A.J. Lujan A.E. Rotmensch J. et al.Intensity-modulated whole pelvic radiotherapy in women with gynecologic malignancies.Int J Radiat Oncol Biol Phys. 2002; 52: 1330-1337Abstract Full Text Full Text PDF PubMed Scopus (374) Google Scholar, 5Lujan A.E. Mundt A.J. Yamada S.D. et al.Intensity-modulated radiotherapy as a means of reducing dose to bone marrow in gynecologic patients receiving whole pelvic radiotherapy.Int J Radiat Oncol Biol Phys. 2003; 57: 516-521Abstract Full Text Full Text PDF PubMed Scopus (149) Google Scholar, 6Mundt A.J. Mell L.K. Roeske J.C. Preliminary analysis of chronic gastrointestinal toxicity in gynecology patients treated with intensity-modulated whole pelvic radiation therapy.Int J Radiat Oncol Biol Phys. 2003; 56: 1354-1360Abstract Full Text Full Text PDF PubMed Scopus (281) Google Scholar), prostate (7Jani A.B. Organ motion and IMRT in prostate cancer therapy.Cancer J. 2003; 9: 244-246Crossref PubMed Scopus (9) Google Scholar, 8Jani A.B. Roeske J.C. Rash C. Intensity-modulated radiation therapy for prostate cancer.Clin Prostate Cancer. 2003; 2: 98-105Abstract Full Text PDF PubMed Scopus (34) Google Scholar, 9Kao J. Turian J. Meyers A. et al.Sparing of the penile bulb and proximal penile structures with intensity-modulated radiation therapy for prostate cancer.Br J Radiol. 2004; 77: 129-136Crossref PubMed Scopus (31) Google Scholar), advanced head-and-neck (10Milano M.T. Vokes E.E. Witt M.E. et al.Retrospective comparison of intensity modulated radiation therapy (IMRT) and conventional three-dimensional RT (3DCRT) in advanced head and neck patients treated with definitive chemoradiation [Abstract].Proc Am Soc Clin Oncol. 2003; 22: 499Google Scholar), and pancreatic and bile duct (11Milano M.T. Chmura S.J. Garofalo M.C. et al.Intensity-modulated radiotherapy in treatment of pancreatic and bile duct malignancies toxicity and clinical outcome.Int J Radiat Oncol Biol Phys. 2004; 59: 445-453Abstract Full Text Full Text PDF PubMed Scopus (142) Google Scholar) malignancies.Anal cancer is well suited for IMRT because avoidance structures such as small bowel, bladder, genitalia, and bone marrow can potentially be spared. Normal tissue tolerance doses form the basis for IMRT dose–volume constraints, though concurrent chemotherapy likely lowers the threshold doses. The present article details our single institution experience of 17 patients with squamous cell cancer of the anal canal treated with IMRT. We hypothesized that IMRT would minimize acute and late toxicity by virtue of sparing nontarget structures, without compromising locoregional control. Our primary goal was to minimize desquamation and gastrointestinal toxicity to reduce treatment breaks. Acute toxicity, disease control, and patient survival are discussed.Methods and materialsSimulation and target contouringPatients underwent CT-based simulation (PQ5000 CT Simulator, Marconi Medical Systems, Cleveland, OH) with 4-mm thick CT slice cuts. Patients were simulated in the supine position. Intravenous contrast was used in all patients. A custom immobilization device (Alpha Cradle, Smithers Medical Product, Inc., North Canton, OH) was used to minimize setup variability. Structures were manually contoured onto the CT scan slices following the International Commission on Radiation Units and Measurements' Report 50 recommendations (12International Commission on Radiation Units and MeasurementsReport no. 50. Prescribing, recording and reporting photon beam therapy. ICRU, Washington, DC1993Google Scholar). The gross tumor volume (GTV) and clinical target volume (CTV) were contoured on axial CT scan slices. The CTV included clinical and suspected subclinical involvement. In all patients, the CTV encompassed the draining lymphatics, which generally included the perirectal, internal iliac, external iliac, and inguinal lymphatics. For the boost dose, the CTV was defined as the GTV. The radiation dose was prescribed to a planning target volume (PTV), which was generated by expanding the CTV by 1 cm, based on previous studies examining pelvic movement at our institution. The PTV design incorporated setup uncertainty and organ motion (13Chen G.T. Jiang S.B. Kung J. et al.Abdominal organ motion and deformation Implications for IMRT.Int J Radiat Oncol Biol Phys. 2001; 51 ([Abstract]): 210Abstract Full Text Full Text PDF Google Scholar).Normal structures were also entered onto the planning CT scan, including: bowel, bladder, perineum and genitalia (vulva in women, penis and scrotum in men), and bone marrow. Corrections were not made for bowel or bladder motion (i.e., contouring these normal structures from serial CT scans or generating a PTV expansion of these structures). This could result in overestimating or underestimating dose exposure were these structures to move out of or into (respectively) higher dose regions, particularly with IMRT planning where there is a larger dose gradient.IMRT planningIntensity-modulated radiation therapy plans were generated using commercial inverse planning software (CORVUS, versions 3.0–5.0, NOMOS Corp., Sewickley, PA), which produces optimal intensity-modulated profiles using a simulated annealing algorithm. Dynamic multileaf collimators were used to shape the fields. Nine-field coplanar plans were used, with fields evenly separated around a 360° arc. The dose–volume constraints of the target and normal tissues were defined for each patient.The PTV and normal structure dose–volume constraints were iteratively adjusted to ensure optimal target coverage while minimizing dose to normal structures and thus optimizing the normal tissue dose–volume histograms (DVH) (14Lawrence T.S. Kessler M.L. Ten Haken R.K. Clinical interpretation of dose-volume histograms The basis for normal tissue preservation and tumor dose escalation.Front Radiat Ther Oncol. 1996; 29: 57-66PubMed Google Scholar). A posterior blocking structure was entered just posterior to the PTV, with the purpose of improving dose conformality to the PTV. This posterior blocking structure encompassed the iliac crests, including the iliac crest bone marrow. The small bowel and external genitalia acted as anterior blocking structures.Typical input parameters for IMRT planning of the initial PTV were as follows: 10–20% of bowel to receive >20–30 Gy with a dose maximum of 50 Gy, 10–20% of bladder to receive >30 Gy with a dose maximum of 45 Gy, 20–40% of the posterior blocking structure to receive >18–25 Gy with a dose maximum of 50 Gy, and 50–60% of genitalia and perineum to receive >40 Gy with a dose maximum of 50 Gy. The IMRT plans were optimized to minimize the volume of PTV receiving 115% of the prescribed dose. Generally, the prescription dose was normalized to the 85% isodose line. The initial pelvic-inguinal plans were considered acceptable with <2–7% of the PTV receiving <100% of the prescribed dose, 110%, and 115%.Comparison of three-dimensional AP/PA plans to IMRT plansIn the first 7 patients treated with IMRT, a pelvic plan using anteroposterior/posterior-anterior (AP/PA) fields was generated for comparison to the IMRT pelvic plan. The boost fields were not included in this comparison. For IMRT plans, the initial pelvic field was planned to receive 45 Gy (i.e., no field reduction). The initial PTV for the AP/PA plan was equivalent to that used in the IMRT plan. Two different AP/PA plans were run for comparison to IMRT: (1) the initial pelvic/inguinal field planned to receive 45 Gy and (2) the initial pelvic/inguinal field planned to receive 30.6 Gy, followed by a reduced (small) pelvic field for an additional 14.4 Gy. The small pelvic field was the same as the initial pelvic field except for a reduction in the upper field edge to the sacroiliac joints, as described by others (15John M. Pajak T. Flam M. et al.Dose escalation in chemoradiation for anal cancer Preliminary results of RTOG 92-08.Cancer J Sci Am. 1996; 2: 205PubMed Google Scholar, 16Constantinou E.C. Daly W. Fung C.Y. et al.Time-dose considerations in the treatment of anal cancer.Int J Radiat Oncol Biol Phys. 1997; 39: 651-657Abstract Full Text PDF PubMed Scopus (104) Google Scholar, 17Martenson J.A. Lipsitz S.R. Wagner Jr, H. et al.Initial results of a phase II trial of high dose radiation therapy, 5-fluorouracil, and cisplatin for patients with anal cancer (E4292) An Eastern Cooperative Oncology Group study.Int J Radiat Oncol Biol Phys. 1996; 35: 745-749Abstract Full Text PDF PubMed Scopus (121) Google Scholar, 18Flam M. John M. Pajak T.F. 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: 2527-2539Crossref PubMed Scopus (867) Google Scholar). The small pelvic field was not reduced laterally off of the inguinals.Conventional three-dimensional AP/PA plans were generated using PlanUNC (19Sailer S.L. Chaney E.L. Rosenman J.G. et al.Three dimensional treatment planning at the University of North Carolina at Chapel Hill.Semin Radiat Oncol. 1992; 2: 267-273Abstract Full Text PDF PubMed Scopus (41) Google Scholar). The dose was prescribed to the PTV, such that >90–98% of the PTV received ≥100% of the prescribed dose, and 105% of the prescribed dose. Custom blocks were used (1-cm margin around the PTV in each beam's-eye view). Segmented fields, variable weighting of fields, and wedges were used to optimize the plan as needed to improve dose homogeneity. All fields were coplanar. Six and 18 MV photons were used with the AP and PA fields, respectively. For the comparison IMRT plans, CORVUS version 4.0, with 6 MV photons were used.Dose volume histograms were obtained for the PTV, small bowel, urinary bladder, genitalia/perineum, and iliac bone marrow. Though encompassed by the posterior blocking structure, the iliac bone marrow was entered as a separate structure for the purpose of obtaining a DVH. Generally the contoured CTV lies immediately adjacent to contoured normal structures, resulting in an overlap of the expanded PTV with portions of these normal structures. Unfortunately, the normal tissue DVHs generated by CORVUS ignore these overlap regions. To circumvent this, the dose matrices from the CORVUS IMRT plans were imported into PlanUNC (19Sailer S.L. Chaney E.L. Rosenman J.G. et al.Three dimensional treatment planning at the University of North Carolina at Chapel Hill.Semin Radiat Oncol. 1992; 2: 267-273Abstract Full Text PDF PubMed Scopus (41) Google Scholar) to generate accurate normal tissue DVHs. This was only done with the 7 patients undergoing dosimetric comparison of IMRT and AP/PA.Patient treatmentAll patients underwent initial biopsy of their anal mass as well as diagnostic CT scanning of the abdomen and pelvis. Seventeen patients with Stage II-III squamous cell cancer of the anal canal were treated with IMRT. Fourteen of 17 received concurrent chemotherapy, whereas 3 with comorbid illnesses not amenable to chemotherapy were treated with radiation alone. Concurrent chemotherapy consisted of 5-fluorouracil (1000 mg/m2/day continuous infusion 96 h starting Day 1 and Day 29) and mitomycin C (10 mg/m2 bolus intravenously first day of both 5-fluorouracil infusions). Of the 14 patients planned to receive chemotherapy, 1 (age 87) was not prescribed mitomycin C. Complete blood counts with differential were obtained weekly.The prescribed radiation dose in those 14 planned to receive chemotherapy ranged from 45.0 to 59.4 Gy (1.8 Gy fraction) with a mean of 52.3 Gy and median of 54.0 Gy. Three of these patients were treated with three different CTVs: an initial pelvic-inguinal field (encompassing pelvic and inguinal lymphatics and gross tumor), followed by a reduced pelvic field (similar to field borders used in Radiation Therapy Oncology Group [RTOG] studies), and then a boost to the GTV. The remainder received an initial pelvic-inguinal field (30.6 Gy in 1 patient) followed by a boost to the GTV. The prescribed dose to the initial pelvic-inguinal field ranged from 30.0 to 50.4 Gy with a mean of 41.3 Gy and a median of 45.0 Gy. Most patients were prescribed 45.0 Gy to the initial pelvic-inguinal field followed by a 9.0 Gy boost to the GTV.Of the 3 patients treated with radiotherapy alone, 2 were prescribed larger fraction sizes (2.25 Gy to a total of 54.0 Gy and 2.5 Gy to a total of 50 Gy), whereas the other was treated to 54.0 Gy in 1.8 Gy fractions.The superior border of the pelvic CTV was generally 2 cm below the L5–S1, resulting in the PTV being approximately 1 cm below L5–S1. This is consistent with the RTOG recommendation of the field edge (50% isodose line) of standard AP/PA fields being at L5–S1.Outcome measuresToxicity was graded using RTOG morbidity scoring criteria (20Trotti A. Byhardt R. Stetz J. et al.Common toxicity criteria: Version 2.0: An improved reference for grading the acute effects of cancer treatment: Impact on radiotherapy.Int J Radiat Oncol Biol Phys. 2000; 47: 13-47Abstract Full Text Full Text PDF PubMed Scopus (707) Google Scholar). Patients were retrospectively analyzed for control and survival outcome. No patient was lost to follow-up. Survival and disease control parameters were calculated using Kaplan-Meier actuarial analysis. Overall survival was defined as time from pathologic diagnosis until death or last date of contact. Progression-free survival (PFS), colostomy-free survival (CFS), local control, and distant control were defined as the time from pathologic diagnosis until an event, death, or last date of contact. PFS events included persistent disease after treatment, local failure or distant failure. CFS events were colostomy placement.ResultsCharacteristics of patients treatedSince October 2000, 17 patients with squamous cell or basaloid/cloacogenic cancer of the anal canal were treated curatively with IMRT. No patients had giant anal condylomata. No patient had known HIV or AIDS. One patient (age 45) had a history of renal transplant–associated immunodeficiency. The patients' ages ranged from 41 to 87 years, with a mean of 63 years and median of 66 years. All patients had an Eastern Cooperative Oncology Group performance status of 0–1. No patients had resection before treatment. The characteristics of the patients are outlined in Table 1. Follow-up from pathologic diagnosis ranges from 5 to 43 months, with a mean 20.7 of months and a median of 20.3 months.Table 1Patient characteristicsNumber17Female12Male5T stage T29 T36 T42N stage N011 N11 N23 N32Stage II11 IIIa1 IIIb5 Open table in a new tab Comparison of IMRT and four-field plansSeven patients were planned with both AP/PA and IMRT plans to compare the plans. Figure 1 depicts a typical IMRT dose distribution on an axial slice through the isocenter. Figure 2 depicts a typical IMRT dose distribution on an axial slice depicting the PTV's inguinal lymphatic region and the genitalia avoidance structure. For IMRT plans, the volume of PTV receiving 110% was 8.2 ± 5.3%, and the volume receiving >115% was 0.29 ± 0.25%.Fig. 2Representative planning target volume (PTV), avoidance structures, and isodose curves for intensity-modulated radiation therapy planning in a male patient. This axial computed tomography (CT) slice shows the PTV encompassing the bilateral inguinal lymphatics, which are noncontiguous with the anorectal PTV volume on this particular slice. This axial CT slice also shows sparing of the genitalia.View Large Image Figure ViewerDownload (PPT)In the 7 patients comparatively planned with AP/PA and IMRT, the mean doses to the small bowel, bladder, genitalia/perineum, and iliac bone marrow are shown in Table 2, and the volumes of these structures receiving doses above threshold doses are shown in Table 3. Comparisons are made between each of the three planning techniques: AP/PA, AP/PA with a field reduction after 30.6 Gy, and IMRT. IMRT significantly reduced the mean doses to the bladder and genitalia/perineum and bladder. IMRT also significantly reduced the mean dose to the bowel as compared with AP/PA without a field reduction; the difference of IMRT compared with AP/PA with a field reduction was borderline significant (p = 0.07).Table 2Mean dose (Gy) to critical structuresp values⁎Two-tailed paired t-test.OrganAP/PA†No field reduction.AP/PA‡Field reduction to sacroiliac joint after 30.6 Gy as described in the text.IMRTAP/PA†No field reduction. vs. AP/PA‡Field reduction to sacroiliac joint after 30.6 Gy as described in the text.AP/PA†No field reduction. vs. IMRTAP/PA†No field reduction. vs. IMRTSmall bowel43.6 ± 3.335.6 ± 3.932.1 ± 0.5<0.00010.0001NSBladder46.2 ± 0.546.0 ± 0.338.9 ± 3.1NS0.0010.001Genitalia/perineum43.9 ± 1.843.9 ± 1.729.1 ± 5.9NS0.00050.0005Iliac marrow24.3 ± 5.720.0 ± 4.924.2 ± 3.8 0.05).Mean ± standard deviation. Two-tailed paired t-test.† No field reduction.‡ Field reduction to sacroiliac joint after 30.6 Gy as described in the text. Open table in a new tab Table 3Volume of critical structures receiving greater than the threshold dose for 45 Gy treatmentOrganThreshold dose (Gy)Volume above threshold (%)p values⁎Two-tailed paired t-test.AP/PA†No field reduction.AP/PA§IMRTAP/PA†No field reduction. vs. AP/PA‡Field reduction to sacroiliac joint after 30.6 Gy as described in the text.AP/PA†No field reduction. vs. IMRTAP/PA‡Field reduction to sacroiliac joint after 30.6 Gy as described in the text. vs. IMRTSmall bowel3091.4 ± 7.987.4 ± 10.154.1 ± 7.2NS<0.000020.00014087.7 ± 11.140.4 ± 25.024.3 ± 9.70.0030.0001NSBladder30100 ± 0100 ± 092.1 ± 12.3NSNSNS40100 ± 099.3 ± 1.544.3 ± 17.8NS0.00020.0002Genitalia/perineum3095.4 ± 4.395.6 ± 4.052.4 ± 31.5NS0.0080.0094085.7 ± 9.885.7 ± 9.55.0 ± 5.2NS<0.00001 40 Gy as compared with AP/PA without a field reduction. IMRT further reduced the volume of small bowel receiving >30 Gy and >40 Gy as compared with AP/PA with a field reduction, though this was not significant (p = 0.22) for the >40 Gy threshold dose. IMRT significantly reduced the volume of bladder receiving >40 Gy (with comparison of IMRT to either AP/PA plan), and significantly reduced the volume of genitalia/perineum receiving >30 Gy and >40 Gy. Genitalia sparing was quite impressive with 5% receiving >40 Gy with IMRT vs. >85% with either AP/PA plan.With IMRT plans (in which the pelvis was prescribed a full 45 Gy), the bone marrow received significantly more mean dose as well as dose above 10 Gy and 20 Gy compared with AP/PA with a field reduction. With IMRT, the bone marrow receiving >30 Gy and >40 Gy was similar in value to that of the AP/PA plans (data not shown).ToxicityThirteen of 17 patients received their planned course of treatment without breaks in radiation or chemotherapy. Two patients received slightly less radiation dose than prescribed. One patient did not receive the last fraction of radiotherapy (after 52.2 Gy) after being admitted to an outside hospital for diminished blood counts and dehydration. Another was poorly compliant from the first week of treatment and refused further radiation after 45.0 Gy of a planned 50.4 Gy. This patient also had numerous short treatment breaks (completing 45.0 Gy in 45 days). Another patient had a 2-week break after being hospitalized for neutropenia and a pulmonary embolus. This patient and 1 other (2 total) did not receive the last cycle of mitomycin C because of low blood cell counts. No other patients had chemotherapy withheld or planned or unplanned treatment breaks. No treatment breaks were attributable to gastrointestinal or skin toxicity.No patients experienced acute Grade ≥3 nonhematologic toxicity. All patients experienced acute Grade 2 dermatitis, namely moist desquamation in the perianal and intergluteal areas. Moist desquamation involving the genitalia generally did not occur. Acute gastrointestinal and bladder toxicity are summarized in Table 4. All 9 patients who experienced acute Grade 2 gastrointestinal toxicity developed diarrhea requiring antimotility agents, though this was easily controlled and readily subsided within 1 month after treatment. No patient has developed Grade ≥3 late toxicity, though follow-up in this series is limited.Table 4Acute gastrointestinal and bladder toxicityGrade012>2Gastrointestinal26⁎1 received 5-fluoruracil but no mitomcycin C, whereas 2 received neither mitomycin C nor 5-fluoruracil.9†1 received neither mitomycin C nor 5-fluoruracil.0Bladder11‡1 received 5-fluoruracil but no mitomycin C, and 1 received neither mitomycin C nor 5-fluoruracil.6§2 received neither mitomycin C nor 5-fluoruracil.00 1 received 5-fluoruracil but no mitomcycin C, whereas 2 received neither mitomycin C nor 5-fluoruracil.† 1 received neither mitomycin C nor 5-fluoruracil.‡ 1 received 5-fluoruracil but no mitomycin C, and 1 received neither mitomycin C nor 5-fluoruracil.§ 2 received neither mitomycin C nor 5-fluoruracil. Open table in a new tab Hematologic toxicity for the 13 patients who received 5-fluorouracil and mitomycin C is summarized in Table 5. Two patients required packed red blood cell transfusions (Grade 3); none required platelet transfusions. Albeit in a small number of patients, there was no discernible correlation (using regression analyses) between grade of hematologic toxicity and the total pelvic dose delivered (among the 13 patients who received 5-fluorouracil and mitomycin C), analyzed either as a continuous variable or as a discrete variable (i.e., dose >30.6 Gy [n = 9] vs. 30.6 Gy [n = 4]).Table 5Acute hematologic toxicityGrade01234Hematologic⁎Worst grade of hematologic toxicity.02245RBC35320WBC02353ANC40234Platelets71221Abbreviations: RBC = red blood cells; WBC, white bloodcells; ANC, absolute neutrophil count.Toxicity among the 13 who received concurrent mitomycin C and 5-fluorouracil. RBC toxicity includes hematocrit and/or hemoglobin toxicity. Worst grade of hematologic toxicity. Open table in a new tab Clinical outcomeFollow-up data are available for all patients included in this study. Fourteen of 17 achieved a complete clinical response based on physical examination, whereas 3 achieved only a partial response and proceeded to colostomy. Of the 14 with a complete clinical response, 9 had a pathologic complete response confirmed on biopsy within 6–8 weeks after chemoradiation, whereas 5 were assessed based on physical examination alone and a biopsy was deemed unnecessary.The 3 patients with a partial response included 1 with T3N3 disease (with the primary tumor measuring 8 cm in size) treated to 59.4 Gy, 1 with T2N3 disease treated to 59.4 Gy and 1 with a T2N0 tumor treated to 54.0 Gy. These 3 patients underwent an abdominal-perineal resection and permanent colostomy shortly after chemoradiation. One patient with an abdominoperineal resection remains disease free at >2 years, 1 is alive and free of disease at >7 months, and the other remains alive at 2.5 years with metastatic disease to the liver (which developed 11 months after diagnosis) and regional nodal disease (developing at 21 months). No other patient has had a local failure or has required a colostomy to date.There have been two distant failures (liver metastases at 7 months and bone metastases at 15 months) among the 14 patients who achieved a CR. One died at 13 months, whereas the other is alive at >2 years. One patient died from lymphoma a
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