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Keywords:

  • anal canal;
  • IMRT;
  • conventional radiation;
  • squamous cell carcinoma;
  • outcomes;
  • toxicity

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONCLUSION
  7. CONFLICT OF INTEREST DISCLOSURES
  8. REFERENCES

BACKGROUND:

The purpose of this study was to compare outcomes in patients with anal canal squamous cell carcinoma (SCCA) who were treated with definitive chemoradiotherapy by either intensity-modulated radiation therapy (IMRT) or conventional radiotherapy (CRT).

METHODS:

Forty-six patients who received definitive chemoradiotherapy from January 1993 to August 2009 were included. Forty-five patients received 5-fluorouracil with mitomycin C (n = 39) or cisplatin (n = 6). Seventeen (37%) were treated with CRT and 29 (63%) with IMRT. The median dose was 54 Gy in both groups. Median follow-up was 26 months (CRT) and 32 months (IMRT). T3-T4 stage (P = .18) and lymph node-positive disease (P = .6) were similar between groups.

RESULTS:

The CRT group required longer treatment duration (57 days vs 40 days, P < .0001), more treatment breaks (88% vs 34.5%, P = .001), and longer breaks (12 days vs 1.5 days, P < .0001) than patients treated with IMRT. Eleven (65%) patients in the CRT group experienced grade >2 nonhematologic toxicity compared with 6 (21%) patients in the IMRT group (P = .003). The 3-year overall survival (OS), locoregional control (LRC), and progression-free survival were 87.8%, 91.9%, and 84.2%, respectively, for the IMRT groups and 51.8%, 56.7%, and 56.7%, respectively, for the CRT group (all P < .01). On multivariate analysis, T stage, use of IMRT, and treatment duration were associated with OS, and T stage and use of IMRT were associated with LRC.

CONCLUSIONS:

The use of IMRT was associated with less toxicity, reduced need for treatment breaks, and excellent LRC and OS compared with CRT in patients with SCCA of the anal canal. Cancer 2011. © 2011 American Cancer Society.

Although rare, squamous cell carcinoma (SCCA) of the anal canal provides a paradigm for organ preservation in the management of cancer. The treatment has evolved from the abdominoperineal resection (APR) to sphincter-preserving nonsurgical therapy with concurrent radiation therapy and chemotherapy.1, 2 In addition to the primary tumor, the pelvic and perirectal lymph nodes also require treatment, leading to irradiation of bowel, bladder, and bone marrow, as well as the external skin and genitalia. As a result, the risk of acute toxicity is high, often leading to interruptions in radiation and extending the overall treatment time.3

Intensity-modulated radiation therapy (IMRT), using inverse-planning that varies beam intensities, allows radiation-dose delivery while sparing adjacent normal tissues. IMRT has been extensively studied in other cancers. However, to date, there are only a few reports on IMRT in the treatment of anal cancer.4-7 Here, we compare the toxicity and clinical outcome of patients with SCCA of the anal canal treated with IMRT versus conventional radiotherapy (CRT).

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONCLUSION
  7. CONFLICT OF INTEREST DISCLOSURES
  8. REFERENCES

Patients

We conducted a retrospective review of patients with SCCA of the anal canal who were treated with primary chemoradiotherapy at Stanford Hospital and Clinics between January 1993 and August 2009. The study was approved by the Stanford Institutional Review Board. Of 72 patients identified, 26 were excluded for having treatment outside Stanford (n = 14), having metastatic disease (n = 10), or presenting with recurrent disease (n = 2). Of the remaining 46 patients who formed the cohort of this study, 17 (37%) received CRT (May 1993-April 2002), whereas 29 (63%) received IMRT (June 2003-August 2009). In 2002, there was an institutional shift in treatment paradigm, and IMRT became the standard treatment technique.

Baseline characteristics of the 46 patients are shown in Table 1. Overall, the patients in the CRT group tended to have more advanced local disease (American Joint Commission on Cancer [AJCC] staging system stage T3 or T4) compared with patients in the IMRT group, although this was not statistically significant (47% vs 28%, P = .18). The incidence of lymph node-positive disease and the overall AJCC stage did not differ significantly between the 2 groups (Table 1). Five patients were human immunodeficiency virus (HIV)-positive (1 in the CRT group and 4 in the IMRT group).

Table 1. Patient Characteristics (N = 46)
CharacteristicCRT, n=17IMRT, n=29P
No. (%)No. (%)
  • CRT indicates conventional radiotherapy; IMRT, intensity-modulated radiation therapy; NS, nonsignificant; NA, not applicable; HIV, human immunodeficiency virus.

  • a

    P represents T1 or T2 compared with T3 or T4.

  • b

    P represents node-negative compared with node-positive.

  • c

    P represents Stage I or II compared with Stage IIIA or Stage IIIB.

Females/Males8/916/13NS
Median age, y6159NS
T-stage  .18a
 T14 (24)3 (10) 
 T25 (29)18 (62) 
 T34 (24)7 (24) 
 T44 (24)1 (3) 
N-stage  .6b
 N012 (71)22 (76) 
 N13 (18)4 (14) 
 N22 (12)2 (7) 
 N301 (3) 
Stage  .40c
 I4 (24)2 (7) 
 II5 (29)17 (59) 
 IIIA6 (35)7 (24) 
 IIIB2 (12)3 (10) 
HIV positive1 (6)4 (14)NS
Radiation therapy dose  NA
 Upper pelvic nodes
  0 Gy1 (6)0 (0) 
  30.6-39.6 Gy13 (76)11 (38) 
  40 Gy1 (6)6 (21) 
  45 Gy2 (12)12 (41) 
 Lower pelvic nodes
  0 Gy1 (6)0 (0) 
  30.6-39.6 Gy6 (35)0 (0) 
  40 Gy0 (0)1 (3) 
  45 Gy10 (59)28 (97) 
 Inguinal nodes
  0 Gy1 (6)0 (0) 
  30.6-39.6 Gy6 (35)4 (14) 
  40 Gy3 (18)3 (10) 
  45 Gy7 (41)22 (76) 
 Primary tumor
   <50 Gy3 (18)1 (3) 
  50-55 Gy9 (53)20 (69) 
  >55 Gy5 (29)8 (28) 

Conventional Radiotherapy

The median dose to the primary tumor and involved nodes was 54 Gy (range, 45-62.4 Gy). Two of 17 patients were treated in the prone position. Most commonly, anterior-posterior/posterior-anterior (AP/PA) ports were used for the pelvis and inguinal nodes using photons (6 MV to 15 MV). The pelvic nodal volumes included the internal and external iliac lymph nodes up to lumbar sacral vertebrae L5/S1. A total dose of 30.6 Gy was delivered to the whole pelvis, followed by a field reduction to the bottom of the sacroiliac (SI) joint to 45 Gy. In 10 patients, the dose to the inguinal nodes (range, 36-59.5 Gy) was supplemented by using electrons with energies determined by the depth of the nodes on the treatment planning computed tomography (CT) scan. One elderly patient had only the primary tumor irradiated to avoid bowel toxicity.

Six patients were treated with a wide AP field, covering the pelvis and bilateral inguinal nodes, and a narrower PA field. The divergence was matched to the medial edge of the inguinal nodal field. The dose to the inguinal nodes was delivered entirely by the anterior field, and a partial transmission block was used over the pelvic portion such that 50% of the pelvic dose at midline was delivered by the anterior field. Additional boosts to the primary site were given via AP/PA fields, bilateral arc, 3-field, 4-field, or 3-dimensional conformal techniques.

Intensity-Modulated Radiation Therapy

In the IMRT group, patients were simulated in the supine position, and a treatment planning18fluorodeoxyglucose positron emission tomography (FDG PET)/CT scan was performed on a GE Discovery LS PET/CT scanner (GE Medical Systems, Milwaukee, Wisconsin). A high-risk planning target volume (PTV) was defined as the primary tumor and gross nodal disease. An intermediate-risk PTV was defined as the internal iliac inferior to the SI joint, the perirectal nodes, as well as the high-risk PTV. A low-risk PTV included the inguinal nodes, the external iliac nodes, and the internal iliac nodes superior to the inferior edge of the SI joint. The superior border was L5-S1. The PTV included a 0.5 cm to 0.7 cm expansion for setup uncertainty. The guidelines for dose prescription evolved over the study period. Thus, the doses were heterogeneous and are shown in Table 1. The median dose delivered was 54 Gy (range, 45-59.4 Gy). All treatment planning was performed on the Eclipse Treatment Planning System (Varian Medical Systems, Inc., Palo Alto, California).

The current practice is to treat the low-risk PTV to 40 Gy at 1.6 Gy per fraction and the intermediate-risk PTV to 45 Gy at 1.8 Gy per fraction. The high-risk PTV is boosted sequentially to an additional 5.4 Gy for T1-2 category tumors or to 9-14.4 Gy for T3-4 stage tumors or lymph node-positive patients.

Chemotherapy

Forty-five of the 46 study patients received fluoropyrimidine-based concurrent chemotherapy. One patient in the CRT group did not receive chemotherapy. 5-FU was given as a continuous infusion in 32 patients (either 1000 mg/m2 on days 1-4 and days 29-32 or 200-225 mg/m2 intravenously daily during radiation therapy) or as oral capecitabine 825 mg/m2 by mouth over 2 daily doses on days of radiation in 13 patients. In the CRT group, 14 (82%) patients received concurrent mitomycin C (10 mg/m2) on day 1 and day 29 and a fluoropyrimidine, and 2 patients received a fluoropyrimidine alone. In the IMRT group, 25 (86%) patients received concurrent mitomycin C/fluoropyrimidine, and 4 patients received induction chemotherapy with cisplatin/fluoropyrimidine.

Dosimetric Comparison

CT-based treatment planning became the standard at our institution in December 1999. After that date, 7 of the 17 patients in the CRT group underwent CT simulation and treatment planning. Five of the 7 patients' treatment planning CT scans were available for dosimetric analysis. Five patients from the IMRT group with identical stage and similar radiation dose were chosen for dosimetric comparison.

Follow-up

Patients were monitored at least once a week during radiation, and symptoms and toxicities were recorded. On the basis of descriptions from the clinical records, these toxicities were then retrospectively reviewed and graded according to the National Cancer Institute Common Terminology Criteria for Adverse events, v.3.0,8 for this study. After the completion of therapy, patients were followed clinically every 2 months to 3 months for 1 year and every 3 months to 4 months during years 2 and 3. After year 3, patients were assessed every 6 months. Routine biopsies were not performed in the absence of persistent or progressive disease.

Statistics

Baseline characteristics were compared by using the Student t test or chi-square test, as appropriate, with P < .05 as the level of statistical significance. Median treatment duration and median duration of treatment breaks were compared by using the Wilcoxon-Mann-Whitney test with P < .05 as the level of significance. The Kaplan-Meier method was used to determine overall survival (OS), progression-free survival (PFS), and locoregional control (LRC). Log-rank analysis determined differences in proportions. Locoregional failure (LRF) was defined as clinical sign of progression at the primary site, inguinal lymph node, pelvic lymph node, or a positive biopsy at the primary site. Persistent but stable disease at the primary site was not defined as LRF on the basis of clinical examination alone in the absence of a positive biopsy. Multivariate analyses were performed by using Cox proportional hazards regression for predictors of survival outcomes, and logistic regression analysis was performed to identify predictors of acute toxicity. Statistical analysis was performed with SAS v.9.2 software (SAS Institute, Cary, North Carolina).

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONCLUSION
  7. CONFLICT OF INTEREST DISCLOSURES
  8. REFERENCES

Toxicity

Severe acute toxicities are listed in Table 2. Three patients in the CRT group and 2 patients in the IMRT group were unable to complete the prescribed course of treatment. In the CRT group, 1 patient stopped at 48 Gy of a planned 59.4 Gy because of severe colitis; 1 patient stopped at 50 Gy of a planned 56 Gy because of desquamation but then suffered a stroke resulting in hemiplegia; and 1 patient stopped at 45 Gy of a planned 50.4 Gy because of moist desquamation. In the IMRT group, 1 patient died of septic shock; another patient stopped at 54 Gy of 59.4 Gy because of complications from coronary symptoms presumed related to 5-FU.

Table 2. Comparison of Treatment Breaks, Toxicity, and Outcome in Patients With Squamous Cell Carcinoma of the Anus Treated With IMRT
 Bazan (N=46)Salama (N=53)Pepek (N=29)a
  • IMRT indicates intensity-modulated radiotherapy; CRT, conventional radiotherapy; NR indicates not reported; GI, gastrointestinal; LRC, locoregional control; CFS, colostomy-free survival.

  • a

    Includes only patients with squamous histology.

  • b

    Reports a value of 18% for all patients but not separately for patients with squamous histology.

Median follow-up, mo32 (IMRT)14.519
 26 (CRT)  
Treatment breaks, %34.5 (IMRT)41.5NRb
 88.0 (CRT)  
Acute GI toxicity, grade 3-4, %7 (IMRT)15.110
 29 (CRT)  
Acute skin toxicity, grade 3-4, %21 (IMRT)37.70
 41 (CRT)  
Acute hematologic toxicity, grade 3-4, %21 (IMRT)58.524
 29 (CRT)  
Overall survival, %88 (3 y) IMRT93.4 (1.5 y)100 (2 y)
LRC, %92 (3 y) IMRT83.9 (1.5 y)95 (2 y)
CFS, %91 (3 y) IMRT83.8 (1.5 y)91 (2 y)

Overall, 17 patients experienced grade >2 acute nonhematologic toxicity with a significantly higher proportion in the CRT group versus IMRT group (65% vs 21%, P = .003, Table 2). In the CRT group, 5 (29%) patients experienced grade 3 or 4 gastrointestinal (GI) toxicity including 1 of whom required a 1-month treatment break. In the IMRT group, 2 (7%) patients experienced grade 3 GI toxicity. Seven (41%) patients in the CRT group experienced grade 3 dermatologic toxicity compared with 6 (21%) patients in the IMRT group. One patient in the CRT group and 2 patients in the IMRT group had grade ≥3 GI and dermatologic toxicity. The proportion of grade >2 hematologic toxicities was similar in both groups (29% CRT vs 21% IMRT).

On univariate analysis, use of IMRT compared with CRT significantly decreased the odds of developing a grade >2 nonhematologic toxicity by 86%. When controlling for age and tumor size, use of IMRT retained significance (odds ratio [OR], 0.16; 95% confidence interval [CI], 0.04 to 0.644; P = .0099)

Treatment Time and Breaks

The median total treatment duration was significantly higher in the CRT group versus the IMRT group (57 vs 40 days, P < .0001). Fifteen (88%) patients in the CRT group required treatment breaks compared with 10 (34.5%) patients in the IMRT group (P = .001). The median treatment break duration was significantly longer in patients treated with CRT compared with IMRT (12 days vs 1.5 days, P < .0001). All 15 patients in the CRT group required treatment breaks secondary to radiation toxicities. In the IMRT group, 3 of the 10 patients had treatment breaks unrelated to side effects from the radiation therapy: 1 patient underwent a 3-day break secondary to noncompliance, 1 patient had a 1-day break because of angina felt to be secondary to capecitabine, and 1 patient had a 3-day break for a pneumonia.

Clinical Response

Of the 46 patients, 43 had adequate follow-up including physical examination data to assess clinical response to treatment. Five (11.6%) patients had a clinically complete response (CR) by the completion of chemoradiotherapy, and 19 (44.2%) patients had a CR by the time of first follow-up at 4-6 weeks. In 16 patients, an abnormality on examination persisted for 8 weeks or longer. The median time to CR was 6 weeks (range, 0-56 weeks). Persistent abnormalities on physical examination resulted in post-therapy biopsies in 12 (28%) patients: 4 patients had positive biopsies, whereas the remaining 8 patients were negative, 2 in the CRT group and 2 in the IMRT group. The physical examination never normalized in 3 of the 8 patients with biopsies negative for recurrent disease.

Clinical Outcome

The median follow-up time for the entire cohort was 28 months (range, 3-117 months) and for the CRT and IMRT groups, it was 26 months (range, 3-117 months) and 32 months (range, 1-77 months), respectively. At the time of this analysis, 34 (74%) patients were alive at last follow-up.

Seven (41%) CRT patients developed a LRF, 5 local and 2 nodal. Of the 2 nodal failures, 1 occurred in the inguinal region, and 1 was in the pelvis with simultaneous distant metastasis in the para-aortic region. Two were treated with an abdominoperineal resection, 2 received salvage chemoradiotherapy, and 3 died shortly after local recurrence. Those patients who were not salvaged included 1 with advanced HIV with poor performance status, 1 who suffered a cerebrovascular accident (CVA) with hemiplegia, and 1 who was placed on comfort care because of chronic abscess and osteomyelitis at the recurrence site. One patient who had only the primary tumor treated remained locally controlled at 3 years post-treatment. Two patients in the IMRT group developed local-only recurrences: 1 treated with APR and 1 that refused further intervention and subsequently died.

The 3-year OS in this study was 72% (Fig. 1A). Median time from completion of chemoradiotherapy to APR was 9 months (range, 4-26 months). The crude colostomy rate was 11%, and the overall colostomy-free survival rate at 3 years was 86% (Fig. 1B). OS (88% vs 52%, P < .01), LRC (92% vs 57%, P < .01), and PFS (84% vs 57%, P < .01) at 3 years were significantly higher for patients undergoing IMRT compared with CRT (Fig. 2A-C). Patients who did not have a treatment break had superior 3-year OS, LRC, and PFS regardless of which type of radiotherapy was used (90% versus 45%, P = .03; 95% versus 67%, P = .02; 89% versus 63%, P = .04, respectively).

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Figure 1. (A) Overall survival for all patients and (B) colostomy-free survival for patients are shown.

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Figure 2. (A) Overall survival by radiation technique, (B) locoregional control by radiation technique, and (C) progression-free survival by radiation technique are depicted.

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Table 3 summarizes the Cox-proportional hazards analyses for OS, LRC, and PFS. Multivariate analysis identified T stage, use of IMRT, and treatment duration as independent predictors of OS. T stage and use of IMRT were independent predictors of LRC. T stage and treatment duration were independent predictors of PFS.

Table 3. Cox Proportional Hazards Multivariate Analysis for OS, LRC, and PFS
ParameterHR OS (95% CI; P)HR LRC (95% CI; P)HR PFS (95% CI; P)Better Prognosis Association
  1. HR indicates hazard ratio; OS, overall survival; LRC, locoregional control; PFS, progression-free survival; IMRT, intensity-modulated radiation therapy; CRT, conventional radiotherapy; CI, confidence interval; P, p-value.

T stage (T1/T2 vs T3/T4)2.42 (1.25-4.67;.0093)4.72 (1.14-19.51;.032)5.70 (1.45-22.43;.012)T1 or T2
Type of radiotherapy (IMRT vs CRT)0.25 (0.06-0.94;.04)0.16 (0.03-0.80;.02)0.36 (0.10-1.32;.12)IMRT
Treatment duration (duration > median)6.18 (1.29-29.55;.02)4.38 (0.90-21.27;.06)5.20 (1.12-24.19;.03)Shorter treatment duration

Dosimetric Comparison of 3D Versus IMRT

Normal tissue sparing was improved with IMRT (Fig. 3), with mean bowel volume above 35 Gy reduced by 27% (228 mL vs 311 mL, P = .02) and mean bowel volume above 45 Gy reduced by 80% (10 mL vs 52.8 mL, P = .13). IMRT reduced dose to the perineum with mean proportions of perineal volume above 30 Gy and 40 Gy of 40.8% and 23.6%, respectively, compared with 66.8% and 60.1% in the CRT group (P = .17 and .10, respectively).

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Figure 3. (A-D) Dose distribution for 3-dimensional radiotherapy (A and C) versus intensity-modulated radiotherapy (B and D) are illustrated.

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DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONCLUSION
  7. CONFLICT OF INTEREST DISCLOSURES
  8. REFERENCES

Toxicity

Although definitive chemoradiotherapy with mitomycin C and 5-FU remains the standard of care for SCCA of the anal canal,9-11 the acute and late toxicities of treatment with standard pelvic radiotherapy can be significant.12 In the RTOG 98-11 randomized trial, a 74% rate of grade 3-4 nonhematologic toxicity was reported for the overall cohort.13 In addition, patients in the mitomycin C arm had a 61% rate of grade 3-4 hematologic toxicity. The current study aimed to determine whether IMRT could reduce treatment toxicity and improve outcome for anal cancer patients by comparing IMRT patients to a group treated with CRT from a single institution. To our knowledge, this is the first article to directly compare non-IMRT with IMRT in this disease site from a single institution.

Salama et al have previously reported on IMRT in a pooled experience from the University of Chicago and Mayo Clinic on 53 patients. In that study, with a median follow-up of 14.5 months, the investigators found that 37% of patients experienced grade 3 dermatologic toxicity and 15% experienced grade 3 GI toxicity.7 In a study by Pepek et al from Duke University, 47 patients were treated with IMRT with a median follow-up of 14 months. Their study reported that no patients with SCCA of the anal canal experienced grade 3 dermatologic toxicity. However, 16% did experience grade 3 GI toxicity (Table 2).6 Although significant, both of these studies have toxicity rates that compare favorably with those from RTOG 98-11. Ultimately, the results of the RTOG 0529 phase 2 trial will provide prospective data on rates of acute toxicity in patients treated with IMRT and concurrent 5-FU/mitomycin C.

Our study had a median follow-up that was twice as long as previously reported studies (32 months for IMRT patients). Our results confirmed reduced toxicity rates compared with those reported in RTOG 98-11. When compared with a cohort of patients treated with CRT from the same institution, we found significantly reduced rates of grade 3-4 acute nonhematologic toxicity. Table 3 shows how the current series compares to prior studies. Also noteworthy is the finding that, in the current study, even when higher doses were delivered in the IMRT group to the regional nodes (Table 1), treatment toxicity was still reduced. This finding further highlights the advantage of IMRT for dose escalation to improve outcome without increasing treatment toxicity.

An important limitation within this study is that fact that, despite the use of a standardized toxicity grading scale, significant subjectivity existed in retrospectively grading toxicity during treatments. As a result, the objective measurement of treatment breaks, duration of treatment breaks, and overall treatment time were also examined. The results showed that the reduction in toxicity was associated with a decrease in treatment breaks (34.5% vs 88%, P = .001), reduced treatment break duration (12 days vs 1.5 days, P < .0001), and an overall reduction in treatment time (57 vs 40 days, P < .0001). Salama et al reported that 41% of patients treated with IMRT required treatment breaks,7 whereas Pepek et al reported treatment breaks in 18%,6 both of which are consistent with the current study. As a caveat, it must be noted that although these numbers are objective, the decision to give a treatment break is far from objective, and different physicians will invariably have different thresholds at which to offer a break. It is likely that given the awareness of the detrimental effects of interrupting radiation, especially in disease sites such as the head and neck, and cervix,14-18 physicians are less willing to offer breaks due to toxicity.

Dosimetrically, we found that IMRT enhanced normal tissue sparing. Our dosimetric results coincide with the findings of other investigators.5, 19, 20 This improvement in normal tissue sparing appears to have lead to reduced grade 3 or 4 nonhematologic toxicities in the IMRT group compared with the CRT group.

Outcome

The median time to complete clinical response was 6 weeks, and only 12% of patients had complete response at the end of therapy. The length of time before complete regression was a maximum of 56 weeks. Findings from other series have demonstrated similarly long regression times. Cummings et al reported a range of 2-36 weeks for complete clinical tumor response.21 Similarly, Schlienger et al found a mean time to complete regression of 3 months, with the longest extending to 1 year.22 These results support continued observation of persistent abnormalities at the completion of chemoradiation, because regression will continue. It is our policy to observe patients with frequent clinical examinations unless signs of progression are noted, at which point biopsy and additional workup are pursued. It is less clear how to manage patients with persistent abnormalities that neither improve or worsen. In this study, 4 of 12 patients with persistent abnormal clinical examination findings had positive biopsies. Imaging studies such as FDG PET could be helpful in assessing residual active disease.

We found improved 3-year OS (88% vs 52%, P < .01), LRC (92% vs 57%, P < .01), and PFS (84% vs 57%, P < .01) in the IMRT group compared with the CRT group. These excellent outcomes are similar to those reported by the other IMRT studies. Indeed, the outcomes in the CRT groups are worse than historical results.10, 11, 13 Although there was no significant difference in TNM stage between the 2 groups, the CRT group had a trend toward more T3-4 disease (47% vs 28%, P = .18), which could have impacted local control. However, the percentages of N+ patients (29% CRT vs 24% IMRT) and overall stage I-II patients (53% CRT vs 66% IMRT) were similar. The chemotherapy regimen was similar as well.

Whereas IMRT should not be dosimetrically superior to CRT in terms of target coverage, the advantage with IMRT is likely that it can reduce overall treatment time by decreasing normal tissue doses resulting in significantly reduced toxicity and treatment duration, thereby possibly improving outcome. In this study, we found that prolonged treatment times and interruptions in treatment were associated with poorer outcomes, similar to previous reports.11, 23-26 However, other studies have shown that treatment breaks have not been associated with worse disease control or survival.27, 28 A recent pooled data analysis of 937 patients treated on RTOG 87-04 and RTOG 98-11 provides more insight on the role of treatment time.29 This analysis found no correlation between duration of radiation therapy and local control. Conversely, total treatment time (stratified as ≤53 days vs >53 days), which was prolonged particularly in the subset of patients from RTOG 98-11 that received neoadjuvant chemotherapy, was associated with higher local failure and colostomy rates. Although this study strongly suggests that neoadjuvant chemotherapy can have a detrimental effect on disease control, presumably by delaying chemoradiation and allowing accelerated repopulation and chemotherapy resistance, delays during chemoradiation may be of less importance. This study offers some reassurance that treatment breaks during radiotherapy may be given without a significant impact on treatment outcome. However, it should be noted that in our patient population, none of whom received induction chemotherapy, the median treatment duration for patients in the CRT group was 57 days compared with 40 days for the IMRT group, while the median RT time in the RTOG pooled analysis was 45 days. Given the finding of worse local control with total treatment duration of >53 days in the latter study, the large disparity in treatment time between the IMRT and CRT groups in the current study could still have partly contributed to the differences in outcome. Therefore, we believe that caution should still be applied when allowing prolonged breaks.

Certainly technical factors could have contributed to the differences in outcome. First of all, we observed that relatively few patients were treated during the CRT time period (17 patients over the course of 10 years). Perhaps the experience of the treating physician could have impacted the quality of the treatment delivered.

Second, the CRT patients were treated during an earlier time period before the widespread use of PET or image-guided radiotherapy to account for setup uncertainty. It is possible that PET-based treatment planning in IMRT patients could have identified previously undetected regions of disease involvement, allowing proper dose delivery.

Finally, in addition, the dose delivery to the pelvic nodes differed. In the CRT group, the upper pelvic nodes received <40 Gy in 76% of patients compared with 38% in the IMRT group. Also all IMRT patients, with 1 exception, received 45 Gy to the lower pelvic nodes versus only 59% of CRT patients. These dose differences might have led to better disease control in the IMRT group. Indeed, 2 nodal failures were observed in the CRT group compared with none seen in the IMRT group. However, one was an inguinal nodal failure, and the other had simultaneous pelvic and para-aortic failures. Currently, there is no evidence that doses higher than 36 Gy are needed for these elective nodal regions. We, therefore, do not believe differences in dose or using PET-based planning had a significant impact in the locoregional outcomes difference. However, we believe further studies on the optimal dosing for anal canal cancer and the use of PET for treatment planning are necessary.

Even though this study has the inherent limitations of being retrospective with small patient numbers and potential imbalances in prognostic factors, our results support further investigation of IMRT for this disease site. The results of RTOG 0529 are awaited to provide survival data in a group of patients treated prospectively with IMRT. Although outcomes are generally excellent, locoregional failure remains a problem, particularly for larger tumors, and dose escalation could be used selectively in those at higher risk. In addition, given the potential morbidity of treatment IMRT could significantly diminish toxicity and improve the therapeutic ratio. Longer follow-up is needed to accurately determine late effects with this relatively new technique.

CONCLUSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONCLUSION
  7. CONFLICT OF INTEREST DISCLOSURES
  8. REFERENCES

In conclusion, our study shows that the use of IMRT is associated with less nonhematologic toxicity and reduced need for treatment breaks compared with CRT in patients with SCCA of the anal canal. Locoregional control and survival for patients treated with IMRT compare favorably with historical data.

REFERENCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONCLUSION
  7. CONFLICT OF INTEREST DISCLOSURES
  8. REFERENCES
  • 1
    Nigro ND, Vaitkevicius VK, Considine BJr. Combined therapy for cancer of the anal canal: a preliminary report. 1974. Dis Colon Rectum. 1993; 36: 709-711.
  • 2
    Poggi MM, Suh WW, Saltz L, et al. ACR Appropriateness Criteria on treatment of anal cancer. J Am Coll Radiol. 2007; 4: 448-456.
  • 3
    Minsky BD. Anal cancer. In: Leibel SA, Phillips TL, eds. Textbook of Radiation Oncology. Philadelphia: WB Saunders; 2004: 913-921.
  • 4
    Chen YJ, Liu A, Tsai PT, et al. Organ sparing by conformal avoidance intensity-modulated radiation therapy for anal cancer: dosimetric evaluation of coverage of pelvis and inguinal/femoral nodes. Int J Radiat Oncol Biol Phys. 2005; 63: 274-281.
  • 5
    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. 2005; 63: 354-361.
  • 6
    Pepek JM, Willett CG, Wu QJ, Yoo S, Clough RW, Czito BG. Intensity-modulated radiation therapy for anal malignancies: a preliminary toxicity and disease outcomes analysis. Int J Radiat Oncol Biol Phys. 2010; 78: 1413-1419.
  • 7
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