Concurrent Chemotherapy and Intensity-Modulated Radiation Therapy for Anal Canal Cancer Patients: A Multicenter Experience
From the Department of Radiation and Cellular Oncology, University of Chicago; Introduction Anal cancer affects 4,010 people each year in the US. Traditionally, patients with anal cancer were managed surgically via an abdominoperineal resection (APR), with an expected 5-year survival of 55% to 71%. Alternatively, patients wishing for an organ-preserving approach were managed with radiotherapy (RT), resulting in 5-year overall survival (OS) of 59% to 65%. Nigro et al pioneered the use of neoadjuvant concomitant fluorouracil (FU), mitomycin (MMC), and RT for anal cancer. Pathologic complete responses (CRs) were found in 23 of 28 patients at the time of surgical resection. Based on these positive results, many institutions enacted protocols to treat anal cancer patients with concurrent FU, MMC, and RT as definitive treatment, reserving APR for incomplete response or disease recurrence. A series of randomized trials established concomitant FU, MMC, and RT as the standard of care for all stages of anal cancer. This organ-preservation strategy has resulted in 5-year OS and colostomy-free survival (CFS) rates of 50% to 78% and 61% to 76%, respectively. However, this sphincter-preserving approach is toxic; 18% of patients experienced acute grade 4 to 5 hematologic toxicity in the US Intergroup trial. In the United Kingdom Coordinating Committee on Cancer Research and European Organisation for Research and Treatment of Cancer trials, significant acute dermatologic toxicity occurred in 49% to 76% of patients, and acute GI toxicity was seen in 33% to 45% of patients. The recently introduced treatment of intensity-modulated radiation therapy (IMRT) is a novel approach to RT planning and delivery. In contrast to conventional RT, IMRT conforms radiation tightly to tumors and high-risk regions, sparing nearby critical normal tissues. This technique is widely accepted in the treatment of prostate and head and neck cancers. Clinical studies demonstrate reduced acute rectal toxicity and xerostomia using IMRT. In the treatment of pelvic malignancies, IMRT maintains disease control while reducing acute and chronic GI toxicity and hematologic toxicity. Given that IMRT has been used to
decrease acute sequelae in other disease sites, we sought
to determine if IMRT could be used in the setting of
concurrent chemotherapy to reduce toxicity in
combined-modality anal cancer therapy. To this end, we analyzed
a cohort of consecutive patients treated with concurrent
chemotherapy and IMRT to determine the clinical
implications of this treatment. Patients and Methods: From October 2000 to June 2006, 53 patients were treated with concurrent chemotherapy and IMRT for anal squamous cell carcinoma at three tertiary-care academic medical centers. Sixty-two percent were T1-2, and 67% were N0; eight patients were HIV positive. Forty-eight patients received fluorouracil (FU)/mitomycin, one received FU/cisplatin, and four received FU alone. All patients underwent computed tomography–based treatment planning with pelvic regions and inguinal nodes receiving a median of 45 Gy. Primary sites and involved nodes were boosted to a median dose of 51.5 Gy. All acute toxicity was scored according to the Common Terminology Criteria for Adverse Events, version 3.0. All late toxicity was scored using Radiation Therapy Oncology Group criteria. Results: Median follow-up was 14.5 months (range, 5.2 to 102.8 months). Acute grade 3+ toxicity included 15.1% GI and 37.7% dermatologic toxicity; all acute grade 4 toxicities were hematologic; and acute grade 4 leukopenia and neutropenia occurred in 30.2% and 34.0% of patients, respectively. Treatment breaks occurred in 41.5% of patients, lasting a median of 4 days. Forty-nine patients (92.5%) had a complete response, one patient had a partial response, and three had stable disease. All HIV-positive patients achieved a complete response. Eighteen-month colostomy-free survival, overall survival, freedom from local failure, and freedom from distant failure were 83.7%, 93.4%, 83.9%, and 92.9%, respectively. Conclusion: Preliminary outcomes suggest that concurrent chemotherapy and IMRT for anal canal cancers is effective and tolerated favorably compared with historical standards. At one time, anal cancer was a disease treated only with surgery; the advent of FU/MMC-based chemoradiotherapy has altered the treatment options. With APR limited to salvage treatment, the majority of patients are spared a colostomy. However, this combined-modality approach is toxic, with many patients requiring protracted treatment interruptions. IMRT is a major advance in RT. By altering radiation intensity across a given treatment field, clinicians have a means of tightly conforming high radiation dose levels around tumors and high-risk regions, while avoiding high doses to nearby normal tissues. The use of this technique in patients with pelvic malignancies has demonstrated decreased acute and chronic GI toxicity rates. We initiated an IMRT-based chemoradiotherapy approach in 2000, with the goal of reducing acute toxicities associated with anal canal cancer treatment. These data support the hypothesis
that concurrent chemotherapy and IMRT can be used to
treat anal cancer patients while decreasing acute
dermatologic toxicity rates. In this cohort, 38% of patients
experienced acute grade 3 dermatologic toxicity and none
experienced grade 4. This is lower than the grade 3 or
greater acute dermatologic toxicity rates seen in
patients treated without a mandated break (78%), and
comparable to the 34% rate experienced by patients who
were mandated to take a 2-week break while enrolled onto
RTOG 92-08. Furthermore, the dermatologic toxicity rate in
our study was lower than that in patients treated with
concurrent FU/MMC (48%) enrolled onto RTOG 98-11. This
lower rate of acute grade 3 to 4 dermatologic toxicity is
important, given that patients enrolled onto RTOG 92-08
with a mandatory 2-week break had a 30% 2-year colostomy
rate compared with a 5-year colostomy rate of 10% from
RTOG 98-11 in patients treated with FU/MMC without a
break. Our cohort tolerated treatment well, with
only 41.5% of patients
needing a break in treatment. Of patients
requiring a treatment break, 12 (57%) of 21 patients
required
The decreased dermatologic toxicity observed in our study is multifactorial. Advances in treatment design and planning, with three-dimensional conformal RT or IMRT, allow improved targeting and normal tissue sparing compared with traditional techniques. Previously, we reported that IMRT had the ability to decrease radiation dose delivered to the small bowel, iliac bone marrow, bladder, and genitalia in anal canal cancer patients treated with IMRT. When we designed treatment volumes for this patient cohort, we routinely avoided unnecessary skin irradiation in sites distant from gross disease. The radiation dose conformality of IMRT likely augments skin sparing away from areas of gross disease. Although acute GI toxicity was present in all patients, it was mild in our patient cohort. Only 15.1% experienced grade 3 GI toxicity. RTOG 98-11, using a similar toxicity-reporting criteria (Common Terminology Criteria for Adverse Events, version 2.0), reported a 34% rate of grade 3 to 4 acute GI toxicity. This low rate of acute GI toxicity is noteworthy when one considers that in our series, the average radiation dose to the pelvis was 45 Gy (higher than that delivered in the RTOG trials). These data suggest that the intentional sparing of dose to the small bowel resulted in decreased acute GI toxicity, despite a higher delivered dose to pelvic nodal regions. The level of acute hematologic toxicity in this cohort was expected given the known hematologic sequelae of concomitant FU, MMC, and pelvic RT. The rate of grade 3 to 4 acute hematologic toxicity, while significant at 58.5%, was comparable to the 60% seen in the FU/MMC arm of RTOG 98-11. Furthermore, most patients were treated without intentional sparing of pelvic bone marrow within the iliac crests. Previous investigations have shown that cervical and endometrial cancer patients treated with concurrent chemotherapy and pelvic IMRT had lower rates of grade 2 or higher WBC toxicity and a lower WBC nadir when compared with patients treated with chemotherapy and conventional RT. It is possible that if a higher priority were placed on reducing radiation dose to the bone marrow, hematologic toxicity could be reduced further. Mell have reported an association between acute hematologic toxicity and the volume of pelvic bones receiving 10 and 20 Gy in cervical cancer patients treated with concurrent cisplatin and pelvic IMRT. Preliminary investigations have demonstrated that a similar association exists in anal cancer patients treated with IMRT and concurrent chemotherapy. It would seem that additional reduction in acute hematologic toxicity could be achieved with reduced IMRT field sizes and intentional sparing of pelvic bone marrow. The CR rate of our patients (92.5%) was similar to that seen in RTOG 87-04, with a pathologic response rate of 92% in patients receiving FU/MMC and pelvic RT. Our crude colostomy rate of 10.5% was comparable to the results of the FU/MMC arms of RTOG 98-11 (10%) and RTOG 87-04 (9%). The 18-month CFS rate in this population of 83.7% is consistent with the 2-year CFS rate of RTOG 87-04 of 80%.These data support the conclusion that anal cancers could be treated with IMRT without compromising local control. Currently, the RTOG is enrolling
patients onto a phase II study (RTOG 0529) combining
concurrent FU/MMC and IMRT. The target accrual is 59
patients, which is similar to the number of patients
presented in our study. The primary goals of RTOG 0529 are to
determine if the combined rate of grade
In conclusion, this analysis demonstrates that concurrent chemotherapy and IMRT is associated with favorable rates of nonhematologic acute toxicity while maintaining high rates of local control and CFS. |
4
days off treatment, and only three patients interrupted
treatment for more than 7 days. This decrease in acute dermatologic
toxicity did not compromise locoregional control.
2
GI and GU events from IMRT and FU/MMC can be decreased by
15% in the first 90 days after the start of treatment
compared with RTOG 98-11. On the basis of RTOG 98-11
reports, acute grade