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
Reviewer: Christine Hill-Kayser, MD
Abramson Cancer Center of the University of Pennsylvania
Last Modified: November 9, 2009
Presenter: Dr. Lisa Kachnic Presenter's Affiliation: Radiation Therapy Oncology Group, Philadelphia, PA Type of Session: Scientific
Definitive chemoradiotherapy with 5-Fluorouracil (5FU) and mitomycin-C (MMC) is considered the standard of care for patients with cancers of the anal canal.
Superiority of this regimen was demonstrated in the Radiation Therapy Oncology Group (RTOG)-98-11 trial, which demonstrated excellent rates of overall survival and local control compared to non-MMC containing regimens.
Unfortunately, combined modality regimens are associated with significant toxicity, mainly affecting the gastrointestinal (GI) and genitourinary (GU) systems and the skin. Toxicities may lead to treatment breaks, which may adversely affect outcomes.
For patients randomized to receive 5FU, MMC, and radiotherapy in the RTOG 9811 trial, incidence of grade 2 or greater skin toxicity was 90%, GI toxicity 67%, and GU toxicity 30%.
Intensity modulated radiotherapy (IMRT) may allow improved dose delivery with relative sparing of normal tissues through use of multiple, modulated beams from multiple angles.
Use of IMRT may also allow delivery of “dose painting” or a simultaneous in-field boost dose to be delivered to higher-risk regions with larger fraction sizes while lower risk regions are being delivered lower dose per fraction.
The technique of dose-painted IMRT (DP-IMRT) is utilized in treatment of anal cancer in some centers.
This technique has potential to reduce normal tissue toxicity while allowing adequate dose delivery; however, its efficacy has not been demonstrated previously. Techniques for delivery of DP-IMRT are also operator-dependent, and may depend on physician, physicist, and dosimetrist experience.
The study described here was undertaken to explore the feasibility and impact on toxicity of use of DP-IMRT as compared to conformal radiotherapy as part of concurrent chemoradiotherapy in treatment of anal cancer.
Materials and Methods
This study was designed as a phase II trial evaluating a similar cohort of patients as that evaluated in the RTOG 98-11 trial. These included patients with non-metastatic primary anal canal tumors, with tumor classification T2-T4 and nodal classification N0-N3.
The primary trial endpoint was a 15% reduction in combined grade 2 or greater GI and GU toxicity compared with the MMC arm of RTOG 98-11.
The study accrual goal was 54 patients in order to achieve 80% study power.
Secondary endpoints included the feasibility of delivering this type of treatment in the cooperative setting (determined to be feasible if 5% or less deviation during IMRT quality assurance), evaluation of all adverse events, and clinical complete response at completion of concurrent chemoradiotherapy.
All patients received 5FU (1,000 mg/m2/day, 96 hour continuous infusion) and MMC (10 mg/m2 IV bolus) on days 1 and 29 of radiotherapy.
Radiotherapy was prescribed as follows:
42 Gray (Gy) delivered in 1.5 Gy daily fractions to elective nodal regions, with 50.4 Gy delivered in 1.8 Gy daily fractions to the primary anal tumor simultaneously.
T2 N1-3 and T3-4 N0-3
45 Gy delivered in 1.5 Gy daily fractions to elective nodal regions, 50.4 Gy in 1.68 Gy daily fractions to nodes 3 cm or less, 54 Gy in 1.8 Gy daily fractions to primary tumor and notes greater than 3 cm.
Patients were treated in prone position, and most patient plans required 7-9 fields.
All radiotherapy plans were subjected to central quality assurance review by two investigators.
63 patients from 38 institutions were enrolled on this trial. Of these 52 were analyzable. The most common reason for elimination from trial analyses was lack of history and physical within 14 days prior to beginning radiotherapy.
Median patient age was 58 years and patients were 81% female. Tumors were classified as T2 in 62% of cases, and 56% of patients had clinically uninvolved nodes.
Of 52 plans that were evaluated, 75% required planning revision based on central review. Of these, half required a second plan revision on re-review.
Of plans that required revision, 79% required recontouring, most often of the mesorectum. In response to this, the trial investigators published a pelvic nodal atlas midway through the described trial.
On final case review, no there were no major deviations concerning planned treatment volumes, 3 cases with major deviations exceeding small bowel dose, and 1 case with a major deviation exceeding femoral head dose.
39 patients (76%) experienced grade 2 or greater GI/GU acute toxicity, a similar rate to that described in the MMC arm of the RTOG 98-11 trial.
The incidence of grade 3/4 toxicity, however, was significantly reduced, with 11/51 (22%) experiencing grade 3/4 acute toxicity in the trial described here, versus 36% in the MMC arm of RTOG-9811 (p = 0.014).
The incidence of dermatologic toxicity was also reduced compared to 98-11. Grade two or greater dermatologic toxicity occurred in 69% of patients studied here, versus 81% in the MMC arm of 98-11 (p = 0.039). Grade three or greater dermatologic toxicity occurred in 20% vs. 47% (p < 0.001).
Median radiotherapy duration was 42.5 days (range 32-59), as compared to 49 (range 0-102) days on the MMC arm of 98-11 (p < 0.001).
Treatment breaks were required for 49% of patients versus 61% on the MMC arm of 98-11 (p = 0.01).
At 8 weeks following completion of treatment, 34 (67%) experienced a complete clinical response. Seven (14%) had persistent but not progressive disease, one had progressive local disease, and 9 were not evaluated.
The authors conclude that dose-painted IMRT in combination with 5FU and MMC is feasible treatment for anal cancer in a multi-institutional setting, but that continued quality assurance review is needed.
They described that this treatment is associated with significant reduction in grade 2 and greater dermatologic toxicity, and grade 3 and greater GI/GU toxicity.
They note that early clinical complete response data are encouraging.
The authors present a well-designed, interesting study that is pertinent to clinical practice.
IMRT is a technique used in many centers for delivery of radiotherapy in the setting of anal cancer, with its main benefits described as reduction of toxicity.
Unfortunately, although anal cancer is associated with good rates of local control, treatment is quite toxic, and treatment breaks may reduce the benefit of aggressive treatment.
In the study presented here, use of dose-painted IMRT appears to reduce rates of acute toxicities as compared to conventional radiotherapy utilized in the RTOG 98-11 study.
This being said, several factors must be kept in mind during evaluation of the results presented here.
First, this study represents a phase II comparison to the group of patients enrolled on the 98-11 study, not a phase three randomized comparison. Although the authors have done a comprehensive comparison of outcomes between the two studies, bias may inherently be present in this type of study design.
Second, clinical outcomes aside from clinical response at time of completion of radiation are not yet available. Although clinical complete response certainly reflects upon efficacy of local treatment, data regarding nodal and/or distant failures are not yet available. As radiation becomes more targeted through techniques such as IMRT, evaluation of nodal recurrence is of utmost important; when treatment volumes are reduced from conventional large fields, a risk of missed disease is inherent, and may be operator dependent. To this end, evaluation of overall survival, local recurrence, and disease-free survival in this will be very important. Additionally, careful attention to IMRT volumes both by individual clinicians and during trial design may well have huge implications with regard to these outcomes.
Along these lines, the authors describe that the vast majority of IMRT plans submitted as part of this study required revised planning, and many revised contouring. In response to this, the authors published an atlas to assist practitioners, and they should be commended for this. Even so, the movement of IMRT as treatment for anal cancer into general practice will require widespread awareness of the necessity of careful contouring and planning for delivery. Conventional radiotherapy may well prove to provide better outcomes than inadequate IMRT.
Lastly, dose delivery to nodal regions as part of this study was lower with regard to daily fractionation than might be considered standard. For example, clinically involved lymph nodes measuring 3 cm or less were delivered 1.68 Gy daily. For radiographically positive disease, some clinicians might recommend higher dose per fraction.
Despite these caveats, the data here is interesting and will likely have important implications in practice as it matures. Data on survival and local control will be awaited by the GI oncology community.
Apr 26, 2012 - Neither induction chemotherapy nor high-dose radiation boost is associated with an improvement in five-year colostomy-free survival in patients with locally advanced anal canal carcinoma, according to a study published online April 23 in the Journal of Clinical Oncology.