Intrarectal amifostine suspension may protect against acute proctitis during radiation therapy for prostate cancer: A pilot study

Singh. IJROBP 2006;65:1008

Purpose: Our goal was to test the ability of intrarectal amifostine to limit symptoms of radiation proctitis.

Methods and Materials: The first 18 patients received 1 g of intrarectal amifostine suspension placed 30–45 min before each radiation treatment. The following 12 patients received 2 g of amifostine. Total dose prescribed ranged from 66 to 76 Gy. All patients were treated with three-dimensional conformal radiation therapy. The suspension remained intrarectal during treatment and was expelled after treatment. For gastrointestinal symptoms, during treatment and follow-up, all patients had a Radiation Therapy Oncology Group (RTOG) grade recorded.

Results: Median follow-up was 18 months (range, 6–24 months). With 2 g vs. 1 g amifostine, there was a nearly significant decrease in RTOG Grade 2 acute rectal toxicity. Seven weeks after the start of radiation therapy, the incidence of Grade 2 toxicity was 33% in the 1-g group (6/18) compared with 0% (0/12) in the 2-g group (p = 0.06). No Grade 3 toxicity or greater occurred in this study.

Conclusion: This trial suggests greater rectal radioprotection from acute effects with 2 g vs. 1 g amifostine suspension. Further studies should be conducted in populations at higher risk for developing symptomatic acute and late proctitis.

Radiation therapy

All patients underwent computed tomographic simulation. Before simulation, liquid contrast, of equivalent volume to the amifostine suspension, was instilled endorectally. Prostate, rectum, and bladder were contoured using treatment planning software. The rectum was contoured from the anus (at the level of ischial tuberosities) for a length of 15 cm or until the rectosigmoid flexure could be identified. The planning target volume was defined as the clinical target volume plus a margin ranging from 0.5 to 1.5 cm at the discretion of the physician. Clinical target volumes, including the decision to treat the pelvic lymph nodes and the seminal vesicles, were based upon clinical examination findings and risk of involvement greater than 15% as determined by the Roach equations using Gleason score and pretreatment prostate-specific antigen. Three-dimensional conformal radiation therapy was delivered to all patients. The plan was evaluated based on dose–volume histogram analysis. No more than 25% of the rectal volume was allowed to receive 70 Gy. The planning target volume was covered by at least 97% of the prescribed dose. Prescription dose ranged from 72 to 76 Gy for most patients. The 2 postoperative patients received 66 Gy.

Amifostine application

Amifostine was reconstituted in saline at a concentration of 50 mg/mL. For the first 18 patients, 1 g/20 mL and, in the next 12 patients, 2 g/40 mL was instilled endorectally at low pressure via 60-cc syringe in the clinic 30 to 45 min before each radiation treatment. This was the same amifostine preparation used for intravenous administration and was not specifically formulated for this study. The first 15 patients alternated prone and lateral positions every 15 min after administration of the amifostine and before treatment. The remaining 15 patients remained prone for 15 min after administration and then were allowed to sit before treatment. Retentions of less than 30 min were considered inadequate for dosing and were documented as such. This occurrence was extremely rare.

Discussion

Several publications have examined the clinical utility of intrarectal amifostine . As in those studies, our study found intrarectal amifostine was feasible and well tolerated.

Both groups had similar dosimetric characteristics. At 7 weeks after the start of radiation therapy, the incidence of Grade 2 toxicity was 33% in the 1-g group (6/18) compared with 0% (0/12) in the 2-g group (p = 0.06). No Grade 3 toxicity or greater occurred in this study.

Aside from the present study, one other study suggests a dose–response to intrarectal amifostine. Ben-Josef et al. studied 29 prostate cancer patients treated with amifostine dose levels ranging from 0.5 to 2.5 g in 40 to 50 mL solution, applied before the first 15 radiation treatments. Pharmacokinetic studies were performed on Days 1 and 10 of treatment. Neither free parent compound nor free active metabolite was detected in the systemic circulation, and there was no systemic toxicity. The authors found that late rectal bleeding developed significantly more often in patients receiving 0.5 to 1 g than in patients receiving 1.5 to 2.5 g amifostine (50% vs. 15%; p = 0.0325)

Notably different from the present study, however, Ben-Josef et al. administered amifostine only in the first 15 days of treatment. Follow-up in our study is as yet too short to fully assess late toxicity. Despite these differences, the findings of Ben-Josef et al. support the suggestion from this study that 2 g vs. 1 g of amifostine has greater efficacy in reducing acute radiation proctitis.

In our experience, there was a very low incidence of acute Grade 2 proctitis. This echoes the previous publications that showed a low incidence of proctitis even in the groups of patients that received less or no amifostine. Such scarcity of moderately symptomatic proctitis in the studied populations precludes any dramatic improvement with addition of intrarectal amifostine. Certainly, the limitations of relatively small cohorts are compounded by a low background incidence of Grade 2 symptoms. Future studies should target populations with a higher incidence of Grade 2 and greater proctitis. Such populations may include those undergoing concurrent chemoradiotherapy for cervical cancer or prostate cancer patients dose escalating beyond 80 Gy with external-beam radiation.

Also, development and validation of instruments more sensitive than the RTOG grade may discriminate small but clinically important reductions in proctitis. In this study, the change from baseline in the EPIC bowel function score was significantly improved in the 2-g group (p = 0.04). Similarly, the EPIC bowel bother score showed a trend toward improvement (p = 0.07). Analysis was performed as previously described. These data are not more fully presented here because, unlike the RTOG score, the EPIC score has not been validated for use in the acute setting.

Our experience and the summarized studies suggest the general efficacy of intrarectal amifostine in reducing the incidence of moderate acute radiation proctitis. The amifostine used in this and other studies was not specifically formulated for rectal administration. Thus, it is possible that a specific formulation for intrarectal administration, such as suppositories, could produce higher local drug concentrations, thereby using less drug or producing further protection.

Conclusions

For reduction of acute radiation proctitis, intrarectal administration of 2 g appears superior to 1 g of amifostine. Further studies to establish efficacy and optimum dose should be considered in populations that have a higher incidence of developing symptomatic acute and late proctitis, possibly with the use of a specific formulation for intrarectal administration.