Postmastectomy hypofractionated and accelerated radiation therapy with (and without) subcutaneous amifostine cytoprotection.

PURPOSE: Postmastectomy radiation therapy (PMRT) provides major local control and survival benefits. More aggressive radiation therapy schemes may, however, be necessary in specific subgroups, provided they are safely administered. We report the tolerance and efficacy of a highly accelerated and hypofractionated regimen (HypoARC). METHODS AND MATERIALS: One hundred twelve high-risk patients who had undergone mastectomy received 10 consecutive fractions of 3.5 Gy in 12 days (thoracic wall and axillary/supraclavicular areas). Two consecutive additional fractions of 4 Gy were given to the surgical scar area (electrons 8-10 MeV) and 1 3.5-Gy fraction to the axilla (in cases with extensive nodal involvement). A minimum follow-up of 24 months (median, 44 months) was allowed before analysis. Of 112 patients, 21 (18.7%) refused to receive amifostine, the remaining receiving tolerance-based individualized doses (500-1000 mg/day subcutaneously). RESULTS: By use of a dose individualization algorithm, 68.1%, 11%, and 18.7% of patients received 1000 mg, 750 mg, and 500 mg/day of amifostine. Patchy moist skin desquamation outside and inside the booster fields was noted in 14 of 112 (12.5%) and 26 of 112 (23.2%) patients, respectively. No case of acute pneumonitis was recorded. High amifostine dose offered a significant skin protection. Within a median follow-up time of 44 months, moderate subcutaneous edema outside and within the booster thoracic area was noted in 5 of 112 (4.4%) and 8 of 112 (7.1%) cases, respectively. Intense asymptomatic radiographic findings of in field lung fibrosis were noted in 4 of 112 (3.6%) patients. Amifostine showed a significant protection against lung and soft tissue fibrosis. A 97% projected 5-year local relapse free survival and 84% 5-year disease-specific survival were recorded. Lack of steroid receptor expression, simple human epidermal growth factor 2 positivity, or triple negative phenotype defined higher metastasis rates but had no effect on local control. CONCLUSIONS: PMRT with HypoARC showed an excellent early and short-term late toxicity profile, and amifostine further reduced early and late radiation sequelae. Encouraging local control rates are obtained in high-risk subgroups.

Postoperative pelvic hypofractionated accelerated radiotherapy with cytoprotection (HypoARC) for high-risk or recurrent prostate cancer.

AIM: We evaluated the feasibility and efficacy of postoperative hypofractionated and accelerated radiotherapy supported with amifostine cytoprotection (HypoARC) in patients with high-risk or recurrent prostate cancer. PATIENTS AND METHODS: Fourty-eight patients were recruited (median follow-up=41 months; range=12-84 months). Twenty-one received HypoARC after surgery and 27 at biochemical relapse. Radiotherapy was given with a 3D-conformal technique, delivering 2.7 Gy/day to the pelvis and 3.4 Gy to the peri-prostatic region for 14 fractions. A 15th fraction increased the total dose to the peri-prostatic area to 51 Gy (15×3.4 Gy) in 19 days. Amifostine was delivered before each radiotherapy fraction at an individualized (by tolerance) dose (0-1000 mg). RESULTS: Amifostine was delivered subcutaneously at 1000 mg in 35/48 (72.9%) patients, while lower doses were tolerated by the remaining patients. Twenty-six (54.2%) patients accomplished therapy without delays, while acute toxicities enforced 1 to 2 week delays in 11/48 patients (22.9%). Grade 2 proctitis was noted in 18.7%, while substantial bleeding occurred in 8.3% of patients. Grade 1 dysurea was noted in 27.1%, while diarrhea grade 2 appeared in 10.4% of patients. High amifostine dose was linked to a significant reduction of proctitis (p=0.04). No severe late toxicities were noted. Within a median of 41 months, 7/48 (14.6%) patients exhibited post-radiotherpy biochemical failure (in four due to metastasis). High-dose (1000 mg) amifostine defined a significantly better outcome (p=0.004), an effect sustained on multivariate analysis. CONCLUSION: Postoperative HypoARC is feasible with low-grade early and late toxicities, and emerges as a candidate for evaluation in randomized trials. The three-fold reduction of the overall treatment time renders HypoARC appealing for busy radiotherapy departments.

Treatment of invasive bladder cancer with conformal hypofractionated accelerated radiotherapy and amifostine (HypoARC).

INTRODUCTION: Radiotherapy (RT) for bladder cancer is as an effective alternative of cystectomy. Although rapid cancer clonogen repopulation contributes to radio-resistance, accelerated RT schemes based on ≤ 2 Gy fractions have failed to improve results. We suggest that accelerated hypofractionation (HypoARC) may be more effective, as it targets both tumors with increased clonogenic activity and tumors with low radio-sensitivity. PATIENTS AND METHODS: Eighty-two bladder cancer patients were treated with concomitant-boost conformal RT (14 × 2.7 Gy to the pelvis and 15 × 3.4 Gy to the bladder, within 19 days). Patients received a daily dose of 0/500/750/1,000 mg of amifostine using a dose-individualization algorithm (15.8%, 8.5%, 19.5%, and 56.1% of patients respectively). RESULTS: Early frequency grade 2-3, dysuria grade 1-2, diarrhea grade 2, and proctitis grade 2 appeared in 10.9%, 15.8%, 8.5%, and 13.4% of patients, respectively. The incidence of late sequelae was low (1.2% grade 2 frequency, 2.4% grade 2-3 dysuria, 2.4% grade 2-3 hematuria, 2.4% grade 2-3 incontinence). Patients receiving 1,000 mg of amifostine experienced significantly lower toxicities. The complete response rate, 3-year local control and disease specific survival rates were 86.6%, 56%, and 63%, respectively. CONCLUSIONS: HypoARC is linked with low early and late radiation toxicity, which is further reduced with the administration of high dose daily amifostine. The control and survival rates compare favorably with previously published data.

Concurrent liposomal cisplatin (Lipoplatin), 5-fluorouracil and radiotherapy for the treatment of locally advanced gastric cancer: a phase I/II study.

PURPOSE: Liposomal drugs have a better tolerance profile and are highly accumulated in the tumor environment, properties that promise an optimal radiosensitization. We investigated the feasibility of the combination of 5-fluorouracil/lecovorin-based radio-chemotherapy with the administration of high weekly dose of a liposomal platinum formulation (Lipoplatin). METHODS AND MATERIALS: Lipoplatin was given at a dose of 120 mg/m(2)/week, 5-fluorouracil at 400mg/m(2)/week (Day 1), whereas radiotherapy was given through 3.5-Gy fractions on Days 2, 3, and 4. Two groups of 6 patients received four and five consecutive cycles, respectively. RESULTS: Minimal nephrotoxicity (18.2% Grade 1) and neutropenia (9% Grade 3) was noted. Fatigue Grade 2 appeared in 25% of cases. Abdominal discomfort was reported by 18% of patients. No liver, kidney, gastric, or intestinal severe acute or late sequellae were documented, although the median follow-up of 9 months is certainly too low to allow safe conclusions. A net improvement in the performance status (from a median of 1 to 0) was recorded 2 months after the end of therapy. The response rates assessed with computed tomography, endoscopy, and biopsies confirmed 33% (2 of 6) tumor disappearance in patients treated with four cycles, which reached 80% (4 of 5) in patients receiving five cycles. CONCLUSIONS: Lipoplatin radio-chemotherapy is feasible, with minor hematological and nonhematological toxicity. The high complete response rates obtained support the testing of Lipoplatin in the adjuvant postoperative or preoperative radio-chemotherapy setting for the treatment of gastric cancer.

Postoperative accelerated radiotherapy with cytoprotection followed by three-dimensional conformal boost in patients with early endometrial/cervical cancer.

AIMS AND BACKGROUND: Adjuvant external beam radiotherapy is highly recommended for uterine carcinomas invading beyond the inner half of the myometrium or cervical stage IIa carcinomas. The addition of a booster intracavitary dose is widely used. METHODS: We assessed the feasibility and toxicity of a hypofractionated accelerated conformal radiotherapy scheme (2.7 Gy per fraction, for 14 consecutive fractions to the pelvis) supported with the cytoprotective agent amifostine (HypoARC). The amifostine dose was individualized (500-1000 mg daily subcutaneously). A booster dose of radiation was given to the vagina and stump using a 6-field 3D-conformal technique (3 x 4 Gy or 4 x 3 Gy) instead of intracavitary radiotherapy. RESULTS: Grade 2 diarrhea appeared in 9/25 (36%) and grade 1 cystitis in 7/25 (28%) cases. Analysis according to the amifostine dose level clearly showed reduced toxicity in patients receiving a daily dose of 750-1000 mg (P < 0.009). Within a median follow-up of 31 months (range, 11-52), there was only one case with grade 2 colitis (the patient had received no amifostine). None of the patients treated has relapsed locally or to distant organs within a median of 31 months of follow-up. CONCLUSIONS: It is concluded that HypoARC followed by 3D-conformal booster dose to the vagina is feasible and convenient for patients and for busy radiotherapy departments, as it reduces the overall time by 50%. When supported by high-dose daily amifostine, it has an impressively low rate of early and late radiation toxicity.

Hypofractionated and accelerated radiotherapy with subcutaneous amifostine cytoprotection as short adjuvant regimen after breast-conserving surgery: interim report.

PURPOSE: Short radiotherapy schedules might be more convenient for patients and overloaded radiotherapy departments, provided late toxicity is not increased. We evaluated the efficacy and toxicity of a hypofractionated and highly accelerated radiotherapy regimen supported with cytoprotection provided by amifostine in breast cancer patients treated with breast-conserving surgery. METHODS AND MATERIALS: A total of 92 patients received 12 consecutive fractions of radiotherapy (3.5 Gy/fraction for 10 fractions) to the breast and/or axillary/supraclavicular area and 4 Gy/fraction for 2 fractions to the tumor bed). Amifostine at a dose of 1,000 mg/d was administered subcutaneously. The follow-up of patients was 30-60 months (median, 39). RESULTS: Using a dose individualization algorithm, 77.1% of patients received 1,000 mg and 16.3% received 750 mg of amifostine daily. Of the 92 patients, 13% interrupted amifostine because of fever/rash symptoms. Acute Grade 2 breast toxicity developed in 6.5% of patients receiving 1,000 mg of amifostine compared with 46.6% of the rest of the patients (p < .0001). The incidence of Grade 2 late sequelae was less frequent in the high amifostine dose group (3.2% vs. 6.6%; p = NS). Grade 1 lung fibrosis was infrequent (3.3%). The in-field relapse rate was 3.3%, and an additional 2.2% of patients developed a relapse in the nonirradiated supraclavicular area. c-erbB-2 overexpression was linked to local control failure (p = .01). Distant metastasis appeared in 13% of patients, and this was marginally related to more advanced T/N stage (p = .06). CONCLUSION: Within a minimal follow-up of 2.5 years after therapy, hypofractionated and accelerated radiotherapy with subcutaneous amifostine cytoprotection has proved a well-tolerated and effective regimen. Longer follow-up is required to assess the long-term late sequelae.

Computed tomography (CT) scan evaluation of late toxicity following hypofractionated/accelerated radiotherapy with cytoprotection (HypoARC) in breast cancer patients treated with conservative surgery.

BACKGROUND: In the present study we evaluated the long-term radiation toxicity of an hypofractionated accelerated radiotherapy scheme supported with amifostine cytoprotection (hypoARC). PATIENTS AND METHODS: A cohort of 32 breast cancer patients, pretreated with conservative surgery and adjuvant doxorubicin or taxane based chemotherapy, were treated with hypoARC. In contrast to the 45 days required for the delivery of standard breast (+/-supraclavicular) radiotherapy, the proposed scheme delivers the whole radiation dose in 16 days (10 fractions of 3.5Gy plus 2 additional 4Gy fractions to the tumor bed), which is convenient for elderly patients or patients residing away from radiotherapy departments. RESULTS: After a minimum follow up of 24 months (range, 24-36), none of the patients showed any clinical signs of lung or arm toxicity. Increased palpable breast density was evident 16 out of 32 cases. Computed tomography (CT) scan evaluation of the lung and breast densities (calculated in Haunsfield units) showed no signs of lung fibrosis, while increased density of the irradiated breast (1.1-1.3-fold) was confirmed in 8 out of 17 patients examined. None of the patients has relapsed locally. CONCLUSIONS: Although longer follow-up is required to confirm safety of the described radiotherapy regimen, these data are encouraging as the toxicity reported within 2 to 3 years of follow-up is even lower than the one expected from standard radiotherapy.