High dose daily amifostine and hypofractionated intensively accelerated radiotherapy for locally advanced breast cancer. A phase I/II study and report on early and late sequellae.

Intrinsic radioresistance, tumor hypoxia and ability of cancer cells to undergo rapid repopulation during radiotherapy are associated with failure of radiotherapy. Tumors with low alpha/beta-ratio values or hypoxic tumors unable to undergo re-oxygenation, are unlikely to be eradicated with standard radiotherapy. Although the therapeutic efficacy of accelerated regimens based on low-dose per fraction may be high since they minimize the adverse role of rapid tumor repopulation, the cellular compartment with low alpha/beta-ratio values (i.e. hypoxic cells) remains a limiting factor. Accelerated hypofractionation, which may be more effective in such tumors, cannot be safely applied unless normal tissues are protected. In the present study we assessed the feasibility of hypofractionated and accelerated radiotherapy supported by cytoprotection (HypoARC) with high dose daily amifostine. Fifteen breast cancer patients with locally advanced disease entered radiation-dose escalation protocoL Twelve consecutive fractions of 3.5-4Gy (5 fractions/week) were given to the breast/chest wall, supraclavicular and axillary area, within 17 days. A high dose of amifostine, at 1,000 mg flat dose, was given 20 minutes before each radiotherapy fraction. Amifostine administration was well- tolerated with minor side-effects (vomiting in 6 out of 15 and hypotention in 2 out of 15 patients). Radiation induced acute skin toxicity was negligible (grade 3 in 1 out of 15 patients). Ten out of 15 patients survived more than 12 months and 7 out of 15 more than 18 months following HypoARC. None of these patients showed any signs of late sequellae, such as lung and myoskeletal fibrosis, or brachial plexopathy. Complete and partial responses were obtained in 11 out of 15 (73%) and in 4 out of 15 (27%) patients, respectively. High dose daily amifostine during hypofractionated radiotherapy is feasible. HypoARC regimen is well-tolerated, effective and has minimal acute and late toxicity to normal breast, chest and axillary tissues.

Concurrent hypofractionated radiotherapy and 5-Fluorouracil for advanced sarcomas of the bone.

Purpose. 5-Fluorouracil (5-FU) has shown radiosensitizing properties in vitro. This paper reports the effects of radiotherapy and concomitant intravenous 5-FU radiosensitization in the treatment of advanced bone sarcomas.Subjects/methods. Four patients with large inoperable bone sarcomas (three chondrosarcomas and one fibrosarcoma) were treated with hypofractionated radiotherapy and concomitant 5-FU bolus injection (300 mg m(-2)) before each fraction of radiotherapy. A radiation fraction of 5 Gy was given twice a week to a normalized total dose (alpha/beta=4 Gy) of 75 Gy.Results. The regimen was well tolerated, the main toxicity being grade I/II diarrhoea in two cases with pelvic irradiation. Treatment interruption for 1 week was necessary in two cases with pelvic disease but not in two patients treated for sarcoma of the extremities. A complete symptomatic relief was obtained in all cases immediately after the third to the fifth fraction and the median duration was 10 months. Computed tomography scan documented a partial response in 2/4 cases.Discussion. Hypofractionated radiotherapy combined with potential lethal damage inhibitors for bone sarcomas requires further investigation.

Hypofractionated radiotherapy with 5-fluorouracil radiosensitization for locally "far advanced" breast cancer.

Seventeen patients who had locally far-advanced breast cancer were treated with hypofractionated radiotherapy (4-5 Gy/fraction, twice a week) and concomitant 5-fluorouracil (5-FU 300 mg/m2 intravenously, 1 hour before every radiotherapy fraction). Fourteen of the seventeen patients had disease that was not responding to chemotherapy. Early toxicity was low and none developed grade III/IV toxicity. Two of the seventeen patients showed moist skin desquamation and four of seventeen had grade II anemia. Of eight patients who survived longer than 12 months, symptomatic breast fibrosis was observed in one (12%), asymptomatic pericarditis in one (12%) and symptomatic radiation pneumonitis in one (12%). Plexopathy and arm edema grade II were observed in one patient and two patients, respectively. Quality of life substantially improved. Complete response was documented in five of the seventeen patients (29%), with pathologic confirmation in three. Seven of the seventeen (41%) patients were considered to be partial responders, four (23%) had a minimal response, and one (6%) progressed during treatment. Local progression-free survival (1-24 months) was achieved in 12 of 17 patients. Four of the seventeen (23%) patients are alive, with no evidence of disease (local or distant) 8 to 24 months after radiotherapy. Hypofractionated chemoradiotherapy with 5-FU is an effective, convenient, and well-tolerated regimen for far-advanced breast tumors.

The impact of overall treatment time on the results of radiotherapy for nonsmall cell lung carcinoma.

PURPOSE: We evaluated the impact of overall treatment time on the disease-free survival (DFS) and local control after radiotherapy for nonsmall cell lung carcinoma. METHODS AND MATERIALS: One hundred fifty-three cases considered as responders to radiotherapy were retrospectively analyzed. Patients with Karnofsky status < 70, pretreated with chemotherapy and with pleural or pericardial effusion, were excluded from the analysis. Radiation dose homogenization was done with calculation of the normalized total dose without (NTD) and with time correction (NTD-T) for alpha/beta = 10 Gy. RESULTS: Kaplan-Meier curves for 2-year DFS showed that any analysis based on radiation dose can prove to be erroneous when the time factor is neglected. Although there was no difference between the 47-55 Gy and 56-64 Gy NTD groups, a log rank test revealed a strong difference (p < 0.0002) between NTD-T groups. No difference was observed for patients with mediastinal involvement. Logistic regression analysis showed a statistical association of dose on 2-year local progression-free probability for different time compartments. For those cases without mediastinal involvement, the daily dose lost because of treatment protraction beyond 20 days after the beginning of radiotherapy was estimated to 0.2 Gy/day. When all cases were considered together this was calculated to 0.45 Gy/day. CONCLUSION: Time factor should not be underestimated when evaluating the results of radiotherapy for nonsmall cell lung cancer. There is strong evidence that prolonged overall treatment time could be a major cause of the failure of radiotherapy to control the local disease.

Hypofractionated radiotherapy with concurrent 5-fluorouracil radiosensitisation for recurrent or locally advanced colorectal cancer. A phase II study.

In a pilot study we treated 19 patients suffering from recurrent or locally advanced inoperable colorectal cancer, with concurrent hypofractionated radiotherapy (4-5 Gy/fraction, 2 fractions per week) and 5-fluorouracil bolus, 1 hour before RT at doses of 300 mg/m2. For 16 patients treated with radical intent the Normalised Total Dose for alpha/beta = 10 Gy ranged between 56-74 Gy (median 62 Gy). The schedule used was very well tolerated. Moderate grade II haematological toxicity was observed in 11% of cases and diarrhoea grade II/III resulting in 2-4 weeks treatment delay was observed in 26% of cases. One case with bowel perforation and one with painful subcutaneous fibrosis was observed during 12-27 months of follow-up. Out of 16 patients treated with radical intent 4 (25%) showed complete response and the overall response rate was 56% (9/16). The one-year symptom-free survival was obtained in 11/16 (69%) radically treated patients. It is concluded that hypofractionated radiochemotherapy with 5-fluorouracil for recurrent or locally advanced colorectal cancer is an effective regimen and has acceptable acute and late toxicity. Further investigation is required.

Radiotherapy alone for non-small cell lung carcinoma. Five-year disease-free survival and patterns of failure.

One hundred and fifty-three patients with inoperable non-small cell lung cancer (NSCLC) treated with radiotherapy alone have been retrospectively analysed. Normalized Total Dose (NTD) as defined by Macejewski, TN-stage (AJC-system) and histology have been examined with respect to 5-year disease-free survival (DFS) and the patterns of failure so as to identify subgroups of patients that routinely should be treated with radical intent. The 5-year DFS for T1, 2-N0, 1 and T3-N0, 1 staged patients was 30% (7/23) and 25% (4/16) respectively when the tumor NTD (a/b = 10 Gy) was 56-64 Gy vs. 12% (5/41) and 0% (0/10) when the NTD was 48-55 Gy. This difference was statistically significant for the squamous cell histology group. The higher doses significantly altered the patterns of death in N0, 1 staged squamous cell carcinoma and adenocarcinoma patients. Forty-five percent (22/55) and 41% (12/29) of squamous cell and adenocarcinoma patients respectively, died from local relapse without evidence of distant metastases when NTD less tha 55 Gy were given vs. 21% (9/42) and 13% (2/15) when the NTD delivered was 56-64 Gy (p < 0.05). Although for N2, 3 staged patients or patients with direct extension of the tumor into the mediastinum death from local relapse occurred in 38% (10/26) of the high NTD treated patients vs. 51% (19/37) of the low-dose treated ones, the difference was not statistically significant. It is concluded that NSCLC patients should not à priori be considered as non-radiocurable. At least 30% of the patients with early local stages can be long-term disease-free survivors with radiation NTD up to 60 Gy and better results are to be expected with higher doses. Advanced T-stage without mediastinal involvement should be treated with radical intent since a high NTD could give cure rates of over 25%. The disappointing results for patients with mediastinal disease could perhaps be attributed to the low NTD delivered. For patients with good performance status, hyperfractionated regimens delivering high tumor doses should be tested and chemotherapy should be adapted to these radiation treatment schedules.

Transurethral 137Cs medium dose rate radiotherapy as a boost for small-sized localized prostatic carcinomas.

The aim of this study is to present preliminary experience with 137Cs medium dose rate (MDR) afterloading transurethral radiotherapy for small-sized (< 2.5 cm) prostatic carcinomas. The phase II protocol comprises 46 Gy of external beam radiotherapy, followed by two insertions (1 week apart) of 137Cs MDR transurethral brachytherapy, each one delivering 8 Gy to a point 0.5 cm from the urethral walls. The treatment is completed with a 14-Gy boost to the prostatic area through lateral external beam fields. Up to now, 9 patients have been treated. The transurethral insertion is a simple procedure, requires no anesthesia and the ultrasonographic observation precisely and easily guided the positioning of the applicator. All 9 patients are alive and disease-free 12-36 months after the end of radiotherapy. One of them presented a mild degree of urethral stricture and none developed chronic proctitis or cystitis. Seven patients were sexually potent before radiotherapy and all of them maintained their potency. Transurethral radiotherapy for prostatic carcinoma requires further investigation. The radiation dose that the procedure delivers to the prostate is higher than the one prescribed for external beam irradiation regimens. Rectal and bladder dose is substantially reduced. Although the prostatic urethra receives a higher dose, the incidence of urethral stricture is low probably because of the small tissue volume (8 cm3) in the high radiation dose area.

Transurethral radiotherapy for benign prostatic hypertrophy-related urethral obstruction. Dosimetry, ethics, and preliminary results.

The aim of this study is to present our preliminary experience in treating BPH-related urine retention, resistant to other medical treatment, with transurethral brachytherapy. We also deal with dosimetric analysis so as to eliminate ethical concerns about the exposure of patients not suffering from cancer to a certain level of body irradiation. Patients suffering from BPH-related urethral obstruction were treated with two transurethral applications (three weeks apart) of Cs137 MDR, which delivered a total of 16 Gy, at 0.5 cm from the urethral walls (dose rate 5-7 Gy/h). The application was done under ultrasonographic observation. Dosimetric calculation of the radiation exposure of the human body during transurethral radiotherapy (TURT) was performed for patients suffering from prostate cancer and treated with external beam radiotherapy and a boost dose through transurethral brachytherapy. For this purpose we used TLDs on skin surface and dosimetric analysis of X-ray films. Five patients treated for BPH urethral obstruction presented no sign of acute toxicity. All of them were weaned of their indwelling catheter immediately after the end of the first application. Obstruction did not recur within 12-18 months of follow-up. The dose delivered outside the prostate ranges from 1-7 cG, depending upon location. Proximal rectal and bladder walls received 1-2 Gy, a dose that is far from inducing acute or late toxicity. The estimated risk for carcinogenesis is negligible, and the expected benefit for the quality of life transcends the risks. No ethical concern is justified for testing transurethral radiotherapy for BPH-related urethral obstruction. TURT seems to be effective and provides durable results. Further investigation is required.