Aromatase inhibitors decrease radiation-induced lung fibrosis: Results of an experimental study.

PURPOSE: In experimental and clinical trials, tamoxifen (TAM) has been shown to increase radiation-induced lung fibrosis (RILF). Furthermore, aromatase inhibitors (AI) have been shown to be superior to TAM in the adjuvant setting and preclinical data suggest that letrozole (LET) sensitizes breast cancer cells to ionizing radiation in other studies. In this experimental study, we evaluated whether AI have any impact on the development of RILF in rats. MATERIALS AND METHODS: 60 female wistar- albino rats were divided into 6 groups: Control (group A), RT alone (group B), RT + TAM (group C), RT + anastrozole (ANA group D), RT + LET (group E), and RT + exemestane (EXE, group F). RT consisted of 30 Gy in 10 fractions to both lungs with an anterior field at 2 cm depth. Equivalent doses for 60 kg adult dose per day of TAM, ANA, LET, and EXE were calculated according to the mean weight of rats and orally administrated with a feeding tube. Percentage of lung with fibrosis was quantified with image analysis of histological sections of the lung. The mean score values were calculated for each group. the significance of the differences among groups were calculated using one way ANOVA test and Tukey HSD post-hoc test. RESULTS: Mean values of fibrosis were 1.7, 5.9, 6.7, 2.5, 2 and 2.2 for groups A, B, C, D, E, and F, respectively (p = 0.000). TAM increased RT-induced lung fibrosis but without statistical significance. Groups treated with RT + AI showed significantly less lung fibrosis than groups treated with RT alone or RT + TAM (p = 0.000). RT + AI groups showed nearly similar RT-induced lung fibrosis than control group. CONCLUSIONS: In this study, we found that AI decreased RT-induced lung fibrosis to the control group level suggesting protective effect.

The impact of trastuzumab on radiation-induced pulmonary fibrosis: results of an experimental study.

There are no data regarding the late toxicity of trastuzumab (T) administration with radiotherapy (RT). In this experimental study, we aimed to asses if concurrent or sequential administration of T has any impact for the development of radiation-induced pulmonary fibrosis in rats. Fifty-four female Wistar-albino rats were divided into 6 groups. First group of rats (Group 1; concurrent T) had irradiation to whole thoracic region concurrently with T. Second group (Group 2: sequential T-RT) received thoracic irradiation, 1 week after T. Third group (Group 3: sequential RT-T) had thoracic irradiation first and they had T injection 1 week after RT. Fourth group (Group 4: T only) had only T application. Fifth group (Group 5: RT) had only RT. The last group (Group 6: sham) of rats were observed without any application. A single dose of 12 Gy was given to both lungs with an anterior field at 2 cm depth. T dose which was equivalent to 6 mg/kg adult dose was calculated for each rat, and injected by the tail vein. As an end point the extent of pulmonary fibrosis for each field was graded on a scale from 0 (normal lung or minimal fibrous thickening) to 4 (total fibrous obliteration of the field) at histopathological examination. The mean value of fibrosis scores were 1.44, 1.77, 1.75 and 1.62 for Group 1, 2, 3 and 5, respectively, without any statistically significant differences among them (P>0.05). The mean value of fibrosis scores for Group 4 and 6 were 0.25 and 0.33, respectively (P>0.05). When the mean value of fibrosis scores of the groups which had RT with or without T, compared with the observation and the T only groups, the difference was significant (P<0.05) (one-way ANOVA and Tukey HSD post hoc tests) As a conclusion: addition of T to thoracic irradiation either sequentially or concomitantly did not increase radiation-induced pulmonary fibrosis in rats.

Radiochemotherapy in the treatment of breast cancer.

Radiotherapy and chemotherapy have established roles in the multidisciplinary management of early breast cancer. The optimal integration of these treatment modalities is controversial. The most common approach is to deliver each treatment modality sequentially. For patients with close surgical margins or with other risk factors for local recurrences, initiation of adjuvant treatment with radiotherapy is recommended. A sandwich regimen is not the preferred schedule because of a decreased dose density for anthracycline- and taxane-based regimens. However, it can be an option for patients receiving adjuvant cyclophosphamide, methotrexate and fluorouracil (CMF). Concomitant radio- and chemotherapy remain in principle an attractive treatment schedule to provide an additive interaction of tumour control and shortening the duration of the overall treatment of time. However, it should be avoided due to the potential risk of augmented cardiac and skin toxicity for anthracyclines. Recent studies revealed an increased locoregional control and a slight toxicity when radiotherapy was given concurrently with cyclophosphamide, mitoxantrone and fluorouracil (CNF). On the other hand, CNF is no longer considered as standard adjuvant chemotherapy in breast cancer because of reports of secondary acute myeloid leukaemias.

The impact of treatment interruptions on locoregional control during postoperative breast irradiation.

PURPOSE: Patients treated in the years 1990-2003 with breast conserving surgery and postoperative adjuvant radiotherapy were retrospectively analyzed in order to determine the impact of radiotherapy interruptions on the treatment outcome. PATIENTS AND METHODS: 470 patients received breast irradiation with (60)Co or with 4MV photon linear accelerator (total dose 50 Gy, range 46-54). Four hundred and sixty-two (98%) patients had boost dose of 10-20 Gy to the tumor bed either with photon or electron irradiation. Irradiation of the lymphatic fields was carried out according to the number of involved nodes. Even one day of treatment break was accepted as treatment interruption. Unplanned treatment interruptions occurred in 423 (90%) patients. A total of 196 (41%) patients had no treatment breaks or had interruptions of 7 days or less and 274 (59%) patients had treatment interruptions longer than 7 days. Locoregional control (LC) and overall survival (OS) rates were estimated by Kaplan-Meier method. The groups were compared with log-rank x(2) and Pearson x(2) tests. RESULTS: For all patients 5-year LC and OS rates were 91% and 85%, and 10-year rates were 86% and 75%, respectively. LC rates for the group of patients without interruptions or with an interruption of less than a week were 95% for 5 years and 90% for 10 years. Five- and 10-year LC rates for the patients with interruptions of 8 days or more were 87% and 83%, respectively (p=0.02). CONCLUSION: This retrospective study shows that postoperative irradiation interruptions of more than a week negatively impact LC.

Vitamin E protects against the development of radiation-induced pulmonary fibrosis in rats.

AIMS: To investigate whether the application of vitamin E with or without pentoxifylline could modify the development of radiation-induced pulmonary fibrosis. MATERIALS AND METHODS: Wistar albino rats were supplemented with either vitamin E or pentoxifylline or with both vitamin E and pentoxifylline after a single dose of 14 Gy thoracic irradiation. Supplementation was started the day after irradiation and continued until the rats were sacrificed. As a quantitative end point, the extent of fibrosis was evaluated with a scale from 0 (normal lung) to 8 (total fibrous obliteration of the field) at pathological examination of the lung tissue. RESULTS: A significant reduction in fibrosis was obtained in the group of rats supplemented with vitamin E with or without pentoxifylline, when compared with the group that had irradiation only. CONCLUSION: This experimental study showed that vitamin E supplementation immediately after irradiation protected rats against radiation-induced pulmonary fibrosis. The combination with pentoxifylline was more effective, although pentoxifylline itself had limited efficacy, which was not statistically significant.

Does pentoxifylline increase radiation response of Ehrlich mammary carcinoma in mice?

PURPOSE: The presence of hypoxic cells in solid tumors is generally considered as a limiting factor for the complete control of tumors by radiation therapy. Pentoxifylline is a methylxanthine derivative that produces hemorrheologic effects which increase tissue oxygen levels. In this study we aimed to determine whether pentoxifylline would enhance the radiation response of Ehlrich mammary carcinoma in mice. MATERIALS AND METHODS: Ehrlich mammary carcinoma cells were subcutaneously transplanted into the nape of 27 male Balb/c mice. Twelve animals were injected with 50 mg/kg of pentoxifylline intraperitoneally (i.p.) and irradiated 30 min after the administration (study group). Fifteen mice were irradiated without receiving pentoxifylline (control group). All animals were exposed to a single dose of 40 Gy with Co60 gamma rays locally to the tumor site. The effect of pentoxifylline was assessed by the reduxtion rate in tumor volume (mm(3)) which was measured at least 3 times a week until mice were dead. RESULTS: The reduxtion rate of tumor volume on day 4, relative to the initial volume, was 42% in the control group and 61.6% in the study group (p=0.24). The survival of mice in the two groups was not significantly different (p=0.08). CONCLUSION: Although the reduction rate of tumor volume was higher in the study group, the difference was not statistically significant. Pentoxifylline can not be considered as a radiation enhancer in Ehrlich mammary carcinoma.

Continuous hyperfractionated accelerated radiotherapy in the treatment of high-grade astrocytomas.

Between May 1993 and January 1995, 36 patients with high-grade astrocytomas were treated with 1.05 Gy continuous hyperfractionated accelerated radiotherapy three times daily to a total target dose of 59.85 Gy in 19 days with 6-h intervals. The median age of the patients was 51 years and the median follow-up was 58 weeks. The median survival rate was 58 weeks and the cumulative survival rate was 22% at 2 years. No severe toxicity occurred in patients treated with this fractionation scheme. These results suggest that continuous hyperfractionated accelerated radiotherapy is an altered fractionation schedule for high-grade astrocytomas with tolerable acute toxicity and survival rates comparable to conventional fractionation and to other altered fractionation schedules.