Effects of smoking and irradiated volume on inflammatory response in the lung of irradiated breast cancer patients evaluated with bronchoalveolar lavage.

Quantitative measurements of the effects of irradiation on normal tissues in humans have been hard to obtain because most tissues are inaccessible and/or direct responses are difficult to quantify in a nondestructive manner. Pneumonitis and fibrotic lung disease are adverse effects seen in varying intensity in patients treated with radiotherapy for carcinomas of the thorax, e.g., breast cancer. In the present study the aim was to evaluate the inflammatory reaction in the underlying parenchyma following postoperative irradiation with bronchoalveolar lavage technique. Twenty-one patients (11 smokers, 10 nonsmokers) with breast cancer stage T1N0M0 received radiotherapy with photons to a target dose of 56 Gy following breast conservative surgery. Nineteen healthy controls were also included. The results showed a clear elevation of neutrophils, mast cells, eosinophils, and lymphocytes in the total irradiated groups, compared to controls. When subclassifying the material according to smoking habit, it was obvious that the smokers displayed a significantly decreased inflammatory reaction, i.e., reduced levels of mast cells and lymphocytes, compared to both nonsmoking controls and patients. Eosinophils were seen in an elevated number in all irradiated patients. Radiological signs of pneumonitis were observed in three patients, all in the nonsmoking group. No correlation was found between the volume of lung irradiated and the inflammatory response. It is concluded that bronchoalveolar lavage is a suitable and sensitive method for investigating radiotherapy-induced reactions in the human lung. Furthermore, ongoing smoking during the treatment depressed the inflammatory response in the lung parenchyma induced by irradiation. The present study as well as earlier observations justify further studies concerning the possibility of interaction of smoking with cancer treatment, both from the view of therapeutic failures and reduced adverse effects.

Effects of sucralfate on acute and late bowel discomfort following radiotherapy of pelvic cancer.

PURPOSE: Radiotherapy, a cornerstone in the management of pelvic cancer, is accompanied by intestinal reactions. Therefore, we investigated the possible effects of sucralfate, an aluminium hydroxide complex of sulfated sucrose used in the treatment of gastric ulcer, in preventing radiation-induced diarrhea and bowel discomfort in patients treated with curative intention for pelvic cancer with external radiotherapy. PATIENTS AND METHODS: The study was double-blind and placebo-controlled and included 70 patients with carcinoma in the prostate or urinary bladder without distant metastases (T1-4No1xMo) and a performance status of greater than or equal to 90% on the Karnofsky scale. Radiotherapy was conventionally delivered with high-energy photons (four-field technique, the total dose 64 Gy, 2 Gy daily, total treatment time 5 to 6 weeks). Dose granules of sucralfate or placebo were dispensed to each patient 2 weeks after radiation started and continued for 6 weeks. All analyses were performed blindly. RESULTS: The frequency of defecation and stool consistency were significantly improved by sucralfate. Fourteen patients in the placebo group and three in the sucralfate group required symptomatic therapy with loperamide. One year later, the patients in the sucralfate group displayed significantly less problems with frequency of defecation, mucus, and blood in the stools compared with the placebo group. There was also a lower intake of loperamide and the weight decrease was less pronounced in the sucralfate group. There was no evidence of adverse effects associated with the use of sucralfate. CONCLUSION: It is suggested that sucralfate can be of beneficial value in diminishing bowel discomfort during treatment and, most importantly, sucralfate also reduces the late bowel disturbances that follow radiotherapeutic treatment of pelvic malignancies. The earlier proposed mechanisms of action (eg, protection of denuded mucosa, cytoprotective properties, binding bile acids) seem adequate to explain the present effects of sucralfate.

Prevention of irradiation-induced bowel discomfort by sucralfate: a double-blind, placebo-controlled study when treating localized pelvic cancer.

Sucralfate, an aluminum hydroxide complex of sulfated sucrose used in the treatment of gastric ulcer, was shown to prevent irradiation-induced diarrhea and bowel discomfort significantly in patients treated for pelvic cancer with external radiotherapy with intent to cure. The double-blind placebo-controlled study included 70 patients with carcinoma of the prostate and urinary bladder without distant metastasis (T1-4NO1xMO) and performance status of greater than or equal to 90% Karnofsky scale. Radiotherapy was administered in a conventional manner with MeV photons and a four-field technique. The total dose was 62-66 Gy and total treatment time of 6.5 weeks. Dose granules of sucralfate or placebo were dispensed to each patient 2 weeks after radiation started and continued for 6 weeks. All analyses were performed blindly. Seven of 34 evaluable patients in the placebo group and 18 of 32 evaluable patients in the sucralfate group did not present with diarrhea during the observation period. The frequency of defecation and stool consistency were significantly improved by sucralfate. Fourteen patients in the placebo group and only three in the sucralfate group required symptomatic therapy with loperamide. There was no evidence of adverse effects associated with the use of sucralfate. Sucralfate can be of beneficial value in diminishing the bowel discomfort during radiotherapy of pelvic malignancies, and the earlier proposed mechanisms of action (e.g., protection of denuded mucosa, cytoprotective properties, binding bile acids) can also be valid for the current effects of sucralfate.

Quality assurance in radiation therapy: multidisciplinary considerations--European experience.

The organization of a multidisciplinary cancer treatment center is very heterogeneous in Europe. In Eastern Europe, there are written concepts of cancer treatment with advanced plans and an acceptable position for radiotherapy. In the future, there will be no principal differences between Eastern and Western Europe. In the development of radiotherapy in Europe, a determining factor seems to be that radiotherapy has been an independent clinical speciality. The problem in Germany can be explained on the basis that only now is radiotherapy separate from diagnostic radiology. In other countries radiotherapy has long been a strong independent speciality, often working with other cancer specialties. Great Britain, France, Belgium, The Netherlands and Italy are the leading countries in the development of radiotherapy. In the Scandanavian countries, radiotherapy has always had a strong position and has been able to develop further by integration with medical oncology. Cooperation between radiotherapists, radiophysicists, surgeons, pathologists, cytologists, etc., has given the cancer patient an opportunity for better overall treatment. The quality assurance in cancer therapy is the teamwork between different specialists before the treatment plan for the patient is decided.

Hyperfractionation as an effective way of overcoming radioresistance.

PURPOSE: To model the influence of hypoxic radioprotection in fractionated treatments over a range of fraction sizes. To determine whether there is a "therapeutic window" of dose per fraction where hypoxic radioresistance could be reduced, and if so, where it occurs in different cell lines. MATERIALS AND METHODS: A mathematical model has been used to simulate the response of cells to low doses of radiation, in the region of clinical interest. We have used the inducible repair variant of the linear quadratic (LQ) equation, with a hypersensitive region (alphaS) at low doses that gradually transforms to the accepted "resistance" in the shoulder region (alphaR). It contains two new parameters, the ratio alphaS/alphaR, and D(C). We have accepted that the "induction dose" D(C) is modified by anoxia to the same extent as the other parameters. We have initially modeled using theoretical parameters and then checked the conclusions with 14 sets of published experimental data for cell lines investigated for inducible repair. RESULTS: We have computed the clinical hypoxic protection (OER') as a function of dose per fraction in simulations of clinical fractionated schedules. We have identified a therapeutic window in terms of dose per fraction at about 0.5 Gy, where the OER' is minimized, regardless of the precise cell survival curve parameters. The minimum OER' varies from one cell line to another, falling to about 1.0 if alphaS/alphaR = 6-10 and even far below 1.0 if alphaS/alphaR > or = 20. DISCUSSION: Hyperfractionation using 0.5 Gy fractions may therefore be more effective than oxygen mimetic chemical sensitizers, since it could even make some tumor cells more sensitive than oxic normal tissues. The tumor lines that benefit most from this type of sensitization are those with the highest intrinsic oxic radioresistance, i.e. those with high SF2 values.

Planning of radiotherapy for patients with hip prosthesis.

The effects of a hip prosthesis on the dose distribution when treating pelvic cancer have been evaluated. A prosthesis of titanium alloy in a water phantom was used as a model. Photon radiation beams with energies of 6, 20, and 50 MV and with a focus phantom distance of 100 cm were directed against the prosthesis. The dose profiles at different depths were measured with the RFA-7 system. The sphere of the prosthesis was inhomogeneous. The dose in a beam behind the prosthesis was reduced with the order of 10-40% and the largest distortion was behind the shaft. Using an opposed four-field technique with the same weight on all the fields, the dose reduction was as large as 7-12% in a string across the target behind the end of the shaft. With 50% weight on the lateral fields, the dose reduction was 4-8% of the average dose. Such an uneven dose distribution may decrease the curability, and a treatment technique not including the prosthesis should be preferred. Finally, a local increase of the dose close to the prosthesis seems to be of limited practical concern even at the highest energies.

Irradiation therapy with multiple small fractions per day in urinary bladder cancer.

In a clinical trial 168 patients with carcinoma of the bladder, T2-T4, were randomized to one of two treatments; 1 Gy 3 times a day to a total of 84 Gy or 2 Gy once a day to a total of 64 Gy. Local eradication of the tumour in the bladder cystoscopically and cytologically at 6 months after completion of treatment and patient survival were analyzed. The results favoured significantly the patients treated with 84 Gy. All patients were followed 5-9 years. The survival was significantly improved in patients with T3 lesions treated with 84 Gy (p less than 0.01). Complications in the bowel requiring surgical treatment were not significantly different between the two groups of patients. The results indicate a therapeutic gain by hyperfractionated radiotherapy in comparison to conventional fractionated radiotherapy.

Managing side-effects in radiotherapy with regard to the gastrointestinal tract.

Three different means of diminishing discomfort during radiation therapy of the gastrointestinal tract are demonstrated and discussed: 1. Use of the smallest possible treatment volumes in medically well developed regions with good possibilities for follow-up of all patients. 2. Regular consultations, with advice concerning food intake and dental hygiene 3. Use of the drug sucralfate, which may improve tolerance against the radiation-induced damage to the gastrointestinal mucosa.

Evaluation of carcinoembryonic antigen, tissue polypeptide antigen, placental alkaline phosphatase, and modified nucleosides as biological markers in malignant lymphomas.

We have evaluated CEA, TPA, PLAP in sera from patients with three different kinds of malignant lymphomas. Six modified nucleosides, psi, m1A, m1G, m1I, m2G, and m2(2)G were analyzed in the urine from the same group of patients. The histological diagnoses were histiocytic lymphoma (21 patients), lymphocytic lymphoma (19 patients) and Hodgkin's disease (23 patients). The patients were classified into four different clinical stages. Consecutive samples were analyzed before and during ongoing radiotherapy and chemotherapy and during the post-treatment period. Our results showed that TPA and PLAP had limited value as biological markers for patients with malignant lymphomas. For CEA a possible correlation with clinical stage was observed only in patients with Hodgkin's disease. The modified nucleosides, especially psi, showed a correlation with clinical stage for patients with all three diagnoses. Elevated levels of psi in urine were in healthy adults 4%, in patients in clinical stage 1 14%, and in patients with advanced disease 62%. Six cases showed a good correlation between the change in clinical stage upon treatment and the parallel change in the level of psi in the urine. Our results suggest that modified nucleosides, especially psi, are valuable as biological markers for patients with malignant lymphomas.

Fractionated irradiation and late changes in rat parotid gland: effects on the number of acinar cells, potassium efflux, and amylase secretion.

Irradiation of head- and neck cancer commonly results in oral dryness and discomfort for the patients due to salivary gland damage. The exact mechanisms behind the inherent radiosensitivity of salivary glands remain to be elucidated. In the present study, we used different in vitro secretory models and quantitative morphological characterization of rat parotid gland following fractionated unilateral irradiation to one gland on a 5-day fraction schedule (Monday-Friday) with 6 MV photons (total dose 30, 35, 40 and 45 Gy) or a two-fractions regimens in 5 days (Monday and Friday) with total dose of 24 and 32 Gy. The contralateral shielded gland served as control, and parallel analyses of irradiated and control glands were performed 180 days following the last irradiation treatment. The relative noradrenaline stimulated electrolyte secretion (86rubidium tracer for potassium) was decreased in the irradiated compared with control glands. The noradrenaline-stimulated exocytotic amylase release was not significantly affected by irradiation, but the gland content of amylase was decreased dose-dependently. The quantitative morphological analysis revealed a dose-dependent decline in the number of acinar cells, whereas the other parenchymal cells (intercalated, striated- and excretory duct cells) were unaffected by the irradiation compared with control glands.

Variations in sensitivity of synchronized Chinese hamster cells to oxic and anoxic X-ray exposures.

V-79 Chinese hamster cells in monolayer cultures on glass surfaces were synchronized by treatment with hydroxyurea and exposed at different times thereafter to X-rays in the air or in oxygen-free argon. Survival determinations indicated that the oxygen enhancement ratio OER as expressed by the ratio of the respective D0 values varied over a narrow range in the different phases of the cell cycle. These changes resulted from cyclic alterations in both aerobic and anaerobic D0 values, and perhaps in n values.

A low dose-fractionation shceme for the radiotherapy of carcinoma of the bladder. Experimental background and preliminary results.

Experimental observations are described which form the basis of a low dose-fractionation scheme designed in an attempt to circumvent the problem presented for radiotherapy by the particular radioresistance of poorly oxygenated cells. In a preliminary investigation the scheme was tested in the treatment of carcinoma of the bladder. A total of 45 patients were included in the trial, randomized to be treated according to either of two fractionation schemes. Scheme I : 100 rad 3 times a day, 5 days a week, a total tumor dose of 8 400 rad, 2 weeks of rest in middle of the treatment period. Scheme II : 200 rad once a day, 5 days a week, a total tumor dose of 6 400 rad, 2 weeks of rest in the middle of the treatment period. The results suggest an improved therapeutic ratio with Scheme I in comparison to Scheme II.

Prevention and therapy of radiation-induced bowel discomfort.

In a double-blind randomized placebo-controlled study, including 70 patients treated with radiotherapy of localized malignancies in the pelvis, the effects of prophylactic sucralfate in preventing bowel discomfort were evaluated. Radiotherapy was delivered in a conventional manner with high-energy photons in a total dose of 62-66 Gy (target dose, 1.8-2.2 Gy) during 6.5 weeks. Dose granules of sucralfate or placebo were given 2 weeks after irradiation started and continued for 6 weeks. All analyses were performed blindly. The patients in the sucralfate group had significantly less problems with acute (5 weeks) and chronic (66 weeks) bowel discomfort. The consumption of loperamide was also reduced in the sucralfate group, and the weight decrease was less pronounced. No adverse effects were seen. Thus, sucralfate seems to be beneficial in minimizing the problems of bowel discomfort during and after irradiation of malignancies in the pelvis. These results are discussed in relation to other related observations.

Sucralfate: prophylaxis of mucosal damage during cancer therapy.

BACKGROUND: Chemotherapy and radiotherapy of different malignancies may be complicated by a variety of side effects, some of which may be related mucosal damage. RESULTS: There is increasing evidence that sucralfate reduces the severity of radiation-induced mucositis in the head and neck, esophagus, and the lower gastrointestinal tract. Sucralfate also seems to protect the skin during radiotherapy and to reduce chemotherapy-induced mucositis. CONCLUSION: Further studies could be of interest to define the clinical significance of sucralfate in reducing the mucosal damage and increasing quality of life during an following cancer therapy.