Normal tissue complication probability models for severe acute radiological lung injury after radiotherapy for lung cancer.

PURPOSE: To derive Normal Tissue Complication Probability (NTCP) models for severe patterns of early radiological radiation-induced lung injury (RRLI) in patients treated with radiotherapy (RT) for lung tumors. Second, derive threshold doses and optimal doses for prediction of RRLI to be used in differential diagnosis of tumor recurrence from RRLI during follow-up. METHODS AND MATERIALS: Lyman-EUD (LEUD), Logit-EUD (LogEUD), relative seriality (RS) and critical volume (CV) NTCP models, with DVH corrected for fraction size, were used to model the presence of severe early RRLI in follow-up CTs. The models parameters, including α/ß, were determined by fitting data from forty-five patients treated with IMRT for lung cancer. Models were assessed using Akaike information criterion (AIC) and area under receiver operating characteristic curve (AUC). Threshold doses for risk of RRLI and doses corresponding to the optimal point of the receiver operating characteristic (ROC) curve were determined. RESULTS: The α/ßs obtained with different models were 2.7-3.2 Gy. The thresholds and optimal doses curves were EUDs of 3.2-7.8 Gy and 15.2-18.1 Gy with LEUD, LogEUD and RS models, and µd of 0.013 and 0.071 with the CV model. NTCP models had AUCs significantly higher than 0.5. Occurrence and severity of RRLI were correlated with patients' values of EUD and µd. CONCLUSIONS: The models and dose levels derived can be used in differential diagnosis of tumor recurrence from RRLI in patients treated with RT. Cross validation is needed to prove prediction performance of the model outside the dataset from which it was derived.

Concomitant radio-chemotherapy based on platin compounds in patients with locally advanced non-small cell lung cancer (NSCLC): a meta-analysis of individual data from 1764 patients.

BACKGROUND: Despite several randomised trials comparing radiotherapy alone with concomitant radio-chemotherapy in patients with locally advanced non-small cell lung cancer (NSCLC), it is not clear whether the addition of chemotherapy improves survival. PATIENTS AND METHODS: This meta-analysis was based on individual patient data from published and unpublished randomised trials which compared radiotherapy alone with the same radiotherapy combined with concomitant cisplatin- or carboplatin-based chemotherapy. Trials with accrual completed after 2000 were excluded. Trials were sought in electronic databases, clinical trial registries and by additional manual searches. The primary endpoint was overall survival analysed using the log-rank test stratified by trials. RESULTS: There were twelve eligible trials that included a total of 1921 patients. The data from 3 trials were not available. Therefore, the analysis was based on 9 trials including 1764 patients. Median follow-up was 7.2 years. The hazard ratio of death among patients treated with radio-chemotherapy compared to radiotherapy alone was 0.89 (95% confidence interval, 0.81-0.98; P = 0.02) corresponding to an absolute benefit of chemotherapy of 4% at 2 years. There was some evidence of heterogeneity among trials and sensitivity analyses did not lead to consistent results. The combination of platin with etoposide seemed more effective than platin alone. CONCLUSIONS: Concomitant platin-based radio-chemotherapy may improve survival of patients with locally advanced NSCLC. However, the available data are insufficient to accurately define the size of such a potential treatment benefit and the optimal schedule of chemotherapy.

Intraoperative radiation therapy for retroperitoneal soft tissue sarcomas.

Treatment of retroperitoneal soft tissue sarcomas is a difficult clinical problem. Despite the improvement in resection rates in the most recent surgical series, local control still remains the main problem because of the high incidence of local recurrences after surgery. Postoperative radiation therapy has not been always successful because of dose-tolerance of surrounding normal structures, which prevent the delivery of adequate doses of radiation. To overcome this limitations, new therapeutic approaches including external-beam radiation and intraoperative radiation therapy (IORT) have been evaluated at some Institutions. The results of IORT with or without external-beam radiation are reviewed and our experience with preoperative radiation and IORT is reported. As treatment of retroperitoneal sarcomas has evolved into combined modalities including preoperative radiation, maximum surgical resection and IORT, a possible improvement in local control rates has been achieved. However, locoregional failures and the incidence of distant metastases remain a challenge, emphasising the need for further improvement in local and distant treatment. The new phase II trial, activated within the Italian Sarcoma Group, with preoperative concurrent chemo-radiation therapy and IORT is presented.

Nasopharyngeal cancer WHO type II-III: monoinstitutional retrospective analysis with standard and accelerated hyperfractionated radiation therapy.

The aim of this study is to assess the impact of prognostic factors in patients with locoregionally advanced nasopharyngeal cancer (NPC), WHO type II-III, treated with two different radiation therapy (RT) schedules: standard radiation therapy (SRT), and accelerated hyperfractionated radiation therapy (HART), with or without sequential chemotherapy. Between January 1986 and December 1999, 78 consecutive NPC patients were treated either with SRT (until August 1993) or with HART (from September 1993). Of the 78 patients, 60 were males and 18 females, the median age was 56 years (range 14-83). Nine patients had a non-keratinizing carcinoma (WHO type II) and 69 an undifferentiated carcinoma (WHO type III). Five-year overall survival rate (OS) was 62%. Two months after RT, 73 patients were in complete remission. Disease-free survival (DFS) rates at 5 years were: 85% for the HART and 59% for the SRT group, respectively. A multivariate analysis, age (hazard ratio, HR=4.17 for > or = 60 vs. <50 years) and N-stage (HR=3.56 for N3a-N3b vs. N0-N1) were significant for survival, whereas N-stage (HR=8.23 for N3a-N3b vs. N0-N1) and RT schedule (HR=0.30 for HART vs. SRT) were significant for DFS. In our experience, HART achieved higher DFS rates than SRT; however, HART did not favourably affect OS. Toxicity was comparable in the two RT schedules.

Radiotherapy and continuous infusion 5-fluorouracil in patients with nonresectable pancreatic carcinoma.

PURPOSE: The current standard local treatment for nonresectable pancreatic carcinoma is radiotherapy (RT) with concurrent 5-fluorouracil (5-FU); however, the optimal schedule for 5-FU administration has not been fully established. In this study, we report on our experience with the combination of RT and continuous infusion 5-FU in a group of patients with locally nonresectable pancreatic carcinoma. METHODS AND MATERIALS: Forty-two patients with adenocarcinoma of the pancreas were enrolled in a prospective clinical trial. RT was delivered using a four-field technique to a total dose of 59.4 Gy in 33 fractions. 5-FU was given through a central venous catheter at a dose of 300 mg/m(2)/day, 7 d/wk, throughout the entire course of RT. RESULTS: All patients completed the RT as planned, and 33 (78%) completed the full regimen of chemotherapy. Ten patients (23%) had a partial response, and 32 (77%) had stable disease. Subjective response, defined as the disappearance of symptoms observed at diagnosis, was also evaluated. Two patients (6%) had a complete, and 24 (75%) a partial, remission of symptoms. The median time to progression was 6.2 months, and the median survival time was 9.1 months. CONCLUSIONS: In terms of local control, the results of our study, with RT and protracted 5-FU infusion, compare well with those of other studies using RT and bolus 5-FU. The control of distant metastatic disease remains an open issue. However, the palliation of symptoms achieved by our treatment schedule in patients with a very poor prognosis and severe symptoms may be regarded as a positive result.

[Timing of radiotherapy in the treatment of breast carcinoma. Review of the literature]. / Timing della radioterapia nel trattamento del carcinoma mammario. Revisione della letteratura.

Combined modality treatments are indicated for most patients with breast cancer. The definition of a proper treatment schedule and of the timing of each modality is a relevant issue that affects the feasibility and the clinical outcome of the treatment. A review of the literature was done on the timing of radiation therapy (RT) in the post-operative treatment of breast cancer. Retrospective studies and randomized clinical trials addressing the issue were considered and grouped according to the combined modality treatments performed. With regard to breast conserving surgery and adjuvant RT, it was verified that a delay up to 8 weeks between breast surgery and start of RT is not associated with an increased risk of local failure if compared with RT started within 4 weeks. Concerning breast conserving surgery followed by adjuvant RT and chemotherapy, the choice of the best schedule is still a complex unresolved issue. More results on sequential schedule of adjuvant RT and chemotherapy from recently published randomized studies are available. The reconstruction of the breast after conservative surgery is rarely necessary and is usually performed immediately after surgical treatment. With regard to mastectomy followed by adjuvant RT and breast reconstruction, it appears from some retrospective studies that autologous tissue transfer offers better results over implants. Concerning the transverse rectus abdominis muscle (TRAM) procedure, either immediate reconstruction before RT or delayed reconstruction after RT was feasible without significative differences in complication rates. Further randomized clinical studies are required to address the unresolved issues linked to the timing of RT. At present the treatment plan should be based on the patient's individual circumstances with regard to risk of metastasis and local failure.

The effect of granulocyte colony-stimulating factor on oral mucositis in head and neck cancer patients treated with hyperfractionated radiotherapy.

We investigated the effect of granulocyte colony-stimulating factor (G-CSF) administration on radiotherapy (RT)-induced oral mucositis in 26 consecutive patients with head and neck neoplasms, stages III and IV, treated with hyperfractionated RT. The first 13 patients were treated with RT alone and the remainder with RT + G-CSF. The two groups of patients were similar in age, sex, PS, primary site, stage, RT schedule and RT volume. Daily mucositis, median mucositis score, day of highest mucositis, requirement of parenteral nutrition, weight loss, treatment break, number of days of RT interruption were analyzed during RT treatment. No statistically significant differences were found between the two groups except for the number of patients who interrupted the treatment: 9/13 patients (69%) in the RT alone group versus 3/13 (23%) in the RT + G-CSF group (p < 0.05). Our observations indicate that G-CSF did not appear to have influenced the objective mucositis although it reduced the number of treatment breaks. In consideration of the cost of G-CSF, its prophylactic administration should be reserved only for patients at high risk of RT interruption.

Reirradiation and lomustine in patients with relapsed high-grade gliomas.

PURPOSE: The aim of this study was to evaluate the toxicity, response, and survival of patients with relapsed high-grade gliomas after radiation therapy (RT) combined with lomustine (CCNU). METHODS AND MATERIALS: Thirty-one patients with relapsed gliomas at least 6 months after completion of RT were reirradiated. Twenty-four patients had a pathological diagnosis of high-grade gliomas, whereas 7 had a radiological diagnosis of relapsed malignant gliomas. The study focused on patients with high-grade relapsed gliomas. A total dose of 34.5 Gy was delivered in 23 fractions over 4.5 weeks. Oral administration of CCNU (130 mg/m2) was begun at the same time as RT, and was repeated every 6 weeks until disease progression, or up to 12 courses. RESULTS: Twelve of 24 patients had surgery before RT plus CCNU treatment. Median interval between RT courses was 14 months (range 6-73). All patients received a complete course of RT, and 22 of 24 patients received at least one course of CCNU. Objective responses were seen in 14 evaluable patients: 3 with partial response, 5 with stable disease, and 6 with progressive disease. Duration of partial response was 20, 9, and 8 months. Median time to progression and overall survival from the onset of retreatment were 8.4 months (range 1-22) and 13.7 months (range 1-63+), respectively. One case of G4 thrombocytopenia was observed. Five patients had G1 or G2 leucopenia and 3 patients had G3 leucopenia. Moderate nausea and vomiting were reported in 4 patients. One patient, after one course of CCNU, refused further chemotherapy. No significant difference in survival from relapse was found between patients who underwent surgery before RT plus CCNU and those who received only RT plus CCNU (p = 0.74). CONCLUSION: Overall, the acute toxicity was moderate, and patient compliance was good. Reirradiation of high-grade glioma was associated with modest subjective and objective response rates. It is remarkable that median overall survival from relapse was 13.7 months.

Combined radiotherapy and bleomycin in patients with inoperable head and neck cancer with unfavourable prognostic factors and severe symptoms.

The aim of this study was to assess the feasibility of concurrent split course radiotherapy and low-dose bleomycin in the treatment of unresectable head and neck cancer with unfavourable prognostic factors and severe symptoms. The clinical outcome of the treatment was assessed in terms of local disease control, symptom relief and toxicity. Between 1990 and 1996, 58 patients with squamous cell carcinoma of the head and neck, stage III or IV, were treated by radiotherapy (50 Gy/20 fractions) and simultaneous bleomycin (60 mg/6 fractions). Local control of disease, overall response, symptom relief and acute toxicity were evaluated. The rate of disease local control was 69% with a median response duration of 7 months (range 2-43+). The symptom relief rate was 81%. Mucositis was the prominent toxicity: G3 mucositis was reported in 27 patients. In conclusion, the treatment was feasible. A good palliation of symptoms and a good rate of local response were obtained. Moreover, toxicity was tolerable and the rate of hospitalisation was low.

Postoperative radiotherapy and surgery in stage I endometrial carcinoma: a 10-year experience.

BACKGROUND: Data from the literature show that the incidence of pelvic recurrences in poor prognosis endometrial carcinoma is significantly reduced by combined surgery and radiotherapy compared to surgery alone. METHODS: In this paper we analyze the results of the combined treatment surgery plus adjuvant Irradiation in patients with endometrial carcinoma with regard to survival, site of progression, and toxicity. The surgical treatment consisted of total abdominal hysterectomy and bilateral salpingo-oophorectomy. Pelvic and para-aortic node dissection was performed. RESULTS: The overall 5-year survival was 88%. Three patients had local failure. Ten patients with local control of disease had distant metastases and 2 had local and distant recurrences. CONCLUSIONS: Our experience confirms the data of the literature. Postoperative irradiation is a safe and well tolerated treatment which can achieve good local control in high-risk stage I endometrial carcinoma. The control of distant metastases remains an open issue.

Combined modality treatment of locally advanced lung cancer.

This paper describes the mechanisms of action of ionizing radiations combined with antineoplastic drugs. Some relevant drugs for the combined modality treatments of locally advanced lung cancer are reported. The meta-analyses including randomized trials comparing single agent (radiotherapy or chemotherapy) versus combined chemotherapy and radiotherapy in patients with unresectable non small cell lung cancer and limited small cell lung cancer are then reviewed. The clinical outcome in relation to different schedules of chemoradiotherapy (sequential, alternating and concurrent) is also focussed.

Radiation treatment of glottic squamous cell carcinoma, stage I and II: analysis of factors affecting prognosis.

PURPOSE: At least in some European Countries, there is still considerable controversy regarding the choice between surgery and radiotherapy for the treatment of patients with early laryngeal-glottic carcinoma. METHODS AND MATERIALS: Two hundred and forty-six patients with laryngeal-glottic neoplasms, Stage I-II, were treated with radical radiotherapy. Before radiotherapy the patients were evaluated to determine the surgical procedure of choice. Either 66-68.4 Gy (33-38 fractions) or 63-65 Gy (28-29 fractions) of radiation therapy (RT) were administered. The overall disease free survival was determined for each subgroup of patients. Univariate and multivariate analyses were performed to determine significant prognostic variables. RESULTS: Five- and 10-year overall survival rates were 83 and 72%, respectively. At a median follow-up of 6 years 204 patients are alive and disease free. No patient developed distant metastases. One patient died of a large local recurrence, 38 patients died of causes unrelated to their tumor, and 3 patients were lost to follow-up. The multivariate analysis confirmed that performance status (PS), macroscopic presentation of the lesion, and persistence of dysphonia after radiotherapy are significant prognostic factors. CONCLUSIONS: According to the multivariate analysis, the patients with PS > 80 and with exophytic lesions are eligible for radical RT. The surgical procedure proposed for each patient was not found to be an independent prognostic factor.

Paclitaxel as a radiosensitiser: a proposed schedule of administration based on in vitro data and pharmacokinetic calculations.

Paclitaxel is efficacious against many human cancers. Because it blocks cells at the radiosensitive G2-M interface, paclitaxel has been investigated as a radiosensitiser. The results have been equivocal and somewhat contradictory. It is impossible to obtain proper pharmacokinetic calculations, aimed at obtaining maximum cytotoxicity and/or radiosensitisation, without knowing (i) how long the drug must be in contact with the cells, (ii) how long the effect lasts after the drug is removed from the cellular environment, (iii) whether the drug acts as a radiosensitiser even when, like cis-platinum, it is added after the radiation and (iv) what the minimum quantity of drug in the cellular environment is required for both chemotoxicity and radiosensitisation. The present work addresses the above questions. Two radioresistant cell lines of human origin were used, A375 melanoma and S549 lung carcinoma, in a clonogenic assay where only colonies with 50 or more cells were counted. For the irradiation, 6 MV X-rays were used. Any G2-M block was quantified by cell cycle kinetics analysis. From the results, a simulation of pharmacokinetics was conducted to calculate the schedule of administration of paclitaxel most likely to achieve and maintain significant chemotoxocity and radiosensitisation. The minimum concentration of paclitaxel for measurable cytotoxicity was 3 nM for both cell lines, but the drug was more toxic to the A549 cells. The minimum concentration for measurable radiosensitisation was 3 nM for A375 and approximately 0.1 nM for A549, but whereas above 3 nM the radiosensitivity increased in A375, it decreased above 1 nM for A549. A minimum of 18 h incubation with the drug was necessary for measurable effects and the radiosensitising effects were lost soon after its removal. There was no radiosensitisation if paclitaxel was added after the radiation, and, at the minimum effective concentrations, it caused only a minor and transient G2-M block. The pharmacokinetic calculations predict that 15 mg/m2 paclitaxel given as a 1 h infusion 5 days/week for 3 weeks during the radiotherapy should achieve both cytotoxicity and radiosensitisation. The mechanism of radiosensitisation by paclitaxel at the concentrations suggested by our results does not appear to be via a G2-M block and is probably concentration dependent. The results imply that low-dose, daily infusions of paclitaxel for as long as possible during a course of radiotherapy are more likely to result in radiosensitisation and prolonged cytotoxicity than high-dose infusions given once a week.

Variations in tumor levels of cis-platinum through a course of fractionated radiotherapy in patients with non-small cell lung cancer.

AIMS AND BACKGROUND: Radiation has been shown to affect the uptake of micromolecules by the tissues within the radiation fields. We measured tumor drug uptake throughout a course of radiotherapy for stage III non-operable non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Thirty patients were treated with radiotherapy consisting of 15 fractions of 300 cGy given over 3 weeks. They were divided into groups of 2. At 1.5 hr before a given fraction of radiotherapy, one group was given i.v. a bolus of 6 mg/m2 CDDP (cis-diamminedichloroplatinum). Between 1.5 and 2 hr after radiotherapy, the patients underwent bronchoscopy, during which a biopsy was taken from the tumor mass. A similar procedure was carried out on a different group of 2 patients at each of the 15 radiotherapy fractions. The amount of platinum in the biopsy sample was measured by atomic absorption spectroscopy and expressed as ng platinum/mg tissue. In another 13 patients, a biopsy was taken before beginning the radiotherapy, and they served as controls. RESULTS: The quantity of platinum/g of tissue in the patients was 11 +/- 4.4 ng/mg tissue. During the course of fractionated radiotherapy, the quantity of platinum/g of tumor varied considerably between radiotherapy fractions. Maximum uptake was at fractions 8 and 9 (92 ng platinum/mg tissue) with the minima during the first few fractions and at fractions 10, 11 and 12 (an average 20 ng platinum/mg tissue). CONCLUSIONS: The cyclical variations in the uptake of CDDP by the tumor tissue during the protracted course of fractionated radiotherapy are probably due to the well-known effects of radiation on vascular function and capillary permeability. The results may have implications for future clinical protocols involving chemo- and radiotherapy for the treatment of the disease.

Solitary thyroid metastasis from a renal cell carcinoma diagnosed and treated 12 years before: a case report.

The authors report a case of a solitary thyroid metastasis in a 62-year-old woman. The clinical history of the patient and the histologic findings are consistent with a renal origin of the tumor.

Endometrial stage I carcinoma treated with surgery and adjuvant irradiation: a retrospective analysis.

AIMS AND BACKGROUND: Data from the literature show that the incidence of pelvic recurrences in poor prognosis endometrial carcinoma is significantly reduced by combined surgery and radiotherapy compared to surgery alone. METHODS: In this paper we analyze the results of the combined treatment surgery and adjuvant irradiation in patients with endometrial carcinoma with regard to survival, site of progression, and toxicity. The surgical treatment consisted of total abdominal hysterectomy and bilateral salpingo-oophorectomy in 40 patients. Pelvic and para-aortic node dissection was performed in 19 patients and lymph node sampling in 5. RESULTS: Overall 5-year survival was 85%. One patient had local failure, and 5 patients with local control of disease had distant metastases. Toxicity was mild and transient. CONCLUSIONS: Our experience confirms the data of the literature. Postoperative irradiation is a safe and well-tolerated treatment that can achieve a good local control in high risk, stage I, endometrial carcinoma. The control of distant metastases remains an open question.

Simultaneous radiochemotherapy in the treatment of inoperable, locally advanced head and neck cancers. A single-institution study.

BACKGROUND: Patients with advanced, inoperable head and neck cancers have cure rates of approximately 10-15%. In these patients, concomitant chemoradiotherapy seems to improve local control and survival. 5-Fluorouracil (5-FU) administered by continuous infusion and cisplatin plus concomitant conventional radiation therapy may be promising in treating advanced, inoperable head and neck cancers. METHODS: Forty-five evaluable patients with primary nonmetastatic, inoperable head and neck cancers were treated. From January 1987 to April 1988, the patients were treated with cisplatin plus radiation therapy (Group 1) and from May 1988 to November 1990, they were treated with the same combination plus 5-FU, given in continuous infusion (Group 2). Clinical and pathologic responses were assessed after radiation therapy was completed. Patients who relapsed underwent salvage surgery, if possible. The disease free and overall survival rates of the patients were evaluated. RESULTS: The overall response rate (complete and partial response) was 93%, 60% of which comprised complete remissions. Despite the high response rates obtained in the two groups, the time to progression for complete responses and the median survival time were unsatisfactory (13 [Group 1] and 10 months [Group 2] and 17 [Group 1] and 16 months [Group 2], respectively). The toxicity rate from the two treatments was not relevant. A Grade II mucositis, according to the World Health Organization, was found in 25 patients, and the treatment was interrupted for 7-10 days in 5. CONCLUSIONS: In this study, despite an improvement in the number of complete responses, the chemotherapeutic regimen with or without 5-FU did not prolong the overall patient survival significantly.

Results of three consecutive combined treatments for malignant gliomas. Ten-year experience at a single institution.

Between 1978 and 1988, 108 consecutive patients with malignant gliomas were treated. The patients were divided into 3 groups as follows: Group I, surgery if possible, otherwise biopsy followed by whole-brain irradiation to a total dose of 34 Gy in 4 fractions, VCR (2 mg i.v.), and BCNU (80 mg/m2 i.v.) repeated every 6 weeks; Group II received irradiation as Group I plus VP16 (75 mg/m2) every 3 weeks and BCNU (50 mg/m2 i.v.) every 6 weeks; Group III received 60 Gy in 30 fractions to the tumor bed plus VCR (2 mg i.v.), BCNU (50 mg/m2 i.v.), and CDDP (15 mg/m2 i.v.) every 6 weeks. In group I, 28 patients had stable disease (SD) and 2 patients showed disease progression (PRO). Median survival time was 9 months (range 1-18). In Group II 22 SD's were observed. Median survival time was 6 months (2-16). In the third group of patients 29 SDs and 14 partial remissions (PR) were recorded. Median survival time in this group was 13 months (range: 3-59+ months). In general, the group of patients treated with radical or subtotal surgery and the group of patients included in neurologic classes I-II and with performance status (PS) > or = 70 had a longer survival. In our experience, patients with grade III and IV astrocytoma receiving treatments similar to those described above showed no difference in survival and response. Regardless of treatment, none of the patients experienced severe toxicity.