Adult brain low-grade astrocytomas: survival after surgery and radiotherapy.

In order to identify prognostic factors of survival, twelve elements of disease and treatment have been evaluated for a population of 49 patients with diffuse low-grade astrocytoma treated with surgical resection and radiotherapy. The survival values were inversely correlated with age and major residual portion. On the other hand, KPS, lobar site, grade II Daumas-Duport lesions, protoplasmatic variant, early epilepsy, hyperfractionated radiotherapy and extent of exeresis were prognostic factors correlated with survival. Tumor extent and radiation total dose were not correlated in a meaningful way. Only KPS was statistically significant when compared to all the prognostic factors. We believe that patient selection according to age, lesion site and histological features are not sufficient to generate a homogeneous tumoral population. The most appropriate therapy for treating low-grade astrocytomas is still an open subject. However, recent studies have shown that the prognostic value of a group of factors is useful to plan controlled studies that compare differentiated treatment protocols.

Current status of surgery for carcinoma of the hypopharynx and cervical esophagus.

Hypopharynx and cervical esophagus represent a critical location for a squamous cell carcinoma, a neoplasm that usually requires extensive surgery. Although morbidity and mortality of resection have markedly decreased over the past decade, the major issue in these patients remains quality of life owing to the need for combination with a laryngectomy to provide radical treatment. Chemoradiation therapy has the potential to downstage and even cure the disease without altering quality of life dramatically. Today, in the absence of randomized trials, the choice between surgery and definitive chemoradiotherapy should be based on clear information and the patient's preference. Salvage surgery is feasible and effective in selected patients.

Clinical results of unconventional fractionation radiotherapy in central nervous system tumors.

Malignant brain tumors (primary and metastatic) are apparently resistant to most therapeutic efforts. Several randomized trials have provided evidence supporting the efficacy of radiation therapy. Attempts at improving the results of external beam radiotherapy include altered fractionation, radiation sensitizers and concomitant chemotherapy. In low-grade gliomas, all clinical studies with radiotherapy have employed conventional dose fractionation regimens. In high-grade gliomas, hypofractionation schedules represent effective palliative regimens in poor prognosis subsets of patients; short-term survival in these patients has not allowed to evaluate late toxicity. In tumors arising within the central nervous system, hyperfractionated irradiation exploits the differences in repair capacity between tumour and late responding normal tissues. It may allow for higher total dose and may result in increased tumor cell kill. Accelerated radiotherapy may reduce the repopulation of tumor cells between fractions. It may potentially improve tumor control for a given dose level, provided that there is no increase in late normal tissue injury. In supratentorial malignant gliomas, superiority of accelerated hyperfractionated over conventionally fractionated schedules was observed in a randomized trial; however, the gain in survival was less than 6 months. At present no other randomized trial supports the preferential choice for altered fractionation irradiation. Also in pediatric brainstem tumors there are no data to confirm the routine use of hyperfractionated irradiation, and significant late sequelae have been reported in the few long-term survivors. Shorter treatment courses with accelerated hyperfractionated radiotherapy may represent a useful alternative to conventional irradiation for the palliation of brain metastases. Different considerations have been proposed to explain this gap between theory and clinical data. Patients included in dose/effect studies are not stratified by prognostic factors and other treatment-related parameters. This observation precludes any definite conclusion about the relative role of conventional and of altered fractionation. New approaches are currently in progress. More prolonged radiation treatments, up to higher total doses, could delay time to tumor progression and improve survival in good prognosis subsets of patients; altered fractionation may be an effective therapeutic tool to achieve this goal.

Micronuclei in cytokinesis-blocked lymphocytes may predict patient response to radiotherapy.

We have applied the cytokinesis-block micronucleus assay to peripheral blood lymphocytes of patients undergoing radiotherapy in pelvic and pulmonary sites, in order to evaluate the individual cytogenetic response. Our cytogenetic data correlated with the equivalent whole-body dose are homogeneous and compare well with the data presented by other authors. We have used an exponential mathematical formula to calculate the attenuation of the cytogenetic effect with time. The k coefficient (cytogenetic recovery factor) in the formula expresses the degree of attenuation. In lymphocytes from patients after radiotherapy, the trend of the micronucleus frequency observed after 2 Gy of in vitro X-irradiation demonstrates that the cytogenetic effect obtained in vitro is added to that obtained in vivo. The k coefficient is inversely proportional to the micronucleus frequency observed after 2 Gy in vitro. The micronucleus assay and the cytogenetic recovery factor are proposed as suitable diagnostic tools for application in the field of radiotherapy.

[High-dose-rate brachytherapy in esophageal carcinoma: the Italian experience]. / Brachiterapia con alto rateo di dose del carcinoma esofageo: esperienza italiana.

The results are reported of HDR intracavitary brachytherapy in 134 esophageal carcinoma patients (110 men and 24 women) treated in 10 Italian centers. Forty-one patients received radical treatment and brachytherapy was often combined with external irradiation and/or chemotherapy. Clinical response rates follow: 56% complete remissions, 34% partial remissions, 10% no response/disease progression and not assessed. Ninety-three patients underwent palliative treatment: dysphagia was reduced in 80% of them and pain was reduced in 71% of them. Treatment-induced esophageal damage consisted in G3-G4 esophagitis (5% of patients), strictures (10%) and fistulas (3%). Complication rates were correlated with fraction dose (9.5% complications for fraction doses < 500 cGy, 20% with doses ranging 500-800 cGy and 38% with fraction doses > 800 cGy). Moreover, the esophagus was more severely injured when small tubes were used (24% with tubes phi < 2 mm, 19% with tubes phi 2-6 mm and 5% with tubes phi > 6 mm). When external irradiation was combined with brachytherapy, dysphagia was more relieved than with brachytherapy alone (89% vs. 71%), with no increase in complication rates. Also the chemotherapy-brachytherapy combination improved swallowing more than brachytherapy alone (88% vs. 79%) and once again complication rates did not increase. To conclude, in the radical treatment of esophageal carcinoma, HDR brachytherapy permits higher radiation doses to be delivered, with fair complication rates. As for palliative treatment, HDR brachytherapy is safe, has low morbidity and provides adequate relief of dysphagia in 80% of patients. We suggest the use of tubes phi > 6 mm and fraction doses ranging 5-6 Gy.

[Effects of immunomodulation on antineoplastic radiotherapy. A controlled clinical study]. / Effetti dell'immunomodulazione nella radioterapia antineoplastica. Studio clinico controllato.

It is well known that thymic hormones can counteract immunodepression due to radiation therapy, preventing and reducing the severity and the number of myelotoxic and hematologic reactions. We tried to confirm these findings in a controlled multicenter clinical study involving 1,060 patients undergoing radiation therapy (580 treated with thymopentin 50 mg s.c. every other day, after irradiation and for at least 6 cycles of 4 weeks each, and 480 control patients). Highly statistically significant results (to the ANOVA test) were obtained in the protection against radiation-induced leukopenia in the treated group; furthermore, the treated patients had a marked reduction (p = 0.003 chi 2 test) in the early delayed reactions to irradiation, namely in the upper aero-digestive tract. In general, we observed a better, but not statistically significant recovery of the blood parameters, lymphocyte subsets and skin tests in the treated group versus the control group. Both of the treated groups showed the same trend for Karnofsky performance status and body weight. The local and general protection provided by thymopentin against the reactions to irradiation could be advantageously used for the administration of higher doses of radiation therapy.

Carboplatin combined with carmustine and etoposide in the treatment of glioblastoma.

The aim of this study was to verify the tolerability and efficacy of therapeutic chemotherapy protocols, employing different combinations of cisplatin, carboplatin, etoposide and carmustine in primary glioblastoma patients. The purpose was focused on 2 end points: the response index to treatment, the TTP (tumor progression) and the ST (survival time). Eighty-four out of a group of 99 consecutive glioblastoma patients, entered this study. Patients were divided into 4 disparate treatment groups: (A) BCNU alone; (B) CDDP + VP-16; (C) CBDCA + BCNU; (D) CBDCA + BCNU + VP-16. The effectiveness and the TTP of the protocols differed, but differences were not statistically significant. Data concerning platinum treatment compare favorably with the best literature results. At 18 months more than half the carboplatin-treated patients are alive. Moreover these patients had a significantly longer ST than those treated with BCNU. We conclude that platinum-based chemotherapy has a beneficial effect on glial tumors.

Primary glial tumor patients treated by combining cis-platin and etoposide.

Thirty eight patients with malignant gliomas (27 GBM and 11 AA) were treated with up to 7 cycles of CDDP + VP16 every month after surgery. Chemotherapy was planned as two cycles before and 5 cycles after radiation (42 Gy) using a three times daily fractionation schedule. No severe toxicity was observed. The object of our study was to investigate the antitumor effectiveness by combining CDDP plus VP16 against primary malignant glial tumors. The time to tumor progression (TTP) and survival time (ST) of the GBM patients in the present study were 38.5 and 68.5 weeks respectively. The TTP of the AA patients was 73 weeks and the ST was not calculated as most patients are still alive. By the 18th. month after surgery, 38% of GBM and 74% of AA patients treated with (CDDP + VP16) are still alive. This study demonstrates that the combination of CDDP and VP16 is effective in patients with malignant gliomas.

Local immunotherapy (beta-IFN) and systemic chemotherapy in primary glial tumors.

Dosage and schedules for the treatment of malignant glial tumors using IFN (interferon) are still uncertain and controversial. In this study we give the preliminary results of treatment in 28 patients with glioblastoma multiforme (GBM). 6 patients were treated with local injection of beta-IFN through an Ommaya reservoir; 4 patients with beta-IFN followed by systemic chemotherapy (Cisplatin + Etoposide), and 18 patients with chemotherapy only. Two end points were evaluated: 1) Whether or not the patients responded to treatment. 2) Length of Time to Tumor Progression (TTP) after surgery. We found that IFN alone was ineffective. Results were improved when local immunotherapy was associated with systemic chemotherapy. New drugs and investigation of possible pharmacological synergism are needed.

Cisplatin and etoposide combination therapy for primary glial tumors: preliminary results.

In this preliminary trial we studied 29 patients with primary malignant glial tumors to investigate the effectiveness of cisplatin combined with etoposide on these tumors. Hyperfractionated radiation therapy was given in the course of chemotherapy. The time to tumor progression in these glioblastoma multiforme (GBM) patients encouraged us to continue this treatment in a phase III study.

[Drug therapy with disodium clodronate combined with radiotherapy of bone metastasis of solid tumors]. / Integrazione farmacologica con disodioclodronato alla radioterapia delle metastasi ossee di tumori solidi.

The largest portion of a radiation oncologist's practice is aimed at the palliative treatment of bone metastases. This trial investigated the impact of disodiumclodronate on radiation therapy results. Two groups of patients with bone metastases were compared: one (176 patients) treated by radiation therapy alone, the other (242 patients) by combined radiotherapy and disodiumclodronate. The evaluated parameters were changes in the volume of bone destruction, pain rating, performance status scale, and percentage of disease progression, as they appeared on pre and post-irradiation CT scans. In the disodiumclodronate group, a significant improvement was observed in the bone metastases from breast, prostate, and non-small cell lung cancers. As for bone metastases from urinary and gastro-intestinal cancers, disodiumclodronate did not prove to be much effective in improving radiation therapy results. Independent of primary tumor location, disodiumclodronate had a marked protective effect on both local disease progression and appearance of new lytic areas. In our experience, response duration was directly correlated with the actual time of disodiumclodronate administration. Toxicity was minimal, which makes it probable for disodiumclodronate to become an important adjunct to bone radiation therapy.

Preliminary data by cis-platin and etoposide using in primary glioblastoma.

In this preliminary study twenty-nine malignant glioma patients after surgery were treated using Cis-platin (CDDP) combined with etoposide (VP16). Superfractionated radiation therapy comes into chemotherapy. The time to tumor progression in GBM patients is encouraging result to continue in this treatment.

Intratumoral beta interferon and systemic chemotherapy. Preliminary data in GBM patients.

Doses and schedules for treatment of malignant glial tumors, using IFN are still uncertain and controversial. In this study preliminary results of treatment of 10 glioblastoma multiforme patients are shown. Six patients were treated with local injection of beta-IFN through an Ommaya reservoir: 4 with beta-IFN followed by systemic chemotherapy (CDDP-VP16); we found that IFN alone was ineffective. Results were improved when local immunotherapy was associated with systemic chemotherapy. New drugs and investigation of possible pharmacological synergism are needed.

A randomized clinical trial comparing radiation therapy v radiation therapy plus cis-dichlorodiammine platinum (II) in the treatment of locally advanced non-small cell lung cancer.

Cis-Dichlorodiammine platinum (II) (cis-DDP) was demonstrated to be a potentiator of radiation therapy (RT) in experimental tumor models and in cultured cells. To assess the effectiveness of a combined modality treatment including RT and a weekly low-dose administration of cis-DDP, from January 1986 to June 1987, 95 patients with unresectable locally advanced non-small cell carcinoma of the lung (stage IIIa, b) were randomized for study. Fifty patients received RT alone at doses of 50 Gy; 45 patients received the same RT plus cis-DDP 15 mg/m2 IV weekly. An overall response rate of 50% and 64% was observed in the RT and RT + cis-DDP group, respectively. No statistically significant differences were detected with regard to median survival time (11 months for RT v 16 months for RT + cis-DDP) and progression-free interval (7 months in the RT arm v 9 months in the RT + cis-DDP arm), but the patterns of the first failure appeared to be affected by treatment. In fact, a lower number of intrathoracic relapses was observed in the RT + cis-DDP arm (12 in the RT + cis-DDP v 23 in the RT arm). Toxicity was mild and the feasibility of this schedule must be remarked. A better local control of disease can be obtained using cis-DDP as a radiation potentiator, but the true influence of this combined modality treatment on the length of survival, and the optimal cis-DDP timing and dosage are still to be evaluated in further clinical trials.

Cis-platin and radiotherapy in the treatment of unresectable lung cancer.

The goal of this pilot study was to verify the efficacy of the association of cisplatin plus radiotherapy in the treatment of lung cancer. Thirty-seven consecutive patients entered the study. They were treated with radiotherapy (four weekly doses of 2.5 Gy for a total of 50 Gy) and cis-platin once weekly (12 mg/m2). Partial remission was obtained in 15 patients, and 1 patient had a complete remission. Three patients previously inoperable underwent surgical treatment. The actuarial survival curve of the 29 evaluable patients showed a mean survival of 8.5 months. The mean survival of the latter is not evaluable because half of the patients are still alive after 12 to 30 months. No hematologic or renal toxicity was observed with the above schedule.