Radio-oncologic therapeutic strategy in curative treatment of non-small-cell bronchial carcinoma

Radiotherapy is an important modality in the postoperative and primary treatment of non-small cell lung cancer. Treatment results are rather unsatisfactory and have not basically changed in the past 15-20 years. In the nearer past, new treatment strategies were developed, which may contribute to a substantial improvement of the poor prognosis. On one hand, novel fractionation schedules using hyperfractionated accelerated radiation show promising results by improving local control. On the other hand, the main interest of many groups is focussed on a combined modality treatment using radiotherapy plus neoadjuvant or concurrent chemotherapy and surgery. There are numerous reports in the literature which document an advantage in survival of combined modalities over radiotherapy alone with improvements concerning local control as well as distant spread. The bases of the encouraging results is the use of a simultaneous or sequential combination of cisplatin-containing chemotherapy and high dose radiation. The following article reviews the relevant data from the literature with main emphasis on radiochemotherapy regimens.     

Nonstandard fractionation schedules in radiation therapy of head and neck cancer: a review

The authors present an updated review of the clinical trials on hyperfractionated and accelerated fractionation schedules in radiotherapy of head and neck cancer. The available results in terms of survival and local control, and acute and late toxicity data are summarized in order to show the current status of this research field. The new breed of fractionation schedules that are on study, designed on the ground of new rationales, are presented as well. Finally, an introductory overview of combination therapy including non standard fractionation radiotherapy associated with chemotherapy is reported.     

Fluconazole sensitivities of Candida species isolated from the mouths of terminally ill cancer patients

BACKGROUND: It has been suggested that tumors respond differently after irradiation with 10 or more fractions than with less fractionated regimens and that extrapolation from experiments with only a few fractions to "curative" regimens may be invalid. To test this hypothesis, we compared hypofractionated-accelerated treatments with "curative" fractionation schedules in human squamous cell carcinoma in nude mice. MATERIAL AND METHODS: FaDu tumors were transplanted subcutaneously into the hindleg of NMRI nu/nu mice. TCD50 values, i.e., the dose necessary to control 50% of the tumors locally, were determined after irradiation under ambient blood flow conditions with 5 and 10 fractions in 5 days, 10 fractions in 10 days, and 30 fractions in 15 days, 6 weeks or 10 weeks. RESULTS: TCD50 values of the hypofractionated regimens were not significantly different and varied from 41 to 46 Gy. The number of fractions given in the same overall time had no measurable effect on local tumor control. The TCD50 after 30 fractions in 6 weeks was 30 Gy higher than after the hypofractionated regimens. This effect was caused by a substantial increase of TCD50 with overall treatment time, the dose recovered per day was 0.82 Gy (95% CI 0.66; 0.96). alpha/beta eff determined from all data was 58 Gy (13; infinite). CONCLUSIONS: The results of the present study compare well with our previous findings after different "curative" fractionation schedules in the same tumor. Thus, our study does not support that tumors respond differently after application of 10 or more fractions compared to less fractionated regimens. The biological mechanisms that govern the radiation response of FaDu tumors appear to be the same for hypofractionated-accelerated and "curative" regimens. Since only one tumor was investigated, these results cannot be generalized at the present time.     

Continuous hyperfractionated accelerated radiotherapy with/without mitomycin C in head and neck cancer

PURPOSE: To evaluate the effect of mitomycin C to an accelerated hyperfractionated radiation therapy. The aim was to test a very short schedule with/without mitomycin C (MMC) with conventional fractionation in histologically verified squamous cell carcinoma of the head and neck region. METHODS AND MATERIALS: From October 1990 to December 1996, 188 patients entered the trial. Tumors originated in the oral cavity in 54, oropharynx in 82, larynx in 20, and hypopharynx in 32 cases, respectively. Patients' stages were predominantly T3 and T4 (158/188, 84%) and most patients had lymph node metastases (144/188, 77%) at diagnosis. Only 22 patients were female, 166 were male, the median age of patients was 57 years (range 34 to 76 years). Patients were randomized to one of the following three treatment options: conventional fractionation (CF) consisting of 70 Gy in 35 fractions over 7 weeks (65 patients) or continuous hyperfractionated accelerated radiation therapy (V-CHART; 62 patients) or continuous hyperfractionated accelerated radiation therapy with 20 mg/sqm MMC on day 5 (V-CHART + MMC; 61 patients). By the accelerated regimens, the total dose of 55.3 Gy was delivered within 17 consecutive days, by 33 fractions. On day 1, a single dose of 2.5 Gy was given, from day 2 to 17 a dose of 1.65 Gy was delivered twice: the interfraction interval was 6 hours or more. RESULTS: Mucositis was very intense after accelerated therapy, most patients experiencing a grade III/IV reaction. The mucosal reaction did not differ whether MMC was administered or not. Patients treated by accelerated fractionation experienced a confluent mucosal reaction 12-14 days following start of therapy and recovered (no reaction) within 6 weeks. The skin reaction was not considered different in the three treatment groups. Those patients treated with additional chemotherapy experienced a grade III/IV hematologic toxicity in 12/61 patients. Initial complete response (CR) was recorded in 43% following CF, 58% after V-CHART, and 67% after V-CHART + MMC, respectively (p < 0.05). Actuarial survival (Kaplan-Meier) was significantly improved in the combined treated patients. Local tumor control was 28%, 32%, and 56% following CF, V-CHART, and V-CHART + MMC, respectively (p < 0.05). CONCLUSION: We conclude that our continuous hyperfractionated accelerated radiation therapy regimen is equal to conventional fractionation, suggesting that by shortening the overall treatment time from 7 weeks to 17 days a reduction in dose from 70 Gy to 55.3 Gy is possible, with maintenance of local tumor control rates. The administration of MMC to the accelerated regimen is tolerable and improves the outcome for patients significantly.     

Radiation Therapy Oncology Group (RTOG) 88-08 and Eastern Cooperative Oncology Group (ECOG) 4588: preliminary results of a phase III trial in regionally advanced, unresectable non-small-cell lung cancer

BACKGROUND: Regionally advanced, surgically unresectable non-small-cell lung cancer represents a disease with an extremely poor prognosis. External-beam irradiation to the primary tumor and regional lymphatics is generally accepted as standard therapy. The use of more aggressive radiation regimens and the addition of cytotoxic chemotherapy to radiotherapy have yielded conflicting results. Recently, however, results from clinical trials using innovative irradiation delivery techniques or chemotherapy before irradiation have indicated that patients treated with protocols that incorporate these modifications may have higher survival rates than patients receiving standard radiation therapy. PURPOSE: On the basis of these results, the Radiation Therapy Oncology Group (RTOG)-Eastern Cooperative Oncology Group (ECOG) elected to conduct a phase III trial comparing the following regimens: 1) standard radiation therapy, 2) induction chemotherapy followed by standard radiation therapy, and 3) twice-daily radiation therapy. METHODS: Patients with surgically unresectable stage II, IIIA, or IIIB non-small-cell lung cancer were potential candidates. Staging was nonsurgical. Patients were required to have a Karnofsky performance status of 70 or more and weight loss less than 5% for 3 months prior to entry into the trial, to be older than 18 years of age, and to have no metastatic disease. Of the 490 patients registered in the trial, 452 were eligible. The disease in 95% of the patients was stage IIIA or IIIB. More than two thirds of the patients had a Karnofsky performance status of more than 80. Patients were randomly assigned to receive either 60 Gy of radiation therapy delivered at 2 Gy per fraction, 5 days a week, over a 6-week period (standard radiation therapy); induction chemotherapy consisting of cisplatin (100 mg/m2) on days 1 and 29 and 5 mg/m2 vinblastine per week for 5 consecutive weeks beginning on day 1 with cisplatin, followed by standard radiation therapy starting on day 50; or 69.6 Gy delivered at 1.2 Gy per fraction twice daily (hyperfractionated radiation therapy). RESULTS: Toxicity was acceptable, with four treatment-related deaths. Three patients subsequently died of chronic pulmonary complications. Compliance with protocol treatment was acceptable. One-year survival (%) and median survival (months) were as follows: standard radiation therapy--46%, 11.4 months; chemotherapy plus radiotherapy--60%, 13.8 months; and hyperfractionated radiation therapy--51%, 12.3 months. The chemotherapy plus radiotherapy arm was statistically superior to the other two treatment arms (logrank P = .03). CONCLUSIONS: In "good-risk" patients with surgically unresectable non-small-cell lung cancer, induction chemotherapy followed by irradiation was superior to hyperfractionated radiation therapy or standard radiation therapy alone, yielding a statistically significant short-term survival advantage.     

Biology and treatment of malignant glioma

A large number of oncogenes have been identified as aberrant in gliomas, but only the erbB oncogene (gene encoding the epidermal growth factor receptor [EGFR]) is amplified in an appreciable number. The loss or mutation of tumor-suppressor genes located on different autosomes may be associated with progression of malignant gliomas. The p53 tumor-suppressor gene (located on chromosome 17) is frequently associated with the loss of one allele in malignant gliomas, although a large number of malignant gliomas have no p53 mutations. Some of the latter tumors have an amplified murine double minute 2 (MDM2) gene, which suppresses p53 gene activity. Genetic material from chromosome 10 may also be lost, especially in glioblastoma multiforme. In addition to the aberrant expression of EGFR, another growth factor, platelet-derived growth factor, or PDGF (ligand and/or receptors) can be overexpressed, giving cells a selective growth advantage. The blood-brain barrier is substantially altered in malignant gliomas, resulting in cerebral edema. Therapy for malignant gliomas includes surgery, radiation therapy, and chemotherapy. Surgical resection that leaves little residual tumor produces longer survival than less vigorous surgery. Radiation therapy to a dose of at least 60 Gy is required to treat malignant gliomas. Increased survival beyond that produced by standard external radiotherapy requires much larger doses; interstitial radiotherapy permits such dosing. Radiosurgery is being tested. Chemotherapy with nitrosoureas is modestly useful but appears to benefit patients with anaplastic astrocytoma more so than those with glioblastoma.     

Irradiation of advanced head and neck cancer with large daily fractions. Preliminary results of a prospectively randomized clinical trial

The irradiation of locally advanced, inoperable, squamous cell caricinomas of the head and neck with conventional fractionation schedules using 200 rads/day has produced poor results. A prospectively randomized, clinical trial has been started comparing conventional with large daily fractions of 400 rads/day for 10-12 treatments. Results suggest that improved tumor control and survival rates might be obtained with the use of large daily fractions.     

Variants of fractionation of irradiation in intracavitary gamma-therapy

Under study was the efficacy of three schedules of dose fractionation in intracavitary gamma-therapy in cervical cancer patients treated on the machine "AGAT-B". Single doses were 1000, 700 and 500 rad, while total dosage at point A depending on the stage of the disease was within the range of 4000-5000 rad. The survival during the first, second and third years following termination of the radiotherapy was found to be identical for patients of all the groups under examination. No differences were noted in them also in the character of early radiation reactions on the part of the adjacent organs. The frequency and severity of late radiation injuries of the urinary bladder, rectum and vagina were related to the dose fractionation regimen.     

Trichloroethylene, tetrachloroethylene, nitrates, and other chemicals in well water in the Fresno-Clovis Metropolitan Area

Conventional treatment of medulloblastoma has involved surgery to the primary tumour and radiotherapy to the primary site and craniospinal axis. However CNS irradiation in a young child may result in significant side effects. Thus new treatment strategies have emerged which include chemotherapy, given in order to delay radiotherapy, to enable radiation dose reduction to the primary site and craniospinal axis, or even to eliminate radiotherapy completely. Such treatments have not yet been adequately evaluated in terms of survival and late effects. We report a retrospective study of 37 patients under the age of 36 months treated with postoperative craniospinal irradiation, in which the radiation dose to the neuroaxis was below conventional dosage. The overall actuarial 10-year survival rate was 44% and the actuarial 10-year relapse tree survival rate was 54%. Both radiotherapy and chemotherapy contributed to morbidity and mortality. Tour of 16 patients who survived longer than 10 years had no hard neurological signs; all but one patient have required extra support at school. Of nine patients available for work, two have obtained employment but only one has maintained this. No young adults have married. Despite lower doses of radiation, all but 1 survivor has significant spine shortening, and all who reached final height were short. Further work is needed to complete the profile of late effects in this group, which should include the survivors own perceptions of quality of life. It is hoped that multimodality treatment and supportive care can sustain acceptable survival rates but reduce the burden of late effects.     

Radiobiologically based assessments of the net costs of fractionated focal radiotherapy

PURPOSE: To assess the potential changes in the net costs of focal radiotherapy techniques at differing doses per fraction and interfraction intervals. METHODS: Linear quadratic radiobiological modeling is used with appropriate variations in the radiosensitivity and tumor cell proliferation parameters. The notional cost of treatment is calculated from the number of fractions, cost per fraction and the cost of treatment failure, which is itself related to (1-TCP) where TCP is the tumor cure probability. Additional Monte Carlo calculations from ranges of radiobiological parameters have been used to simulate the cost of treatment of tumor populations. RESULTS: The optimum dose per fraction (and optimum overall cost) for conventional (nonfocal) radiotherapy is generally at low doses of around 2 Gy per fraction. The use of hyperfractionated and accelerated radiotherapy in addition to focal radiotherapy techniques appear to be indicated for more radioresistant tumors and if tumor proliferation is extremely rapid, but the need for treatment acceleration is much reduced where effective focal techniques are used. CONCLUSIONS: Radiobiological and economic modeling can be used to guide clinical choices of dose fractionation techniques providing the key radiobiological parameters are known or if the ranges of likely parameters in a tumor population are known. Focal radiotherapy, by the introduction of changes in the physical dose distribution, produces an upward shift in the optimum dose per fraction and a reduced dependency on overall treatment time.     

Study on clinical application of multiple fractions per day radiation therapy with concomitant boost technique for esophageal cancer

A continuous multiple fractions per day irradiation (MFD) using twice-a-day (BID) fractionation in the similar form of concomitant boost was devised for the treatment of advanced esophageal cancer. From Oct. 1985 to July 1991 60 patients were entered in this clinical trial and were compared with 64 patients who were treated with conventional once-a-day irradiation (CF) from July 1977 to July 1989 in survival, local control, acute and late effect. The altered fractionation schedule employed continuous concomitant boost technique with reduced field for primary site being irradiated twice-a-day. Daily fraction size were 2 Gy with large field including primary and regional lymphatics and 1.1, 1.15 and 1.2Gy with concomitant boost. Total dose of 62, 63 and 64Gy were administered in 40 fraction for 5 weeks. Acute reaction caused radiation mediastinitis, pneumonitis and esophagitis, but severe injury which interrupted treatment did not occur. Late reaction consisted of 8 radiation induced stricture [RIS] (13.3%), 2 radiation induced pericarditis(3.3%) and 1 bronchial ulcer(1.7%) in MFD. Particularly, RIS in 3.2Gy/2f/day group of MFD developed with higher frequency than in CF and another daily fraction size. Patients treated with CF and MFD experienced 5 year loco-recurrence free survival of 27.3% and 57.2% respectively (P < 0.001), which translated into 5 year cause-specific survival 13.9% and 31.5%, respectively (P < 0.05). Significant advantage in adjusted local-recurrence free survival using multivariable analysis was shown (P < 0.005). Also, a border line advantage in adjusted survival using clinical stage is now appearing in MFD as a consequence of the increased local control rate. There was no significant difference in survival and local-recurrence free survival among each daily dose groups. We concluded that our regimen of MFD using optimal daily dose of 3.15Gy/2f/day with continuous concomitant boost technique resulted in improved local control and survival rate of treatment of esophageal cancer without severe late reaction.     

Concomitant infusion cisplatin and hyperfractionated radiotherapy for locally advanced nasopharyngeal and paranasal sinus tumors

PURPOSE: This is a prospective study to improve the therapeutic ratio in the treatment of patients with locally advanced nasopharyngeal and paranasal sinus tumors by using split-course concomitant infusion cisplatin chemotherapy and hyperfractionated radiotherapy. METHODS AND MATERIALS: From 1983 to 1993, 21 patients with locally advanced nasopharyngeal and paranasal sinus tumors (T3 and T4, or recurrent tumors involving the facial bones and/or the base of the skull) were treated with a regimen of split-course hyperfractioned radiotherapy (1.2 Gy/fraction/bid) and concomitant infusion cisplatin (5-10 mg/m2/24 h). The therapy was given in three separate 2-week sessions with 1 to 2 week breaks between sessions. Seventeen of 21 patients were treated with curative intent with cumulative radiation doses ranging from 64.8 to 70.8 Gy. Four patients were treated with palliative intent to a total dose of less than 60 Gy or to a limited field due to previous irradiation. RESULTS: Sixteen of 17 patients (94%) treated curatively achieved a complete response. Of the 16 patients who achieved complete response, 7 patients (50%) were alive at the time of analysis (36 to 126 months). One patient was alive at 4 years with no evidence of disease, and died in 10 years at the age of 80 of unknown cause. Two patients died of local recurrence at 21 and 45 months and one patient died of a cerebrovascular accident at 12 months with disease status unknown. Five patients died of distant metastases. The one patient who had a partial response died in 25 months with local disease and metastases to the bone and lung. Four patients that were previously irradiated received a reduced total dose or treated to a limited irradiation field. All had near complete responses, but died within a year of treatment, with the exception of one patient who died at 23 months. Acute reactions included intense erythema of the mucosa in all patients. Five of 21 (23%) developed punctate mucositis and 3 of 21 (14%) developed confluent mucositis. Hematologically, one patient developed neutropenia (1800 WBC/mm3) and one developed thrombocytopenia (38,000/mm3). A rising creatinine was observed in three patients (2.0, 1.7, 1.7) all of whom were treated with the higher 10 mg/m2/day dose of infusional cisplatin. In all three of these cases, the creatinine slowly returned to normal over a 6-month period. Hormonal evaluations were performed in three patients and all were within normal ranges. There was no evidence of neck fibrosis or trismus. One patient with gross recurrent disease of the orbit developed blindness of the involved eye due to corneal opacification. The orbital area had been reirradiated in this patient. CONCLUSIONS: Concomitant infusion cisplatinum with hyperfractionated radiation improved tumor control, but did not increase normal tissue injury. Acute reactions were minimized by splitting the treatment with a 1- to 2-week break after each 2 weeks of radiation treatment. Late complications were not increased by using a hyperfractionated radiation regimen. The local failure rate was only 18% (3 of 17 patients), but the distant failure rate was 35% (6 patients). Further investigation is needed to prove if adjuvant chemotherapy after concomitant chemoradiation improves survival by decreasing the distant failure in such advanced cases.     

Principles of treatment of malignant gliomas in adults: an overview

The cornerstone of conventional treatments of malignant gliomas in adults has been surgical debulking, radiation therapy and chemotherapy. Almost always a combination of these treatments is used. With these conventional treatments the outcome, as measured by survival and quality of life, has remained universally dismal. Novel treatments, which are at different stages of laboratory and clinical trials, may offer a ray of hope for treatment of malignant gliomas. Development of these methods are directly related to the discoveries, over the past two decades, of cellular and molecular mechanisms involved in the genesis of brain tumors. Understanding of the mechanisms of tumor genesis may open new avenues of effective treatments for this devastating cancer.     

Resection, biopsy, and survival in malignant glial neoplasms. A retrospective study of clinical parameters, therapy, and outcome

Between July, 1984, and October, 1988, 263 patients (163 male, 100 female), aged from 4 to 83 years (mean 52 years), with malignant brain gliomas underwent surgical procedures: stereotactic biopsy in 160 and resection in 103 patients. There were 170 grade IV astrocytomas, 17 grade IV mixed oligoastrocytomas, 44 grade III astrocytomas, 22 grade III mixed oligoastrocytomas, and 10 malignant oligodendrogliomas. Overall median survival time was 30.1 weeks for grade IV gliomas, 87.7 weeks for grade III gliomas, and 171.3 weeks for malignant oligodendrogliomas. Multivariate analysis in 218 newly diagnosed cases revealed that the variables most strongly correlated with survival time were: tumor grade, patient age, seizures as a first symptom, a Karnofsky Performance Scale score of less than 70%, tumor resection, and a radiation therapy dose greater than 50 Gy. The proportions of patients receiving tumor resection versus biopsy in each of these prognosis factor groups were similar. Since most of the 22 patients with midline and brain-stem tumors were treated with biopsy alone, these were excluded. Considering 196 newly diagnosed patients with cortical and subcortical tumors, grade IV glioma patients undergoing resection of the contrast-enhancing mass (as evidenced on computerized tomography and magnetic resonance imaging) and postoperative external beam radiation therapy lived longer than those undergoing biopsy only and radiation therapy (median survival time 50.6 weeks and 33.0 weeks, respectively; Smirnov test, p = 0.0380). However, survival in patients with resected grade III gliomas was no better than in those with biopsied grade III lesions (p = 0.746). The authors conclude that, in selected grade IV gliomas, resection of the contrast-enhancing mass followed by radiation therapy is associated with longer survival times than radiation therapy after biopsy alone.     

Radiotherapy for nasolacrimal tract epithelial cancer

PURPOSE: Tumors of the lacrimal sac are rare and have traditionally been treated surgically. We investigated the use of irradiation for treatment. METHODS AND MATERIALS: Three consecutive patients with primary epithelial cancer of the nasolacrimal apparatus were treated with irradiation. A tumor dose of 52-66 Gy was delivered with conventional fractionation to fields limited to the primary site and immediately surrounding tissues. RESULTS: Local tumor control was achieved in all three patients. Two patients subsequently developed metastatic cervical adenopathy; both were controlled with irradiation to the neck. One of these two died of distant metastases. Two patients are alive and well at 13 years and at 26 months. CONCLUSION: We conclude that epithelial lacrimal sac tumors are controllable by radiation therapy and with a good cosmetic result. Poorly differentiated lesions require elective cervical nodal irradiation.     

Enhancement of tumor radiation response by the antivascular agent 5,6-dimethylxanthenone-4-acetic acid

PURPOSE: 5,6-dimethylxanthenone-4-acetic acid (DMXAA) selectively damages tumor vasculature and is currently in clinical trial as an antitumor agent. Its ability to induce synthesis of tumor necrosis factor (TNF), and its apparent selectivity for poorly-perfused regions in tumors, suggests it possible use in combination with radiotherapy. This investigation examines activity of DMXAA as a radiation modifier using two murine tumors. METHODS AND MATERIALS: Tumor growth delay was evaluated using i.m. RIF-1 and MDAH-MCa-4 tumors irradiated in unanaesthetised, restrained mice (cobalt-60) using single dose or multiple fractions (8 x 2.5 Gy over 4 days) with DMXAA administered i.p. at various times in relation to irradiation. RESULTS: Administration of DMXAA (80 micromol/kg, i.p.) immediately after radiation resulted in a large increase in tumor growth delay, giving a radiation dose modifying factor of 2.3 for RIF-1 and 3.9 for MDAH-MCa-4. The combination was less active when radiation was given 1-4 h after DMXAA, but was highly active 12-48 h after DMXAA. At the latter times, clamping the tumor blood supply caused a large increase in radioresistance. These studies suggest that cells surviving DMXAA are hypoxic for only a short period. DMXAA increased overall growth delay when administered daily during fractionated irradiation, giving an approximately additive response. CONCLUSIONS: The marked synergy between DMXAA and single dose ionising radiation may reflect the complementarity of these agents at the microregional level, with DMXAA preferentially killing hypoxic cells in poorly perfused regions. Despite additional hypoxia shortly after DMXAA treatment, surviving cells appear to reoxygenate quickly which makes it feasible to use DMXAA before and during fractionated radiotherapy. The combination of fractionated radiation and DMXAA appears to be less effective than for single dose radiation (possibly because of the smaller contribution of hypoxia under these conditions), but may be therapeutically useful.     

Induction therapy for esophageal cancer with paclitaxel and hyperfractionated radiotherapy: a phase I and II study

OBJECTIVE: Induction chemoradiotherapy followed by surgery may improve survival rates among patients with esophageal carcinoma. We designed a novel intense induction regimen with paclitaxel and high-dose hyperfractionated radiotherapy to maximize complete response rates. METHODS: Forty patients with esophageal cancer were treated in a phase I and II trial of induction chemotherapy (cisplatin, 5-fluorouracil, and paclitaxel) at three dosage levels (75, 125, and 100 mg/m2) and concurrent hyperfractionated radiotherapy (45 Gy to the mediastinum, 58.5 Gy to the tumor). The mean age was 62 years, and 32 patients (80%) had adenocarcinoma. Twenty-eight of 40 (70%) patients had locally advanced tumors (T3, or stage IIB or greater). RESULTS: The average hospitalization for induction treatment was 17 days. Toxicity was substantial, with esophagitis necessitating nutritional support the most common complication. The maximum tolerated dose of paclitaxel was 100 mg/m2. Two patients died during induction treatment. Thirty-six patients (90%) underwent resection. The median length of stay was 10 days, and two patients died after the operation. Fourteen of 36 patients (39%) had a pathologic complete response. Patients who received all prescribed chemotherapy had a higher pathologic complete response rate (50%) than did patients who required dose reduction (17%; p = 0.076). The 2-year survival rate was 61% (95% CI 35% to 86%) with a median follow-up of 11.9 months. CONCLUSIONS: Paclitaxel at a dose of 100 mg/m2 appears to have acceptable toxicity. The high pathologic complete response rate in this regimen is encouraging, but it is associated with substantial toxicity. The toxicity of this regimen is not acceptable and will require substantial reduction in the radiation component. Survival data are too short-term to confirm enhanced survival.     

Genetic relatedness and diversity of Cryptococcus neoformans strains in the Maltese Islands

PURPOSE: Pilocarpine, a salivary stimulant, has been shown to protect salivary glands from gamma-radiation-induced damage during the radiotherapy of head and neck tumors. This study was performed to determine whether pilocarpine affects the survival of squamous carcinoma cells, line SCC-25, following gamma-radiation treatment. METHODS AND MATERIALS: The survival of squamous carcinoma tumor cells, line SCC-25, following the exposure of cells to pilocarpine at concentration of 0-100 ng/ml given for 0-1 h prior to radiation at dose of 0-20 Gy was determined by an in vitro colony-formation assay. RESULTS: The survival fractions of SCC-25 cells were identical for the control and pilocarpine-treated samples at all tested conditions. Calculated Do and Dq values did not depend on the presence of pilocarpine and were not affected by the time of incubation prior to irradiation. CONCLUSION: Pilocarpine, at clinically relevant concentrations, given to the SCC-25 cells 1 h prior to or at the time of irradiation did not affect survival of SCC-25 cells in vitro. Pilocarpine does not sensitize or protect these tumor cells from the effects of y-radiation, suggesting that this agent should not compromise the tumoricidal effects of radiotherapy.     

Controlled trial of falecalcitriol versus alfacalcidol in suppression of parathyroid hormone in hemodialysis patients with secondary hyperparathyroidism

Since the first reports in the late 1950's, a large amount of data have been collected. The analysis of the main evidence from the major randomized trials will be analyzed in this paper according to preoperative, postoperative and chemoradiation approaches. Fifteen randomized preoperative trials were reported; they have been grouped according to the fractionation schedule. In the hypofractionation group (5 Gy for fraction), all five studies that delivered 3-5 doses in one week had a significant improvement in local control and one of them also showed improvement in survival. Operative mortality was higher in the radiotherapy arm if inadequate techniques had been applied. In 3 out of 8 studies with conventional fractionation there was a significant improvement in local control, but no impact in survival was detected. No studies with total dose lower than 34 Gy had an improvement in local control. None of the six randomized postoperative studies showed an improvement in local control or survival. In all trials the local control rate was uniform; ranging from 76% to 84%. Toxicity was higher in the radiotherapy arm. One preoperative and five postoperative randomized studies that used chemoradiation were analyzed. One postoperative chemoradiation study showed a significant improvement in survival in comparison to the surgery arm, and another showed the same advantage compared to the postoperative arm. Protracted infusional administration of 5FU concomitant to radiotherapy showed better survival than bolus administration. No advantages were shown in using MeCCNU or Levamisole in two studies. Toxicity was high and related to the dose and the modality of administration of the drugs in order to adequately treat the different stages of rectal cancer, patients must be carefully selected in order to prescribe the most effective and the least toxic treatment for the individual stage; organ preservation should be an essential goal for its impact on quality of life, and the cost estimates should be taken into account.     

Placental transfer and maternally acquired neonatal IgG immunity in human immunodeficiency virus infection

PURPOSE: The effect of the sensitizer razoxane on soft tissue sarcomas (STS) was prospectively evaluated in a randomized, controlled trial. The main purpose of the study was to determine the response rates and local control under the combined treatment compared to irradiation alone. METHODS AND MATERIALS: Between 1978 and 1988, 144 patients entered the study; 130 were evaluable for response, toxicity, or survival. The patients were randomized to receive radiotherapy alone or radiotherapy with razoxane. They were divided into postoperative cases and patients with gross disease (unresectable primaries, recurrent disease, or metastatic disease). The median radiation dose was 60 Gy postoperatively, and 56-58 Gy in patients with gross disease. The dose difference has palliative reasons. Razoxane was given orally at a daily dose of 150 mg/m2 during the time of the radiotherapy, starting 5 days before the first irradiation. In general, the groups were comparable as to their prognostic factors. There was some imbalance, however, in favor of the postoperative group reveiving radiotherapy alone. RESULTS: Between the patient groups treated postoperatively in an adjuvant form, there were no substantial differences in local control and survival. Among 82 patients with gross disease, the treatment with radiotherapy and razoxane led to an increased response rate compared to photon irradiation alone (74 vs. 49%). The local control rate was likewise improved (64 vs. 30%;p < 0.05). The acute toxicity was somewhat higher in the sensitizer arm, but there was no difference in the occurrence of late complications. CONCLUSIONS: Radiotherapy combined with razoxane seems to improve the local control in inoperable, residual, or recurrent STS compared to radiotherapy alone. The combined treatment is a fairly well tolerated procedure at low costs. It can be recommended for inoperable primary STS or gross disease after incomplete resection, conditions which are still associated with limited local control and a grave prognosis.