Individualized higher dose of 70-75 Gy using five-fraction robotic stereotactic radiotherapy for non-small-cell lung cancer: a feasibility study.

OBJECTIVE: To determine whether robotic stereotactic radiotherapy of 70-75 Gy delivered in five fractions results in an improved therapeutic ratio, compared with three fractions, in the treatment of peripheral non-small-cell lung cancer (NSCLC), in which case doses of up to 85 Gy in five fractions may be feasible. MATERIALS AND METHODS: Between December 2006 and May 2010, 20 patients (9 female, 11 male, aged 65 to 88) were treated using the CyberKnife® Robotic Radiosurgery System for NSCLC with doses ranging from 67 Gy to 75 Gy based on location, histopathological type, grade of histopathological differentiation, tumor diameter/volume, and normal tissue constraints, with the doses being delivered in five fractions over 5 to 8 days. Tumor diameters ranged from 1.5 cm to 3.4 cm (median: 2.5 cm). Patients with Stage I to IV NSCLC were treated, and the results and observations were analyzed for clinical characteristics and outcomes including toxicity. All patients, except one who had refused surgery, had co-morbid conditions that precluded a lobectomy. RESULTS: Twenty patients were followed every three months by positron emission tomography/computed tomography (PET/CT). Mean follow-up was 23 months (range: four to 58 months). Local control was achieved in all treated tumors. Three patients expired, and three developed new regional metastases, none of which was within the planning target volume (PTV). The remainder of the patients demonstrated no evidence of recurrence or continued growth detectable by PET/CT. There was no toxicity above Grade 1. CONCLUSIONS: It is feasible to treat peripheral NSCLC with individualized maximal tolerable doses ranging from 67 Gy to 75 Gy in five fractions chosen on the basis of location, histopathological type, grade of histopathological differentiation, tumor diameter/volume, and normal tissue constraints.

Application of robotic stereotactic radiotherapy to peripheral stage I non-small cell lung cancer with curative intent.

AIMS: To determine the effectiveness of robotic stereotactic radiotherapy with image guidance and real-time respiratory tracking against early stage peripheral lung cancer. MATERIALS AND METHODS: We treated patients with stage I non-small cell lung cancer (NSCLC) with CyberKnife and analysed their clinical characteristics and outcomes. All patients had co-morbid conditions that precluded lobectomy. The clinical target volume (CTV) included the gross tumour volume (GTV) and a 6mm margin in all directions to account for microscopic extension. The planning target volume (PTV) equalled CTV+2mm in all directions for uncertainty. Tumour motion was tracked using a combination of Synchrony and Xsight Spine tracking methods with the aid of a single gold marker implanted in the centre of the tumour, or using the newer Xsight Lung method without markers for selected tumours. A 60-67.5 Gy dose was prescribed to the 60-80% isodose line (median 65%) and given in three to five fractions. Patients were followed every 3 months for a median of 27.5 months (range 24-53 months). RESULTS: Of the 67 patients with NSCLC stage IA or IB treated between January 2004 and December 2008, we report the results of a cohort of 31 with peripheral stage I tumours of 0.6-71 cm(3) volume treated between January 2004 and December 2007 with total doses between 60 and 67.5 Gy in three to five fractions. The median D(max) was 88.2 Gy and the median V(95) of the PTV was 99.6% or 27.9 cm(3). No grade 3 or above toxicity was encountered. Four cases of radiation pneumonitis and one case of oesophagitis were observed. In those patients whose pre- and post-treatment results were available, no change in pulmonary function tests was observed. Actuarial local control was 93.2% for 1 year and 85.8% for up to 4.5 years. One-year overall survival was 93.6% and 83.5% for up to 4.5 years, as projected by Kaplan-Meier analyses. CONCLUSIONS: In this small cohort of patients with stage I peripheral NSCLC, robotic stereotactic radiotherapy seems to be a safe and obviously superior alternative to conventionally fractionated radiotherapy, with results that may be approaching those obtained with lobectomy without the associated morbidity.

What's in a shape? Children represent shape variability differently than adults when naming objects.

Children and adults often generalize a word to objects of the same shape. However, the shape properties on which generalization is based are unknown. We investigated the degree to which two shape dimensions were represented categorically by children and adults when learning names for objects. Multidimensional scaling techniques were used to establish the perceptual similarity of two sets of objects in Experiment 1. In Experiments 2 and 3, children (from 2;8 to 4;5 years of age) and adults participated in two tasks in which they learned a novel name for an exemplar. We then examined how often the novel name was generalized to different objects and to line drawings of the objects. In one task, participants generalized the names from memory; in a second task the exemplar was in front of the participant during generalization. Adults accepted names more often to objects that fell "within" the proposed shape boundaries than to objects that fell "across" the boundaries. Children, however, were just as likely to generalize names to novel objects that fell within as to objects that crossed the boundaries.

Radical prostatectomy: geographic and demographic variation.

OBJECTIVES: Previous reports have documented a geographic variation in the use of radical prostatectomy. We examined whether this phenomenon can be explained by factors other than geography alone. METHODS: This study was based on the data from nine geographic regions of the Surveillance, Epidemiology, and End Results (SEER) program for the years 1983 through 1994. Patients with localized or regional prostate cancer were included in the analysis. Logistic regression analysis was used to investigate the influence of geographic and demographic factors on the use of radical prostatectomy. The squared multiple correlation coefficient R(2) was used to measure the proportion of variation in the selection of radical prostatectomy explained by each factor of interest. RESULTS: As previously reported, the use of radical prostatectomy was significantly associated with geographic location; the degree of geographic variation varied as a function of age and was most dramatic in the youngest (younger than 45 years) and the oldest (75 years or older) groups. Overall, however, geography explained less than 2% of the total variation in the use of radical prostatectomy. Age was the most important factor that influenced the use of radical prostatectomy. CONCLUSIONS: Geography explains only a small proportion of the variation in the use of radical prostatectomy. In fact, of the factors examined, only age appeared to meaningfully explain the variation in the use of radical prostatectomy. Overall, our ability to explain the variation in the use of radical prostatectomy remains meager, and new factors must be identified if we are to better understand how patients and physicians make clinical decisions.

The influence of beam energy on the outcome of postoperative radiotherapy in head and neck cancer patients: secondary analysis of RTOG 85-03.

PURPOSE: To determine whether any difference in toxicity or efficacy occurs when head and neck cancer patients are treated postoperatively with (60)C0, 4 MV, or 6 MV photon beam. METHODS AND MATERIALS: This is a secondary analysis of the Intergroup Study 0034. Three hundred ninety-two patients were evaluable for comparison between treatment with (60)C0, 4 MV, or 6 MV photon beam. All patients had advanced but operable squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx. Patients were randomized following surgical resection to receive treatment with either postoperative irradiation alone, or postoperative irradiation plus three cycles of cisplatin and 5-fluorouracil. Patients were categorized as having either "low risk" or "high risk" treatment volumes based on whether the surgical margin was 5 mm or less, presence of extra capsular nodal extension, and/or carcinoma in situ at the surgical margins. Low-risk volumes received 50-54 Gy, and high-risk volumes were given 60 Gy. Patients were compared in regards to acute and late radiotherapy toxicities as well as overall survival and loco-regional control according to the beam energy used. RESULTS: One-hundred fifty-seven, 140, and 95 patients were treated by (60)C0, 4 MV, and 6 MV, respectively. No differences were seen in acute or late toxicity among treatment groups. Locoregional control was achieved in 75%, 79%, and 80% of patients treated with (60)C0, 4 MV, or 6 MV (p = 0.61). Patients treated with 6 MV had a higher incidence of ipsilateral neck failure as first event (13%) than patients treated by (60)C0 and 4 MV (9%). This difference was not statistically significant. CONCLUSION: No differences in outcome, acute, or late toxicity were discernible in patients with advanced head and neck cancer treated with (60)C0, 4 MV, or 6 MV. This result should be interpreted with caution as increased incidence, albeit nonsignificant, of ipsilateral neck recurrence was observed in patients treated with 6 MV and the power of the study to detect a statistically significant difference is small.

Planning ahead: goal-directed problem solving by 2-year-olds.

On tasks that require overcoming an obstacle along an existing path to a physically present goal, infants and very young children evince planning. In each of 3 experiments, the authors tested 21- and 27-month-olds' ability to construct a path to a mentally re-presented goal. Across experiments, the authors varied the number and type of cues to the solution provided. After exposure to the goal-state configuration of problems, both age groups showed evidence of planning (Experiment 1). Demonstration of the initial step in the solution path in Experiment 2 was not as effective as exposure to the goal state in Experiment 1. Even with specification of a greater proportion of the goal path, goal-state configuration information was particularly effective in facilitating performance (Experiment 3). The results suggest productive generation of solutions to novel problems by young children; planning is facilitated by goal-state configuration information.

If memory serves, will language? Later verbal accessibility of early memories.

Of major interest to those concerned with early mnemonic process and function is the question of whether early memories likely encoded without the benefit of language later are accessible to verbal report. In the context of a controlled laboratory study, we examined this question in children who were 16 and 20 months at the time of exposure to specific target events and who subsequently were tested for their memories of the events after a delay of either 6 or 12 months (at 22-32 months) and then again at 3 years. At the first delayed-recall test, children evidenced memory both nonverbally and verbally. Nonverbal mnemonic expression was related to age at the time of test; verbal mnemonic expression was related to verbal fluency at the time of test. At the second delayed-recall test, children evidenced continued accessibility of their early memories. Verbal mnemonic expression was related to previous mnemonic expression, both nonverbal and verbal, each of which contributed unique variance. The relevance of these findings on memory for controlled laboratory events for issues of memory for traumatic experiences is discussed.

Hyperfractionated radiation therapy and 5-fluorouracil, cisplatin, and mitomycin-C (+/- granulocyte-colony stimulating factor) in the treatment of patients with locally advanced head and neck carcinoma.

BACKGROUND: The authors had previously reported preliminary results of a treatment regimen of concurrent hyperfractionated radiation therapy and chemotherapy in patients with locally advanced head and neck carcinoma that demonstrated both feasibility and high local control. In an attempt to reduce acute mucosal and hematologic toxicity, granulocyte-colony stimulating factor (G-CSF) was added during the second phase of this study. METHODS: Seventy patients (53 with Stage IV and 17 with Stage III disease) were entered between May 1988 and June 1995 into a Phase I/II trial of concurrent radiation therapy (74.4 gray (Gy) total dose; 1.20 Gy twice daily), 5-fluorouracil (1000 mg/m2/24 hours for 72 hours), and cisplatin (50 mg/m2) for 3 cycles with the addition of mitomycin C (8 mg/m2) in Cycle 2. G-CSF was added after the initial entry of 34 patients. RESULTS: At a median follow-up of 41 months (range, 12-80 months), 44 patients were alive with a projected median overall survival of 54 months. Grade 3/4 mucositis, observed in 65% of patients, was equally prevalent and prolonged in both G-CSF-treated (+) and G-CSF-naive (-) patients. Grade 3/4 leukopenia was present in 45% and 36% of G-CSF- and G-CSF+ patients, respectively. The 3-year locoregional control and cause specific survival rates were 68% and 75%, respectively. CONCLUSIONS: This regimen was feasible and effective but caused severe mucositis. No benefit was derived from the addition of G-CSF. This regimen deserves further modification to reduce acute mucositis toxicity yet maintain the high locoregional control rate.

Five-chlorodeoxycytidine and biomodulators of its metabolism result in fifty to eighty percent cures of advanced EMT-6 tumors when used with fractionated radiation.

PURPOSE: To extend our findings in previous radiation and biochemical studies with five rodent tumors, in which we used one and occasionally two or three irradiations. The extent of control of the EMT-6 mammary adenocarcinoma was determined using fractionated radiation (12 irradiations) over a 3-week period using the radiosensitizer 5-chloro-2'-deoxycytidine (CldC) and biomodulators of its metabolism: N-(Phosphonacetyl)-L-aspartate (PALA), tetrahydrouridine and 5-fluoro-2'-deoxycytidine (FdC). METHODS AND MATERIALS: Mammary adenocarcinoma EMT-6 tumors implanted 1 week prior to therapy in BALB/c mice were subjected to single daily doses of focused radiation, not exceeding a total of 60 Gy, on days 2-5 of each week. N-(Phosphonacetyl)-L-aspartate (PALA) was administered on the first day of therapy. Five-fluoro-2'-deoxycytidine and CldC were administered in the morning and afternoon, respectively, of the next 2 days, and CldC was administered on the fourth day. Tetrahydrouridine was always coadministered with FdC or CldC. Drug and radiation treatments overlapped for 3 weeks. RESULTS: Fifty to 80% cures (usually 70%) were obtained with no apparent morbidity and the same moderate weight loss that occurs with radiation alone. Neither tumor regrowth delay nor cures were obtained with drugs or radiation alone. An apparent threefold dose increase effect was obtained with the end point: "days to reach 4 times initial tumor volume." Increasing the radiation dose threefold (without drugs) resulted in four out of five deaths; increasing the dose twofold (without drugs) resulted in extensive weight loss and hair loss in the entire ventral area and no cures. Increasing the dose of drugs or radiation 1.5-fold, in the complete protocol, did not result in increased morbidity. Comparative studies with Iododeoxyuridine demonstrate the heightened efficacy of CldC. CONCLUSIONS: One cannot achieve the same results obtained with CldC and the modulators by merely increasing the dose of radiation. There is a significant window of safety in this approach. The evidence we have obtained with EMT-6, the fifth rodent tumor we have studied with CldC, as well as the demonstrated and proposed reasons for its superior efficacy over 5-Iododeoxyuridine (and 5-Bromodeoxyuridine), drugs in current use, indicate that CldC will allow more aggressive treatment of human tumors with radiation than is now feasible.

Phase I trial of low dose N-phosphonacetyl-L-aspartic acid and high dose 5-fluorouracil administered concomitantly with radiation therapy for unresectable localized adenocarcinoma of the pancreas.

BACKGROUND: Preclinical and clinical data suggest that N-phosphonacetyl-L-aspartic acid (PALA) can augment the cytotoxic effects of 5-fluorouracil (5-FU). In addition, the combination of 5-FU and radiation therapy has been used with success in prolonging survival and providing palliation of symptoms in patients with advanced unresectable pancreatic carcinoma. This Phase I study was undertaken to determine the feasibility and evaluate the qualitative and quantitative toxicities of PALA and escalating doses of 5-FU administered concomitantly with radiation therapy in patients with locally advanced nonmetastatic pancreatic adenocarcinoma. METHODS: Ten previously untreated patients with advanced nonmetastatic adenocarcinoma of the pancreas were treated with 250 mg/m2 of PALA given as an intravenous bolus followed 24 hours later by 5-FU, which was given by continuous 24-hour infusion every week. The 5-FU doses were assigned according to a Phase I drug escalation (1000 mg/m2, 1300 mg/m2, and 1700 mg/m2). Radiation therapy was delivered concurrently with chemotherapy at a dose of 180 cGy per fraction (900 cGy per week) over 6 1/2 weeks. PALA and 5-FU were continued weekly after the end of radiation therapy, with disease assessments made every 8 weeks. Chemotherapy was continued until the disease progressed. RESULTS: All 10 patients were evaluable. The maximum tolerated dose (MTD) of 5-FU was 1300 mg/m2. Two of the four patients treated at the 1700 mg/m2 dose level experienced dose-limiting toxicities, nausea/vomiting and mucositis, respectively. Toxicities were mild to moderate at the 1000 mg/m2 and 1300 mg/m2 dose levels. Two patients treated with 5-FU at the 1300 mg/m2 dose level had complete responses, and one patient treated at the 1700 mg/m2 dose level had a partial response. The median survival was 12.5 months, and four patients survived more than 1 year. CONCLUSIONS: PALA and 5-FU administered concomitantly with radiation therapy is an active regimen in locally advanced, unresectable pancreatic cancer. Dose-limiting toxicities are nausea/vomiting and mucositis. The MTD of 5-FU is 1300 mg/m2. The regimen is well tolerated and administered in an outpatient setting.

The role of steroids in the management of metastatic carcinoma to the brain. A pilot prospective trial.

This prospective study attempted to evaluate the indications for glucocorticoids which are commonly given to patients with brain metastases. Twelve patients with histologically confirmed malignancies and radiographically documented brain metastases were enrolled. Patients were scored for general performance status and neurologic function class. All subjects were given high-dose dexamethasone (HDD) for 48 hours and then randomized to receive either intermediate-dose dexamethasone (IDD) or no steroids with cranial radiotherapy. Of these 12 study patients, 3 achieved a complete response, 1 partial response, and 8 nonresponses to HDD. Seven patients had IDD, while five received no IDD. Although a small sample size prevented any statistical analysis, this study does suggest that the place for using glucocorticoids in treating patients with metastatic carcinoma to the brain remains uncertain and should be evaluated in a cooperative prospective trial.

Retreatment of intracranial gliomas.

Although intracranial gliomas carry a poor long-term prognosis, retreatment at the time of tumor progression may prolong survival and maintain or improve the quality of life. Thirty-three patients who underwent retreatment with surgery, radiotherapy, and chemotherapy were reviewed retrospectively. Median survival after initiation of retreatment was 8 months for glioblastoma, 13 months for anaplastic astrocytoma, 22 months for astrocytoma, and 47 months for oligodendroglioma/mixed glioma. Survival was significantly better for younger patients and for those with better functional status. One third of patients were neurologically improved by surgery. Surgical morbidity was minimal (2.1%); there was no surgical mortality. Chemotherapy and radiotherapy produced expected adverse reactions. Retreatment of intracranial gliomas carries acceptable risk and is beneficial in selected patients. Decisions regarding retreatment must be carefully individualized with consideration of the quality of life and the wishes of the patient and family.

Long-term follow-up of gliomas treated with fractionated stereotactic irradiation.

Eighteen patients have been treated for gliomas with fractionated stereotactic linear accelerator (LINAC) irradiation. A plastic halo ring secured with skull pins allows daily attachment of the patient to the stereotactic frame mounted on the linear accelerator. The patients received 9-31 fractions of 1.8-3 Gy/fraction over periods of 20-49 days. Total doses delivered stereotactically where 16-60 Gy (90% isodose) delivered to 3-7 cm diameter tumors. The six patients with glioblastoma had a median survival of 16 months (range 7-60 months). The two patients with anaplastic astrocytoma survived 7 and 78 months. Most of the patients with high grade tumors also received other adjuant treatments. Of the ten patients with low grade gliomas, one expired 66 months after treatment, and the remainder are alive 22-82 months after treatment. One pediatric patient displayed evidence of focal radiation injury with visual loss. No patient developed initial recurrence of tumor outside the focally irradiated field. Stereotactic localization of irradiation protects surrounding brain tissue; fractionation improves the therapeutic ratio. These extended follow-up data indicate that stereotactic restriction of radiation fields in treatment of gliomas does not result in deterioration of survival results. Further investigation is warranted into the use of higher focal fractionated radiation doses to attempt to improve local control and survival.

A multivariate analysis of clinicopathologic factors for predicting outcome in uterine sarcomas.

This study involved a comprehensive review of the histologic slides of 62 patients who were diagnosed with uterine sarcoma from 1978 through 1988 at a single institution. In addition, DNA content (ploidy level) could be determined from the H & E slides of these tumors using image analysis. Also, 42 of these cases had retrievable cell blocks on which DNA analysis was performed by means of flow cytometry. A linear regression analysis found a high degree of correlation (r = 0.8) between the measurement of the DNA index of these tumors by these two techniques. All cases were retrospectively restaged using the newly adopted FIGO surgical staging criteria which found the following distribution: 22 (35.5%) Stage I, 10 (16.1%) Stage II, 12 (19.4%) Stage III, and 18 (29%) Stage IV. A multivariate analysis of 60 evaluable patients using the Cox proportional hazard model found that surgical staging was the most significant prognostic factor with respect to the endpoint of overall survival (P = 0.00004). Both patient age at diagnosis and mitotic index were independent from surgical staging in predicting outcome. Furthermore, there was a trend suggesting that DNA index also had prognostic value. Of particular interest was that patients with diploid tumors (DNA index, 0.9-1.1) had a 5-year overall survival of 72% and did not approach median survival; however, hyperdiploid tumors (DNA index > 1.1) and hypodiploid tumors (DNA index < 0.9) were associated with median survivals of 18 and 12 months, respectively. In conclusion, this study supports the use of surgical staging of patients with uterine sarcomas in order to optimally determine their chance for survival. Further biologic investigations which may result in identifying those patients who could benefit from adjunctive treatment are recommended.

Is a surgical resection leaving positive margins of benefit to the patient with locally advanced squamous cell carcinoma of the head and neck: a comparative study using the intergroup study 0034 and the Radiation Therapy Oncology Group head and neck database.

PURPOSE: The purpose of this study was to determine whether or not for patients with squamous cell carcinomas of the head and neck, a surgical resection leaving positive margins followed by postoperative adjuvant therapy improves the outcome compared to a matched group of patients treated with definitive radiotherapy alone. METHODS AND MATERIALS: From January 1985 through January 1990 a consortium of national cooperative groups (Radiation Therapy Oncology Group, Cancer and Leukemia Group B, Eastern Cooperative Oncology Group, Northern California Oncology Group, Southeast Group, and Southwest Oncology Group) conducted a phase III clinical trial testing the efficacy of adjuvant chemotherapy for patients with resectable, squamous cell carcinomas of the head and neck. One hundred and nine patients were excluded from this study due to positive surgical margins. These patients have been followed prospectively with regards to local/regional tumor control, development of distant metastases, and survival. The postoperative treatment of these patients was not specified by the protocol but the majority of patients received postoperative radiotherapy +/- chemotherapy. These patients were compared with a matched group of patients from the Radiation Therapy Oncology Group head and neck database of patients treated with definitive radiotherapy alone using a standard fractionation schema. Matching parameters included primary tumor site, T-stage, N-stage, Karnofsky performance status, and age. RESULTS: Actuarial curves are presented for local/regional control and survival. At 4 years the local/regional control rate is 44% for the positive margin patients compared to 24% for the patients from the data base (p = 0.007). However, there is no significant difference between the survival curves (p = 0.76) with respective median survivals being 18.1 months vs. 17.9 months and 4-year survivals being 29% vs. 25%. CONCLUSION: While an incomplete excision followed by postoperative therapy does not seem to improve survival compared to treatment with radiotherapy alone, it appears to yield significantly better local/regional control. This would argue for its applicability in selected palliative settings. A follow-up, Phase III trial for patients with advanced tumors may be warranted to test traditional resectability criteria.

Dose rate effect of 125I irradiation on normal rabbit eyes and experimental choroidal melanoma.

The dose rate effect of radiation by 125I plaque on choroidal melanoma and normal intraocular tissue was studied. In the first part of the experiment, high activity plaques (HAP) and low activity plaques (LAP) were implanted on rabbit eyes with experimental Greene choroidal melanoma to deliver a total dose of 10,000 cGy to the tumor apex. The mean dose rate calculated at 0.5 mm from the inner sclera in eight eyes with high activity plaques was 3341.5 cGy hr-1 (1 cGy = 1 rad) while that in ten eyes with low activity plaques was 239.9 cGy hr-1. For tumors less than 1.0 mm in height, both groups showed complete tumor regression at the tumor implantation site after plaque treatment. For tumors more than 1.0 mm in height, two out of two eyes in the low activity plaque group and one of four eyes in the high activity plaque group failed to show complete tumor regression. Both LAP and HAP were effective in eradicating tumors, but logistic regression analysis demonstrates that HAP was more effective than LAP when adjustment was made for initial tumor height (P = 0.032). Nine tumor control eyes without 125I plaque implantation demonstrated marked tumor growth within 3 weeks. In the second part of the experiment, 125I plaques were implanted on the sclera of 12 normal rabbits' eyes. Six received high dose rate plaque treatment, while the other six received low dose rate plaque treatment. Clinical and histologic examinations demonstrated more damaging effects to the normal chorioretinal tissues at the plaque implantation site in the high dose rate plaque group at 24 weeks of follow-up. These results suggest that high dose rate plaques are more effective than low dose rate plaques when tumor height is statistically controlled. However, high dose rate delivery increases the damaging effects on normal intraocular tissue.

In vitro potentiation of radiation cytotoxicity by recombinant interferons in cervical cancer cell lines.

BACKGROUND: This investigation, which evaluates the combination of radiation and interferon, bridges two clinical treatments of cancer. Radiation therapy (RT) is an integral part of cervical cancer treatment; interferons (IFN), however, are classified as modifiers of biologic response. The authors evaluated the radiation-modulation effects of recombinant alpha-IFN and beta-IFN on two different human cervical cancer cell lines: ME-180 and SiHa. The radiation sensitivity based on the cell growth rate (logarithmic growth phase versus confluence) was also evaluated. METHODS: Control cells and cells pretreated with either alpha-IFN or beta-IFN were exposed to RT at doses of 0, 2, 5, 10, and 15 Gy. The pretreated cells received IFN at doses of 100, 500, 1000 and 5000 IU/ml for 24 hours. The adenosine triphosphate bioluminescence assay was used to measure the surviving fractions after 7 days of incubation. The data were analyzed using the linear-quadratic model and the radiosensitivity index D. The combined effects of IFN and RT on cytotoxicity were evaluated using the synergistic interaction formula for anticancer agents. RESULTS: The ME-180 and SiHa cell lines had the same mean inactivation D values of 13.2 when radiated at confluence. Irradiation of ME-180 and SiHa cells in the logarithmic growth phase resulted in mean inactivation D values of 7.5 and 10.2, respectively. Enhanced radiosensitivity was observed in all IFN-RT combinations. Synergism was observed in the majority of experiments. CONCLUSIONS: Recombinant alpha-IFN and beta-IFN potentiate the radiotoxicity of two cervical cancer cell lines. ME-180 cells were less sensitive to IFN alone than were SiHa cells, but they showed higher a radiosensitizing effect from both IFN. Proliferating cells were more sensitive than confluent cells to RT by itself and to RT-IFN combinations.

Survival comparison of radiosurgery-eligible and -ineligible malignant glioma patients treated with hyperfractionated radiation therapy and carmustine: a report of Radiation Therapy Oncology Group 83-02.

PURPOSE: The purpose is twofold: (1) to identify the malignant glioma patients treated in a trial of hyperfractionated radiotherapy (RT) and carmustine (BCNU) who may have been eligible for a stereotactic radiosurgery (SRS) boost; and (2) to compare survival of such patients with that of those considered SRS-ineligible. PATIENTS AND METHODS: From January 1983 to July 1989, 778 malignant glioma patients were enrolled on Radiation Therapy Oncology Group (RTOG) 83-02, a randomized phase I/II hyperfractionated RT dose-escalation trial with BCNU chemotherapy. The SRS criteria used in a single-institution trial were applied to these patients; they are: Karnofsky performance status (KPS) of greater than 60; well-circumscribed tumor less than 4.0 cm; no subependymal spread; and a location not adjacent to brainstem or optic chiasm. RESULTS: Eighty-nine patients (11.9%) were identified as potentially SRS-eligible. The median survival times (MST) and 18-month survival rates of the 89 eligible and 643 ineligible patients were 14.4 versus 11.7 months and 40% versus 27%, respectively (P = .047). The MST and 18-month survival rate of the 544 SRS-ineligible patients with KPS greater than 60 were 12.1 months and 29%, respectively, and were not statistically inferior to the survival of the SRS-eligible group (P = .21). Multivariate analysis revealed age, KPS, and histopathology to be strongly predictive of survival, and SRS eligibility was also significantly predictive (P = .047). CONCLUSION: SRS-eligible patients enrolled on RTOG 83-02 had survival superior to that of the SRS-ineligible group, and this advantage is mainly due to the selection of a subgroup with a high minimum KPS.

Synergistic antitumor activity of cisplatin and interleukin 1 in sensitive and resistant solid tumors.

The antitumor activity of cis-diamminedichloroplatinum(II) (cP) and human recombinant interleukin-1 alpha (IL-1 alpha) was studied in RIF-1 and SC VII solid tumor models and in a cP-resistant subline of RIF-1 designated RIF-R1cP. In RIF-1 tumors, clonogenic cell survival after cP plus IL-1 alpha combinations was highly schedule and IL-1 alpha dose dependent. More than additive clonogenic cell kill was seen when cP was given 6 h before, but not 8 h before or at 2-6 h after IL-1 alpha. Time course studies indicated that maximal clonogenic cell killing was achieved within 4-6 h after the cP plus IL-1 alpha combination, with little or no recovery for up to 24 h. In vivo dose-response studies indicated that cP plus IL-1 alpha combinations induced more clonogenic cell kill than cP alone in all three tumor models, and analysis by the median effect principle indicated highly synergistic antitumor activity. Dexamethasone but not indomethacin inhibited the synergistic interaction. IL-1 alpha had no effect on the cytotoxicity of cP in SCC VII cells in vitro, and neither in vitro hypoxia nor in vivo ischemia, induced by clamping tumor blood supply, significantly affected cP clonogenic cell killing. Increased clonogenic cell killing was seen, however, after removal of the clamp, implicating reperfusion events, such as oxyradical stress, as a potential mechanism for increased cP cytotoxicity in SCC VII solid tumors. The data from our model systems provide a rationale for additional work to define the mechanisms of the synergistic antitumor activity of the cP plus IL-1 alpha combination and indicate that IL-1 alpha might be a useful adjunct to increase the clinical efficacy of cP-containing strategies for both sensitive and cP-resistant cancers.