Selective dose escalation of chemoradiotherapy for locally advanced esophageal cancer.

This phase II study assessed the use of concurrent continuous infusion of 5-fluorouracil and weekly carboplatin plus paclitaxel with selective radiation dose escalation for patients with localized esophageal cancer. Patients with esophageal carcinoma were staged by thoracic and abdominal computed tomography, endoscopic ultrasound, and positron emission tomography scans. Patients received a continuous infusion of 5-fluorouracil 225 mg/m(2) on days 1 to 38 and intravenous paclitaxel 45 mg/m(2) and carboplatin AUC 2 on days 1, 8, 15, 22, 29, and 36. Radiotherapy was delivered in 1.8-Gy fractions, 5 d/wk for 5.5 weeks. Six to 8 weeks after initial therapy, patients without metastatic progression but with a positive biopsy, or less than partial response received a 9-Gy boost with the same concurrent chemotherapy. Twenty-four patients were enrolled: 18 patients were enrolled initially; 6 additional patients were enrolled following a protocol amendment designed to reduce the esophagitis by adding the radioprotectant amifostine. Median follow-up was 30 months. Twenty (83%) patients had adenocarcinomas of the lower esophagus/gastroesophageal junction. Seventeen patients (81%) attained at least a partial response. Six patients received boost treatment. At 4 years, overall survival was 28%, cause-specific survival was 38%, locoregional control was 61%, and distant metastasis-free survival was 52%. Radiation delays ranged from 0 to 62 days (median, 8 d), primarily owing to esophagitis. In total, 28% of patients developed esophageal strictures requiring dilatations. There were no differences in esophageal strictures, local control, or survival with the addition of amifostine.

Candidates for prostate radioactive seed implantation treated by external beam radiotherapy.

PURPOSE: We report the prostate-specific antigen-based freedom from biochemical failure after conventional and three-dimensional conformal external beam radiotherapy for patients who would have been candidates for 125I implantation monotherapy. MATERIALS AND METHODS: Patients included in the study were required to have prostate-specific antigen values < or = 20, T stage < or = 2b, and Gleason score sum of 2 to 6. All patients underwent external beam irradiation with curative intent and a minimum follow-up from completion of treatment of at least 1 year. In addition, all patients had to have pretreatment and follow-up prostate-specific antigen measurements and no history of hormonal manipulation, orchiectomy, or radical prostatectomy. A total of 187 patients meeting these criteria were treated between March 1988 and June 1995, and they form the study group for this analysis. Freedom from biochemical failure was defined as prostate-specific antigen value that failed to be maintained at 1 ng/mL or less or an increase in prostate-specific antigen value of 0.5 ng/mL or more in 1 year even if prostate-specific antigen value was less than 1 ng/mL. RESULTS: Among the 187 patients, the median pretreatment prostate-specific antigen value was 7.4 ng/mL (0.3-19.9 ng/mL). The median follow-up was 34 months. Twenty-three percent of patients had a Gleason score sum of 2 to 4, and 77% had a Gleason score sum of 5 to 6. Clinical stages were T1 in 33% and T2 in 67%. One hundred twenty-five patients were treated by conventional external beam radiotherapy with a median dose of 69.5 Gy (60-71 Gy), and 62 patients were treated by three-dimensional conformal external beam radiotherapy with a median dose of 76.4 Gy (71.6-87 Gy). The overall freedom from biochemical failure was 75% at 4 years. Rates of freedom from biochemical failure by pretreatment prostate-specific antigen levels were 91% for prostate-specific antigen value < or = 4 ng/mL, 65% for prostate-specific antigen value > 4 but < or = 10 ng/mL, and 30% for prostate-specific antigen value > 10 ng/mL. Pretreatment prostate-specific antigen value was a statistically significant prognosticator, with lower values associated with favorable freedom from biochemical failure outcome in univariate and multivariate analyses. Conventional versus three-dimensional treatment, T1 versus T2 stage, and Gleason score sum 2 to 4 versus 5 to 6 did not show statistically significant difference in freedom from biochemical failure. CONCLUSIONS: Although our overall results after external beam radiotherapy for early-stage prostate cancer patients are less favorable than the best results published for 125I implantation monotherapy, our results are comparable to those in most other studies with implantation monotherapy. This most likely results from selection bias as well as our stricter definition of freedom from biochemical failure. In addition, for our subset of patients, there was no statistically significant improvement in the 4-year freedom from biochemical failure with the use of higher doses.

Gamma knife radiosurgery for malignant melanoma brain metastases.

PURPOSE: To evaluate the efficacy and toxicity of gamma knife radiosurgery in the treatment of melanoma metastases to the brain. PATIENTS AND METHODS: We retrospectively reviewed 55 patients with single or multiple intracranial melanoma metastases treated at the University of California, San Francisco, with gamma knife radiosurgery from 1991 through 1995. Sixteen patients were treated with gamma knife radiosurgery for recurrence following previous radiation therapy, 11 received radiosurgery as a boost to whole-brain radiation therapy, and 28 had radiosurgery alone for initial management of brain metastases. The median minimum radiosurgery tumor dose for 140 treated lesions was 19 Gy (range, 10-22 Gy) prescribed at the 35% to 90% isodose contour (median, 50%). The median total target volume per patient was 6.1 cc (range, 0.25-28.3 cc). RESULTS: With a median follow-up of 75 weeks in living patients, the median survival times were 35 weeks overall: 35 weeks for patients with solitary metastases versus 33 weeks for those with multiple metastases. A factor that was significant in univariate analysis of survival was total target volume treated. This parameter remained significant on multivariate analysis. The actuarial median freedom from progression analyzed by lesion for 113 lesions in 46 patients with imaging follow-up was 89 weeks with 6-month and 1-year actuarial freedom from progression rates of 89% (95% confidence interval, 80%-95%) and 77% (95% confidence interval, 62%-87%). In univariate analysis, improved freedom from progression was associated with smaller target volume treated, smaller maximum diameter, or higher prescribed dose. Four patients (7%) developed acute Radiation Therapy Oncology Group grade > or = 2 morbidity, and five patients (9%) developed late grade > or = 2 morbidity. DISCUSSION: Median survival and freedom from progression in patients treated with radiosurgery for melanoma metastatic to the brain are comparable to results in published radiosurgery series of grouped histologies. For melanoma patients, total intracranial tumor volume appears to be of greater prognostic significance than the absolute number of metastases treated. We conclude that gamma knife radiosurgery is effective and should be considered among various management strategies.

Stereotactic radiosurgery for malignant melanoma to the brain.

This article offers support for using radiosurgery in the treatment of patients with melanoma brain metastases. Although patients with multiple metastases may fare somewhat worse than patients with single metastases, the difference is not statistically significant. The only significant prognostic factor that we were able to identify was smaller total target volume (favorable factor), although further study with longer follow-up and more patients may reveal other factors. Radiosurgery is appealing to patients and physicians because it is noninvasive and requires minimal hospitalization and recovery. Gamma Knife therapy offers patients a rapid method for achieving local control, which may be particularly important for patients who would otherwise be considered for specific protocols (such as some using IL-2) which preclude enrollment unless intracranial disease is controlled. We conclude that stereotactic radiosurgery is an effective treatment modality, with acceptable toxicity, for patients with either solitary or multiple melanoma metastases to the brain.

Antigenic cancer cells that escape immune destruction are stimulated by host cells.

Cancers induced by UV light in murine skin often regress completely when transplanted into normal syngeneic recipients and grow progressively only in T-cell-deficient hosts. Heritable cancer variants that grow progressively and kill normal mice occasionally evolve in vivo. It is surprising that most of these variants appear to retain their antigenicity and immunogenicity. We have compared three such variants (4102-PRO, 6132A-PRO, and 6134-PRO) with the parental tumors to determine why the variants acquired progressive phenotypes without antigen loss. We found that all three variants grew substantially faster than the parental tumors in T-cell-deficient hosts; one variant, 6132-PRO, also grew faster in vitro. Furthermore, the growth of all of the variants was stimulated by soluble factors released by tumor-induced peritoneal exudate cells, and all attracted more leukocytes than the parental cells. Finally, pretreatment of mice with antigranulocyte antibody reduced the growth of variant but not parental 4102 and 6134A tumor cells. The treatment reduced the growth of both the parental and the variant 6132A lineage cells. We found no evidence for acquired resistance of variant tumors to immune destruction by a host defense mechanism. The parental cells did not grow faster in beige nude mice deficient in natural killer and alpha beta T cells or in SCID mice deficient in B and T cells. The variant parental cells had a similar sensitivity to lysis by polyinosinic-polycytidic acid-induced natural killer cells or thioglycolate- and LPS-induced macrophages. Together, our results are consistent with the notion that these variants escape from immune destruction in vivo by attracting leukocytes that stimulate tumor cell growth.