Phase II trial of cisplatin and alpha-interferon in advanced malignant melanoma.

PURPOSE: To evaluate the antitumor activity of combination cisplatin (CDDP) and alpha-interferon (alpha-IFN) in advanced, measurable metastatic melanoma. PATIENTS AND METHODS: Adult patients with metastatic melanoma were required to have bidimensionally measurable lesions and a Karnofsky performance status > or = 60%. Serum creatinine < or = to 1.5 mg/dL, creatinine clearance > or = 60 mL/min, adequate organ and bone marrow function, and radiologic proof of the absence of brain metastases were required. CDDP 40 mg/m2 intravenously (IV) on day 1 and day 8, and alpha-IFN 3 million units/m2 subcutaneously on days 1 to 5 and 8 to 12 were administered every 3 to 4 weeks. RESULTS: Forty-two patients were entered onto this phase II trial and were assessable for response and toxicity. Three patients achieved complete responses (CRs) that lasted 31+, 5, and 8+ months. Seven patients had partial responses (PRs) and a median response duration of 4.4 months. The overall objective response rate was 24% (95% confidence interval, 12% to 39%). Toxicities were mild. Only 11% of the courses required dose reduction of alpha-IFN, and three of 128 courses required CDDP dose reduction for reversible nephrotoxicity. CONCLUSION: The combination of moderate-dose CDDP and alpha-IFN as administered in this schedule is well tolerated and possesses encouraging activity in metastatic melanoma.

A clinical interactive technique for MR-CT image registration for target delineation of intracranial tumors.

Replacement of current CT-based, three-dimensional (3D) treatment planning systems by newer versions capable of automated multi-modality image registration may be economically prohibitive for most radiation oncology clinics. We present a low-cost technique for MR-CT image registration on a "first generation" CT-based, 3D treatment planning system for intracranial tumors. The technique begins with fabrication of a standard treatment mask. A second truncated mask, the "minimask," is then made, using the standard mask as a mold. Two orthogonal leveling vials glued onto the minimask detect angular deviations in pitch and roll. Preservation of yaw is verified by referencing a line marked according to the CT laser on the craniocaudal axis. The treatment mask immobilizes the patient's head for CT. The minimask reproduces this CT-based angular treatment position, which is then maintained by taping the appropriately positioned head to the MR head coil for MR scanning. All CT and MR images, in DICOM 3.0 format, are entered into the treatment planning system via a computer network. Interactive registration of MR to CT images is controlled by real-time visual feedback on the computer monitor. Translational misalignments at the target are eliminated or minimized by iterative use of qualitative visual inspection. In this study, rotational errors were measured in a retrospective series of 20 consecutive patients who had undergone CT-MR image registration using this technique. Anatomic structures defined the three CT orthogonal axes from which angular errors on MR image were measured. Translational errors at the target isocenter were within pixel size, as judged by visual inspection. Clinical setup using the minimask resulted in overall average angular deviation of 3 degrees +/-2 degrees (mean +/- SD) and translational deviation within the edges of the target volume of typically less than 2 mm. The accuracy of this registration technique for target delineation of intracranial tumors is compatible with practice guidelines. This method, then, provides a cost-effective means to register MR and CT images for target delineation of intracranial tumors.

Particle beam radiation therapy in prostate cancer: is there an advantage?

Hadron therapy uses heavy particles to deliver therapeutic ionizing energy. Each particle's inherent attributes determine the pattern of energy deposited by its beam, expressed in macro (conformability to a three-dimensional target volume) and micro (radiobiologic properties) distributions. Mass and charge regulate the inherent properties; beam energy provides a controllable, variable characteristic. Generally, heavy charged particles provide superior macrodosimetric properties; heavy particles (charged or not) have microdosimetric characteristics that produce high linear energy transfer (LET). Neutron macrodosimetry is similar to that of photons. Protons and helium ions possess superior macrodosimetric properties, plus microdosimetric characteristics resulting in low LET, yielding beam characteristics that approach the ideal for clinical radiotherapy. Hadron therapy for prostate cancer has been limited by the availability of appropriate treatment facilities. Nonetheless, encouraging results have been obtained. Neutron therapy demonstrated improved overall survival in a multi-institutional randomized trial, and improved local disease control in a subsequent trial. Proton radiation forms the boost component of several conformal dose-escalation studies. A Loma Linda University study demonstrated low treatment-related morbidity despite a prostate dose of 75 CGE; late-morbidity data were superior to published reports from multi-field, conformal photon therapy. A Phase III dose-escalation study of protons for early prostate cancer is proceeding.

What is the role of radiation in the treatment of subfoveal membranes: review of radiobiologic, pathologic, and other considerations to initiate a multimodality discussion.

BACKGROUND: Single-dose-fraction conformal proton beam and multiple-fraction X ray dose schedules have been used to treat subfoveal neovascular membranes. All schedules successfully controlled membrane progression, stabilized vision in most patients, and increased visual acuity in some. Conformal protons also decreased the radiation dose to healthy tissues outside the designated volume (16 mm in diameter). It appears that radiation therapy could be useful and cost-effective, but neither the optimal time-dose schedule single or multiple dose fractions nor the type of radiation proton conformal beam or x-ray therapy are defined. METHODS: By means of an extensive literature survey, we reviewed the rationale for using radiation to treat subfoveal neovascularization, examined a paradigm of radiation interaction with tissue, reviewed the histopathology of neovascular membranes, and documented the role of growth factors in the pathophysiology of the disease. Accepting that the eye is an extracranial brain extension, and that its microvasculature has properties similar to brain microvessels, we reviewed the radiobiologic response of brain microvessels. We also revisited the controversy concerning the efficacy of single-dose-fraction vs. multifraction schedules. RESULTS: This paper outlines parameters within which radiation therapy's role might be defined, and proposes a clinical radiation-biology scoring program to evaluate radiation effects, based on the SOMA concept. CONCLUSION: A prospective, controlled clinical trial is feasible and is indicated to determine radiation therapy's role in managing the proliferative component of age-related macular degeneration.

Dose response of rat retinal microvessels to proton dose schedules used clinically: a pilot study.

PURPOSE: This preclinical rat pilot study quantifies retinal microvessel, endothelial, and pericyte population changes produced by proton irradiation METHODS AND MATERIALS: The left eyes of rats were irradiated with single doses of 8, 14, 20, and 28 Gy protons; right eyes, with two fractions. Animals were euthanized, and eyes were removed; elastase digests were prepared, and cell populations were counted in sample fields. Results were compared with unirradiated controls. RESULTS: Progressive time- and dose-dependent endothelial cell loss occurred following all schedules. Cell loss was significantly different from control values (p < 0.001) following 28 Gy and following 20 Gy (p < 0.05) in a single dose. Endothelial cell loss was the same for single- and split-dose schedules. Progressive endothelial cell loss produced vessel collapse and acellular vessel strands. Endothelial cells were in the G(0) phase of the mitotic cycle. 28 Gy produced photoreceptor cell loss. CONCLUSION: The retinal digest is an elegant bioassay to quantify the microvessel population response. Single- and split-dose schedules appear to yield similar outcomes, in terms of endothelial cell density.

Phase I/II study of proton beam irradiation for the treatment of subfoveal choroidal neovascularization in age-related macular degeneration: treatment techniques and preliminary results.

PURPOSE: Age-related macular degeneration is the prevalent etiology of subfoveal choroidal neovascularization (CNV). The only effective treatment is laser photocoagulation, which is associated with decreased visual acuity following treatment in most patients. This study assessed both the response of subfoveal CNV to proton beam irradiation and treatment-related morbidity. We evaluated preliminary results in patients treated with an initial dose of 8 Cobalt Gray Equivalents (CGE) using a relative biological effectiveness (RBE) of 1.1. METHODS AND MATERIALS: Twenty-one patients with subfoveal CNV received proton irradiation to the central macula with a single fraction of 8 CGE; 19 were eligible for evaluation. Treatment-related morbidity was based on Radiation Therapy Oncology Group (RTOG) criteria; response was evaluated by Macular Photocoagulation Study (MPS) guidelines. Fluorescein angiography was performed; visual acuity, contrast sensitivity, and reading speed were measured at study entry and at 3-month intervals after treatment. Follow-up ranged from 6 to 15 months. RESULTS: No measurable treatment-related morbidity was seen during or after treatment. Of 19 patients evaluated at 6 months, fluorescein angiography demonstrated treatment response in 10 (53%); 14 (74%) patients had improved or stable visual acuity. With a mean follow-up of 11.6 months, 11 (58%) patients have demonstrated improved or stable visual acuity. CONCLUSION: A macular dose of 8 CGE yielded no measurable treatment morbidity in patients studied. Fluorescein angiography demonstrated that regressed or stabilized lesions were associated with improved visual acuity as compared with MPS results. In the next phase, a dose of 14 CGE in a single fraction will be used to further define the optimal dose fractionation schedule.

Combined proton and photon conformal radiation therapy for locally advanced carcinoma of the prostate: preliminary results of a phase I/II study.

PURPOSE: A study was developed to evaluate the use of combined photons and protons for the treatment of locally advanced carcinoma of the prostate. This report is a preliminary assessment of treatment-related morbidity and tumor response. METHODS AND MATERIALS: One hundred and six patients in stages T2b (B2), T2c (B2), and T3 (C) were treated with 45 Gy photon-beam irradiation to the pelvis and an additional 30 Cobalt Gray Equivalent (CGE) to the prostate with 250-MeV protons, yielding a total prostate dose of 75 CGE in 40 fractions. Median follow-up time was 20.2 months (range: 10-30 months). Toxicity was scored according to the Radiation Therapy Oncology Group (RTOG) grading system; local control was evaluated by serial digital rectal examination (DRE) and prostate specific antigen (PSA) measurements. RESULTS: Morbidity evaluation was available on 104 patients. The actuarial 2-year rate of Grade 1 or 2 late morbidity was 12% (8% rectal, 4% urinary). No patients demonstrated Grade 3 or 4 late morbidity. Treatment response was evaluated on 100 patients with elevated pretreatment serum PSA levels. The actuarial 2-year rate of PSA normalization was 96%, 97%, and 63% for pretreatment PSAs of > 4-10, > 10-20, and > 20, respectively. The 13 patients with rising PSA demonstrated local recurrence (3 patients), distant metastasis (8 patients), or no evidence of disease except increasing PSA (2 patients). CONCLUSIONS: The low incidence of side effects, despite the tumor dose of 75 CGE, demonstrates that conformal protons can deliver higher doses of radiation to target tissues without increasing complications to surrounding normal tissues. The initial tumor response, as assessed by the high actuarial rate of normalization with pretreatment PSA < or = 20, and the low rate of recurrences within the treatment field (2.8%), are encouraging.

Conformal proton therapy for prostate carcinoma.

BACKGROUND: The role and optimum dose of radiation to eradicate prostate cancer continues to be evaluated. Protons offer an opportunity to increase the radiation dose to the prostate while minimizing treatment toxicity. METHODS: Six hundred forty-three patients with localized prostate cancer were treated with protons, with or without photons. Treatments were planned with a 3D planning system; patients received 74-75 CGE (Cobalt Gray Equivalent) at 1.8-2.0 CGE per fraction. Patients were evaluated for response to therapy and treatment-related toxicity. RESULTS: The overall clinical disease-free survival rate was 89% at 5 years. When post-treatment prostate-specific antigen (PSA) was used as an endpoint for disease control, the 4.5-year disease-free survival rate was 100% for patients with an initial PSA of < 4.0 ng/ml, and 89%, 72%, and 53% for patients with initial PSA levels of 4.1-10.0, 10.1-20.0, and > 20.0, respectively. Patients in whom the post-treatment PSA nadir was below 0.5 ng/ml did significantly better than those whose nadir values were between 0.51-1.0 or > 1.0 ng/ml: the corresponding 5-year disease-free survival rates were 91%, 79%, and 40%, respectively. Minimal radiation proctitis was seen in 21% of patients; toxicity of greater severity was seen in less than 1%. CONCLUSION: Proton therapy to 74-75 CGE produced minimal treatment-related toxicity and excellent PSA normalization and disease-free survival in patients with low initial PSA levels. A prospective randomized dose-escalation trial is now underway to help define the optimum dose of radiation for patients with early stage prostate cancer.

Visual detection of granulocyte surface antigens using the avidin-biotin complex.

A visual test for detection of granulocyte surface markers using the avidin-biotin complex (ABC) has been developed. That this assay is highly specific, reproducible, and sensitive was determined by studying the expression of HLA antigens on granulocytes with monoclonal antibodies. Further, using granulocyte specific alloantisera, the results of the ABC test compared well to data from leukoagglutination assays and indirect immunofluorescence tests. The assay is particularly advantageous in that granulocytes can be stored, only small amounts of cells and sera are needed, and heterogeneous cell populations can easily be studied.

Pilot study of cytokine profiles in prostate cancer patients undergoing proton or conventional radiotherapy.

The mechanisms responsible for normal tissue late effects following radiotherapy are largely unknown and currently no method for predicting such risks is available. Abnormal levels of cytokine production induced by radiation has been suggested as a contributing factor by multiple investigators. The purpose of the present study was to evaluate plasma levels of transforming growth factor-beta 1 (TGF-beta 1), basic fibroblast growth factor (bFGF), tumor necrosis factor-alpha (TNF-alpha), and interleukin-1 beta (IL-1 beta) in patients with prostate cancer scheduled for radiotherapy (protons, photons, or combination of both). It has been recently shown that ionizing radiation can increase expression of these cytokines and there are indications that they may be associated with morbidity. Blood samples were obtained from 20 subjects (age 51-80) before, during the first week, and immediately after the end of therapy; 3 healthy volunteers served as controls. Significant positive correlations (p<0.05) were obtained between bFGF, IL-1 beta, and TNF-alpha and the integral dose of radiation during the first week of treatment. Correlations approaching significance (p<0.1) were obtained with bFGF and acute treatment-related morbidity. A higher integral dose (due to larger irradiated volumes) was delivered with conventional photon compared to proton irradiation. No significance was obtained with any of the cytokines and pretreatment prostate specific antigen (PSA) levels, patient age, grade or stage of disease, or the integral dose by the end of radiation treatment. These results show that large changes occur in the plasma levels of certain cytokines early after initiation of radiotherapy and that treatment of larger volumes is more likely to induce these changes. Our data support further investigation of the role of cytokines during radiotherapy.

Conformal proton therapy for early-stage prostate cancer.

OBJECTIVES: To assess the effect of proton radiation on clinical and biochemical outcomes for early prostate cancer. METHODS: Three hundred nineteen patients with T1-T2b prostate cancer and initial prostate-specific antigen (PSA) levels 15.0 ng/mL or less received conformal radiation doses of 74 to 75 cobalt gray equivalent with protons alone or combined with photons. No patient had pre- or post-treatment hormonal therapy until disease progression was documented. Patients were evaluated for biochemical disease-free survival, PSA nadir, and toxicity; the mean and median follow-up period was 43 months. RESULTS: Overall 5-year clinical and biochemical disease-free survival rates were 97% and 88%, respectively. Initial PSA level, stage, and post-treatment PSA nadir were independent prognostic variables for biochemical disease-free survival: a PSA nadir 0.5 ng/mL or less was associated with a 5-year biochemical disease-free survival rate of 98%, versus 88% and 42% for nadirs 0.51 to 1.0 and greater than 1.0 ng/mL, respectively. No severe treatment-related morbidity was seen. CONCLUSIONS: It appears that patients treated with conformal protons have 5-year biochemical disease-free survival rates comparable to those who undergo radical prostatectomy, and display no significant toxicity. A Phase III randomized dose-escalation trial is underway to define the optimum radiation dose for early-stage prostate cancer.

Treatment of macular degeneration with proton beams.

Subfoveal neovascular membranes (SNVMs) are a leading cause of severe visual loss in the elderly in the United States. Previously, the only treatment that could halt progression of this disease was laser photocoagulation, which was, however, accompanied by immediate reduction in visual acuity. A single narrow proton beam was used to irradiate 45 patients to either 8 or 14 Cobalt Gray Equivalent. The alignment technique and dosimetry of these treatments are described. The proton beam direction, range, and modulation were planned with the assistance of an eye-specific planning program. A single anterior beam was used, with patients looking nasally toward a blinking fixation light at an angle of 30 degrees. Patients were aligned using a light field projected through a slit collimator. Patients' positions were monitored during treatment with a short-focal-length camera. Depth dose in a flat phantom was measured with a small-diameter parallel plate ionization chamber. Lateral profiles were measured at several depths with silver halide film. Each treatment session lasted 15 min, of which 1 min consisted of beam delivery. The proton beam stopped in the orbital cavity, delivering no primary proton dose to the brain. Dose to the center of the lens of the involved eye was less than 0.5% of the dose delivered to the macula. Treatments of SNVMs with proton beams require only a short visit to the hospital, little immobilization effort, and a minimal amount of treatment room and beam time. Compared to previous treatment trials using x-ray beams, the dose to nonocular tissues is reduced significantly.

Phase I trial of interleukin-2 plus doxorubicin.

Interleukin-2 (IL-2) and doxorubicin have synergistic antitumor activity in selected animal models and may interact favorably in the therapy of human tumors. In order to explore the interactions between these agents and to define a maximum tolerated dosage for the combination, we performed a phase I clinical trial of IL-2 administered by continuous intravenous infusion (c.i.) plus doxorubicin given by intravenous bolus. Fifteen patients were treated on one of two schedules; the first seven patients received IL-2, 9 mIU/m2/day (3 patients) or 13.5 mIU/m2/day (4 patients) by c.i. on days 1-5, 8-12, and 15-19 with doxorubicin, 25 mg/m2 on day 14. Eight patients received IL-2, 18 mIU/m2/day by c.i. on days 1-5 and 8-12 with doxorubicin, 25 mg/m2 (4 patients) or 50 mg/m2 (4 patients) on day 7. The toxicities of the combination were no greater than those expected from each agent individually. Patients at all three planned IL-2 dosage levels received similar percentages of the planned total dosage (median 100%; > 95% in 60% of cycles), and all patients received the planned dosages of doxorubicin with only one brief delay for resolution of hyperbilirubinemia. The doses recommended for further study are IL-2, 18 mIU/m2/day, on days 1-5 and 8-12 with doxorubicin, 50 mg/m2 on day 7, a regimen which is not associated with significant organ toxicity.

Nasopharyngeal carcinoma: repeat treatment with conformal proton therapy--dose-volume histogram analysis.

PURPOSE: To analyze control, survival, and complication rates of conformal proton radiation for recurrent nasopharyngeal carcinoma. MATERIALS AND METHODS: Sixteen patients with nasopharyngeal carcinoma initially treated with 50.0-88.2 Gy photons were re-treated with protons to additional doses of 59.4-70.2 CGE. Local-regional control and survival were correlated with extent of relapse, recurrence versus persistence, and prescribed dose and were subjected to dose-volume histogram analysis. Mean follow-up was 23.7 months (range, 4-47 months). RESULTS: Twenty-four-month actuarial overall and local-regional progression-free survival rates were both 50%. The 24-month actuarial overall survival rates for patients with "optimal" dose-volume histogram coverage versus "suboptimal" coverage were 83% and 17%, respectively (P = .006). Doses to critical structures were low (0-22.0 Gy); no central nervous system side effects supervened. CONCLUSION: Adequate tumor coverage, as evaluated by using dose-volume histogram analysis, was found to be the most important variable influencing local-regional control and survival. No central nervous system complications were observed; increases in the dose to adjacent critical structures are being evaluated.