James D. Kolker

Acute toxicity during external-beam radiotherapy for localized prostate cancer: Comparison of different techniques

PURPOSE The chronic and acute toxicities associated with conventional radiotherapy of localized prostate cancer are well documented. However, the degree and incidence of toxicities with conformal techniques are not known. Studying side effects associated with modern radiotherapeutic techniques is more important now since there has been a general trend to use computerized tomography-based techniques in recent years; beams eye view-based conformal techniques are also becoming more commonplace. It is possible that the local disease control can be improved with the delivery of higher doses than currently used. Conformation of the treatment volume to the target volume may facilitate such dose-escalation. However, prior to such dose-escalation, it is important to know the toxicities associated with such techniques with conventional doses. METHODS AND MATERIALS We have compared week-by-week acute toxicities associated with conventional (Group A, 16 patients), computerized tomography-based, manual (Group B, 57 patients) and beams eye view-based (Group C, 43 patients) techniques during 7 weeks of radiotherapy. Group B and C patients were treated contemporaneously (1988-1990). RESULTS Acute side effects gradually increased from week 1 through weeks 4-5 and generally declined or plateaued after that. The incidence of acute toxicities was significantly less with the beams eye view/based technique than with the other two methods. For instance, the percentages of Grade 2 acute genitourinary toxicities for Groups A, B, and C were as follows: Week 1-0, 0, 0; Week 2-6, 0, 0; Week 3-6, 9, 2; Week 4-12, 14, 9; Week 5-35, 14, 9; Week 6-31, 16, 7; Week 7-33, 8, 8, respectively. The p values associated with differences in acute genitourinary toxicities for Weeks 1-7 using chi-square test were 0.072, 0.627, 0.389, 0.538, 0.123, 0.06, and 0.012; the p values for acute gastrointestinal toxicities were 0.512, 0.09, 0.031, 0.031, 0.003, < 0.0001, and 0.004, respectively. Pairwise comparison (Wilcoxon rank-sum test) showed statistically significant lower acute toxicity in Group C than Group B (e.g., p values, Weeks 1-7 for gastrointestinal toxicity: 0.633, 0.056, 0.010, 0.014, < 0.0001, < 0.0001, and < 0.0001, respectively) in the latter part of the treatment course. No correlation was found between the extent of toxicity and the patient age or the overall treatment time. Also, no correlation was found between the degree of toxicity and the radiation dose and fraction size, within the narrow ranges used (65-70 Gy and 180-200 cGy, respectively). A trend suggesting increased severity of toxicity with increase in the volume of treatment was seen. CONCLUSION The findings in this retrospective study need to be confirmed by other prospective studies.

Stereotactic radiosurgery to the resection bed for intracranial metastases and risk of leptomeningeal carcinomatosis

OBJECT Following resection of a brain metastasis, stereotactic radiosurgery (SRS) to the cavity is an emerging alternative to postoperative whole-brain radiation therapy (WBRT). This approach attempts to achieve local control without the neurocognitive risks associated with WBRT. The authors aimed to report the outcomes of a large patient cohort treated with this strategy. METHODS A retrospective review identified 91 patients without a history of WBRT who received Gamma Knife (GK) SRS to 96 metastasis resection cavities between 2007 and 2013. Patterns of intracranial control were examined in the 86 cases with post-GK imaging. Survival, local failure, and distant failure were estimated by the Kaplan-Meier method. Prognostic factors were tested by univariate (log-rank test) and multivariate (Cox proportional hazards model) analyses. RESULTS Common primary tumors were non-small cell lung (43%), melanoma (14%), and breast (13%). The cases were predominantly recursive partitioning analysis Class I (25%) or II (70%). Median preoperative metastasis diameter was 2.8 cm, and 82% of patients underwent gross-total resection. A median dose of 16 Gy was delivered to the 50% isodose line, encompassing a median treatment volume of 9.2 cm(3). Synchronous intact metastases were treated in addition to the resection bed in 43% of cases. Patients survived a median of 22.3 months from the time of GK. Local failure developed in 16 cavities, for a crude rate of 18% and 1-year actuarial local control of 81%. Preoperative metastasis diameter ≥ 3 cm and residual or recurrent tumor at the time of GK were associated with local failure (p = 0.04 and 0.008, respectively). Distant intracranial failure occurred in 55 cases (64%) at a median of 7.3 months from GK. Salvage therapies included WBRT and additional SRS in 33% and 31% of patients, respectively. Leptomeningeal carcinomatosis developed in 12 cases (14%) and was associated with breast histology and infratentorial cavities (p = 0.024 and 0.012, respectively). CONCLUSIONS This study bolsters the existing evidence for SRS to the resection bed. Local control rates are high, but patients with larger preoperative metastases or residual/recurrent tumor at the time of SRS are more likely to fail at the cavity. While most patients develop distant intracranial failure, an SRS approach spared or delayed WBRT in the majority of cases. The risk of leptomeningeal carcinomatosis does not appear to be elevated with this strategy.

Concomitant Chemoradiotherapy, Neutron Boost, and Adjuvant Chemotherapy for Anaplastic Astrocytoma and Glioblastoma Multiforme

The survival rate for patients with malignant gliomas is poor. We describe the results of a prospective study using concomitant chemoradiotherapy, neutron boost, and adjuvant chemotherapy for patients with malignant gliomas. Forty-two patients with anaplastic astrocytoma (AA) and glioblastoma multiforme (GBM) were treated with postoperative photon radiation 45 Gy/25 fraction (fxs) with concomitant continuous intravenous infusion of 5-fluorouracil at 300 mg/m2/day x 5 days and hydroxyurea 0.5 g orally every 12 hr for 6 days for 5 consecutive weeks, followed by a neutron boost of 450 N cGy/6 fxs delivered twice weekly. Adjuvant chemotherapy with procarbazine, CCNU, and vincristine (PCV) was given up to 1 year or until tumor progression. Thirty-four patients (81%) had GBM and 8 patients (19%) had AA. Sixteen patients (38%) were ineligible for the neutron boost because of large tumors or poor performance status and instead received a photon boost with concomitant chemotherapy for a total dose of 60-65 Gy to the tumor. The overall median survival is 68 weeks at a median follow-up of 203 weeks (range 166-302 weeks for the 11 patients remaining alive); 7/8 patients with AA are alive, 2 of these with progressive disease. For AA the median survival is not reached at a median follow-up of 203 weeks (range 166-302 weeks for the 7 patients alive with AA). Time to tumor progression for the 1 dead patient with AA was 35 weeks and the other 2 patients failed at 171 weeks and 179 weeks following treatment. The median survival for the 34 patients with GBM was 62 weeks; 4/34 patients with GBM are alive at 285, 238, 216, and 206 weeks. Multivariate survival analysis in the 34 patients with GBM revealed age and Karnofsky performance status as important prognostic factors. Extent of surgery and neutrons did not affect survival. Concomitant chemoradiotherapy was well tolerated by all patients. The only toxicities observed were mucositis < or = grade II in 3 patients (7%) and mild myelosuppression in 1 patient (2.4%). Adjuvant PCV was well tolerated. Continuous concomitant chemoradiotherapy was well tolerated by all patients with acceptable side effects. The survival rate for the patients with GBM suggests no significant impact on the prognosis for these patients. Patients with AA did well; however, the patient numbers are small.

Efficacy and safety of stereotactic body radiation therapy for the treatment of pulmonary metastases from sarcoma: A potential alternative to resection.

Oligometastatic sarcoma pulmonary metastases (PM) are typically treated with resection and/or chemotherapy. We hypothesize that stereotactic body radiotherapy (SBRT) can be an alternative to surgery that can achieve high rates of local control (LC) with limited toxicity.

Instant-mix whole brain photon with neutron boost radiotherapy for malignant gliomas

From July 1985 through March 1987, 44 consecutive patients with supratentorial, nonmetastatic anaplastic astrocytoma (AA) and glioblastoma multiforme (GBM) were treated with whole brain photon irradiation with concomitant neutron boost at the University of Chicago. All patients had biopsy proven disease and surgery ranged from biopsy to total gross excision. Whole brain photon radiation was given at 1.5 Gy per fraction, 5 days weekly for a total dose of 45 Gy in 6 weeks. Neutron boost radiation was prescribed to a target minimum dose that included the pre-surgical CT tumor volume plus 1 cm margin. Neutrons were administered 5-20 minutes prior to photon radiation twice weekly and a total dose of 5.2 Gyn gamma was administered over 6 weeks. Median follow-up was 36 months. The median survival was 40.3 months for anaplastic astrocytoma (10 patients) and 11 months for glioblastoma multiforme (34 patients) and 12 months for the overall group. Variables that predicted longer median survival included histology (AA vs. GBM), age (less than or equal to 39 years vs. older), and extent of surgery (total gross or partial excision vs. biopsy) whereas tumor size and Karnofsky performance status did not have a significant influence. The median survival of the anaplastic astrocytoma group was better than expected compared to the RTOG 80-07 study (a dose-finding study of similar design to this study) and historical data. Reasons for this are discussed.

Gamma Knife radiosurgery to four or more brain metastases in patients without prior intracranial radiation or surgery

Data on stereotactic radiosurgery (SRS) for four or more metastases are limited. Existing studies are confounded by significant proportions of patients receiving prior whole‐brain radiation therapy (WBRT) or concurrent WBRT with SRS. Furthermore, published results disagree about the impact of tumor volume on overall survival. A retrospective review identified 38 patients without prior intracranial radiation or surgery who received Gamma Knife (GK) as sole treatment to ≥4 brain metastases in a single session. Twenty‐eight cases with follow‐up imaging were analyzed for intracranial progression. Prognostic factors were examined by univariate (log‐rank test) and multivariate (Cox proportional hazards model) analyses. Common primary tumors were non‐small cell lung (45%), melanoma (37%), and breast (8%). Cases were recursive partitioning analysis class II (94%) or III (6%). Patients harbored a median five tumors (range 4–12) with median total tumor volume of 1.2 cc. A median dose of 21 Gy was prescribed to the 50% isodose line. Patients survived a median 6.7 months from GK. Local treatment failure occurred in one case (4%) and distant failure in 22 (79%). On multivariate analysis, total tumor volume ≥3 cc was significantly associated with distant failure and worsened overall survival (P = 0.042 and 0.040). Fourteen patients (37%) underwent salvage WBRT at a median 10.3 months from GK and seven patients received repeat GK. GK as sole initial treatment for four or more simultaneous metastases spares some patients WBRT and delays it for others. Increased total tumor volume (≥3 cc) is significantly associated with worsened overall survival.

Age-related reference ranges for complexed prostate-specific antigen and complexed/total prostate-specific antigen ratio: results from East Texas Medical Center Cancer Institute screening campaign

The East Texas Medical Center Cancer Institute conducted a regional prostate cancer screening campaign over a 3-year period from 1998 through 2000. Total prostate-specific antigen (tPSA), complexed PSA (cPSA), and cPSA/tPSA ratio (c/tPSA) values were determined. To better define prostate cancer in the population, we chose to determine age-based reference ranges for these PSA isoforms in apparently healthy men. Participants (N = 12,902) between the ages of 20 and 94 were screened and demographic information and serum tPSA and cPSA values were collected across 41 centers throughout East Texas. Men with an abnormal digital rectal examination, a follow-up biopsy indicating prostatic disease, or any clinical signs and symptoms of prostatic disease were excluded. Sera from 7541 evaluable men were tested with the Bayer Immuno 1 PSA and cPSA methods at East Texas Medical Center. The resulting PSA data were then stratified by decade of age to determine age-related reference ranges for each PSA species. The cPSA values increased across all age decades: 40 to 49 years, 1.45 ng/mL; 50 to 59, 1.92 ng/mL; 60 to 69, 2.49 ng/mL; and 70 to 79, 2.77 ng/mL (95th percentile). tPSA levels also increased with age: 1.81 ng/mL, 2.45 ng/mL, 3.17 ng/mL, and 3.57, respectively. Comparatively, the c/tPSA levels remained constant (0.87), regardless of age. The upper limits of tPSA and cPSA values reported here suggest that men should be screened using lower cutoff values than are currently in use. These limits may more accurately identify prostate cancer among otherwise healthy men.