John Lamond

A multiinstitutional outcome and prognostic factor analysis of radiosurgery for resectable single brain metastasis

PURPOSE Recent randomized trials of selected patients with single brain metastasis comparing resection followed by whole-brain radiotherapy (WBRT) to WBRT alone have shown a statistically significant survival advantage for surgery and WBRT. A multiinstitutional retrospective study was performed, which identified comparable patients who were treated with stereotactic radiosurgery (RS) and WBRT. METHODS AND MATERIALS The RS databases of four institutions were reviewed to identify patients who met the following criteria: single-brain metastasis; no prior cranial surgery or WBRT; age > 18 years; surgically resectable lesion; Karnofsky Performance Status (KPS) > or = 70 at time of RS; nonradiosensitive histology. One hundred twenty-two patients were identified who met these criteria. Patients were categorized by: (a) status of the primary, (b) status of non-CNS metastasis, (c) age, (d) baseline KPS (from 70-100), (e) histology, (f) time from diagnosis of primary to the detection of the brain metastasis, (g) gender, and (h) tumor volume. RS was performed with a linear accelerator based technique (peripheral dose range was 10-27 Gy, median was 17 Gy). WBRT was performed in all but five patients who refused WBRT (dose range was 25-40 Gy, median was 37.5 Gy). RESULTS The median follow-up for all patients was 123 weeks. The overall local control rate (defined as lack of progression in the RS volume) was 86%. Intracranial recurrence outside of the RS volume was seen in 27 patients (22%). The actuarial median survival from date of RS is 56 weeks, and the 1-year and 2-year actuarial survival rates are 53% and 30%. The median duration of functional independence (sustained KPS > or = 70) is 44 weeks. Nineteen of 77 deaths were attributed to CNS progression (25% of all deaths). Multivariate analysis revealed the following factors to be statistically significant predictors of survival: baseline KPS (p < .0001) and absence of other sites of metastasis (p = 0.008). CONCLUSION The RS in conjunction with WBRT for single brain metastasis can produce substantial functional survival, especially in patients with good performance status and without extracranial metastasis. These results are comparable to recent randomized trials of resection and WBRT. The advantages of RS over surgery in terms of cost, hospitalization, morbidity, and wider applicability strongly suggest that a randomized trial to compare RS with surgery is warranted.

A cost-effectiveness and cost-utility analysis of radiosurgery vs. resection for single-brain metastases

PURPOSE The median survival of well-selected patients with single-brain metastases treated with whole-brain irradiation and resection or radiosurgery is comparable, although a randomized trial of these two modalities has not been performed. In this era of cost containment, it is imperative that health-care professionals make fiscally prudent decisions. The present environment necessitates a critical appraisal of apparently equi-efficacious therapeutic modalities, and it is within this context that we present a comparison of the actual costs of resection and radiosurgery for brain metastases. METHODS AND MATERIALS Survival and quality of life outcome data for radiation alone or with surgery were obtained from two randomized trials, and radiosurgical results were obtained from a multiinstitutional analysis that specifically evaluated patients meeting surgical criteria. Only linear accelerator radiosurgery data were considered. Cost analysis was performed from a societal view point, and the following parameters were evaluated: actual cost, cost ratios, cost effectiveness, incremental cost effectiveness, cost utility, incremental cost utility, and national cost burden. The computerized billing records for all patients undergoing resection or radiosurgery for single-brain metastases from January 1989 to July 1994 were reviewed. A total of 46 resections and 135 radiosurgery procedures were performed. During the same time period, 454 patients underwent whole-brain radiation alone. An analysis of the entire bill was performed for each procedure, and each itemized cost was assigned a proportionate figure. The relative cost ratios of resection and radiosurgery were compared using the Wilcoxon rank sum test. Cost effectiveness of each modality, defined as the cost per year of median survival, was evaluated. Incremental cost effectiveness, defined as the additional cost per year of incremental gain in median survival, compared to the next least expensive modality, was also determined. To calculate the societal or national impact of these practices, the proportion of patients potentially eligible for aggressive management was estimated and the financial impact was determined using various utilization ratios for radiosurgery and surgery. RESULTS Both resection and radiosurgery yielded superior survival and functional independence, compared to whole brain radiotherapy alone, with minor differences in outcome between the two modalities; resection resulted in a 1.8-fold increase in cost, compared to radiosurgery. The latter modality yielded superior cost outcomes on all measures, even when a sensitivity analysis of up to 50% was performed. A reversal estimate indicated that in order for surgery to yield equal cost effectiveness, its cost would have to decrease by 48% or median survival would have to improve by 108%. The average cost per week of survival was

The potential of topoisomerase I inhibitors in the treatment of CNS malignancies: report of a synergistic effect between topotecan and radiation

310 for radiotherapy,

Concentration and timing dependence of lethality enhancement between topotecan, a topoisomerase I inhibitor, and ionizing radiation

524 for resection plus radiation, and

Radiation lethality enhancement with 9-aminocamptothecin: Comparison to other topoisomerase I inhibitors

270 for radiosurgery plus radiation. CONCLUSIONS For selected patients, aggressive strategies such as resection or radiosurgery are warranted, as they result in improved median survival and functional independence. Radiosurgery appears to be the more cost-effective procedure.

Angiosarcoma of the Head and Neck Managed by a Combination of Multiple Biopsies to Determine Tumor Margin and Radiation Therapy: Report of Three Cases and Review of the Literature

SummaryDespite innovations in imaging, surgery, and radiation therapy, local failure remains the principle clinical problem in most CNS malignancies. To date, chemotherapy has not made a major impact in the treatment of most adult CNS tumors. The inroads made by chemotherapy in pediatric CNS malignancies suggest that novel drugs, or drug combinations, may improve therapy. Topoisomerase I (Topo I) inhibitors are a relatively new group of chemotherapy drugs with a novel mechanism of action. Drugs in this group currently undergoing clinical trials are the Camptothecin analogues Topotecan, CPT-11, and 9-aminocamptothecin. There is substantial preclinical and some clinical evidence to suggest that these drugs could be useful in the treatment of CNS malignancies. Preclinical studies with the water soluble Topo I inhibitor, Topotecan, demonstrate antineoplastic activity in a variety of CNS malignancies. In addition, Topotecan has good CNS penetration in primates, and recent preliminary phase I and II clinical trials of Topotecan in pediatric and adult CNS malignancies have been promising. In this paper, we describe the unique mechanism of action, antineoplastic activity, and radiosensitizing properties of Topo I inhibitors. We present the first report demonstrating potentiation of radiation lethality by Topotecan in a human glioma (1354) cell line. The dose enhancement ratio was 3.2 at 10% survival. Thus, there is evidence to suggest that Topo I inhibitors may be beneficial in the treatment of CNS neoplasms on the basis of their antineoplastic activity alone, as well as their radiosensitizing effects. Two clinical trials which utilize concurrent Topotecan and radiation in the treatment of pediatric and adult CNS malignancies are discussed.

Stereotactic body radiation therapy for patients with heavily pretreated liver metastases and liver tumors.

PURPOSE Topotecan (TPT) is a water-soluble Topoisomerase I (Topo I) inhibitor with reported antineoplastic activity against a variety of solid tumors (including nonsmall cell lung, small cell lung, ovarian, breast, esophageal, and head and neck primaries) and leukemias. We sought to determine: (1) if TPT enhanced the lethal effects of ionizing radiation: and (b) the biological and biochemical characteristics of the enhancement. METHODS AND MATERIALS Quiescent human radioresistant melanoma (U1-Mel) cells were x-irradiated (1-12 Gy) and exposed to various TPT concentrations (0.1-300 microM) either before (for 4 h), during, or after (for 4 h) radiation. Survival was determined via colony forming assays and normalized to correct for drug cytotoxicity. The effects of TPT on radiation-related potential lethal damage repair (PLDR) and sublethal damage repair (SLDR) were measured. A modification of the SDS-KCl assay was used to quantify DNA-Topo I complexes. RESULTS Enhanced radiation lethality by TPT was observed using quiescent U1-Mel cells. The sensitizer enhancement ratio (SER) after a 4 h postirradiation exposure of 4 microM TPT was 1.6 at 10% survival. The effect was: (A) dependent on drug concentration, with lethality enhancement and minimal drug lethality alone in the 2-10 microM range for a 4 h posttreatment; (b) dependent on timing, with enhancement observed only when drug was present at the time of, or shortly after, radiation; and (c) irreversible, with inhibition of PLDR and SLDR. Exposure to TPT during or after radiation substantially elevated DNA-Topo I complexes (four- to tenfold) over control levels and complex formation correlated to some degree with loss of survival. CONCLUSIONS TPT enhanced radiation lethality in vitro at low drug concentrations that are clinically feasible. The rationale and design of an ongoing Phase I trial which utilizes concurrent TPT and radiation is discussed.

Survival and Control Prognosticators of Recurrent Gynecological Malignancies of the Pelvis and Para-aortic Region Treated with Stereotactic Body Radiation Therapy

PURPOSE Preclinical studies have demonstrated differences in potency, solubility, and tumor specific activity among the camptothecin (CPT) analogues. 9-Aminocamptothecin (9-AC) has demonstrated greater potency in animal studies than other clinically available Topoisomerase I (Topo I) inhibitors. We sought to determine: (a) if 9-AC enhanced the lethal effects of ionizing radiation to a greater extent than other Topo I inhibitors; and (b) the biological and biochemical characteristics of the enhancement. METHODS AND MATERIALS Quiescent radioresistant human melanoma (U1-Mel) cells were x-irradiated (1-7 Gy) and exposed to various concentrations of 9-AC (0.1-100 microM), either before (for 4 h), during, or after (for 4 h) irradiation. Survival was determined via colony forming assays and normalized to correct for drug cytotoxicity. The effect of 9-AC on radiation-related potential lethal damage repair PLDR) (PLDR) was also measured. A modification of the SDS-KCl assay was used to quantify DNA-Topo I complexes. RESULTS Enhancement of radiation lethality was observed using confluent U1-Mel cells. The sensitizer enhancement ratio (SER) after a 4 h postirradiation exposure of 10 microM 9-AC was 2.5 at 10% survival. Toxicity from the drug alone was greater than topotecan (TPT), but less than CPT. The radiation synergy effect was: (a) dependent on drug concentration (> or = 2 microM); (b) dependent on timing, with enhancement present only when the drug was present at the time of, or shortly after, radiation; and (c) irreversible, with inhibition of PLDR. Exposure to 9-AC during or after irradiation substantially elevated the number of DNA-Topo I complexes (four- to tenfold) over control levels and correlated with enhanced loss of survival. CONCLUSION 9-Aminocamptothecin enhanced radiation lethality in vitro at low drug concentrations with characteristics similar to other Topo I inhibitors. A greater SER, but greater lethality with the drug alone, was obtained in comparison to TPT. The clinical implications of these findings remain unexplored.

A “Red Shell” concept of increased radiation damage hazard to normal tissues just outside the PTV target volume

background. Cutaneous angiosarcoma (AS) is a rare, often multicentric vascular tumor of the head and neck region with a rather poor prognosis. The original clinical size of the tumor rarely correlates to the degree of microscopic tissue invasion. Treatment by surgical excision sometimes requires very wide excision. Treatment by radiation or electron beam appears less mutilating but its efficacy is not well documented. objective. To present our experience with a combined surgical delineation of tumor margins followed by radiation treatment. methods. We treated three patients with extensive AS of the scalp and face. Prior to radiation, in two cases the tumor margins were determined by grid‐pattern punch biopsies. In the third patient, the tumor margins were determined by Mohs mapping system. All three patients then received radiation either by rotational arc electron beam (n = 2) and standard radiation. results. One patient developed two local recurrences in non‐irradiated areas plus a metastatic cervical node, all of which responded to additional electron beam. The patient has no evidence of disease (NED) after 30 months of observation. The other two patients were treated by electron beam and radiation have NED at 5 and 1 years follow‐up, respectively. conclusions. Local control of AS of the scalp may be achieved by assessment of the tumor margin by peripheral biopsies or Mohs technique followed by electron beam and radiation.

Acute toxicity after cyberknife-delivered hypofractionated radiotherapy for treatment of prostate cancer.

We present our initial experience with CyberKnife stereotactic body radiation therapy (SBRT) in a heavily pretreated group of patients with liver metastases and primary liver tumors. From October 2007 to June 2009, 48 patients were treated at the Philadelphia CyberKnife Center for liver metastases or primary liver tumors. We report on 30 patients with 41 discrete lesions (1–4 tumors per patient) who received an ablative radiation dose (BED ≥ 79.2 Gy10 = 66 Gy EQD2). The treatment goal was to achieve a high SBRT dose to the liver tumor while sparing at least 700 cc of liver from radiation doses above 15 Gy. Twenty-three patients were treated with SBRT for metastatic cancer to the liver; the remainder (n = 7) were primary liver tumors. Eighty-seven percent of patients had prior systemic chemotherapy with a median 24 months from diagnosis to SBRT; 37% had prior liver directed therapy. Local control was assessed for 28 patients (39 tumors) with 4 months or more follow-up. At a median follow-up of 22 months (range, 10–40 months), 14/39 (36%) tumors had documented local failure. A decrease in local failure was found with higher doses of SBRT (p = 0.0237); 55% of tumors receiving a BED ≤ 100 Gy10 (10/18) had local failure compared with 19% receiving a BED > 100 Gy10 (4/21). The 2-year actuarial rate of local control for tumors treated with BED > 100 Gy10 was 75% compared to 38% for those patients treated with BED ≤ 100 Gy10 (p = 0.04). At last follow-up, 22/30 patients (73%) had distant progression of disease. Overall, seven patients remain alive with a median survival of 20 months from treatment and 57 months from diagnosis. To date, no patient experienced persistent or severe adverse effects. Despite the heavy pretreatment of these patients, SBRT was well tolerated with excellent local control rates when adequate doses (BED > 100 Gy10) were used. Median survival was limited secondary to development of further metastatic disease in the majority of patients.