The radiation oncologist's perspective on stereotactic radiosurgery

Unfavorable gliomas: The basis for single-fraction stereotactic radiosurgery (SRS) is largely historical in nature and rooted in conventional thinking. This is derived from the original use of SRS in the treatment of arteriovenous malformations (AVMs), where the benefit of single-fraction high-dose radiation is clearly optimal in terms of addressing AVM obliteration kinetics. However, tumor cell kinetics are not the same as AVM obliteration kinetics and therefore may not be optimally addressed by single-fraction SRS. In addition, fractionated (F) SRS, as compared to single-fraction SRS, should allow for sparing of normal tissue damage. The relatively noninvasive nature of SRS allows for the potential of exploiting the use of FSRS and also allows for consideration of delivering FSRS in a split-course fashion. This provides an additional advantage over what can normally be achieved by use of stereotactic brachytherapy, in that sterotactic brachytherapy is likely to be performed only once in the course of a patient's primary treatment. This strategy exploits tumor and/or normal tissue cell kinetics, inclusive of attempting to counteract the initial accelerated tumor growth phase pre-CEBRT(conventional external beam radiation therapy), thereby decreasing the rate of clinical tumor progression during CEBRT. This split-course design should also help to counteract the effect of accelerated tumor repopulation post-CEBRT. Our unique experience with this approach in patients with unfavorable gliomas will be reviewed. Brain metastases: While whole brain radiation therapy (WBRT) remains a standard of care in patients with brain metastases, is potential neurocognitive morbidity remains a poorly understood concern. Despite this, and with an increasing role of surgery and/or SRS in the primary management of patients with brain metastasis, recently reported experiences withholding WBRT as part of primary therapy for brain metastases have not analyzed the potential effects on neurological functional status and/or neurocognition associated with the increased risk of brain tumor recurrence seen with such a strategy. We recently evaluated the risk of symptomatic brain tumor recurrence and associated neurologic deficit in 36 patients treated for newly diagnosed unresected brain metastases treated by Gamma Knife SRS alone followed by planned observation. Among the 17 patients (47%) developing brain tumor recurrence, 71% (12/17) were symptomatic and 59% (10/17) had an associated neurologic deficit. Also of interest, the author (WFR) performed a secondary analysis of a randomized phase III study of accelerated hyperfractionation (AH) versus standard accelerated fractionation (AF) in patients with unresected brain metastases. Control of brain metastases had a significant impact on MMSE. It is only among patients with 'uncontrolled" brain metastases that a drop in MMSE score is seen. Details of these studies, along with others, will be reviewed and implications with regards to the complementary role of WBRT in patients undergoing SRS for brain metastases will be discussed.     

A phase II study of concomitant hyperfractionated radiation therapy and double dose intra-arterial cisplatin for squamous cell carcinoma of the head and neck

This successor phase II study evaluates the tolerability and efficacy of concomitant hyperfractionated radiation therapy (HFX-RT) and double dose intra-arterial (IA) cisplatin in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN). In doing so, this study represents further resurgence of the potential use of IA chemotherapy in the management of SCCHN. This has been enabled by the evolution of angiographic catheter/microcatherter technology. Between 1997 and 1999, 24 patients with locally advanced T4/T3 SCCHN were treated with HFX-RT (76.8- 81.6 Gy at 1.2 Gy bid over 6-7 weeks) and high-dose IA cisplatin (150mg/m2 given at the start of and during RT boost treatment [start of week 6 and 7]). Twenty-two patients (92%) had T4 disease and 14 (58%) N2/ N3 disease. Acute toxicity was limited to two grade 4 (8%) and 19 grade 3 (79%) mucosal events; and single grade 3 hematologic, infectious and skin events. Eight patients (33%) were unable to receive the second planned dose of IA cisplatin. Twenty-two patients had complete response (92%) at the primary site. Among 17 patients with positive neck disease 12 (71%) achieved complete response in the neck. Follow-up ranges from 7-30 months (median = 18 months) with 14 patients alive without disease, 2 alive with disease, 7 dead of disease and 1 dead of intercurrent disease. While concomitant HFX-RT and double dose IA cisplatin as used in this study is associated with encouraging response rates in this highly unfavorable subset of patients with locally advanced SCCHN it was not feasible. Future investigation of this novel treatment strategy utilizing modern angiographic catheter/microcatherter technology will involve a single dose of IA cisplatin with HFX-RT and dose intensification using neoadjuvant therapy.     

What margins are necessary for incorporating mediastinal nodal mobility into involved-field radiotherapy for lung cancer?

The mobility of mediastinal nodes was studied on multiple CT scans of the thorax from patients with non-small-cell lung cancer.

A total of 10 enlarged mediastinal nodes/masses were identified in 8 patients with non-small-cell lung cancer. Nodal locations were classified using the Naruke/ATS-LCSG system, and between 3 and 6 scans were available for each site. The CT data sets were coregistered, and the contoured nodes were automatically projected onto the initial planning CT scan. An encompassing nodal volume (ENV) of all contours of a particular node was manually contoured on all scans. Individual nodal volumes were expanded in three dimensions to establish additional margins required to encompass the ENV.

The mean volume of nodes studied ranged from 0.8 to 23.2 cc. The addition to individual nodes of a margin of 5 mm was found to result in a mean ENV coverage of ≥95% at all sites. For individual nodes at locations N4R, N5, and N6, however, the coverage ranged from 87.8% to 92.6%.

The addition of a margin of 5 mm to individual mediastinal nodes seems to be adequate to account for variations in both contouring and mobility.     

Risk of symptomatic brain tumor recurrence and neurologic deficit after radiosurgery alone in patients with newly diagnosed brain metastases: results and implications

PURPOSE: A single-institution experience using primary stereotactic radiosurgery (SRS) alone in the management of newly diagnosed brain metastases was analyzed to identify the risk of symptomatic brain tumor recurrence (BTR) and neurologic deficit associated with such a treatment strategy. METHODS AND MATERIALS: Thirty-six patients were treated for newly diagnosed single/multiple brain metastases using SRS alone followed by planned observation. SRS minimum tumor dose ranged from 8 to 25 Gy (median: 20 Gy). Factors evaluated in analysis of treatment outcome included number of metastases, site of metastasis, primary tumor site, histology, extent of intracranial and extracranial disease, and interval to diagnosis of brain metastasis. RESULTS: Median and 1-year survival for the entire group was 9 months and 36%, respectively. BTR anywhere in the brain occurred in 47% (17/36) of patients. Forty-seven percent of BTR (8/17) recurred at the site of original metastasis; 35% (6/17) recurred at both original [corrected] and distant sites in the brain, and 18% (3/17) recurred at distant only [corrected] brain sites. Seventy-one percent (12/17) of the patients were symptomatic at the time of recurrence, and 59% (10/17) had an associated neurologic deficit. Multivariate analysis found that only the extent of disease was a predictor of BTR. Patients who had disease limited to the brain only had a BTR rate of 80% (8/10) vs. 35% (9/26) who had disease involving the brain, primary site, and/or other extracranial metastatic sites (p = 0.03). CONCLUSIONS: Use of primary SRS alone in this setting is associated with an increasingly significant risk of BTR with increasing survival time. In addition, the majority of such recurrences are symptomatic and associated with a neurologic deficit, a finding not analyzed in recently reported experiences withholding whole brain radiation therapy as part of the primary treatment of brain metastasis.     

Rechtsprobleme der stationären Rehabilitation

Ohne Zusammenfassung RID="*" ID="*"Erweiterte Fassung eines Vortrags anl?sslich des 20j?hrigen Bestehens der Fachkliniken Hohenurach in Bad Urach. Prof. Dr. iur. Hans Kamps und Dr. iur. Regine Kiesecker, Bezirks?rztekammer Südwürttemberg, Haldenhaustra?e 11, D-72770 Reutlingen     

Interval pathologic assessments in patients treated with concurrent hyperfractionated radiation and intraarterial cisplatin (HYPERRADPLAT)

BACKGROUND: To minimize surgical morbidity, surgery should be performed within 2 to 3 months of completion of radiation therapy with or without chemotherapy. Pathologic demonstration of cancer at this interval is commonly used to justify early surgical salvage of residual primary head and neck cancer. These assumptions regarding head and neck cancer in patients treated with concurrent hyperfractionated radiation therapy and intraarterial supradose cisplatin (HYPERRADPLAT) have never been evaluated. METHODS: Post-HYPERRADPLAT clinical and pathologic findings in 42 patients with stage III and IV head and neck cancer were compared with their disease outcomes. All patients underwent an interval analysis of response at 6 to 10 weeks after completion of therapy, 28 of these patients had biopsies of the primary tumor site performed. RESULTS: Clinical findings of cancer with pathologic confirmation up to 4 months after therapy can be associated with eventual complete response (CR). Pathologic CR's from deep incisional biopsies can be associated with recurrent disease within 2 months. Six HYPERRADPLAT-treated patients underwent interval surgical resection of primary disease, and only the four patients with cancer identified in the resection specimen died of recurrent disease. CONCLUSION: In patients treated with HYPERRADPLAT, interval clinical and pathologic assessments may be misleading. Only observation of progressive disease is an accurate predictor of local failure. New evaluation techniques such as metabolic imaging and molecular analysis warrant exploration as tools for interval cancer evaluations.     

The feasibility of dose escalation using concurrent radiation and 5-fluorouracil therapy following pancreaticoduodenectomy for pancreatic carcinoma

We evaluated the feasibility of dose escalation using external beam radiation therapy (RT) and 5-fluorouracil (5-FU) following pancreaticoduodenectomy for pancreatic carcinoma. Fourteen patients who underwent pancreaticoduodenectomy for stage I–III adenocarcinoma of the pancreas received postoperative high-dose chemoradiation. RT was given at 1.8-Gy daily fractions to total doses of 54 Gy for patients with negative surgical margins (n = 12), and 64.8 Gy for those with gross residual disease (n = 2). Concurrent 5-FU was given as a continuous infusion (CI) at 225 mg/m² per day (n = 9) beginning or day 1 and continuing until the completion of RT, or by bolus injection at 500 mg/m² per day (n = 5) during weeks 1 and 4 of RT. Follow-up ranged from 32 to 36 months (median, 35 months). All patients were able to complete the planned high-dose postoperative chemoradiation and none required a treatment break. No grade 4 acute toxicity was observed. Grade 3 acute toxicity was limited to 2 patients. Two patients developed grade 3 (n = 1) or 4 (n = 1) subacute toxicity, all gastrointestinal-related. There have been no fatal toxicities and no grade 3 or 4 late toxicity has been observed. The 3-year survival is 21%. Dose escalation of postoperative 5-FU chemoradiation following pancreaticoduodenectomy for pancreatic carcinoma is well tolerated. Further dose-intensification of postoperative adjuvant therapy in these patients appears feasible and is being evaluated in a recently activated national trial. Received for publication on Feb. 16, 1999; accepted on June 10, 1999     

High telomerase activity and high HTRT mRNA expression differentiate pure myxoid and myxoid/round-cell liposarcomas

Molecular markers characterizing the transition of a myxoid to a more round-cell liposarcoma have not been described. To examine whether telomerase activity, hTRT and hTR mRNA expression were associated with tumor progression in myxoid liposarcoma, we investigated a total of 28 myxoid liposarcomas (13 pure myxoid tumors, 14 mixed-type tumors, and 1 pure round-cell variant) from 19 patients. Telomerase activity was detected by using the fluorescent PCR-based TRAP-assay. Expression of hTRT and hTR mRNAs was determined by the semi-quantitative RT-PCR. On the basis of only one tumor sample per patient, telomerase activity was found in 9 of 9 myxoid/round-cell liposarcomas and in 3 of 10 pure myxoid tumors. Elevated hTRT expression was found in 13 of 17 liposarcomas. All telomerase-positive tumors showed hTRT expression, whereas there were 3 cases showing hTRT expression without telomerase activity. HTR mRNA expression was elevated in all 19 liposarcomas. Thus, only the levels of telomerase activity and of hTRT mRNA expression differentiated pure myxoid liposarcoma and myxoid/round-cell liposarcoma (p < 0.003 and p = 0.029, respectively). We believe that high levels of telomerase activity and of hTRT expression are associated with tumor progression from low-grade pure myxoid to higher-grade malignant round-cell liposarcoma, and may consequently represent a useful prognostic marker for this histological sub-type of soft-tissue tumors.     

Promoter hypermethylation of p16INK4a, E-cadherin, O6-MGMT, DAPK and FHIT in adenocarcinomas of the esophagus, esophagogastric junction and proximal stomach

Although the incidence of Barrett's carcinomas (BC) and proximal gastric adenocarcinomas (PGC) is increasing, little is known about different epigenetic changes in these etiopathogenetically distinct entities. Therefore, 29 adenocarcinomas [10 BC, 7 PGC and 12 tumors of the esophagogastric junction (JC)] and corresponding non-tumor controls (NT) were examined using methylation-specific PCR. The most striking result was a significantly higher promoter methylation frequency of O6-methylguanine methyl transferase (MGMT) in BC compared with JC and PGC (0.7 vs. 0.08 vs. 0.29, respectively; p = 0.011; methylation exclusively in tumors), confirmed immunohistochemically by a significant loss of MGMT protein in BC (p = 0.006). Therefore, MGMT might become a prognosticator and key for chemotherapy with alkylating agents in BC. Frequencies of p16INK4a promoter methylation were 0.5 (BC), 0.42 (JC) and 0.29 (PGC; n.s.), but methylation was almost absent in NT controls. As immunonegative tumors slightly outnumber methylation-positive cases, other mechanisms of gene inactivation must be discussed. Methylation of E-cadherin was rarely observed (1/10 BC, 0/12 JC and 2/7 PGC). This is the first report on promoter methylation of death-associated protein kinase (DAPK) and fragile histidine triad gene (FHIT) in BC; both DAPK (BC 0.7, JC 0.92 and PGC 0.86) and FHIT (BC 0.88, JC 1.0 and PGC 1.0) were found to be highly methylated, suggesting that epigenetic silencing of these tumor suppressors is a common event in adenocarcinomas of the upper gastrointestinal tract, including BC. DAPK (0.54 on average) and FHIT methylation (0.77 on average) were also observed in NT samples. This might constitute an early epigenetic precursor lesion in the normally-appearing tissue surrounding the tumor.     

Low concentrations of flavonoids are protective in rat H4IIE cells whereas high concentrations cause DNA damage and apoptosis

Dietary flavonoids possess a wide spectrum of biochemical and pharmacological actions and are assumed to protect human health. These actions, however, can be antagonistic, and some health claims are mutually exclusive. The antiapoptotic actions of flavonoids may protect against neurodegenerative diseases, whereas their proapoptotic actions could be used for cancer chemotherapy. This study was undertaken to determine whether a cytoprotective dose range of flavonoids could be differentiated from a cytotoxic dose range. Seven structurally related flavonoids were tested for their ability to protect H4IIE rat hepatoma cells against H(2)O(2)-induced damage on the one hand and to induce cellular damage on their own on the other hand. All flavonoids proved to be good antioxidants in a cell-free assay. However, their pharmacologic activity did not correlate with in vitro antioxidant potential but rather with cellular uptake. For quercetin and fisetin, which were readily taken up into the cells, protective effects against H(2)O(2)-induced cytotoxicity, DNA strand breaks, and apoptosis were detected at concentrations as low as 10-25 micromol/L. On the other hand, these flavonoids induced cytotoxicity, DNA strand breaks, oligonucleosomal DNA fragmentation, and caspase activation at concentrations between 50 and 250 micromol/L. Published data on quercetin pharmacokinetics in humans suggest that a dietary supplement of 1-2 g of quercetin may result in plasma concentrations between 10 and 50 micromol/L. Our data suggest that cytoprotective concentrations of some flavonoids are lower by a factor of 5-10 than their DNA-damaging and proapoptotic concentrations.