Stereotactic radiosurgery and radiotherapy for brainstem metastases: An international multicenter analysis.

Brainstem metastases (BSM) present a significant neuro-oncological challenge, resulting in profound neurological deficits and poor survival outcomes. Stereotactic radiosurgery (SRS) and fractionated stereotactic radiotherapy (FSRT) offer promising therapeutic avenues for BSM despite their precarious location. This international multicenter study investigates the efficacy and safety of SRS and FSRT in 136 patients with 144 BSM treated at nine institutions from 2005 to 2022. The median radiographic and clinical follow-up periods were 6.8 and 9.4 months, respectively. Predominantly, patients with BSM were managed with SRS (69.4%). The median prescription dose and isodose line for SRS were 18 Gy and 65%, respectively, while for FSRT, the median prescription dose was 21 Gy with a median isodose line of 70%. The 12-, 24-, and 36-month local control (LC) rates were 82.9%, 71.4%, and 61.2%, respectively. Corresponding overall survival rates at these time points were 61.1%, 34.7%, and 19.3%. In the multivariable Cox regression analysis for LC, only the minimum biologically effective dose was significantly associated with LC, favoring higher doses for improved control (in Gy, hazard ratio [HR]: 0.86, p < .01). Regarding overall survival, good performance status (Karnofsky performance status, ≥90%; HR: 0.43, p < .01) and prior whole brain radiotherapy (HR: 2.52, p < .01) emerged as associated factors. In 14 BSM (9.7%), treatment-related adverse events were noted, with a total of five (3.4%) radiation necrosis. SRS and FSRT for BSM exhibit efficacy and safety, making them suitable treatment options for affected patients.

A nested case-control study on radiation dose-response for cardiac events in breast cancer patients in Germany.

BACKGROUND: Previous studies with the majority of breast cancer (BC) patients treated up to 2000 provided evidence that radiation dose to the heart from radiotherapy (RT) was linearly associated with increasing risk for long-term cardiac disease. RT techniques changed substantially over time. This study aimed to investigate the dose-dependent cardiac risk in German BC patients treated with more contemporary RT. METHODS: In a cohort of 11,982 BC patients diagnosed in 1998-2008, we identified 494 women treated with 3D-conformal RT who subsequently developed a cardiac event. Within a nested case-control approach, these cases were matched to 988 controls. Controls were patients without a cardiac event after RT until the index date of the corresponding case. Separate multivariable conditional logistic regression models were used to assess the association of radiation to the complete heart and to the left anterior heart wall (LAHW) with cardiac events. RESULTS: Mean dose to the heart for cases with left-sided BC was 4.27 Gy and 1.64 Gy for cases with right-sided BC. For controls, corresponding values were 4.31 Gy and 1.66 Gy, respectively. The odds ratio (OR) per 1 Gy increase in dose to the complete heart was 0.99 (95% confidence interval (CI): 0.94-1.05, P = .72). The OR per 1 Gy increase in LAHW dose was 1.00 (95% CI: 0.98-1.01, P = .68). CONCLUSIONS: Contrary to previous studies, our study provided no evidence that radiation dose to the heart from 3D-conformal RT for BC patients treated between 1998 and 2008 was associated with risk of cardiac events.

Neoadjuvant capecitabine combined with standard radiotherapy in patients with locally advanced rectal cancer: mature results of a phase II trial.

PURPOSE: The objective of this expanded phase II trial was to confirm the safety results of the preceding phase I study and establish the efficacy of neoadjuvant radiochemotherapy with capecitabine in rectal cancer in a multicenter setting. PATIENTS AND METHODS: 96 patients (63% male, age 34-81 years) with advanced rectal cancer (cT3-4 or cN+) from seven university centers in Germany were recruited. All were to receive a total irradiation dose of 50.4-55.8 Gy with conventional fractions. Capecitabine was given at an oral dosage of 825 mg/m(2)bid on each day of the radiotherapy period with the first daily dose applied 2 h before irradiation, followed by surgery 6 weeks later. RESULTS: Most of the patients suffered from an advanced primary tumor (cT3: 57%, cT4: 40%) with lymph node involvement in 60%. After neoadjuvant treatment, with a mean of 99% of the scheduled radiation dose actually delivered, a clinical response rate of 68% (95% confidence interval: 57-78%) was observed. Out of 87 evaluable patients undergoing surgery, a sphincter-preserving procedure could be performed in 51% and R0 resection in 94%. A pathologically complete response was achieved in six patients (7%, 95% confidence interval: 3-14%). The comparison of initial diagnosis and pathologic findings showed a downstaging in 61%. Acute toxicity with > 5% incidence of NCI (National Cancer Institute) grade >/= 3 included lymphopenia (12%), leukopenia (6%), and diarrhea (7%). Mild to moderate hand-foot syndrome occurred in 12% only. After a median follow-up of 48 months, the 5-year overall survival and tumor control data were, with regard to patient selection, in the expected range with an overall survival of 65%, a relapse-free survival of 47%, and a local recurrence rate after 5 years of 17%. CONCLUSION: The data clearly confirm that capecitabine is an adequate substitute for 5-fluorouracil in preoperative chemoradiation of rectal cancer with a favorable safety profile.

In vivo dosimetry with semiconducting diodes for dose verification in total-body irradiation. A 10-year experience.

BACKGROUND AND PURPOSE: For total-body irradiation (TBI) using the translation method, dose distribution cannot be computed with computer-assisted three-dimensional planning systems. Therefore, dose distribution has to be primarily estimated based on CT scans (beam-zone method) which is followed by in vivo measurements to ascertain a homogeneous dose delivery. The aim of this study was to clinically establish semiconductor probes as a simple and fast method to obtain an online verification of the dose at relevant points. PATIENTS AND METHODS: In 110 consecutively irradiated TBI patients (12.6 Gy, 2 x 1.8 Gy/day), six semiconductor probes were attached to the body surface at dose-relevant points (eye/head, neck, lung, navel). The mid-body point of the abdomen was defined as dose reference point. The speed of translation was optimized to definitively reach the prescribed dose in this point. Based on the entrance and exit doses, the mid-body doses at the other points were computed. The dose homogeneity in the entire target volume was determined comparing all measured data with the dose at the reference point. RESULTS: After calibration of the semiconductor probes under treatment conditions the dose in selected points and the dose homogeneity in the target volume could be quantitatively specified. In the TBI patients, conformity of calculated and measured doses in the given points was achieved with small deviations of adequate accuracy. The data of 80% of the patients are within an uncertainty of +/- 5%. CONCLUSION: During TBI using the translation method, dose distribution and dose homogeneity can be easily controlled in selected points by means of semiconductor probes. Semiconductor probes are recommended for further use in the physical evaluation of TBI.

The burden of pain of inpatients undergoing radiotherapy--discrepancies in the ratings of physicians and nurses.

BACKGROUND: The aim of this study was to rate the burden of pain of cancer patients receiving radiotherapy from the point of view of the patients themselves as well as the physicians and nurses caring for the patient, and to examine possible differences in the ratings. PATIENTS AND METHODS: 68 cancer patients received a pain questionnaire about pain intensity and subjective well-being. At the same time, physicians and nurses answered 7 pain-related questions about each patient. RESULTS: 34% of the patients reported strong or very strong pain in the past week, 8% even unbearable pain. 66% felt psychologically distressed, 70% developed anxiety because of pain. 74% believed that pain is an essential part of the disease. Nurses and physicians often underestimate patients' burden of pain. Nevertheless, the rating of the nurses is more accurate than that of the physicians. CONCLUSION: Physicians and nurses often underestimate pain intensity. It seems that several patients are unable or unwilling to express their pain or that therapists lack adequate methods of pain assessment. To optimize pain treatment, communication between patients, physicians and nurses needs to be improved.

Retrospective analysis of the superior vena cava syndrome in irradiated cancer patients.

BACKGROUND: A carcinoma is the underlying cause of superior vena cava syndrome (SVCS) in 95-97% of patients. The aim of our study is to retrospectively analyse the outcome of patients after local radiotherapy compared to literature data. PATIENTS AND METHODS: In 35 consecutively registered patients, irradiated because of SVCS, different primary carcinomas (lung, breast, head-and-neck, Non-Hodgkin's lymphoma) were ascertained. Distant metastases had already been diagnosed in 33 patients. Chemotherapy had previously been given in seven patients. RESULTS: In 30 patients, radiotherapy obtained a reduction of symptoms within 5-9 days. However, in seven patients, radiotherapy had to be stopped early because of local progress and tumor induced complications. Local recurrences were observed in six patients. The 1-year overall survival rate was 15.6%. Survival rate depended significantly on the performance status (p < 0.004). CONCLUSION: Based on literature data our results are comparable regarding the incidence, the radio-oncological procedure and the response to treatment. These data confirm that radiotherapy is the standard treatment in most patients suffering from SVCS. However, it should be determined if endovascular stenting, which is more frequently considered in the last few years in patients with a tumor induced SVCS, may be a useful option as a simultaneous or sequentially given treatment to optimize the palliative effect.

Concomitant radiochemotherapy with temozolomide in non-selected patients with newly diagnosed high-grade gliomas.

BACKGROUND: Malignant gliomas still present a medical challenge, despite decades of continuous extensive research with optimization of surgical techniques, radiotherapy and systemic treatments. PATIENTS AND METHODS: From 1999 to 2004, 104 patients with WHO grade III and IVgliomas underwent surgery and received concomitant radiotherapy combined with concomitant oral temozolomide. Patients with progressive disease received sequential 5-day cycles of temozolomide at 28-day intervals. RESULTS: The median overall survival was 19.7 and 15.0 months for patients with WHO grade III versus IV gliomas, respectively. Patient compliance was good and toxicity moderate. The overall survival was as long as 18.0 months in a subgroup of subjects with glioblastoma, performance status >60% and complete radiochemotherapy. CONCLUSION: Although our patients had more negative characteristics (age, performance, biopsy only), the results confirmed those from recently published optimistic phase III trial data and indeed surpassed them in some cases.

Evaluation of tartrate-resistant acid phosphatase (TRACP) 5b as bone resorption marker in irradiated bone metastases.

BACKGROUND: The aim of our study was to evaluate if the determination of the active isoform 5b of tartrate-resistant acid phosphatase (TRACP 5b) provides the possibility to monitor the effect of local radiotherapy in bone metastases and if TRACP 5b will predict further osseous progression. MATERIALS AND METHODS: In 48 breast cancer patients with bone metastases, patients' characteristics, diagnostic imaging and laboratory investigation, tumor- and therapy-related parameters were registered at the beginning and the end of radiotherapy, as well as 6 and 12 weeks afterwards. TRACP 5b activity was measured using a solid phase immunofixed enzyme activity assay with the monoclonal antibody O1A. RESULTS: During follow-up, progression in another part of the skeleton was diagnosed in 31 patients (65%). There was a significant decrease of TRACP 5b in patients without progression in non-irradiated regions, whereas in progressive disease, TRACP 5b levels remained stable with a slightly increasing tendency (p < 0.007). In patients with < or =3 metastases, all TRACP 5b values were significantly lower than the values of those with >3 metastases (p = 0.01). CONCLUSION: In patients without further osseous progression, TRACP 5b is able to monitor the effectiveness of local radiotherapy. The estimation of sensitivity and specificity based on each TRACP 5b value demonstrates that the ability to discriminate between those patients with or without osseous progression increases with time.

Multimodality treatment including postoperative radiation and concurrent chemotherapy with weekly docetaxel is feasible and effective in patients with oral and oropharyngeal cancer.

BACKGROUND: To examine the feasibility and efficacy of weekly docetaxel with concurrent radiation as postoperative treatment in a multimodality approach to oral and oropharyngeal cancer. PATIENTS AND METHODS: 94 patients (Table 1) with primary resectable squamous cell carcinoma of the oral cavity and oropharynx (UICC stage I 14%, II 15%, III 18%, IV 53%; Table 2) were treated with a multimodality therapy program consisting of neoadjuvant intra-arterial high-dose chemotherapy (cisplatin 150 mg/m(2) with parallel systemic sodium thiosulfate 9 g/m(2) for neutralization), followed by surgery of the primary and neck, and postoperative concurrent radiation and chemotherapy with weekly docetaxel (20-30 mg/m(2); Table 3). Chronic toxicities were followed over a period of 5 years. RESULTS: At a median follow-up of 4 years, the 5-year survival rate for all 94 patients was 80%, and disease-free survival was 73% (Figures 1 and 2). Among patients with advanced disease (stage III and IV), survival was 83 and 59%, respectively (Figure 4). Grade 3 and 4 mucositis was the main acute toxicity necessitating supportive care. Long-term toxicity appears to be moderate (Table 4). The maximum tolerated dose of weekly docetaxel was 25 mg/m(2). CONCLUSIONS: Concurrent radiation and chemotherapy with weekly docetaxel is a feasible postoperative treatment in a multimodality approach to oral and oropharyngeal cancer, resulting in high overall and disease-free survival. This approach warrants further evaluation in prospective randomized trials.

Erythropoietin to treat head and neck cancer patients with anaemia undergoing radiotherapy: randomised, double-blind, placebo-controlled trial.

BACKGROUND: Anaemia is associated with poor cancer control, particularly in patients undergoing radiotherapy. We investigated whether anaemia correction with epoetin beta could improve outcome of curative radiotherapy among patients with head and neck cancer. METHODS: We did a multicentre, double-blind, randomised, placebo-controlled trial in 351 patients (haemoglobin <120 g/L in women or <130 g/L in men) with carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx. Patients received curative radiotherapy at 60 Gy for completely (R0) and histologically incomplete (R1) resected disease, or 70 Gy for macroscopically incompletely resected (R2) advanced disease (T3, T4, or nodal involvement) or for primary definitive treatment. All patients were assigned to subcutaneous placebo (n=171) or epoetin beta 300 IU/kg (n=180) three times weekly, from 10-14 days before and continuing throughout radiotherapy. The primary endpoint was locoregional progression-free survival. We assessed also time to locoregional progression and survival. Analysis was by intention to treat. FINDINGS: 148 (82%) patients given epoetin beta achieved haemoglobin concentrations higher than 140 g/L (women) or 150 g/L (men) compared with 26 (15%) given placebo. However, locoregional progression-free survival was poorer with epoetin beta than with placebo (adjusted relative risk 1.62 [95% CI 1.22-2.14]; p=0.0008). For locoregional progression the relative risk was 1.69 (1.16-2.47, p=0.007) and for survival was 1.39 (1.05-1.84, p=0.02). INTERPRETATION: Epoetin beta corrects anaemia but does not improve cancer control or survival. Disease control might even be impaired. Patients receiving curative cancer treatment and given erythropoietin should be studied in carefully controlled trials.

Re-186 HEDP conditioning therapy in patients with advanced acute lymphoblastic leukemia before allogeneic bone marrow transplantation.

The authors present their experience with dose calculation of Retin1,1-hydroxyethylidene-186-diphosphonate (Re-186 HEDP) therapy used as part of an intensified conditioning regimen before allogeneic stem cell transplantation in 2 patients with advanced acute lymphoblastic leukemia during the second partial or third complete remission. Kidneys were shielded during total-body irradiation (TBI) to limit the TBI-mediated renal radiation dose to 7 Gy. The aim of this dose calculation of Re-186 HEDP therapy was to deliver additional radiotherapy to the red bone marrow without exposing more than an additional 5 Gy to the kidneys in addition to the TBI standard dose of 12.6 Gy. Pretherapeutic kidney scintigraphy (Tc-99m mercaptoacetyltriglycine) showed normal results. Thus, dynamic Tc-99m methylene diphosphonate bone scintigraphy was used to calculate the expected bone marrow and kidney doses. A total amount of 8.8 GBq (238 mCi) Re-186 HEDP was given to patient no. 1 and 14.3 GBq (387 mCi) Re-186 HEDP was given to patient no. 2. Re-186 HEDP activity was monitored based on its gamma radiation measurement daily for 5 days in patient no. 1 and 7 days in patient no. 2. Therapeutic Re-186 isotope distribution and biologic half-life correlated well with the prediction by a pretherapeutic Tc-99m methylene diphosphonate scan. The calculated effective Re-186 bone marrow dose was 3.3 Gy for patient no. 1 and 5.6 Gy for patient no. 2. Effective kidney doses were 1.6 Gy and 2.1 Gy respectively. No unexpected complications occurred after completing conditioning and allogeneic stem cell transplantation. Posttransplant kidney function remained normal. Patient no. 1 remains in a second complete remission of his advanced acute lymphoblastic leukemia 18 months after HEDP therapy. Patient no. 2 relapsed 5 months after transplantation and eventually died as a result of progressive disease. The authors conclude that Re-186 HEDP will be able to increase the total additional bone marrow dose. In patients in whom the kidney dose is limited to 5 Gy in addition to TBI, doses near 10 Gy can be achieved on the bone marrow.

Tartrate-resistant acid phosphatase 5b as serum marker of bone metabolism in cancer patients.

BACKGROUND: The serum marker tartrate-resistant acid phosphatase isoform 5b (TRACP 5b) is considered a specific parameter of osteoclast activity and a useful marker of bone resorption. Regarding the utility of TRACP 5b in bone metastases, this review aims to draw clinically relevant conclusions. MATERIALS AND METHODS: The available literature data regarding the laboratory methods, the characteristics of TRACP 5b and the clinical data, as well as our own results about TRACP 5b in cancer patients has been reviewed. RESULTS: In contrast to enzymatic assays, two new assays based on a monoclonal antibody and on heparin-induced inhibition of TRACP 5a, respectively, demonstrated low biological and analytical variabilities in healthy subjects as well as in patients with osteoporosis. Up to now, only a few studies have evaluated the utility of TRACP 5b in cancer patients with bone metastases. In these studies, the sensitivity of TRACP 5b was higher compared to other markers. Furthermore, TRACP 5b activity correlates with the response to the treatment of bone metastases. CONCLUSION: Although the clinical data available are promising, the results are still preliminary. In addition to further evaluation of the analytical method, more studies in cancer patients are needed to establish TRACP 5b in the diagnostic procedure and in the therapy monitoring of bone metastases.

Radiation enhancement by gemcitabine-mediated cell cycle modulations.

The purpose of this study was to investigate the exact dose dependency and time dependency of the radiation-enhancing effect of gemcitabine (2',2'difluoro desoxycytidine [dFdC]) in in vitro experiments (HeLa cells: cancer of the uterine cervix, #4197 cells: oropharyngeal squamous cell carcinoma), and to correlate this effect with the underlying changes in cell cycle distribution. Cell viability was determined fluorometrically after exposure to dFdC (0-20.0 micro mol/l), irradiation (0-37.5 Gy), and both modalities. Combining both therapies, cells were exposed to dFdC (0-10.0 micro mol/l) for 24 hours before further treatment and irradiated (0-30 Gy) immediately afterwards with or without removal of dFdC. For cell cycle analysis by flow cytometry, cells were irradiated (0-40 Gy) or treated with dFdC (0.012-1.0 micro mol/l, 24-48 hours). Additionally, cells were exposed to dFdC (2.0 micro mol/l, 0-4 hours). Cell cycle kinetics were evaluated using bromodeoxyuridine (BrdU) (10 micro mol/l) S-phase labeling, given either 30 minutes before or in the last hour of dFdC treatment (2.0 micro mol/l, 0-6 hours). The fluorometric assay revealed that dFdC enhances radiation-induced cytotoxicity at marginally toxic or nontoxic concentrations (<37 nmol/l). Radiation resulted in the anticipated G2/M arrest already at 2 Gy. DFdC induced concentration and exposure time-dependent cell cycle changes that were better resolved using BrdU, demonstrating a pronounced S-phase arrest already at 12 nmol/l. BrdU-pulse labeling revealed that the cell cycle block occurred at the G1/S boundary. Our data reconfirm the already known radiation enhancement, the S-phase specific activities of dFdC, and the relevance of the synchronized progression of cells through the S-phase with regard to the radiosensitizing properties of low-dose dFdC. However, we could demonstrate that before progressing in the S-phase, cells were blocked and partially synchronized at the more radiosensitive G1/S boundary. Furthermore, cells progressing past the block might accumulate proapoptotic signals caused by both radiation and dFdC, which will also results in cell death.

[Combined radiotherapy and gemcitabine. Evaluation of clinical data based on experimental knowledge]. / Kombination von Radiotherapie und Gemcitabine. Bewertung der klinischen Daten auf der Basis experimenteller Erkenntnisse.

BACKGROUND: In experimental studies the nucleoside analog Gemcitabine (2',2' difluorodesoxycytidine) clearly demonstrates radiation enhancing properties. After describing the pharmacological Gemcitabine-related data and the clinical studies regarding combined radiochemotherapy and taking under consideration the in-vitro data and the results provided by animal models, this overview is aimed to draw clinically relevant conclusions, resulting in the improvement of treatment approaches. MATERIALS AND METHODS: The available literature data regarding the metabolism and the mechanism of action, the evaluation of possible schedules of administration, and combined radiochemotherapy including Gemcitabine has been reviewed. Publications reporting experimental data in vitro and in vivo as well as our own experimental results have been incorporated. RESULTS: In clinical phase I and II studies, the favorable tumor response is accompanied by a high incidence of grade III-IV toxicities whereby the maximum-tolerated dose (MTD) of the various schedules of administration used is always lower compared to the MTD of single-agent treatment. In in-vitro and in-vivo data addressing the description and the evaluation of the radiation enhancing mechanism (especially influence on cell cycle, depletion of the dATP pool, induction of apoptosis, inhibition of DNA synthesis, reduction of DNA repair) this effect is already observed with non and moderately toxic Gemcitabine concentrations and depends on drug concentration and exposure time. Independent of the fractionation effect of radiotherapy, the radiation enhancement is persistent for at most 72 hours after the end of drug exposure. Taking under consideration the single dose per day and the target volume, a prolonged infusion and/or a twice-weekly administration of Gemcitabine at low concentration each and simultaneous radiotherapy are presumably considered to resemble the experimental data. CONCLUSION: It is without doubt that data provided by clinical studies are of highest relevance for the evaluation of an optimized radiochemotherapy with Gemcitabine. However, although it is often difficult to transfer experimental data into the clinical situation, these data offer the possibility to develop an improved schedule of administration in patient treatment based on rational evidence in tumor biology.