Long-term results of pulsed irradiation of skin metastases from breast cancer. Effectiveness and sequelae.

PURPOSE: The concept of pulsed brachytherapy suggested by Brenner and Hall requires an unusual fractionation scheme. Effectiveness and sequelae of this new irradiation method were observed in patients with disseminated cutaneous metastases of breast cancer. PATIENTS AND METHODS: A flexible, reusable skin mold (weight 110 g) was developed for use with a pulsed dose rate (PDR) afterloader. An array of 18 parallel catheters (2 mm diameter) at equal distances of 10 or 12 mm was constructed by fixation of the catheters in a plastic wire mesh. The array is sewn between 2 foam rubber slabs of 5 mm thickness to provide a defined constant distance to the skin. Irradiations are possible up to a maximum field size of 20 x 23.5 cm using a nominal 37 GBq Ir-192 source. Pulses of 1 Gy reference dose at the skin surface are applied at a rate of 1 pulse every 1.2 hours (0.8 Gy per hour). The dose distribution is geometrically optimized to provide a homogeneous skin dose (100% +/- 10%). The 80% dose level lies at 5 mm below the skin surface. Between April 1994 and December 1997, 52 patients suffering from cutaneous metastases at the thoracic wall were treated with 54 fields and total doses of 38 to 50 Gy (median 42 Gy) applying 2 PDR courses with a pause of 4 to 5 weeks. RESULTS: Forty-six patients (48 fields) were eligible for evaluation in June 1998. The median follow-up was 16 months (range 7.1 to 46.2 months). Local control was achieved in 40 out of 48 fields (83%) or 41 of 46 patients (89%), respectively. Moist desquamation occurred in 52% of the patients. Late reactions were judged after a minimum follow-up of 6 months. Thirty-two fields had been previously irradiated with external beam therapy to doses of 40 to 60 Gy. Regardless of whether the skin was preirradiated or not all patients surviving long enough developed telangiectasia within 2 years after PDR irradiation. In preirradiated patients (n = 32) skin contractures and/or skin necrosis occurred in 12% each. In newly irradiated patients (n = 14) no contractures or skin necrosis were observed. CONCLUSIONS: Pulsed brachytherapy is an effective and time-sparing method for the treatment of cutaneous metastases from breast cancer. Skin reactions are comparable to the sequelae of orthovoltage therapy. Two sessions of approximately 20 Gy PDR were tolerated on preirradiated skin without severe sequelae.     

Fundamental studies on efficacy of intraoperative radiotherapy on pancreatic carcinomas transplanted into the pancreas of hamsters

Efficacy of intraoperative electron beam radiotherapy (IOER) on N-nitrosobis (2-hydroxypropyl) amine (BHP) induced pancreatic carcinomas transplanted into the pancreas of the Syrian golden hamsters were studied and the following results were obtained. 1. Selective electron beam application to the carcinoma transplanted into the pancreas of hamsters was accomplished using an electron beam collimator. 2. Intra-pancreatic transplantability of BHP-induced serially transplantable subcutaneous pancreatic carcinomas was 100%. 3. Intra-pancreatic transplanted pancreatic carcinomas disappeared in 2 out of 19 hamsters (11%) by 10 Gy irradiation and 7 out of 15 (47%) by 20 Gy irradiation given 2 weeks after intra-pancreatic transplantation. 4. In contrast to the linear growth of tumor size in the non-irradiated group, the tumor size showed an electron dose-dependent reduction in the irradiated group. 5. Histologically, marked necrosis was noted in the irradiated group, and the intensity of necrosis differed between the 10 Gy and 20 Gy groups. 6. Direct invasion of tumor to the stomach, small intestine, large intestine, liver and abdominal wall was noted. Its incidence tended to decrease as the electron dose increased (5/19 or 26% for the control group, 4/19 or 21% for the 10 Gy group, and 1/17 or 6% for the 20 Gy group), although the difference was not statistically significant. 7. The incidences of liver and lymph node metastasis were not different between the non-irradiated and the irradiated groups. These results suggest that selective IOER on BHP-induced pancreatic carcinomas has an effectiveness to kill cancer cells in hamsters.     

Tumor induction in mice after local irradiation with single doses of either carbon-ion beams or gamma rays

Abstract

Purpose: To determine the dose-dependent relative biological effectiveness (RBE) for tumor prevalence in mice receiving single localized doses to their right leg of either carbon ions (15, 45 or 75 keV/μm) or 137Cs gamma rays.

Methods and materials: A total of 1647 female C3H mice were irradiated to their hind legs with a localized dose of either reference gamma rays or 15, 45 or 75 keV/μm carbon-ion beams. Irradiated mice were evaluated for tumors twice a month during their three-year life span, and the dimensions of any tumors found were measured with a caliper. The tumor induction frequency was calculated by Kaplan-Meier analysis.

Results: The incidence of tumors from 50 Gy of 45 keV/μm carbon ions was marginally higher than those from 50 Gy of gamma rays. However, 60 Gy of 15 keV/μm carbon ions induced significantly fewer tumors than did gamma rays. RBE values of 0.87 + 0.12, 1.29 + 0.08 or 2.06 + 0.39 for lifetime tumorigenesis were calculated for 15, 45 or 75 keV/μm carbon-ion beams, respectively. Fibrosarcoma predominated, with no Linear Energy Transfer (LET)-dependent differences in the tumor histology. Experiments measuring the late effect of leg skin shrinkage suggested that the carcinogenic damage of 15 keV/μm carbon ions would be less than that of gamma rays.

Conclusions: We conclude that patients receiving radiation doses to their normal tissues would face less risk of secondary tumor induction by carbon ions of intermediate LET values compared to equivalent doses of photons.     

Flow cytophotometric measurements before and during radiotherapy of head and neck tumors

The DNA index and proliferation activities were determined by flow cytophotometry in 59 tumors of the head and neck area. 35 tumors (59%) were aneuploid, 24 (41%) were diploid. Aneuploid tumors showed a tendency to increased formation of lymph node metastases, an increased risk of relapse as well as a shorter relapse-free interval. No correlation was found between the primary tumor stage and the incidence of aneuploid tumors. Whereas aneuploid tumors developed frequently regional recurrences, only local recurrences were observed in diploid tumors. A number of biopsies was additionally performed during radiotherapy in twelve tumors. After 10 or 20 Gy, aneuploid tumors showed a considerably increased number of S and S2 + M phase cells. In diploid tumors, substantial modifications of the cell cycle phases were not found, because it is not possible in these cases to distinguish between normal cells and tumor cells.     

Reirradiation for Recurrent Neck Metastases of Head-and-Neck Tumors Using CT-Guided Interstitial 192Ir HDR Brachytherapy

PURPOSE: To report the therapeutic results obtained with CT-guided interstitial high-dose-rate brachytherapy (HDR-BRT) as exclusive treatment for recurrent neck metastases of head-and-neck tumors. PATIENTS AND METHODS: Between 1995 and 1999, 49 patients with prior radiation therapy (RT) with or without surgery for primary head-and-neck tumors were treated for recurrent neck metastases located within previously irradiated volumes. All patients had fixed lymphadenopathy with a mean tumor volume of 96 cm(3) (range, 15-452 cm(3)). There were 38 males and eleven females with a mean age of 60 years (range, 28-79 years). All patients had previously received RT as primary or adjuvant treatment with a mean dose of 54 Gy (range, 45-80 Gy). 36 patients (73%) underwent surgery, and 26 (53%) received adjuvant or palliative chemotherapy. The accelerated hyperfractionated interstitial HDR-BRT (2 x 3.0 Gy/day) delivered 30 Gy in 37/49 (75%) and 36 Gy in 12/49 implants (25%). RESULTS: At a minimum 6-week follow-up, the response rate was 83% (41/49) with complete remission in 20% (10/49) and partial remission in 63% (31/49) of the implanted tumor sites. 8/49 patients (17%) did not respond to the treatment. After 19 months of median follow-up, the local control rate was 69% and a total of 15/49 patients (30%) experienced local disease progression. Of these, nine (18%) had locoregional progression and six (12%) progression within the treated volume. The median post-BRT survival was 14 months. The overall survival rate was 52% at 1 year, 31% at 2 years, and 6% at 3 years. CONCLUSION: In patients with recurrent cervical lymphadenopathy of head-and-neck tumors, exclusive interstitial HDR-BRT can provide palliation and tumor control.     

Long-Term Results of Pulsed Irradiation of Skin Metastases from Breast Cancer Effectiveness and Sequelae

Purpose: The concept of pulsed brachytherapy suggested by Brenner and Hall requires an unusual fractionation scheme. Effectiveness and sequelae of this new irradiation method were observed in patients with disseminated cutaneous metastases of breast cancer. Patients and Methods: A flexible, rusable skin mold (weight 110 g) was developed for use with a pulsed dose rate (PDR) afterloader. An array of 18 parallel catheters (2 mm diameter) at equal distances of 10 or 12 mm was constructed by fixation of the catheters in a plastic wire mesh. The array is sewn between 2 foam rubber slabs of 5 mm thickness to provide a defined constant distance to the skin. Irradiations are possible up to a maximum field size of 20 2 23.5 cm using a nominal 37 GBq Ir-192 source. Pulses of 1 Gy reference dose at the skin surface are applied at a rate of 1 pulse every 1.2 hours (0.8 Gy per hour). The dose distribution is geometrically optimized to provide a homogeneous skin dose (100% - 10%). The 80% dose level lies at 5 mm below the skin surface. Between April 1994 and December 1997, 52 patients suffering from cutaneous metastases at the thoracic wall were treated with 54 fields and total doses of 38 to 50 Gy (median 42 Gy) applying 2 PDR courses with a pause of 4 to 5 weeks. Results: Forty-six patients (48 fields) were eligible for evaluation in June 1998. The median follow-up was 16 months (range 7.1 to 46.2 months). Local control was achieved in 40 out of 48 fields (83%) or 41 of 46 patients (89%), respectively. Moist desquamation occurred in 52% of the patients. Late reactions were judgeg after a minimum follow-up of 6 months. Thirty-two fields had been previously irradiated with external beam therapy to doses of 40 to 60 Gy. Regardless of whether the skin was preirradiated or not all patients surviving long enough developed telangiectasia within 2 years after PDR irradiation. In preirradiated patients (n = 32) skin contractures and/or skin necrosis occurred in 12% each. In newly irradiated patients (n = 14) no contractures or skin necrosis were observed. Conclusions: Pulsed brachytherapy is an effective and time-sparing method for the treatment of cutaneous metastases from breast cancer. Skin reactions are comparable to the sequelae of orthovoltage therapy. Two sessions of approximately 20 Gy PDR were tolerated on preirradiated skin without severe sequelae. Hintergrund: Das Konzept der von Brenner und Hall inaugurierten gepulsten Brachytherapie basiert auf einem unüblichen Fraktionierungsschema. Die Effektivität und die Folgen dieser neuen Bestrahlungsmethode wurden an Patienten mit disseminierten Hautmetastasen des Mammakarzinoms nachbeobachtet. Patienten und Methode: Es wurde eine flexible, wiederverwendbare Hautmoulage (Gewicht 110 g) für ein PDR-Afterloading-Gerät entwickelt. Die Bestrahlungsmoulage enthält 18 äquidistant (10 oder 12 mm) angeordnete Bestrahlungskatheter (2 mm Durchmesser), welche in ein Plastiknetz eingezogen sind. Die Vorrichtung liegt zwischen zwei Platten aus festem Schaumgummi von 5 mm Dicke als Distanzhalter zur Haut. Die Brachytherapiemoulage erlaubt eine maximale Feldgröße von 20 2 23,5 cm auf der Haut. Die PDR-Bestrahlungen werden mit einer nominal 37 GBq Ir-192-Quelle mit Pulsen von 1 Gy und einer Pulsperiode von 1,2 Stunden durchgeführt (durchschnittliche Dosisleistung: 0,8 Gy/Stunde). Die routinemäßige Anwendung der geometrischen Optimierung ermöglicht eine Homogenität der Hautoberflächendosis von - 10%. Die 80%-Isodose liegt 5 mm unter der Hautoberfläche. Von April 1994 bis Dezember 1997 wurden 52 Patientinnen mit Hautmetastasen an der Thoraxwand mit 54 Feldern und Referenzdosen zwischen 38 und 50 Gy (median 42 Gy) behandelt, wobei jeweils zwei PDR-Serien mit einem Pausenintervall von vier bis fünf Wochen appliziert wurden. Ergebnisse: Im Juni 1998 wurden 46 Patientinnen (48 Felder) ausgewertet. Die mediane Nachbeobachtungszeit betrug 16 Monate (7,1 bis 46,2 Monate). In 40 von 48 Feldern (83%) bzw. bei 41 von 46 Patienten (89%) wurde eine lokale Kontrolle erreicht. Feuchte Epitheliolysen traten bei 52% der Patientinnen auf. Späte Strahlenreaktionen wurden nach einer minimalen Nachbeobachtungszeit von sechs Monaten geprüft. 32 der Bestrahlungsfelder waren nach externer Strahlenbehandlung mit Dosen zwischen 40 und 60 Gy vorbelastet. Unabhängig von der Vorbelastung entwickelten alle Patientinnen Teleangiektasien innerhalb von zwei Jahren nach der PDR-Brachytherapie. Im vorbelasteten Kollektiv (n = 32) traten bei jeweils 12% der Patientinnen Hautkontrakturen und/oder kleinere Hautnekrosen auf. Im nicht vorbelasteten Kollektiv (n = 14) wurden keinerlei Kontrakturen oder Hautnekrosen beobachtet. Schlussfolgerungen: Die gepulste Brachytherapie ist eine zeitsparende und effektive Methode zur Behandlung von Hautmetastasen bei Narbenrezidiven des Mammakarzinoms. Die Hautreaktionen sind vergleichbar mit der Orthovoltbestrahlung. Eine PDR-Split-Course-Bestrahlung von zweimal 20 Gy wird auch von der vorbelasteten Haut ohne schwerwiegende Strahlenfolgen toleriert.     

Efficacy of whole brain radiotherapy combined with fractionated stereotactic radiotherapy in metastatic brain tumors, and prognostic factors

PURPOSE: We attempted to analyze the effectiveness of whole brain radiotherapy (WBRT) combined with fractionated stereotactic radiotherapy (FSRT) in brain metastases. METHODS: Thirty-seven metastatic brain tumors in 29 patients without previous treatment were treated with WBRT plus FSRT, from October 1996 to February 2002. Four of the patients received stereotactic radiosurgery (SRS) prior to WBRT. Non-small cell lung cancer was the most common type of primary tumor (20/29). The total dose to the whole brain ranged from 30 Gy to 40 Gy, and the boost dose from FSRT ranged from 12 Gy to 40 Gy. End points were survival rate and local control rates. Factors influencing survival were evaluated. RESULTS: Median survival was 13 months, and actuarial survival rates at one and two years were 81% and 39%, respectively. Actuarial one and two year local control rates for all lesions were 78% and 71%, respectively. Survival was significantly associated with age, tumor size, presence of active extracranial tumors, and performance status. No acute or delayed complications were observed. CONCLUSIONS: We believe that WBRT plus FSRT should be included in the treatment options for metastatic brain tumors, and we consider the effect of this non-invasive method to be quite good in patients with good prognostic factors, although other invasive modalities could also be effective in them.     

肺癌骨转移放疗止痛效果临床分析

目的 分析骨转移癌放疗止痛疗效。方法 将189例原发灶为肺癌的骨转移癌计221个病灶的放疗结果进行回顾性分析。放疗方案分为2种剂量分割组:(1)常规分割组:2Gy/次,5次/周,总剂量30～50Gy,共163个病灶;(2)中～低分割组:3～5Gy/次,2～3次/周,总剂量20～40Gy,共58个病灶。对不同病理类型和原发灶控制情况下的放疗结果进行分层分析。结果 常规分割、中-低分割组有效率分别为90.7%和87.9%(χ²=1.229,P>0.05),总有效率为90.0%。小细胞癌、非小细胞肺癌的有效率分别为92.4%和89.0%(χ²=0.668,P>0.05)。原发灶控制与未控制的有效率为88.4%和91.7%(χ²=0.787,P>0.05)。结论 放疗是一种有效止痛方式,可作为骨转移癌首选治疗方法。不同分割剂量放疗对骨转移疼痛的缓解程度无影响,放疗疗效与原发灶病理类型及原发灶控制与否关系不明显。     

实验肿瘤局部照射动物模型的改进

目的对局部照射肿瘤实验动物模型进行改进以提高肿瘤放疗增敏药物增敏实验结果的可靠性。方法分别在小鼠腿上皮下（传统方法）和小鼠脚背皮下（改进方法）接种肝癌H22细胞,使其生长成实体瘤;用5Gyγ射线照射肿瘤后,每隔1d测量肿瘤的长、宽、高并计算肿瘤体积,连续观察24d。结果将肿瘤接种于小鼠腿上皮下时,照射组的肿瘤体积和质量与对照组之间的差异无统计学意义（t=0．55、0．70,P均〉0．05）;而将肿瘤接种于脚背皮下时,照射组的肿瘤体积和质量均明显低于对照组（t=2．25,P〈0．05;t=3．14,P〈0．01）。结论肿瘤接种于小鼠脚背皮下的方法,操作简单、方便、易行且实验结果准确、可靠。     

Alpha-radioimmunotherapy of intraperitoneally growing OVCAR-3 tumors of variable dimensions: Outcome related to measured tumor size and mean absorbed dose.

The purpose of this work was to (a) investigate the efficacy of radioimmunotherapy using 211At-MX35 F(ab')2 or 211At-Rituximab F(ab')2 (nonspecific antibody) against differently advanced ovarian cancer in mice; (b) image the tumor growth on the peritoneum; and (c) calculate the specific energy and mean absorbed dose to tumors and critical organs. METHODS: Two experiments with 5-wk-old nude mice (n = 100 + 93), intraperitoneally inoculated with approximately 1 x 10(7) NIH:OVCAR-3 cells, were done. At either 1, 3, 4, 5, or 7 wk after inoculation animals were intraperitoneally treated with approximately 400 kBq 211At-MX35 F(ab')2 (n = 50 + 45), approximately 400 kBq 211At-Rituximab F(ab')2 (n = 25 + 24), or unlabeled Rituximab F(ab')2 (n = 25 + 24). At the time of treatment 29 animals were sacrificed and biopsies were taken for determination of tumor sizes using scanning electron microscopy (SEM). Eight weeks after each treatment the animals were sacrificed and the presence of macro- and microscopic tumors and ascites was determined. The specific energy and mean absorbed dose to tumors were calculated. The activity concentration was measured in critical organs and abdominal fluid. RESULTS: When given treatment 1, 3, 4, 5, or 7 wk after cell inoculation the tumor-free fraction (TFF) was 95%, 68%, 58%, 47%, 26%, and 100%, 80%, 20%, 20%, and 0% when treated with 211At-MX35 F(ab')2 or 211At-Rituximab F(ab')2, respectively. The SEM images revealed maximum tumor radius of approximately 30 mum 1 wk after cell inoculation, increasing to approximately 340 mum at 7 wk. Specific energy to cell nuclei varied between 0 and approximately 540 Gy, depending on assumptions regarding activity distribution and tumor size. The mean absorbed dose to thyroid, kidneys, and bone marrow was approximately 35, approximately 4, and approximately 0.3 Gy, respectively. CONCLUSION: Treatment with 211At-MX35 F(ab')2 or 211At-Rituximab F(ab')2 resulted in a TFF of 95%-100% when the tumor radius was < or =30 microm. The TFF was decreased (TFF < or = 20%) for 211At-Rituximab F(ab')2 when the tumor radius exceeded the range of the alpha-particles. The specific antibody gave for these tumor sizes a significantly better TFF, explained by a high mean absorbed dose (>22 Gy) from the activity bound to the tumor surface and probably some contribution from penetrating activity.     

Influence of local hyperthermia combined with radiation on tumor growth and lung metastases of transplantable Lewis lung carcinoma growing in hind legs

The influence of combination of local hyperthermia and radiation on tumor growth and metastases was studied using Lewis lung carcinoma. Tumors growing intramuscularly in the right hind legs of C57BL/6 mice were irradiated at 10 Gy of radiation dose and immersed in a water bath. Time and number of development of metastases were determined according to size and number of lung colonies at 19 days after tumor implantation. Local hyperthermia at 42.8, 43.3 or 43.5 degrees C for 30 min immediately after or before irradiation enhanced the growth delay of tumor with irradiation or with hyperthermia alone. Development of metastases several days after heating was also inhibited by the combination of heating and irradiation. These effects were diminished with hyperthermia applied 3 hr or more after irradiation. Promotion of metastases around the time of heating by severe hyperthermia with above 43.3 degrees C alone was not inhibited by combination with radiation, regardless of their sequence. Radiation had no effect on the number of metastases developed by the heating. However, irradiation 48 hr or more before severe heating reduced the number of metastases developed by the heating.     

Reduced tumor growth with combined radiofrequency ablation and radiation therapy in a rat breast tumor model

PURPOSE: To determine whether use of combined radiofrequency (RF) ablation and external-beam radiation therapy increases end-point survival beyond that with either RF ablation or radiation therapy alone in an animal tumor model. MATERIALS AND METHODS: With a protocol approved by the institutional animal care and use committee, R3230 mammary adenocarcinoma (12.5 mm +/- 0.6 [standard deviation]) was implanted subcutaneously into 107 female Fischer 344 rats. Initially, 42 tumors were randomized into four treatment groups: (a) RF ablation (70 degrees C for 5 minutes) alone, (b) RF ablation followed by radiation therapy with a total dose of 20 Gy, (c) 20-Gy radiation alone, and (d) no treatment. Another 19 tumors were randomized to receive (e) RF ablation (70 degrees C for 5 minutes) followed by 5-Gy radiation, (f) 5-Gy radiation alone, or (g) no treatment. Animals were followed up until survival end point (either until tumor growth to 30 mm in diameter, or for 120 days if no tumor was seen in mammary fat pad or chest wall). Results were analyzed with the Kaplan-Meier method. Histopathologic analysis was performed in 15 additional tumors at survival end point and 18 other representative tumors at other specified end points. RESULTS: Combined RF ablation and 20-Gy radiation resulted in complete local control in nine (82%) of 11 tumors, compared with one (9%) of 11 tumors treated with RF ablation alone and one (17%) of six treated with RF ablation and 5-Gy radiation (P < .001). No local control was achieved in rats with radiation therapy alone or in controls. Median end-point survival was 12 days for controls, 20 days with RF ablation or 5-Gy radiation alone, 30 days with RF ablation plus 5-Gy radiation, 40 days with 20-Gy radiation alone, and 120 days with RF ablation plus 20-Gy radiation. Mean end-point survival was 13 days +/- 5 (standard deviation) for the control group, 34 days +/- 31 with RF ablation alone, and 43 days +/- 16 with 20-Gy radiation alone. Mean survival was significantly greater with 20-Gy radiation and RF ablation combined: 94 days +/- 34 (P < .001 compared with all other groups). Mean survival for rats that received 5-Gy radiation with RF ablation versus without was 46 days +/- 37 versus 24 days +/- 11, respectively. CONCLUSION: Combined RF ablation and external-beam radiation therapy increased animal survival compared with that with either of the treatments alone or with no treatment.     

CT-gesteuerte Brachytherapie

PURPOSE: To assess safety and efficacy of CT-guided brachytherapy of liver malignancies. PATIENTS AND METHODS: 21 patients with 21 liver malignancies (19 metastases, two primary liver tumors) were treated with interstitial CT-guided brachytherapy applying a (192)Ir source. In all patients, the use of image-guided thermal tumor ablation such as by radiofrequency or laser-induced thermotherapy (LITT) was impeded either by tumor size > or = 5 cm in seven, adjacent portal or hepatic vein in ten, or adjacent bile duct bifurcation in four patients. Dosimetry was performed using three-dimensional CT data sets acquired after CT-guided positioning of the brachytherapy catheters. RESULTS: The mean tumor diameter was 4.6 cm (2.5-11 cm). The mean minimal tumor dose inside the tumor margin amounted to 17 Gy (12-20 Gy). The proportion of the liver parenchyma exposed to > 5 Gy was 18% (5-39%) of total liver parenchyma minus tumor volume. Nausea and vomiting were observed in six patients after brachytherapy (28%). One patient demonstrated obstructive jaundice due to tumor edema after irradiation of a metastasis adjacent to the bile duct bifurcation. We commonly encountered asymptomatic increases of liver enzymes. Local control rates after 6 and 12 months were 87% and 70%, respectively. CONCLUSION: CT-guided brachytherapy is safe and effective. This technique displays broader indications compared to image-guided thermal ablation by radiofrequency or LITT with respect to tumor size or localization.     

Neutron therapy (dT, 14 MeV) for recurrence of rectal cancer: interim analysis from Münster.

For rectal recurrent cancer and macroscopic residual disease after surgery neutron radiotherapy has been suggested to be superior to photon radiotherapy. At the d,T generator in Münster (14 MeV) 20 patients have been treated with a combined photon-/neutron-radiotherapy: two patients with residual disease after surgery: among the 18 patients with rectal recurrence 15 for pain relief; all for tumor control. Tumor resection had been carried out in five recurrent tumors. Six patients presented with distant metastases. 30 to 40 Gy photons for tumor region and potential microscopic spread with 2 Gy per fraction and 5 to 10 Gy neutrons for macroscopic tumor volume with 0.7 to 1.6 Gy per fraction were applied using multiple fields (three to five). The mean follow-up period is nine months. Pain relief was achieved in eleven of 15 patients (73%), the onset of pain was fast, the probability for a pain-free period is 46% for nine months and for survival 56% for twelve months. Side-effects were slight to moderate beside a severe subcutaneous fibrosis in two patients. The superiority of neutrons to photons in rectal recurrent cancer remains questionable and is to be proven in a prospective trial comparing different schedules for frequency, onset and duration of pain relief, tumor control, survival and side-effects.     

Reirradiation of Locally Recurrent Nasopharyngeal Carcinoma

PURPOSE: To study the efficacy of reirradiation as salvage treatment in patients with locally recurrent nasopharyngeal carcinoma. PATIENTS AND METHODS: Between 1993 and 2000, 20 consecutive patients (twelve males and eight females) with nasopharyngeal cancer, previously irradiated in different Hungarian institutions, were reirradiated for biopsy-proven locally recurrent tumor. Histologically, 85% of the patients had WHO type III, 5% type II, and 10% type I disease. Stages I-IV (AJCC 1997 staging system) were assigned to five (25%), seven (35%), five (25%), and three (15%) patients, respectively; none of them had distant metastases, and only eight (40%) displayed regional dissemination. The median time period between termination of primary treatment and local recurrence was 30 (range, 10-204) months.Brachytherapy was the method most frequently used: in ten cases alone (especially for rT1 tumors), and in eight cases in combination with external beam therapy. Two patients with locally advanced disease underwent external beam therapy only. The median dose in the event of brachytherapy alone was 20 Gy (4 x 5 Gy or 5 x 4 Gy, range, 16-36 Gy), and the dose range for exclusive external irradiation was 30-40 Gy. In cases of combined irradiation, a median 20-Gy brachytherapy (range, 16-40 Gy) was associated with 30-40 Gy of external irradiation. Radiotherapy was supplemented by neck dissection (six patients), nasopharyngectomy (one patient), or chemotherapy (eleven patients). RESULTS: 16 patients were reirradiated once, three twice, and one patient three times, with a median equivalent dose for tumor effect of 36 Gy (mean, 44 Gy; range, 19-117 Gy; the estimated alpha/beta-ratio was 10 Gy). The median equivalent dose of reirradiation for late effect on normal tissue (with an estimated 70% delivery of the tumor dose) amounted to 30 Gy (mean, 37 Gy; range, 13-101 Gy, estimated alpha/beta-ratio 3 Gy). After a median follow-up of 37 (range, 12-72) months, the overall survival was 60% (12/20). Seven of the twelve surviving patients are currently tumor-free. After primary irradiation, xerostomy occurred in all patients as an unavoidable side effect of treatment. Following reirradiation, a severe (grade 3 or higher) late toxicity (CTC criteria, version 2) has been observed in two tumor-free patients (10%) so far (necrosis of soft palate and paresis of glossopharyngeal nerve). CONCLUSION: Retreatment of nasopharyngeal carcinoma with radiotherapy (preferably a combined modality), can result in longterm local control and survival in a substantial proportion of patients, at the price of an acceptable morbidity.     

Modification of spontaneous lung metastasis by local radiation combined with or without immunomodifier

This study was carried out to determine the effect of local irradiation of the NFSa tumors on the incidence of lung metastases. The spontaneous lung metastases were found in those animals whose tumors had grown in size bigger than 10 mm in diameter. The incidence of metastases and the number of lung nodules were increased in those animals of irradiated group when compared to those of control group with the same size. This is probably because the irradiation of tumors resulted some retardation in their growth and thus, the irradiated tumors took a longer time to reach a given size than those unirradiated control tumors. The incidence of spontaneous lung metastases was significantly reduced by subcutaneous administration of OK-432 (2.5KE/mouse) locally into the surroundings of the tumor immediately after irradiation. The administration of OK-432 after the metastasis development was no longer effective. Both of intraperitoneal and subcutaneous administrations of OK-432 into opposite side of unirradiated thigh showed no suppression of metastasis. These results suggest that an appropriate immunostimulation combined with radiotherapy may be important for the suppression of tumor metastases.     

Influence of large peritumoral vessels on outcome of radiofrequency ablation of liver tumors

PURPOSE: The effect of large vessels (>/=3 mm) contiguous to hepatic tumors was evaluated with respect to clinical tumor recurrence rates after radiofrequency (RF) ablation. MATERIALS AND METHODS: The first 105 malignant liver tumors treated by RF ablation therapy at our institution with pathologic analysis or a minimum of 6 months of clinical follow-up were reviewed. The original pretreatment imaging studies were reviewed by a radiologist who was blinded to the cases, and, based on lesion contiguity to vessels of at least 3 mm, the lesions were categorized as perivascular or nonperivascular. Treatment outcomes with respect to local tumor recurrence between these two groups were then compared. Logistic regression analysis was performed to take into account other variables and to determine whether this categorization was an independent predictor of treatment outcome. RESULTS: There were 74 nonperivascular tumors and 31 perivascular tumors. Mean tumor size was 2.4 cm and mean follow-up was 11.3 months. Residual or locally recurrent tumors were documented in 20 of 105 cases (19%). In the nonperivascular group, five of 74 (7%) had either incompletely treated tumor (manifested within 6 months) or local recurrence beyond 6 months. In the perivascular group, 15 of 31 (48%) had incompletely treated or locally recurrent tumor (P <.001). Subanalysis of lesion size (61 tumors 4 cm), tumor type (40 hepatocellular carcinomas, 48 colorectal metastases, and 17 other metastases), access (53 intraoperative, 52 percutaneous), and RF device (45 Radiotherapeutics electrodes, 18 Rita electrodes, and 42 Radionics electrodes) showed similar results. Multivariate logistic regression analysis showed that presence or absence of a large peritumoral vessel is an independent, and the dominant, predictor of treatment outcome. CONCLUSION: The presence of vessels at least 3 mm in size contiguous to hepatic tumors is a strong independent predictor of incomplete tumor destruction by RF ablation. Modified ablation strategies should be considered to improve destruction of these tumors.     

Comparison of Short-Course versus Long-Course Whole-Brain Radiotherapy in the Treatment of Brain Metastases

BACKGROUND AND PURPOSE: Whole-brain radiotherapy (WBRT) is the most common treatment for brain metastases. Most of these patients have a poor survival prognosis. Therefore, a short radiation program is preferred, if it provides a similar outcome as longer programs. This study compares 20 Gy in five fractions (treatment time: 1 week) to longer programs, with higher doses including 30 Gy in ten fractions (2 weeks) and 40 Gy in 20 fractions (4 weeks). PATIENTS AND METHODS: Data regarding 1,085 patients treated with WBRT for brain metastases were retrospectively analyzed. 387 patients received 20 Gy in five fractions, and 698 patients received higher doses (30 Gy in ten fractions, n = 527, or 40 Gy in 20 fractions, n = 171). In addition, eight potential prognostic factors were investigated including age, sex, Karnofsky Performance Score (KPS), tumor type, interval from tumor diagnosis to WBRT, number of brain metastases, extracranial metastases, and recursive partitioning analysis (RPA) class. Subgroup analyses were performed for each RPA class individually. RESULTS: The WBRT schedule had no significant impact on survival (p = 0.415). On multivariate analysis, improved survival was significantly associated with age < or = 60 years (risk ratio [RR]: 1.28; p < 0.001), KPS > or = 70 (RR: 1.73; p = 0.002), lack of extracranial metastases (RR: 1.27; p = 0.007), interval from tumor diagnosis to WBRT > 8 months (RR: 1.19; p = 0.011), and lower RPA class (RR: 1.56; p < 0.001). The subgroup analyses for each RPA class did not reveal a significant association between WBRT schedule and survival. CONCLUSION: Short-course WBRT with 20 Gy in five fractions is preferable for most patients, because it is associated with similar survival as longer programs and is less time-consuming.     

Prognostic Impact of Tumor Perfusion in MR-Imaging Studies in Ewing Tumors

BACKGROUND: Intratumoral hypoxia is associated with poor prognosis in various solid tumors. Severe and long-lasting hypoxia results in necrosis. The presence of necrosis therefore might also be correlated with unfavorable outcome. This has been demonstrated for head and neck cancers, gliomas and adult soft tissue sarcomas. We have investigated whether or not the patterns of contrast enhancement and the presence of visible necrosis on pretreatment MR images has prognostic impact in Ewing tumors. PATIENTS AND METHODS: From December 1993 though March 1997, 79 patients with Ewing tumors were prospectively analyzed for the presence and amount of necrosis in their tumors. The median age was 12 years (range 4-30 years). The median follow-up at the time of this analyses was 3 years. All patients were treated according to the multicentric EICESS-92 protocol with multi-agent chemotherapy (VACA or VAIA or EVAIA) and local therapy (radiotherapy with 50-60 Gy or surgery or surgery with pre- or postoperative irradiation with 45-50 Gy). For the measurement of necrosis, gadolinium contrast-enhanced T1-weighted MR images were used. Necrosis was defined as non-perfused areas in the tumor and the necrotic volume was expressed as percentage of total volume. RESULTS: Out of 79 tumors, 10 (13%) showed no necrosis, 30 (38%) had 1-25% necrosis, 21 (27%) had 26-50% necrosis and the remaining 18 (23%) more than 50% necrosis. There was a correlation between tumor size and necrosis (p = 0.001): the median tumor volume increased with amount of necrosis (47 cm3 in non-necrotic tumors, 59 cm3 vs 280 cm3 vs 284 cm3 for tumors with 1-25% vs 26-50% vs > 50% necrosis). Tumor site (central location vs proximal extremities vs distal extremities) had no impact on necrosis (p = 0.71). 23 out of 79 patients had metastases (M1) at the time of diagnosis. The frequency of metastatic spread increased with the amount of necrosis: 1/10 (10%) patients with non-necrotic tumors had metastases vs 7/30 (23%) vs 6/21 (28%) vs 9/18 (50%) for tumors with 1-25% vs 26-50% vs > 50% necrosis. "Unfavorable" metastatic spread (bone or multiple metastases) was only noted in patients with high amount of necrosis (> 25% necrosis) whereas even large tumors did not show unfavorable metastases if they contained no or only small amounts of necrosis. All patients with non-necrotic tumors survived event-free during the observation period. Patients with necrotic tumors had a 3-year event-free survival of 55% (p = 0.06 vs tumors without necrosis). CONCLUSIONS: The presence of non-perfused (presumably necrotic) areas on pretreatment contrast-enhanced MR-images is associated with an increased risk of metastases, especially an unfavorable pattern of metastatic spread at diagnosis. This observation may be explained by a more aggressive biological behavior of hypoxic tumor cells. The small group of patients with non-necrotic tumors (13%) had an excellent prognosis suggesting that the absence of necrosis might be helpful in identifying a very favorable prognostic subgroup in Ewing tumors.