Long-term analysis of clinical outcome and complications in locally advanced cervical cancer patients administered concomitant chemoradiation followed by radical surgery.

OBJECTIVE: Preoperative chemoradiation (CT/RT) has been shown to achieve encouraging results in terms of clinical outcome in locally advanced cervical cancer (LACC). The study aims at analyzing the long-term results of this multimodal approach in a single institution series of 184 cases. METHODS: Patients underwent whole pelvic irradiation combined with cisplatin and 5-fluorouracil. After evaluation of clinical response, patients were triaged to surgery. Surgical morbidity was classified according to Chassagne grading system. Univariate and multivariate analyses were used to assess the prognostic and predictive role of clinicopathological parameters. RESULTS: Clinical response was observed in 96.1% of cases. A total of 174 cases were submitted to radical surgery: 124 patients (71.3%) showed complete/microscopic pathological response. In multivariate analysis, clinical response, stage of disease, and histotype predicted response to CT/RT. With a median follow-up of 58 months, recurrence and death of disease were observed in 42 and 40 patients, respectively. The 5-year DFS was 75.5%, while the 5-year OS was 77.4%. Patients with no residual disease showed a significant longer DFS than patients with microscopic (p value = 0.0128), and macroscopic (p value = 0.0001) residual tumor after treatment. In multivariate analysis, residual tumor and stage of disease were the two most relevant prognostic factors for DFS and OS. As far as long-term toxicity is concerned, 8 out of 22 complications were grade 3/4. CONCLUSION: Preoperative CT/RT is worth further investigation in LACC patients, providing encouraging survival outcomes and a favourable long-term toxicity profile.

Recurrent uterine cancer after surgery: magnetic resonance imaging patterns and their changes after concomitant chemoradiation.

PURPOSE: Our primary objective was to describe the magnetic resonance (MR) imaging patterns of recurrent uterine cancer after surgery and their changes following concurrent chemoradiation. The secondary objective was to identify MR imaging predictors of outcome. MATERIALS AND METHODS: Twenty-two consecutive women with biopsy-proven recurrent uterine cancer after surgery (cervix 13 patients, endometrium nine patients) were enrolled in this prospective study. Inclusion criteria were MR imaging at diagnosis and during follow-up and eligibility for concurrent chemoradiation. MR images were assessed for signal intensity of the pelvic relapse on T2-weighted images, site of relapse and infiltration of adjacent organs. Pre- and posttreatment MR images were compared on the basis of the same criteria. The 3D volume of relapses after treatment was calculated, and tumour response to treatment was evaluated as complete, partial, no change or disease progression. RESULTS: Recurrences appeared hyperintense on T2-weighted images in 22/22 (100%) patients. Pelvic relapse site was vagina in 5/22 (23%), vaginal vault in 9/22 (41%), vaginal vault with extension to the pelvic wall in 5/22 (23%) and pelvic wall in 3/22 (13%). Infiltration of adjacent organs was detected in 9/22 (41%) patients. The mean volume of recurrences on pretreatment MR images was 38.83 cm(3). On posttreatment MR images, relapses appeared hypointense in 19/22 (86%) patients and hyperintense in 3/22 (14%). The mean volume of recurrences on posttreatment MR images was 18.01 cm(3). Complete response was seen in 11/22 (50%) patients, partial response in 8/22 (36%) and no change in 3/22 (14%). CONCLUSIONS: MR imaging can provide an evaluation of all parameters necessary for planning treatment and assessing response to treatment.

Intraluminal brachytherapy without stenting in intrahepatic papillary cholangiocarcinoma: a case report.

A 46-year-old female patient, with mild cholestasis by a large papillary cholangiocarcinoma involving the left hepatic duct, received intraluminal brachytherapy (50 Gy at 1 cm from the source axis) with the aim to relieve biliary obstruction without stent positioning. The patient presented with haemobilia and vegetant lesions in the left main biliary duct, and thus she had a high risk of early stent obstruction. Eighteen months after the treatment the patient presented tumour progression in the controlateral hepatic lobe, but had a patent left hepatic duct, without signs of cholestasis and/or cholangitis. Based on this and other published reports, intraluminal brachytherapy may be tested in a setting different from standard setting with the aim to safely palliate jaundice in patients with intraductal tumour growth in the biliary tract.

Concomitant gemcitabine (Gemzar) and extended nodes irradiation in the treatment of pancreatic and biliary carcinoma: a phase I study.

BACKGROUND: The rationale for combining cytotoxic agents, such as gemcitabine, and radiotherapy is based on their ability to act as radiation sensitizers and to improve overall response rate. Several studies on pancreatic or biliary carcinoma evaluated the maximum tolerated dose (MTD) of gemcitabine when combined with irradiation of the macroscopic tumor. However, most of these neoplasms metastasize to the regional lymph nodes. Aim of this report is to determine the MTD of weekly gemcitabine when combined with extended field irradiation (tumor plus nodal irradiation). PATIENTS AND METHOD: 15 patients entered the study. Of these 5 patients were treated with chemoradiation after radical surgical resection. External beam radiation (ERT) was delivered to the tumor (or tumor bed) and regional lymph nodes by using a three-field technique. The initial dose of gemcitabine was 100 mg/m(2) administered as short intravenous infusion once a week. At each dose level 3 patients were treated, and if no grade 3-4 toxicity (considered as dose-limiting toxicity, DLT) was recorded, dose escalation was applied with 50 mg/m(2) increments until the MTD was established. RESULTS: All patients were evaluable for acute toxicity. There were no treatment-related deaths. No DLT occurred at the first 4 dose levels (100-250 mg/m(2)). At the 5th dose level (300 mg/m(2)), 3 patients experienced DLT: 1 had grade 3 gastrointestinal toxicity (painful erosion of gastric mucosa), 1 had uncomplicated grade 3 leukopenia and 1 grade 3 change in liver biochemistry tests. In addition, all 10 unresected patients were evaluated for response, 4 of whom had progressive disease (1 local; 2 distant; 1 local and distant) and 6 had no change. The median follow-up was 21 months. CONCLUSION: Based on this study, the recommended dose for weekly short infusional gemcitabine combined with radiation therapy to the tumor and lymph nodes is 250 mg/m(2). This value is suggestive of a correlation between acute toxicity and inclusion of lymph nodes in the irradiated volume. Moreover, different infusion modalities, as continuous infusion gemcitabine, should be tested more accurately.

Cyclooxygenase-2 (COX-2) expression in locally advanced cervical cancer patients undergoing chemoradiation plus surgery.

PURPOSE: To investigate whether cyclooxygenase-2 (COX-2) could be a marker of clinical outcome in cervical cancer patients undergoing concomitant chemoradiation plus surgery. METHODS AND MATERIALS: The study included 33 locally advanced cervical cancer patients; all underwent neoadjuvant chemoradiation, and responsive patients underwent radical surgery. Immunohistochemistry was performed with rabbit antiserum against COX-2. RESULTS: COX-2 integrated density values (IDVs) in the tumor component ranged from 1.4 to 72.3 (median 15.0); in stromal inflammatory cells, COX-2 IDVs ranged from 1.4 to 96.0 (median 16.0). A statistically significant inverse relation was found between the COX-2 IDVs of the tumor vs. the stromal inflammatory component (r = -0.52, p = 0.0017). When the ratio between COX-2 IDV in the tumor vs. the stromal compartment was 1) tumor/stroma COX-2 IDV ratio. Patients with a high tumor/stroma COX-2 IDV ratio had a shorter disease-free survival than did those with a low tumor/stroma COX-2 IDV ratio (p = 0.030). Similarly, those with a high tumor/stroma COX-2 IDV ratio had a shorter overall survival (p = 0.033). CONCLUSION: The assessment of COX-2 status in both the tumor and the stromal compartment could provide additional information in the prognostic characterization of cervical cancer patients administered concomitant chemoradiation plus surgery.

Preoperative chemoradiation with raltitrexed ('Tomudex') for T2/N+ and T3/N+ rectal cancers: a phase I study.

The use of raltitrexed ('Tomudex') as concomitant chemotherapy during preoperative radiotherapy in chemonaïve patients with stage II/III rectal cancer has been examined in this study and its recommended dose in conjunction with radiotherapy investigated. Forty-five Gray (Gy) of radiotherapy (1.8 Gy daily, 5 days per week) was delivered to the posterior pelvis, followed by a 5.4 Gy boost. Single doses of raltitrexed (2.0, 2.5 and 3.0 mg/m(2)) were administered on days 1, 19 and 38. Only 1 of the 15 patients entered experienced a dose limiting toxicity (DLT) (grade 3 leucopenia) at the 3.0 mg/m(2) dose level. The overall response rate was 80% (five complete responses, seven partial responses). These preliminary data suggest that raltitrexed is a well tolerated and effective treatment when combined with preoperative radiotherapy in patients with stage II/III rectal cancer. The recommended dose of raltitrexed for future phase II studies will be 3.0 mg/m(2).

Quality handbook in radiotherapy. Brachytherapy: personal experience.

Brachytherapy is a conventional method of radiation therapy characterized by peculiar technical, clinical, operational and radioprotection problems. Therefore, the management of a service or department of brachytherapy requires a specific organization aimed at Quality Assurance. In this report, the personal experience with the drawing up of a Quality Handbook of brachytherapy with reference to the method used and the structure of the document, is described.

Phase I-II trial of preoperative chemoradiation in locally advanced cervical carcinoma.

BACKGROUND: 5-Fluorouracil and cisplatin are characterized by in vitro synergism as well as radiosensitization. A phase I-II study was carried out on patients with invasive cervical carcinoma (FIGO IIB-IIIA) undergoing concomitant chemoradiation with 5-fluorouracil and cisplatin followed by radical surgery. METHODS: Twenty-six patients of 53 years median age, 24 with IIB tumor and 2 with IIIA tumor, all with squamous carcinoma, entered the study. The chemoradiation protocol included external radiotherapy to the pelvis: 39.6 Gy (180 cGy/daily); 5-fluorouracil: 1 g/m(2)/daily, in continuous intravenous infusion days 1-4 and 27-30; cisplatin: 20 mg/m(2)/daily days 1-4 and 27-30. Four weeks after the end of chemoradiotherapy, patients underwent restaging and then radical surgery with pelvic and lumboaortic lymphadenectomy. RESULTS: Twenty-six patients are evaluable for acute toxicity and 24 are evaluable for objective and pathologic response. Grade 3-4 thrombocytopenia or leukopenia was observed in 6 patients and grade 3 acute gastrointestinal toxicity in 3. After chemoradiation CR and PR were observed in 64 and 36% of cases, respectively (CR + PR = 100%). Two patients were excluded from surgery for other diseases. The remaining 24 patients were operated on; 23/24 patients showed negative section margins. The histology of the surgical specimen showed the absence of disease in 13 patients (54.2%), microscopic residual tumor in 4 patients (16.6%), residual disease 1 cm in 2 patients. Median follow up was 33 months. Two-year actuarial local control was 91.7%. CONCLUSIONS: This study showed a particularly high rate of pathologic responses (complete + Tmic: 70.8%) and local control (2 years = 91.7%) in patients with advanced cervical cancer undergoing moderate doses of radiotherapy with concomitant chemotherapy followed by radical surgery.

Prognostic significance of anemia and role of erythropoietin in radiation therapy.

Anemia represents a common finding in cancer patients, especially at an advanced stage. Anemia has an impact on the quality of life and at the same time seems to markedly limit the disease control that can be achieved with radiotherapy. The results of a series of clinical studies published in the last decade allow some general observations: 1. the administration of erythropoietin, especially if associated to ferrous sulfate is able to increase hemoglobulin levels in cancer patients undergoing radiation therapy (combined with concomitant chemotherapy); 2. erythropoietin stimulation of hemoglobin in anemia decreases the need for blood transfusion in cancer patients; 3. tumor response to radiation therapy appears to be enhanced by erythropoietin-induced hemoglobulin increase. Further clinical studies are required for assessment of indications, identification of optimal administration modalities, cost-analysis of this promising therapy for patients undergoing radiation therapy.

Combined modality treatment in unresectable extrahepatic biliary carcinoma.

PURPOSE: Cancers of the extrahepatic biliary tract are rare. Surgical resection is considered the standard treatment, but is rarely feasible. Several reports of combined modality therapy, including external beam radiation, often combined with chemotherapy and intraluminal brachytherapy, have been published. The purpose of this study was to evaluate the effect of chemoradiation plus intraluminal brachytherapy on response, local control, survival, and symptom relief in patients with unresectable or residual extrahepatic biliary carcinoma. METHODS AND MATERIALS: From February 1991 to December 1997, 20 patients (14 male, 6 female; mean age 61 +/- 12 years; median follow-up 71 months) with unresectable (16 patients) or residual (4 patients), nonmetastatic extrahepatic bile tumors (common bile duct, 8; gallbladder, 1; Klatskin, 11) received external beam radiation (39.6-50.4 Gy); in 19 patients, 5-fluorouracil (96-h continuous infusion, days 1-4 at 1,000 mg/m(2)/day) was also administered. Twelve patients received a boost by intraluminal brachytherapy using (192)Ir wires of 30-50 Gy, prescribed 1 cm from the source axis. RESULTS: During external beam radiotherapy, 8 patients (40%) developed grade 1-2 gastrointestinal toxicity. Four patients treated with external-beam plus intraluminal brachytherapy had a clinical response (2 partial, 2 complete) after treatment. For the total patient group, the median survival and time to local progression was 21.2 and 33.1 months, respectively. Distant metastasis occurred in 10 (50%) patients. Two patients who received external beam radiation plus intraluminal brachytherapy developed late duodenal ulceration. Two patients with unresectable disease survived more than 5 years. CONCLUSION: Our data suggest that chemoradiation plus intraluminal brachytherapy was relatively well-tolerated, and resulted in reasonable local control and median survival. Further follow-up and additional research is needed to determine the ultimate efficacy of this regimen. New chemoradiation combinations and/or new treatment strategies (neoadjuvant chemoradiation) may contribute, in the future, to improve these results.

Research trends in the treatment of neoplasms of the exocrine pancreas.

To-date, the therapeutic standards, defined by randomized studies for carcinoma of the exocrine pancreas are disappointing. Obviously, there is much interest in the improvement of these results based on the evidence of additional clinical trials. To identify some trends in the clinical research in this field, some characteristics of 31 ongoing trials, described in the web site of the National Cancer Institute were examined. 28/31 trials are coordinated by Centers of the U.S.A. and 3/31 trials specifically concern symptom palliation. Excluding the latter, 4 trials enroll patients with operable neoplasms, 8 with inoperable tumors, 4 with metastatic neoplasm and 12 involve both latter categories. Four of the 5 phase I or I-II studies concern concomitant radiochemotherapy of inoperable neoplasms; the 16 phase II studies and the 7 phase III studies involve the use of different combined modality therapies in all patient categories. Overall, 18 trials test innovative treatment modalities (new drugs, immunotherapy, monoclonal antibodies). Eight trials include the evaluation of the quality of life between endpoints. Based on this assessment of some of the ongoing clinical trials, hopefully, there will be: 1. a greater interest in the prospective therapies for this neoplasm, especially at the European level, considering the high incidence of this disease; 2. more careful attention to the possibility of downstaging of locally advanced neoplasms considering the present, proven possibility to achieve better clinical responses in pancreatic carcinoma; 3. a more widespread interest in the establishment of parameters for the quality of life, considering the frequently "palliative" intent of available therapies.

Research trends in the treatment of prostatic neoplasms.

Prostatic carcinoma, in the male population ranks first as incidence and second as cause of oncologic mortality. In the last decades, significantly better clinical results were achieved both in diagnosis and therapy. The latter covers a broad range of possibilities, including standard surgery, nerve-sparing surgery, combined surgery and hormonotherapy, cryosurgery, external beam radiotherapy, brachytherapy, conformal radiotherapy, combined hormone and radiation therapy, as well as conventional hormonotherapy. However, there is still much controversy on the role of the screening, the most appropriate staging modalities, the most adequate treatment in the various presentations of the disease. The present trends of the clinical research in this field are directed towards the identification of factors involved in the onset of this neoplasm and the possibility of decreasing its incidence with programs of chemoprevention, the identification of new biological markers able to assess the biological potential of the disease, the comparison between the main treatment modalities of localized carcinoma (surgery, brachytherapy, external beam radiotherapy) and the definition of parameters predictive of the response to the various treatments to better personalize the therapy of the single patient, the development of treatments based on genetic therapy and of effective systemic therapies able to control the hormone-resistant advanced disease and to clarify the impact of the different therapies on the quality of life and health care costs.

Economic and organizational aspects in the management of prostate cancer.

In the last decade a rapid increase in the incidence of prostate cancer was observed. The reasons for this increase are associated to the progressive population aging, especially in the developed countries as well as to the growing number of identified cases with the widespread use of prostate specific antigen. A number of aspects of the disease are still to be considered in depth: the natural history of the disease in patients with early diagnosis, the potential costs of screening programs in financial, social and psychologic terms, the effectiveness and especially cost-effectiveness of different treatments and follow-up for local and advanced forms. Because of the long natural history of prostate cancer and the effectiveness of hormonal treatments used as salvage after failure of primary therapy, the differences in survival among the various therapeutic options, from radical prostatectomy to radiotherapy, or simple clinical control in selected cases are probably minor. This is the reason why future clinical studies should necessarily be based on multidimensional evaluations, taking into account the clinical outcome as well as the quality of life and costs of the different treatment modalities examined.

[Preoperative radiochemotherapy in pancreatic cancer: preliminary results]. / La radiochemioterapia preoperatoria del carcinoma pancreatico: risultati preliminari.

AIMS AND BACKGROUND: The prognosis of pancreatic cancer remains poor. Surgery, when feasible, is rarely curative. Radiation therapy (RT) and concomitant 5-fluorouracil (5-FU) have been shown to improve survival in locally advanced pancreatic cancer. In an attempt to improve resectability and disease control, we used preoperative chemoradiation in a combined modality therapy protocol. The purpose of this study was to evaluate our initial results in terms of acute toxicity and response. METHODS: From October 1995 to May 1998, 20 patients (11 males, 9 females; mean age, 60.1 years; median follow-up, 28 months) with unresectable (12 patients) or resectable (8 patients) non-metastatic pancreatic tumors, received external beam radiation (39.6 Gy) plus 5-FU (96 hours continuous infusion, days 1-4 at 1000 mg/m2/day). After 4 weeks, patients were evaluated for surgical resection. In resected patients, electron-beam intraoperative radiation therapy (10 Gy) was given before reconstruction. Thereafter, in resected patients, adjuvant chemotherapy was prescribed (6 courses: 5-FU, mitomycin C, adriamicine). RESULTS: During chemoradiation, no patients developed grade 3-4 acute toxicity. Three out of twelve (25%) patients with unresectable tumors had tumor downstaging. No patients showed partial or complete responses. Four out of twenty patients (20%) had minimal tumor response. Three patients showed disease progression after chemoradiation (liver or peritoneal metastases). Nine patients underwent surgical resection and IORT, with 1 postoperative death. The median survival time for the 20 patients was 9.4 (18.5 and 8.3 months in resected and unresected patients, respectively). CONCLUSION: Our preliminary results suggest that preoperative 5-FU chemoradiation was well tolerated and may result in tumor downstaging but the response-rate is still low. Based on the impact of surgical resection on survival, an improvement in local response rate is necessary.

Cervical cancer response to neoadjuvant therapy: MR imaging assessment.

PURPOSE: To determine the accuracy of magnetic resonance (MR) imaging in evaluating the invasive cervical carcinoma response to concurrent chemotherapy and radiation therapy. MATERIALS AND METHODS: MR imaging was performed before and after concurrent chemotherapy and radiation therapy in 18 patients with locally invasive cervical carcinoma. Surgery followed neoadjuvant therapy in all patients. The presence of a lesion, signal intensity, zonal anatomy integrity, vaginal and parametrial invasion, and lymph node enlargement was determined. Posttreatment MR and histopathologic findings were correlated. RESULTS: Fourteen patients had histopathologic confirmation of MR findings: Twelve had true-negative and two had true-positive findings. (Two had microscopic neoplastic foci beyond the spatial resolution of MR images; these foci do not change surgical treatment planning and probably do not influence prognosis. Therefore, these two patients were considered to have complete response). Four patients had false-positive findings; the hyperintense lesion on posttreatment MR images was due to a tunnel cluster pattern (focal hyperplasia of the endocervical glands with inflammation) in three patients and necrosis in one patient, without any evidence of neoplastic tissue. Thirty-three of 36 parametrial halves and 67 of 72 vaginal fornices were correctly interpreted on posttreatment images. Involvement of three parametrial halves and five fornices was overestimated at MR, because edema or inflammation was not distinguishable from tumor. CONCLUSION: MR imaging is 78% accurate in evaluation of tumor response; in 22% of patients, however, benign conditions were not distinguishable from tumor.

Radiation, hormonotherapy, survival and local control in prostatic carcinoma.

The combination of concomitant external beam radiotherapy (ERT) and neoadjuvant hormonotherapy was shown to be able to significantly improve local control and disease-free survival in locally advanced prostatic carcinoma. (RTOG study 8610). Aim of this analysis was to assess the clinical results observed in a population of patients undergoing this combined treatment and, more particularly, to examine the prognostic impact of local control. 84 patients (T2: 47%, T3: 49.4%, T4: 3.6%) underwent concomitant ERT (dose to pelvic volume: 45 Gy; mean dose to prostatic volume: 65 Gy) and neoadjuvant hormonotherapy (flutamide: 250 mg three times/daily for 30 days; LH-RH analogue: 1 oral dose every 28 days starting 2 months prior to radiotherapy and for its whole duration). With a median follow-up of 36 months, 3.6% of patients were deceased; hematogenous metastases and local disease progression were recorded in 16.7% and 4.8% of patients, respectively. Local disease progression was shown to be significantly correlated with the incidence of metastases. In fact, the actuarial incidence of metastases at 5 years was 100% and 27% in patients with and without local recurrence (p = 0.0043) respectively. Overall, metastases-free local and biochemical recurrence-free survival was 89.2%, 66.5%, 85.0% and 41.9% respectively. At univariate analysis (logrank) the clinical stage (T) was shown to be significantly correlated with the incidence of metastases (p = .0004) and local progression (p < .0001). In conclusion, this study has confirmed the low rate of local progression with the combination of hormonotherapy and radiotherapy and the significant correlation of local control with the incidence of hematogenous metastases.

Cancer of the anal canal and local control.

Concomitant radiochemotherapy is the standard treatment of squamous cell carcinoma of the anal canal. It can afford a high local control rate though the same impact has not been observed on survival. A few reports have concerned the impact of local control on distant metastases and survival. From 1988 to 1998 at the "Divisione di Radioterapia" of the "Università Cattolica del S. Cuore" of Rome 30 patients with squamous cell carcinoma of the anal canal were treated for cure. Treatment consisted of two cycles of radiotherapy (23.4 Gy) with a 4-5 week split in each cycle. 5FU (100 mg/sqm/24 h) was administered in continuous infusion for the first 4 days of therapy; mitomycin C (10 mg/sqm bolus) was administered on day 1, 4-6 weeks after the end of cycle 2 of concomitant radiochemotherapy, patients received a boost of interstitial brachytherapy. Local control on T of all patients was 84% at 5 years. Six patients showed locoregional recurrence: 3 recurrences on T and 4 disease progressions in locoregional lymph nodes. 3 of 6 patients underwent salvage surgery. The initial extent of the disease, the patient's age and brachytherapy boost did not have a statistically significant influence on local control. Two of the 30 patients showed liver metastases, and at their appearance, one patient was free of local disease while the other showed locoregional progression after Miles' operation for salvage. The metastasis-free interval was not significantly influenced by local control, although at 5 years, 96% of patients with local control of T were free of metastases vs 75% of those with recurrence on T (p = 0.22). Overall actuarial survival at 5 years was 75%. The behavior of survival in our experience seemed to be significantly influenced by local control: in the group with local control, 5-year survival was 85% vs 40% of patients with local recurrence (p = 0.01).

Radiotherapy, local control and survival in cervical carcinoma.

The natural history of cervical carcinoma is characterized by a close correlation between local control and survival. Local eradication of the disease is justified for the obvious impact on the quality of life as well as on long-term survival. A series of analyses carried out in the last decades have elucidated the role of a number of prognostic factors in local control. Among treatment modalities applied to attain this aim, particular interest has been focused in recent years on concomitant radiation and chemotherapy. While some experiences have shown promising results, the precise role of this combination will be defined based on the outcomes of some randomized studies now in progress. Among the modalities of concomitant radiation and chemotherapy, some authors have proposed the following sequence: neoadjuvant chemotherapy and surgical resection. It is an aggressive approach potentially associated to major side-effects. This therapeutic modality will require an accurate assessment of clinical results both in terms of clinical response, local control and effects on organ function and quality of life.

Radiotherapy, local control and survival in brain tumors.

High grade glial brain tumors and brain metastases are a complex subject with still unsatisfactory therapeutic results for the frequent absence of early and precise diagnosis as well as for the limited therapeutic interval between the tumor and presumed healthy tissues. The therapeutic problems of cellular hypoxia, the rapid recovery of sublethal damage for neoplastic cells, the rapid regrowth, have led to a number of efforts to deliver the dose of radiotherapy in various associations. The constant technological trend to increase the high dose gradient to the peripheral tumor, is reported.