[Conformal irradiation technique for the peri- and retrobulbar space in endocrine orbitopathy]. / Konformations-Bestrahlungstechnik für den Peri- und Retrobulbärraum bei endokriner Orbitopathie.

The clinical target volume (CTV) for the irradiation of the endocrine orbitopathy (Graves ophthalmopathy) includes the peri- und retrobulbar space with the extraocular muscles. We present here a conformal irradiation technique aimed at optimal coverage of the CTV. The irradiation technique consists of two rotation fields with a central lens block and two lateral fixed fields with dorsal blocking. In each Gantry position, the lenses are faded out through the central lens block. The isocenter of the two rotation fields is located in the lenses. For quality assurance of this irradiation technique, verification of the dose distribution was performed by film dosimetry using the humanoid Aldersone phantom. The use of this irradiation technique yielded a dose distribution with conformal CTV coverage of the peri- and retrobulbar space and of the extraocular muscles. The film dosimetry of the Aldersone phantom showed a maximal deviation of 5% between the measured and the calculated dose distribution. The radiation load to the eye lenses was 25% of the applied total dose.

Selection and delineation of lymph node target volume for lung cancer conformal radiotherapy. Proposal for standardizing terminology based on surgical experience.

PURPOSE: To select and delineate the target volumes for definitive or postoperative radiotherapy for lung cancer. METHODS AND MATERIALS: The lymphatics of the lung and the dissemination of tumor cells to the intra- and extrathoracic lymph nodes are described. The incidence of involvement of the different lymph node sites in the chest is analyzed. The involvement of the contralateral hilar and/or supraclavicular lymph nodes and the consequences for target volume selection for curative radiotherapy are discussed. CT-based nodal classification and distribution of lymph nodes in the chest in CT-axial slices are presented. The sentinel node concept (SNC) and the preliminary data available for lung cancer are described. RESULTS: A critical review of the current TNM classification for lung cancer and the implications for target volume selection is given. The individual target volume selection and delineation have to be based on clinical and pathological data from large surgical. studies and upon the individual pathological and diagnostic patient data. The selection and delineation of the clinical target volumes for definitive and for postoperative radiotherapy, dependent on the lymph node involvement, are presented. CONCLUSIONS: Criteria for the selection and delineation of the clinical target volumes for definitive and for postoperative conformal radiotherapy in axial CT slices under consideration of site, size and stage of the lung cancer are described. Recommendations for target volume selection for definitive or postoperative radiotherapy are presented.

Acute toxicity and changes in quality of life during a combined radio-chemotherapy of glioblastomas with topotecan (Hycamtin).

BACKGROUND: Because of the pronounced radioresistance of glioblastoma multiforme the prognosis of this disease remains poor. Therefore, we investigated the impact of an additional simultaneous chemotherapy with the topoisomerase-I inhibitor topotecan (Hycamtin) on the quality of life and toxicity of radiotherapy. PATIENTS AND METHODS: In this multicenter trial patients with histologically proven glioblastoma multiforme underwent a simultaneous radio-chemotherapy. Including pilot phase 60 patients, 41 male and 19 female, were treated. Age ranged from 26 to 76 years, the mean was 57 years. Conventional fractionated conformal radiotherapy was performed with daily doses of 2.0 Gy to a total dose of 60 Gy. 1 hour prior to irradiation 0.5 mg (absolute dose) of topotecan were administered intravenously resulting in a cumulative dose of 15 mg. Besides hematologic and non-hematologic toxicity, quality of life was assessed by Karnofsky index and Spitzer index. Additionally local control and survival time were recorded. RESULTS: 57 patients completed the combined therapy. Median administered dose of radiation was 60 Gy (16-76 Gy). Median cumulative topotecan dose was 15 mg (7.5-18.5 mg). Grade-III toxicity was found in six cases (two hematologic, two motoric disorder, one infection, one nausea) and grade-IV toxicity in three cases (one esophagitis, one motoric disorder, one mental disorder). Two patients died of septic disease most likely caused by steroid induced immunosuppression. Mean Karnofsky index and Spitzer index initially, at the end of therapy and 6 weeks after therapy showed values of 87%, 81% and 80% and 19 points, 18 points and 19 points, respectively. Median survival time was 15 months. CONCLUSION: This multimodal approach for patients with glioblastoma multiforme is well tolerated. Quality of life remains preserved and outpatient treatment is possible. The relatively long median survival time even for patients bearing macroscopic tumors is promising.

Target volume definition and target conformal irradiation technique for breast cancer patients.

The aim of this study was to present the target volume and irradiation technique in the most complex situation where the breast or chest wall and the locoregional lymphatics (mammaria interna lymph nodes, axillary and supraclavicular lymph nodes) have to be irradiated. The study comprised 125 breast cancer patients treated with curative intent after primary surgery in the last two years at our institute. In 62 cases the target volume included the breast or chest wall and the locoregional lymphatics, which were treated using our irradiation technique. The target conformal irradiation technique is a multiple non-opposed beams one isocenter technique developed to protect the heart and lungs. This technique, consisting of several rotation beams modulated with wedge filters and individual lung absorbers as well as additional fixed beams, was used in our study to apply a homogeneous dose of 46 to 56 Gy to the target volume; the irradiation technique was optimized by means of dose-volume histograms. After pre-localization, the patients underwent computerized tomographic scanning, with sections at 1.0 cm intervals. Contouring of target volume and organs at risk was carried out with a MULTIDATA workstation for regions of interest (mammaria interna and/or axillary and/or supraclavicular lymphatics and the breast or chest wall) as well as the organs at risk, such as heart and lung parenchyma. Planning target volume coverage was examined by three-dimensional isodose visualization for all CT axial sections for each patient. To determine the incidence of acute or late side effects on the lung parenchyma, conventional chest x-rays and CT studies were carried out at 1 month, 3 months and 6 months after completion of radiotherapy. Dose-volume histogram analysis revealed that this irradiation technique permits the application of a homogeneous dose to the target volume, conforming to the ICRU norms. The maximum dose applied to the ipsilateral lung parenchyma was less than 50-70% of the prescribed dose in the target volume. For left-located primaries, the highest dose applied to the myocardium is less than 30-50% of the dose in the target volume. Acute side effects, such as radiation pneumonitis, were noted in 8% (5/62) of the treated patients. Late side effects (grade I) in the lung were observed in 6.4% of the patients (4 patients) and occurred only in areas that had received more than 70% of the prescribed dose. We conclude that it is possible to apply a homogeneous dose distribution with a one isocenter multiple beams irradiation technique to the most complex target volume, such as the breast or chest wall and the locoregional lymphatics, with a minimum of side effects guaranteed.

Sentinel node concept in breast cancer.

BACKGROUND/PURPOSE: It seems that there exists a specific lymph node center called sentinel node (SN) which appears to be the primary site of metastases. The sentinel node concept (SNC) is fundamentally based on the orderly progression of tumor cells within the lymphatic system. It is the most important new concept in surgical and radiation oncology. The purpose is to present the biological significance, the diagnostic and clinical basis of the sentinel node concept in breast cancer patients. MATERIAL AND METHODS: Lymphoscintigraphy and gamma probe biopsy is necessary to show predictable lymph flow to the regional sentinel node, to multiple sentinel nodes or unpredictable lymph flow to extra-regional sentinel nodes and for performing sentinel node procedure. The standard protocol for the evaluation of the sentinel node metastases consists of extensive histopathological investigation including step Hematoxylin & Eosin (H&E) stained sections and immunohistochemistry. RESULTS: A high rate of success of the identification of the sentinel node for breast cancer was reported. The presence or absence of metastasis in this node is a very accurate predictor of overall nodal status. The temptation to examine the sentinel node with the greatest possible degree of accuracy highlights one of the major problems related to sentinel node biopsy. The success of the sentinel node procedure depends primarily on the adequate functional capacity necessary for sufficient uptake to ensure the accurate identification. In negative sentinel-node patients a complete axillary lymph node dissection is avoidable. In sentinel-node positive patients and clinically negative patients a postoperative radiotherapy would permit an adequate tumor control. The last 2 procedures permit a low morbidity. In the actual TNM classification it was recently introduced a definition of a "pN0" patient based on sentinel node biopsy. New target volumes are defined for adjuvant radiotherapy or lymphatic basins could be spared from unnecessary irradiation. CONCLUSION: The sentinel node concept seems to revolutionize the treatment of early breast cancer. Biopsy of the sentinel node is a highly accurate, minimally invasive method of staging patients and can substantially reduce the morbidity and costs of treatment by avoiding unnecessary complete axillary lymph node dissection. The procedure may lead to a more justifiable approach to adjuvant therapy strategies with low complication rates. The identification of the individual lymphatic flow pattern would permit the irradiation of the individual locoregional lymphatic basin.

Long-term survival following postmastectomy locoregional recurrence of breast cancer.

Only a few reports describe long-term survivors following locoregional recurrence of breast cancer after mastectomy. We analyzed 145 patients who were treated for an isolated postmastectomy breast cancer recurrence at our department between 1979 and 1992. All patients were free from distant metastases at the time of recurrence. Nineteen of these patients remained free from distant metastases after a follow-up of more than 10 years following recurrence. Clinical and histopathological characteristics of these 19 patients were analyzed. Primary tumors were small with almost all being T1 or T2 primaries. The majority of survivors had negative axillary node status (16/19 [84%]). Locoregional recurrences were mainly chest wall recurrences (16/19 [84%]) and all recurrences were smaller than 5 cm (19/19). Only 7 patients showed a typical scar recurrence. Sixteen patients had a single recurrent nodule. Early recurrences (<1 year after mastectomy) were rare (n=2). Treatment of recurrence consisted of tumor excision in all cases followed by radiotherapy in 16 patients (including 6 patients who had undergone elective irradiation following mastectomy), hormonal therapy in 6 and chemotherapy in 1 case. In all patients local control at the recurrence site was achieved. Cure after postmastectomy recurrence seems possible in a subgroup of patients (small primary tumor with negative axilla, small and solitary chest wall recurrence) provided adequate therapy is prescribed. Treatment of these patients should not be regarded as palliative therapy.

Locoregional recurrence of breast cancer following mastectomy: always a fatal event? Results of univariate and multivariate analysis.

PURPOSE: The outcome of patients with local-regional breast cancer recurrence after mastectomy often is described as fatal. However, certain subgroups with favorable prognoses are thought to exist. To determine these favorable subgroups, we analyzed prognostic factors for their influence on postrecurrence survival by univariate and multivariate analysis. METHODS AND MATERIALS: Between 1979 and 1992, 145 patients with their first isolated locoregional recurrence of breast cancer following modified radical mastectomy without evidence of distant metastases were treated at the Department of Radiation Oncology of the University of Wurzburg. Thirty-nine percent of patients (n = 67) had had postmastectomy radiotherapy, representing 7% of patients who had received routine postmastectomy irradiation at our institution. Systemic adjuvant hormonal therapy had been applied in 24% and systemic chemotherapy in 19% of patients. Several combinations were used. Treatment of recurrences consisted of surgical tumor excision in 74%, megavoltage irradiation in 83%, additional hormonal therapy in 41%, and chemotherapy in 12% of patients, employing different combinations. Local control in the recurrent site was achieved in 86%. Median follow-up for patients alive at the time of analysis was 8.9 years after recurrence. We tested different prognostic factors, including prior treatment and treatment of recurrence, for their influence on postrecurrence survival, using univariate and multivariate analysis. RESULTS: Eighty-two of the 145 patients (57%) developed distant metastases within the follow-up period. Metastases-free rate was 42% at 2 years and 36% at 10 years following recurrence. With development of distant metastases, the survival rate deteriorated. Recurrences appeared within the first 2 years from primary surgery in 56% of patients, and in 89% within 5 years. Overall, 2-year and 5-year survival rates following local-regional recurrence were 67% and 42%, respectively. Univariate analysis revealed statistically significant worsening of survival rates for pT3 + 4 primary tumors, primary axillary lymph node involvement, tumor grading 3 + 4, lymphatic vessel invasion, blood vessel invasion, tumor necrosis, negative estrogen (ER) and progesterone (PR) hormonal receptor status, postmastectomy chemotherapy and hormonal therapy, short time to recurrence (< 1 year), combined recurrences and supraclavicular site of recurrence, non-scar recurrence, size of the largest recurrent nodule > 5 cm, multiple recurrent nodules, no surgical excision of recurrence, small target volume of irradiation, chemotherapy for recurrence, and no local control within the recurrence site. The 2-year and 5-year survival rates ranged from 68% to 94%, and from 33% to 65%, respectively, in the favorable subgroups compared to 2-year and 5-year survival rates ranging from 20% to 59% and 0% to 35%, respectively, in the unfavorable subgroups. Multivariate analysis showed that site of recurrence and number of recurrent nodules have the strongest influence on postrecurrence survival, but time to recurrence, age at time of recurrence, local control in recurrent site as well as primary pT and axillary status, and the presence of tumor necrosis in the primary tumor specimen showed additional independent influences on survival. Thus, we identified a highly favorable subgroup of patients with a single chest wall or axillary recurrent nodule (in a patient aged > 50 years), a disease-free interval of > or = 1 year, pT1-2N0 primary tumor, and without tumor necrosis, and whose recurrence is locally controlled. This group (12 patients) had 5- and 10-year survival rates of 100% and 69%, respectively. CONCLUSION: We conclude that locoregional recurrence of breast cancer following mastectomy is not always a sign of systemic disease. Our data support previous findings, that subgroups with favorable prognosis exist and they still have a chance for cure, demanding comprehensive local treatment. (ABSTR

[Bone metastasis in breast carcinoma]. / Die Skelettmetastase beim Mammakarzinom.

113278891978 and 1988 278 patients with metastatic disease of breast cancer were treated at the Clinic of Radiotherapy of the University of Würzburg. 192 of these patients developed skeletal metastases. Particularly the skeletal axis was affected. In 58.3 percent (162 patients) skeletal metastasis was the first metastasis. The median age of the patients was 62.5 years at time of diagnosis of skeletal metastasis. Median interval between primary diagnosis of breast cancer and diagnosis of skeletal metastasis was 2.9 years. Median survival of patients with skeletal metastasis was 1.7 years. Skeletal metastases could not worse survival time, if other metastases already existed. Because of the relatively good prognosis we have to improve and combine the local and systemic therapy.

[Adjuvant whole-brain irradiation in small-cell bronchial carcinoma]. / Zur Frage der adjuvanten Ganzhirnbestrahlung beim kleinzelligen Bronchialkarzinom.

PURPOSE: To analyse if prophylactic cranial irradiation in small cell lung cancer for improved survival is indicated; if adjuvant irradiation could cure the microscopic disease; if and how late effects could be minimized. PATIENTS AND METHODS: Data from randomized trials and retrospective studies are critically analysed related to the incidence of central nervous system (CNS) metastases in limited disease patients in complete remission with or without prophylactic cranial irradiation. The mechanisms of late effects on CNS of prophylactic cranial irradiation and combined treatment are presented. RESULTS: Prophylactic cranial irradiation could decrease the incidence of CNS metastases but could not improve survival. A subgroup of patients (9 to 14%) most likely to benefit from prophylactic cranial irradiation includes patients who are likely to have an isolated CNS failure. The actual used total dose in the range 30 to 40 Gy could only conditionally decrease the CNS failure. Higher total and/or daily doses and combined treatment are related with potentially devastating neurologic and intellectual disabilities. CONCLUSIONS: No prospective randomized trial has demonstrated a significant survival advantage for patients treated with prophylactic cranial irradiation. Prophylactic cranial irradiation is capable of reducing the incidence of cerebral metastases and delays CNS failure. A subgroup of patients most likely to benefit from prophylactic cranial irradiation (9 to 14%) includes patients who are likely to have an isolated CNS failure, but this had yet to be demonstrated. The toxicity of treatment is difficult to be influenced. Prophylactic cranial irradiation should not be given concurrently with chemotherapy, a larger interval after chemotherapy is indicated. The total dose should be in the range 30 to 36 Gy and the daily fraction size not larger than 2 Gy.

[Radiochemotherapy of non-small-cell bronchial carcinoma. A report of experience]. / Radiochemotherapie des nichtkleinzelligen Bronchialkarzinoms. Ein Erfahrungsbericht.

PURPOSE: To investigate the survival of patients with inoperable non-small-cell lung cancer treated with combined radiochemotherapy. Frequency of local progression versus systemic dissemination after radiotherapy respectively radiochemotherapy. Extend of the toxicity of a combined modality treatment. PATIENTS AND METHODS: 60 inoperable patients (42 M0- and 18 M1-stage) with non-small-cell lung cancer who had received combined radiochemotherapy (RT+CT) were examined retrospectively. Different drugs or drug combinations were used. The sequence of radiotherapy and chemotherapy also differed. The survival was compared to that of another group of patients who had received at least 50 Gy with definitive radiotherapy at the same period of time (RT: N = 135). The Karnofsky performance index (KPI) was on an average of 80% in both groups. The primary of patients with systemic disease was treated by radiation when it became symptomatic or when it showed an evident progression. RESULTS: The two investigated treatment groups were comparable regarding KPI, histology, stage, tumor dose and age. The survival was significantly better when chemotherapy was added to radiotherapy. The median survival times in months were as follows: M0: RT 10.6/RT+CT 14.7; M1: RT 6.0/ RT+CT 9.3. Local tumor control was the major problem with or without chemotherapy (local progression of about 70% in both groups). The toxicity of radiochemotherapy was acceptable (bone marrow toxicity WHO-grade 4: 10.5%: nausea WHO-grade 4: 3%). CONCLUSION: In the absence of medical contraindications and with a KPI of at least 70% a combined radiochemotherapy in patients with inoperable non-small-cell lung cancer seems to be possible even if high radiation doses are used. Randomized studies are necessary to prove the impact on survival of an additional chemotherapy.

Omission of the pelvic irradiation in stage I testicular seminoma: a study of postorchiectomy paraaortic radiotherapy.

PURPOSE: To review the survival, cure rate, and pattern of relapse or progression of patients with histologically confirmed Stage I testicular seminoma who underwent orchiectomy and radiation therapy to paraaortic lymphatics only. The pelvic ipsilateral lymph nodes were not irradiated. METHODS AND MATERIALS: Between 1978 and 1992, 150 patients with Stages I or II testicular seminoma received treatment at the Department of Radiation Oncology of the University of Wuerzburg. The distribution by stage was Stage I, 117 patients of which 93 were pT1 N0 M0 and 24 were pT2 N0 M0. Four patients were staged as Stage II (pT3 N0 M0), and in 29 patients the T Stage was not specified. Eighty-six patients from the 117 Stage I (pT1-pT2, N0 M0 according to the TNM classification) seminoma received postorchiectomy irradiation, and are analyzed for outcome in this article. The distribution of the Stage I patients by pT Stage was 71 pT1 and 15 pT2 patients. All these 86 patients had their paraaortic nodes (the biological target volume extending from top of L1 to the bottom of L5) irradiated with four field technique. Tumor dose was specified at normalization point along the central axis. The median tumor dose was 30 Gy given in 1.8-2.0 Gy fractions. Elective irradiation to the ipsilateral hemipelvis (iliac nodes) was totally abandoned. RESULTS: The 10-year disease-free survival and overall survival were 95.3 and 100%. No recurrence in the irradiated field was noted. Four patients (4.7%) experienced relapse of disease outside the treated volume. The most common site of solitary failure was the ipsilateral hemipelvis (one iliacal and one inguinal). One patient developed metastatic disease to the lung. One patient developed a mediastinal recurrence with superior vena cava syndrome and was successfully salvaged by mediastinal irradiation and chemotherapy. CONCLUSIONS: Recommendation for the future management of Stage I seminoma include: reduced biological target volume to the paraaortal lymph nodes (from lumbar vertebra L1 to L5). Complete elimination of irradiation to the pelvic nodes is warranted. Radiation dose should not exceed 30 Gy.

[Usefulness of prophylactic whole brain irradiation in small-cell bronchial carcinoma]. / Der Nutzen der prophylaktischen Ganzhirnbestrahlung (PCI) beim kleinzelligen Bronchialkarzinom.

PURPOSE: An analysis of the incidence of brain metastases in small cell lung cancer, time of occurring during the course of disease, and the prognosis of these patients depending on the use of prophylactic cranial irradiation for three well defined patient groups. MATERIAL AND METHODS: A retrospective study included 133 unselected patients with histologically proven SCLC who were treated from 1985-1990 in our department. From these, 118 patients without CNS metastases at primary diagnosis were divided into three well defined patient groups: group I consisted of 23 patients who achieved a complete remission after primary therapy and who were subsequently treated with PCI, group II consisted of 23 patients in complete remission without PCI. Group III consisted of 72 patients without CNS metastases at the primary diagnosis and without PCI treatment since they did not achieve a complete response after primary therapy. The primary therapy consisted of combined radiochemotherapy or only chemotherapy. Sixteen patients were treated only by irradiation. RESULTS: The overall incidence of CNS metastases for all 133 patients was 33.1%. The incidence of new CNS metastases in group I was 21.7% in group II 26.1%, and in group III 22.2%. The average time to development of CNS metastases after primary diagnosis was different for the three groups: in group I 15.4 months, in group II 9.5 months and in group III 8.4 months. No statistical significance was noted. Median survival time for group I was 16.1 months, for group II 13.8 months and 8.4 months for the group III. No statistical significance was achieved between group I and II (P > 0.05). CONCLUSIONS: These data suggest that treatment with PCI appears to be ineffective in reducing the incidence of subsequently CNS metastases or to improve survival of SCLC patients. We recommend the use of PCI only in well defined clinical studies.

[Does primary tumor affect the prognosis in postmastectomy locoregional recurrence in breast carcinoma?]. / Beeinflusst der Primärtumor die Prognose bei lokoregionärem Rezidiv nach Mastektomie wegen Mammakarzinom?

BACKGROUND: Prognosis following locoregional recurrence of breast cancer after mastectomy often is described as fatal. However, certain subgroups with better prognosis are supposed. We analysed established prognostic factors for their influence on post recurrence survival in order to discriminate favourable from unfavourable subgroups. PATIENTS AND METHODS: Between 1979 and 1989 163 patients with a local or regional recurrence of breast cancer following mastectomy were treated at the Department of Radiation Oncology of the University of Würzburg. One hundred and forty had an isolated recurrence, without evidence of distant disease at the time of recurrence. Median follow up for patients alive at the time of analysis was 102 months from diagnosis of recurrence. Thirteen prognostic factors were tested. RESULTS: Out of the 140 patients 94 (58%) developed distant metastases within the follow-up period. Metastatic-free rate was 42% at 5 years and 38% at 10 years following recurrence. Recurrences occurred in 50% of patients within the first 2 years from primary surgery, in 83% within 5 years. In univariate analysis statistically significant influence on survival rates was found for pT, pN-status, lymphatic vessel invasion, blood vessel invasion, tumor necrosis, hormonal receptor status, presence or development of distant metastases, time to recurrence and site and extension of recurrence. Two- and 5-year survival rates ranged from 64% to 81% and from 40% to 60%, respectively in the favourable subgroups compared to a survival rate ranging from 15% to 44% at 2 years and 0% to 29% at 5 years in the unfavourable subgroups. In patients with involved axillary lymph nodes, the absolute number of nodes did not prove to have significant influence on overall survival. Histopathological grading did not reach statistical significance levels although an influence on survival was observed. Preceding adjuvant radiotherapy did not influence post-recurrence survival rates. Also preceding adjuvant systemic therapy showed no significant impact on survival. Multivariate analysis demonstrated that primary axillary status correlated most strongly with overall survival (p < 0.001) followed by tumor necrosis (p < 0.01). CONCLUSIONS: The mentioned prognostic factors may be useful in determining the adequate (local and systemic) therapy and the best time for it. Our data support previous findings, that certain subgroups with favourable prognostic features exist and they might still have a chance for cure by an adequate local treatment, whereas subgroups of patients with unfavourable prognostic factors have to receive systemic therapy immediately following local therapy because of the forthcoming systemic progression.

The clinical relevance of lymphatic and blood-vessel invasion in breast-cancer patients.

We reviewed 795 patients treated between 1978 and 1988 at the Department of Radiation Oncology of the University of Wuerzburg to study the influence of lymphatic vessel (LVI), blood vessel (BVI) invasion within the primary tumor on distant recurrence and survival following mastectomy or conservative treatment. Among them there were 140 patients with LVI and 18 patients with BVI. In the LVI positive group 75% of patients had axillary lymph nodes involved. In the BVI positive group 94% were nodal positive. The mean number of involved axillary nodes was higher in the group with LVI (4.6) as well as in the group with BVI (9.6) in comparison to the groups with absence of LVI (1.2) or BVI (1.7). LVI and BVI have a distinct impact on survival (P<0.001, P<0.01 respectively) and metastatic-free interval (P<0.001, P<0.01 respectively). The 2- and 5-year survival rates were 78% and 42% for the LVI group compared to 89% and 71% respectively for the LVI negative group. The corresponding 2- and 4.5-year survival rates for the BVI positive group were 68% and 40% compared to 87% and 70% respectively for the BVI negative group. The 5-year metastatic-free rate was 50% in the LVI group compared to 68% in the group without LVI. In the BVI group 53% were free of distant disease at 5 years compared to 66% in the group without BVI. This study suggests that from the biological point of view, LVI and BVI is a sign of agressive disease with poor prognosis. Patients with intra- or peritumoral LVI or BVI represent high risk groups for distant recurrence.