Screening for intra-anal squamous intra-epithelial lesions in women with a history of human papillomavirus-related vulvar or perianal disease: results of a screening protocol.

AIM: Women with a history of human papillomavirus (HPV)-related cervical, vaginal or vulvar high-grade squamous intra-epithelial lesions (HSILs) or cancer are at increased risk of developing anal squamous intra-epithelial lesions (SILs) or a squamous cell carcinoma of the anus (SCCA). Screening for intra-anal SILs with high-resolution anoscopy (HRA) in high-risk populations is a subject of debate. In this study we aimed to answer the following question: what is the prevalence of intra-anal (H)SIL in women with HPV-related vulvar and/or perianal disease using HRA for screening? METHOD: A retrospective study was performed to evaluate the prevalence of intra-anal (H)SIL in women with a history of vulvar and/or perianal HSIL or (superficially invasive) squamous cell carcinoma (SCC). This study was performed between 2015 and 2018 following implementation of a protocol for intra-anal screening using HRA. RESULTS: Twenty-seven patients, 10 with a history of (superficially invasive) SCC (four vulvar, five perianal, one multizonal) and 17 with HSIL as the worst diagnosis (two perianal, 15 multizonal) were screened for intra-anal lesions using HRA. No anal cancer was found at screening, 6 (22%) patients were diagnosed with intra-anal HSIL and 12 (44%) patients with intra-anal low-grade SIL. CONCLUSIONS: We found a high prevalence of intra-anal HSIL in women previously diagnosed with vulvar and perianal HSIL. Given the clear link between HSIL and SCCA, screening for intra-anal lesions in women with HPV-related genital pathology seems warranted. Future studies should focus on the effect of HSIL treatment on the prevention of anal cancer.

HPV-negative squamous cell carcinoma of the anal canal is unresponsive to standard treatment and frequently carries disruptive mutations in TP53.

BACKGROUND: Human papillomavirus (HPV), p16 expression, and TP53 mutations are known prognostic factors in head and neck squamous cell carcinoma, but their role in squamous cell carcinoma of the anal canal (SCCAC) is less well established. The objective of this study was to determine the prognostic significance of tumour HPV status, p16 and p53 expression, and mutations in TP53 in patients with SCCAC receiving (chemo)radiotherapy. METHODS: Human papillomavirus DNA was determined using an INNO-LiPA-based assay in tumour tissue of 107 patients with locally advanced SCCAC. Patients were treated with radiotherapy, with or without concurrent chemotherapy consisting of a fluoropyrimidine and mitomycin C. Expression of p16 and p53 was determined using immunohistochemistry. Exons 2-11 of TP53 in tumour tissue were sequenced. RESULTS: DNA of high-risk HPV types was detected in 93 out of 107 tumours (87%), all of which overexpressed p16 (HPV+/p16+). Of 14 HPV-negative (HPV-) tumours (13%), 10 (9%) were p16-negative (HPV-/p16-) and 4 (4%) overexpressed p16 (HPV-/p16+). Patients with HPV-/p16- disease had inferior 3-year locoregional control (LRC) (15%) compared with patients with HPV+/p16+ tumours (82%, P<0.001) and HPV-/p16+ tumours (75%, P=0.078). Similarly, 3-year overall survival (OS) was 35% (HPV-/p16-) vs 87% (HPV+/p16+, P<0.001) and 75% (HPV-/p16+, P=0.219). Disruptive mutations in TP53 were found in 80% of HPV-/p16- tumours vs 6% of HPV+/p16+ tumours (P<0.001). In multivariate analysis, HPV-/p16- status was an independent predictor of inferior LRC and OS. CONCLUSIONS: HPV- tumours are frequently TP53 mutated. HPV-/p16- status is a strong predictor for reduced LRC and OS, and alternative treatment strategies for patients with HPV-/p16- disease need to be explored.

Chemoradiotherapy with capecitabine for locally advanced anal carcinoma: an alternative treatment option.

BACKGROUND: Capecitabine is an established treatment alternative to intravenous 5-fluorouracil (5-FU) for patients with rectal cancer receiving chemoradiotherapy. Its place in the treatment of locally advanced anal carcinoma (AC), however, remains undetermined. We investigated whether capecitabine is as effective as 5-FU in the treatment of patients with locally advanced AC. METHODS: One hundred and five patients with squamous cell AC stage T2-4 (T2>4 cm), N0-1, M0 or T1-4, N2-3, M0, were included in this retrospective study. Forty-seven patients were treated with continuous 5-FU (750 mg m(-2)) on days 1-5 and 29-33, mitomycin C (MMC, 10 mg m(-2)) on day 1, and radiotherapy; 58 patients were treated with capecitabine (825 mg m(-2) b.i.d. on weekdays), MMC (10 mg m(-2)) on day 1, and radiotherapy. The primary end points of the study were: clinical complete response rate, locoregional control (LRC) and overall survival (OS). Secondary end points were: colostomy-free survival (CFS), toxicity and associations of genetic polymorphisms (GSTT1, GSTM1, GSTP1 and TYMS) with outcome and toxicity. RESULTS: Clinical complete response was achieved in 41/46 patients (89.1%) with 5-FU and in 52/58 patients (89.7%) with capecitabine. Three-year LRC was 76% and 79% (P=0.690, log-rank test), 3-year OS was 78% and 86% (P=0.364, log-rank test) and CFS was 65% and 79% (P=0.115, log-rank test) for 5-FU and capecitabine, respectively. GSTT1 and TYMS genotypes were associated with severe (grade 3-4) toxicity. CONCLUSIONS: Capecitabine combined with MMC and radiotherapy was equally effective as 5-FU-based chemoradiotherapy. This study shows that capecitabine can be used as an acceptable alternative to 5-FU for the treatment of AC.

Outcome of patients with primary central nervous system lymphoma treated outside clinical trials.

Reports on the outcome of patients with primary central nervous system lymphoma (PCNSL) are mainly based on results obtained in the context of clinical trials. However, due to poor performance status and cognitive impairment, most patients are actually treated outside clinical studies. The aim of this retrospective study was to get more insight into the outcome of HIV-negative PCNSL patients, treated between 2000-2010 in two hospitals (one academic centre and one categorical cancer centre). Fifty-two patients were identified. Eight patients were treated with corticosteroids only. Sixteen patients received high-dose methotrexate (MTX)-based chemotherapy, ten received radiotherapy and 18 patients were treated with a combination of MTX-based chemotherapy and radiotherapy. At a median follow-up of 63.1 months, the median overall survival for all patients was 24.4 months (95% CI: 11.5-39.8 months), with an event-free survival of 14 months (95% CI: 7.3-24.4 months). Causes of death were progressive PCNSL in 29 patients, MTX toxicity in four patients and epileptic seizures in one patient. These results are comparable with the outcome of prospective clinical trials in this disease, which still has a relatively poor prognosis.

Prolonged low dose IL-2 and thalidomide in progressive metastatic renal cell carcinoma with concurrent radiotherapy to bone and/or soft tissue metastasis: a phase II study.

Metastatic renal cell cancer is one of the immuno-sensitive tumors. Apart from the immuno-modulating agents IFNalpha and IL-2, thalidomide has been reported to be effective in this type of cancer. However, bone metastases and bulky metastases, show limited response to immunotherapy, are often site of recurrent disease and are therefore often treated later with radiotherapy. In this phase II study, we evaluated toxicity and efficacy of the combination of continuous low dose (1 mIU/m2) s.c. IL-2 and thalidomide (200 mg once daily) in 22 patients with progressive metastatic renal cell cancer. In addition, 13 soft tissue lesions and two bone metastases in 13 patients were concurrently treated with fractionated radiotherapy. T cell number and activation in blood was measured by immunoflowcytometry. Nearly all patients developed grade 1-2 toxicity consisting of fatigue, sensory neuropathy, constipation and dizziness. Five patients had a grade 3-4 toxic event: four patients with deep venous thrombosis requiring anticoagulant therapy, and one patient who developed radiation myelopathy. On systemic response evaluation ten patients showed ongoing SD with a mean progression free survival of 9 months. One patient showed a PR (at an irradiated site). Regarding local response to irradiation, seven lesions showed a PR for a mean time period of 8.7 months, whereas seven were stable for 6 months. The radiation response of one lesion was not evaluable. Immunoflowcytometry showed an increase in number and activation of lymphocytes (mainly Natural Killer--NK-cells), which was absent or even decreased in irradiated patients. The combination of sc. low dose IL-2, thalidomide and radiotherapy is feasible, but relatively toxic and does not lead to higher responses at non-irradiated sites. The combination of immunotherapy and concurrent radiotherapy is effective at 60% of the relatively large evaluable sites. Progressive myelopathy developed in one patient, possibly due to radiotherapy in combination with thalidomide.

High response rates and lasting remissions after low-dose involved field radiotherapy in indolent lymphomas.

PURPOSE: To study the response rates and duration of response after low-dose (4 Gy) involved field radiotherapy (LD-IF-RT) in patients with recurrent indolent lymphoma. PATIENTS AND METHODS: A total of 109 assessable patients (304 symptomatic sites) were irradiated (53 males and 56 females; median age, 62 years; range, 35 to 93), including 98 patients with follicular lymphoma (43 grade 1 and 55 grade 2), nine extranodal marginal zone lymphomas of mucosa-associated lymphoid tissue-type and two patients with lymphoplasmacytoid lymphoma. Bulky disease (> or =5 cm) was present in 52% of all patients. A median of two prior regimens (range, 0 to 11) preceded LD-IF-RT. The median time since diagnosis was 41 months (range, 2 to 358 months). Time to (local) progression was calculated according to the Kaplan-Meier method. Differences in response rates between treatments within the same patient were compared using the McNemar test. RESULTS: The overall response rate was 92%; complete response was reached in 67 patients (61%), partial response in 34 patients (31%), stable disease in six patients (6%), and progressive disease in two patients (2%). The median time to progression was 14 months. The median time to local progression was 25 months. The 67 patients with complete response showed a median time to progression of 25 months and a median time to local progression of 42 months. None of the factors studied (age, sex, follicular lymphoma grade, radiotherapy regimen, number of previous regimens and previous history, number of positive sites or largest lymphoma diameter) were found to be related to response rate. CONCLUSION: LD-IF-RT is a valuable asset in the management of patients with follicular lymphoma and should be considered in patients with recurrent disease.

Radiation-induced glomerular thrombus formation and nephropathy are not prevented by the ADP receptor antagonist clopidogrel.

PURPOSE: To assess the effects of kidney irradiation on glomerular adenosine diphosphatase (ADPase) activity and intraglomerular microthrombus formation, and their correlation to the development of renal functional impairment. METHODS AND MATERIALS: C3H/HenAf-nu(+) mice were given single-dose or fractionated kidney irradiations. Glomerular ADPase activity was measured using a cerium-based histochemical method. Microthrombus formation within the glomeruli was assessed by a semiquantitative immunohistochemical analysis of fibrinogen/fibrin deposits. Renal function was assessed by the [(51)Cr]EDTA retention assay. RESULTS: The ADPase activity was significantly reduced, to approximately 50% of pretreatment value, 4--40 weeks after 10--16 Gy single-dose irradiation and at 44 weeks after 20 x 2 Gy. No dose--effect relationship was found. An approximately fourfold increase in glomerular fibrinogen/fibrin staining was observed at 1 year after irradiation. This increase was not influenced by treating the mice with daily, oral clopidogrel, a platelet ADP receptor antagonist, which reduced platelet aggregation by more than 75%. Radiation-induced impairment of glomerular filtration was also not affected by the clopidogrel treatment. CONCLUSION: These data indicate that irradiation significantly reduced glomerular ADPase activity, which correlated with an increased glomerular fibrinogen/fibrin deposition. We were not able to reduce these prothrombotic changes, nor to protect against radiation nephropathy, by pharmacological intervention with an ADP-receptor antagonist.

Increased glomerular Vwf after kidney irradiation is not due to increased biosynthesis or endothelial cell proliferation.

Kuin, A., Citarella, F., Oussoren, Y. G., Van der Wal, A. F., Dewit, L. G. H. and Stewart, F. A. Increased Glomerular Vwf after Kidney Irradiation is not due to Increased Biosynthesis or Endothelial Cell Proliferation. Radiat. Res. 156, 20-27 (2001). Irradiation of the kidney induces dose-dependent, progressive renal functional impairment, which is partly mediated by vascular damage. It has previously been demonstrated that reduced renal function is preceded by an increased amount of von Willebrand factor (Vwf) in the glomerulus. The underlying mechanism and significance of this observation are unknown but, since it is an important mediator of platelet adhesion, Vwf in increased amounts could be implicated in glomerular thrombosis, resulting in impairment of renal function. Increased Vwf could be the result of increased biosynthesis by endothelial cells, or from increased numbers of endothelial cells after compensatory proliferation induced by irradiation, or it could be secondary to other events. In the present study, expression levels of mRNA for glomerular Vwf and glomerular cell proliferation rates were measured in control mouse kidneys and after irradiation with a single dose of 16 Gy. There were no significant changes in mRNA ratios for Vwf/beta-actin at 10 to 30 weeks after irradiation compared with unirradiated samples, whereas increased amounts of Vwf protein were seen in the glomeruli at these times. Labeling studies with IdU or staining for Ki67 demonstrated that glomerular proliferation was increased from 10 to 30 weeks after irradiation. Despite the increased proliferation rates, there was an absence of glomerular hyperplasia and no increase in the endothelial cell surface coverage in the glomeruli. Staining with antibodies against smooth muscle actin (SMAalpha) revealed that the observed proliferation mainly involved mesangial cells. These results indicate that the increased presence of glomerular Vwf after irradiation is not due to an increased number of endothelial cells per glomerulus, or to an increased production of Vwf. It is presumably secondary to other events, such as increased release of Vwf by damaged endothelial cells or entrapment of Vwf in the irradiated mesangial matrix.

Radiation nephropathy--the link between functional damage and vascular mediated inflammatory and thrombotic changes.

The extent of radiation-induced nephropathy, which develops progressively over periods of months to years after treatment, is strongly influenced by both total dose and dose per fraction. In this study we examined the relationship between the early expression of various thrombotic and inflammatory markers of endothelial cell (EC) damage in irradiated mouse kidneys and the subsequent development of nephropathy. Decreased levels of glomerular ADPase and increased levels of glomerular Vwf were seen from 4 or 20 weeks after irradiation, respectively. These pro-thrombotic changes were associated with increased fibrin/fibrinogen deposits, indicative of microthrombus formation, at later times. These events were, however, not sensitive to changes in total dose or dose per fraction, therefore they cannot be quantitatively linked to the development of radiation nephropathy. Increased leucocyte invasion of the renal cortex was also seen after irradiation; this was quantitatively dependent on both total dose and dose per fraction. Linear quadratic analysis of the leucocyte dose-response curves yielded an alpha/beta ratio of 7.7 Gy, which is significantly greater than the alpha/beta ratio or 2.7 Gy determined for nephropathy, indicating less fractionation sensitivity for the inflammatory response. We conclude that inflammatory changes contribute to, but do not entirely explain, radiation nephropathy. The role of thrombotic changes is less clear.

Influence of acetylsalicylic acid on development of radiation-induced nephropathy.

PURPOSE: Previous studies have demonstrated that long-term treatment with acetylsalicylic acid (ASA) can significantly reduce the renal functional impairment that develops after high doses of irradiation. The effect is hypothesized to be mediated by selective inhibition of thromboxane A2 synthesis and inhibition of platelet aggregation. The present study was undertaken to investigate this phenomenon further using more clinically relevant fractionated and re-irradiation schedules. METHODS AND MATERIALS: Groups of mice were given bilateral renal irradiation with a series of four or 20 daily fractions of X-rays, or 10 daily fractions with a single dose of re-irradiation (0-10 Gy) after 27 weeks. Half the mice received ASA in drinking water (2.4 g x l(-1)) from 1 week before the start of irradiation and continuously throughout the follow-up period. Renal function was assessed by clearance of [51Cr]EDTA, about every 4 weeks for up to 80 weeks after the start of treatment. Histological damage in representative groups of mice was also assessed. RESULTS: Oral administration of ASA caused inhibition of thromboxane A2 synthesis (to < 36% of controls) and a strong inhibition of platelet aggregation in whole mouse blood (ex vivo). Prolonged treatment with ASA also resulted in a small, non-significant reduction of radiation-induced renal functional damage. No reduction in histological damage was seen in the ASA treated mice. CONCLUSION: Long-term oral administration of ASA gave only a modest, non-significant reduction of renal radiation injury after clinically relevant fractionated irradiation schedules.

In vitro and in vivo expression of endothelial von Willebrand factor and leukocyte accumulation after fractionated irradiation.

Previous investigations have demonstrated an increased release of von Willebrand factor (VWF; also known as vWF) in endothelial cells after high single-dose irradiation in vitro. We have also found increased levels of Vwf protein in mouse glomeruli after a high single dose of renal irradiation in vivo. In addition, increased numbers of leukocytes were observed in the renal cortex after irradiation in vivo. The aim of the present study was to investigate and quantify these biological processes after clinically relevant fractionated irradiation and to relate them to changes in renal function. A significantly greater increase in release of VWF was observed in cultured human umbilical vein endothelial cells (HUVECs) after fractionated irradiation (20 x 1.0 Gy) than after a single dose of 20 Gy (147% compared to 115% of control, respectively, P < 0.0005). In contrast with the in vitro observations, glomerular Vwf staining was lower after fractionated irradiation in vivo (20 x 2.0 Gy or 10 x 1.6 Gy +/- re-irradiation) than after a single dose of 16 Gy. The number of leukocytes accumulating in the renal cortex was also lower after fractionated in vivo irradiation than after a single radiation dose. The onset of these events preceded renal functional and histopathological changes by approximately 10 weeks. These data indicate that radiation-induced changes in endothelial VWF expression after in vivo irradiation may be distinct from the in vitro observations. Increased VWF expression may reflect pivotal processes in the pathogenesis of late radiation nephropathy and provide a clue to appropriate timing of pharmacological intervention.

Target volumes in radiotherapy for high-grade malignant glioma of the brain.

Delineation of the clinical target volume (CTV) in radiation treatment planning of high-grade glioma is a controversial issue. The use of computerized tomography (CT) and magnetic resonance imaging (MRI) has greatly improved the accuracy of tumor localization in three-dimensional planning. This review aims at critically analyzing available literature data in which tumor extent of high-grade glioma has been assessed using CT and/or MRI and relating this to postmortem observations. Attention is given to the pattern of tumor spread at initial presentation and to tumor recurrence pattern after external beam irradiation. Special emphasis is given to the site of tumor regrowth after radiation treatment in relation to the boundaries of the CTV. Guidelines for delineating CTV will be inferred from this information, taking data on radiation effects on the normal brain into account.

Increased expression of glomerular von Willebrand factor after irradiation of the mouse kidney.

Ionizing irradiation has been shown to induce an increased release of von Willebrand factor (vWF) in human endothelial cells in vitro. The present study was undertaken to investigate whether an increase in expression of vWF also occurs in glomerular endothelial cells in vivo after irradiation of the kidney. Increased expression of vWF may initiate prothrombotic changes, and the resultant vascular damage could cause renal failure. The amount of adherent leukocytes in the renal cortex after irradiation was also quantified, since this may contribute to the histological changes that occur after irradiation. Changes in expression of glomerular vWF and in the amount of leukocytes were related to the development of impairment of renal function, as assessed with the [51Cr]EDTA retention assay. Mice were given bilateral irradiation (single dose of 16 Gy) or were sham-irradiated and were sacrificed at intervals of 1 day to 40 weeks after irradiation. Immunohistochemical analysis of kidney cryosections was performed using a polyclonal vWF antibody or monoclonal CD45 antibody (leukocyte common antigen). The amount of glomerular vWF staining and CD45 staining in the renal cortex (percentage surface coverage) was quantified using a computerized image analyzer. The mean glomerular vWF staining in the nonirradiated kidneys was 34.4 +/- 6.2% (mean +/- SEM, 10 weeks after sham treatment). After irradiation, the expression of glomerular vWF increased gradually from 10 weeks to 53.4 +/- 3.6% at 40 weeks. The total number of leukocytes in the renal cortex of nonirradiated mice at 10 weeks after sham treatment was low, with a mean area of 1.0 +/- 0.09%, whereas in the irradiated kidneys the relative tissue area covered by leukocytes increased to 7.6 +/- 2.1% at 40 weeks. These alterations preceded impairment of renal function. The extent to which these changes are causally related to impairment of function will be the subject of future study using specific antithrombotic and anti-inflammatory agents.

Delayed gastric emptying after standard pancreaticoduodenectomy versus pylorus-preserving pancreaticoduodenectomy: an analysis of 200 consecutive patients.

BACKGROUND: It has been suggested that pylorus-preserving pancreaticoduodenectomy (PPPD) is associated with a high incidence of delayed gastric emptying and consequently with a prolonged hospital stay compared with standard Whipple's resection. The aim of this prospective study was to evaluate whether the incidence of delayed postoperative gastric emptying was different after both procedures. STUDY DESIGN: From 1989 to 1996, 200 consecutive patients underwent pancreatic head resection (100 standard pancreaticoduodenectomy [PD]; 100 PPPD). The groups were compared with regard to patient characteristics, operative indices, postoperative morbidity, hospital stay, and mortality. Delayed gastric emptying was defined as nasogastric suction for > or = 10 days or delay of regular diet until > 14 days postoperatively. RESULTS: Operative time and blood loss were higher for PD: 6 versus 4.8 hours (p < 0.0001) and 1,580 versus 1,247 mL (p < 0.001), respectively. Postoperative morbidity was 48% after PD and 44% after PPPD (not significant [NS]). Hospital mortality was 6% and 1% after PD and PPPD, respectively (NS). Delayed gastric emptying occurred in 34 patients after PD and in 37 after PPPD (NS). Median days of gastric suction was 3 versus 6 days for PD and PPPD (p < 0.0001). A regular diet was tolerated after a median of 10 and 11 days for PD and PPPD, respectively (NS). Postoperative hospital stay was shorter for patients who underwent PPPD: 20 versus 18 days (p < 0.03). Patients with intraabdominal complications (n = 52) showed a higher incidence of delayed gastric emptying (p < 0.0001). CONCLUSIONS: Our results show that PPPD is a safe procedure associated with less operative time and blood loss than PD. After PPPD, patients require longer postoperative nasogastric intubation than after PD, suggesting some form of early postoperative gastric stasis. There is, however, no difference in the incidence of delayed gastric emptying or the first postoperative day on which a regular diet is tolerated between these surgical procedures. Intraabdominal complications are major risk factors for delayed gastric emptying.

Iodine-123 metaiodobenzylguanidine in the assessment of late cardiac effects from cancer therapy.

Recognition of adverse late cardiac effects from cancer therapy may enable identification of patients with risk of cardiotoxicity upon cancer retreatment. In this study the feasibility of using iodine-123 metaiodobenzylguanidine (123I-MIBG) heart scintigraphy to detect abnormalities of the myocardial adrenergic neurone function in the late period after cancer therapy was evaluated in relation to the left ventricle ejection fraction (LVEF) in 18 cancer patients: 11 had undergone thoracic irradiation involving the heart, in five cases in combination with anthracycline therapy, 11-228 months (median 60 months) before radionuclide tests, while seven had not received previous anthracycline and/or radiotherapy (controls). The 123I-MIBG cardiac uptake, expressed as a heart-to-mediastinum ratio on planar images after 4h, ranged from 1.21 to 1.76 (median 1.56) in cancer therapy patients, which was significantly decreased (P=0.0006) in comparison with controls (range 1.81- 2.06, median 1.9). The myocardial 123I-MIBG washout, calculated from planar images after 15 min and 4 h, and LVEF also showed significant differences, but with some overlap in individual cases. In cancer therapy patients, cardiac abnormalities seen on planar images and additional single-photon emission tomographic images varied from focal defects to diffusely reduced myocardial uptake. It is concluded that 123I-MIBG heart scintigraphy, which is able to identify cardiac adrenergic neurone abnormalities in the follow-up period after cancer therapy, may help to identify relapsed patients who are at increased risk of developing cardiotoxicity during retreatment with cardiotoxic therapy modalities.

Dose homogeneity in boron neutron capture therapy using an epithermal neutron beam.

Simulation models based on the neutron and photon Monte Carlo code MCNP were used to study the therapeutic possibilities of the HB11 epithermal neutron beam at the High Flux Reactor in Petten. Irradiations were simulated in two types of phantoms filled with water or tissue-equivalent material for benchmark treatment planning calculations. In a cuboid phantom the influence of different field sizes on the thermal-neutron-induced dose distribution was investigated. Various shapes of collimators were studied to test their efficacy in optimizing the thermal-neutron distribution over a planning target volume and healthy tissues. Using circular collimators of 8, 12 and 15 cm diameter it was shown that with the 15-cm field a relatively larger volume within 85% of the maximum neutron-induced dose was obtained than with the 8- or 12-cm-diameter field. However, even for this large field the maximum diameter of this volume was 7.5 cm. In an ellipsoid head phantom the neutron-induced dose was calculated assuming the skull to contain 10 ppm 10B, the brain 5 ppm 10B and the tumor 30 ppm 10B. It was found that with a single 15-cm-diameter circular beam a very inhomogenous dose distribution in a typical target volume was obtained. Applying two equally weighted opposing 15-cm-diameter fields, however, a dose homogeneity within +/- 10% in this planning target volume was obtained. The dose in the surrounding healthy brain tissue is 30% at maximum of the dose in the center of the target volume. Contrary to the situation for the 8-cm field, combining four fields of 15 cm diameter gave no large improvement of the dose homogeneity over the target volume or a lower maximum dose in the healthy brain. Dose-volume histograms were evaluated for the planning target volume as well as for the healthy brain to compare different irradiation techniques, yielding a graphical confirmation of the above conclusions. Therapy with BNCT on brain tumors must be performed either with an 8-cm four-field irradiation or with two opposing 15- or 12-cm fields to obtain an optimal dose distribution.