Juhani Collan

Boron Neutron Capture Therapy in the Treatment of Locally Recurred Head-and-Neck Cancer: Final Analysis of a Phase I/II Trial

PURPOSE To investigate the efficacy and safety of boron neutron capture therapy (BNCT) in the treatment of inoperable head-and-neck cancers that recur locally after conventional photon radiation therapy. METHODS AND MATERIALS In this prospective, single-center Phase I/II study, 30 patients with inoperable, locally recurred head-and-neck cancer (29 carcinomas and 1 sarcoma) were treated with BNCT. Prior treatments consisted of surgery and conventionally fractionated photon irradiation to a cumulative dose of 50 to 98 Gy administered with or without concomitant chemotherapy. Tumor responses were assessed by use of the RECIST (Response Evaluation Criteria in Solid Tumors) and adverse effects by use of the National Cancer Institute common terminology criteria version 3.0. Intravenously administered L-boronophenylalanine-fructose (400 mg/kg) was administered as the boron carrier. Each patient was scheduled to be treated twice with BNCT. RESULTS Twenty-six patients received BNCT twice; four were treated once. Of the 29 evaluable patients, 22 (76%) responded to BNCT, 6 (21%) had tumor growth stabilization for 5.1 and 20.3 months, and 1 (3%) progressed. The median progression-free survival time was 7.5 months (95% confidence interval, 5.4-9.6 months). Two-year progression-free survival and overall survival were 20% and 30%, respectively, and 27% of the patients survived for 2 years without locoregional recurrence. The most common acute Grade 3 adverse effects were mucositis (54% of patients), oral pain (54%), and fatigue (32%). Three patients were diagnosed with osteoradionecrosis (each Grade 3) and one patient with soft-tissue necrosis (Grade 4). Late Grade 3 xerostomia was present in 3 of the 15 evaluable patients (20%). CONCLUSIONS Most patients who have inoperable, locally advanced head-and-neck carcinoma that has recurred at a previously irradiated site respond to boronophenylalanine-mediated BNCT, but cancer recurrence after BNCT remains frequent. Toxicity was acceptable. Further research on novel modifications of the method is warranted.

Complement activation in circulation and central nervous system after rituximab (anti-CD20) treatment of B-cell lymphoma.

Rituximab (IDEC-C2B8, Mabthera®, Rituxan®), a chimeric monoclonal antibody against the B-cell specific CD20-antigen, has been demonstrated to be effective in the treatment of non-Hodgkins B-cell lymphoma (B-NHL). Previous in vitro studies have shown that direct complement-dependent cytotoxicity (CDC), ADCC and apoptosis are important in the rituxi-mab-induced killing of lymphoma cells. It is, however, unknown whether rituximab penetrates the blood-brain barrier. Therefore, we studied rituximab levels and complement (C) activation in blood and cerebrospinal fluid (CSF) following intravenous rituximab therapy in a patient with relapsing non-Hodgkins lymphoma with central nervous system (CNS) involvement. Longitudinal samples from blood and CSF were taken at 13 time-points during the treatment period. The results show that the C cascade becomes activated in blood during the first mAb infusion (C3a-desArg concentration rose from 55 to 138 μg/ml during the first 2 hours). After the first infusion the proportions of lymphocytes positive for the CD 19- and CD20-antigens in the peripheral blood were reduced from 41% and 35%, respectively, to a level of 2% (for both). In CSF the rituximab concentration increased after successive infusions, but remained below 0.55 μg/ml (compared to a Cmax of 400 μg/ml in peripheral blood). Although a minor and delayed C activation response was seen in the CSF the treatment did not clear CD20-positive cells away from the CNS. Thus, it appears that an intact blood-brain barrier restricts the entry of rituximab into the CNS. Possible options to circumvent this would be dose escalation or intrathecal rituximab treatment.

Commissioning of MRI‐only based treatment planning procedure for external beam radiotherapy of prostate

In radiotherapy, target tissues are defined best on MR images due to their superior soft tissue contrast. Computed tomography imaging is geometrically accurate and it is needed for dose calculation and generation of reference images for treatment localization. Co‐registration errors between MR and computed tomography images can be eliminated using magnetic resonance imaging‐only based treatment planning. Use of ionizing radiation can be avoided which is especially important in adaptive treatments requiring several re‐scans. We commissioned magnetic resonance imaging‐only based procedure for external radiotherapy, treatment planning of the prostate cancer. Geometrical issues relevant in radiotherapy, were investigated including quality assurance testing of the scanner, evaluation of the displacement of skin contour and radiosensitive rectum wall, and detection of intraprostatic fiducial gold seed markers used for treatment localization. Quantitative analysis was carried out for 30 randomly chosen patients. Systematic geometrical errors were within 2.2 mm. The gold seed markers were correctly identified for 29 out of the 30 patients. Positions of the seed midpoints were consistent within 1.3 mm in magnetic resonance imaging and computed tomography. Positional error of rectal anterior wall due to susceptibility effect was minimal. Geometrical accuracy of the investigated equipment and procedure was sufficient for magnetic resonance imaging‐only based radiotherapy, treatment planning of the prostate cancer including treatment virtual simulation. Magn Reson Med, 2013.

L-BORONOPHENYLALANINE-MEDIATED BORON NEUTRON CAPTURE THERAPY FOR MALIGNANT GLIOMA PROGRESSING AFTER EXTERNAL BEAM RADIATION THERAPY: A PHASE I STUDY

PURPOSE To investigate the safety of boronophenylalanine-mediated boron neutron capture therapy (BNCT) in the treatment of malignant gliomas that progress after surgery and conventional external beam radiation therapy. METHODS AND MATERIALS Adult patients who had histologically confirmed malignant glioma that had progressed after surgery and external beam radiotherapy were eligible for this Phase I study, provided that >6 months had elapsed from the last date of radiation therapy. The first 10 patients received a fixed dose, 290 mg/kg, of L-boronophenylalanine-fructose (L-BPA-F) as a 2-hour infusion before neutron irradiation, and the remaining patients were treated with escalating doses of L-BPA-F, either 350 mg/kg, 400 mg/kg, or 450 mg/kg, using 3 patients on each dose level. Adverse effects were assessed using National Cancer Institute Common Toxicity Criteria version 2.0. RESULTS Twenty-two patients entered the study. Twenty subjects had glioblastoma, and 2 patients had anaplastic astrocytoma, and the median cumulative dose of prior external beam radiotherapy was 59.4 Gy. The maximally tolerated L-BPA-F dose was reached at the 450 mg/kg level, where 4 of 6 patients treated had a grade 3 adverse event. Patients who were given >290 mg/kg of L-BPA-F received a higher estimated average planning target volume dose than those who received 290 mg/kg (median, 36 vs. 31 Gy [W, i.e., a weighted dose]; p = 0.018). The median survival time following BNCT was 7 months. CONCLUSIONS BNCT administered with an l-BPA-F dose of up to 400 mg/kg as a 2-hour infusion is feasible in the treatment of malignant gliomas that recur after conventional radiation therapy.

Scintigraphy in prediction of the salivary gland function after gland-sparing intensity modulated radiation therapy for head and neck cancer

BACKGROUND AND PURPOSE To evaluate salivary gland scintigraphy in prediction of salivary flow following radiation therapy. PATIENTS AND METHODS Twenty patients diagnosed with head and neck cancer were treated with intensity modulated radiation therapy with an intention to spare the salivary gland function. The total quantitative saliva secretion was measured prior to and 6 and 12 months after therapy, and the function of the major salivary glands was monitored using Tc-99m-pertechnetate scintigraphy. Two models were designed for prediction of the post-treatment salivary flow: an average model, based on the average proportions of saliva produced by each of the four major glands in healthy subjects, and an individual model, based on saliva produced by each gland as measured by scintigraphy prior to therapy. These models were compared with volume-based (Lyman) normal tissue complication probability models using two published sets of model parameters. RESULTS The D(50) for the parotid and the submandibular gland function assessed at 6 and 12 months after radiotherapy was approximately 39Gy. The scintigraphy-based individual model predicted well the measured post-treatment saliva flow rates. The correlation coefficient between the predicted stimulated and the measured saliva flow rate was 0.77 (p<0.0001) at 6 months and 0.55 (p=0.034) at 12 months after completion of radiotherapy. The relative changes in unstimulated and stimulated salivary flow rates showed similar dependency on the cumulative radiation dose. CONCLUSIONS Salivary gland function assessed by scintigraphy prior to radiotherapy is useful in prediction of the residual salivary flow after radiotherapy.

A Phase I/II Trial of Gefitinib Given Concurrently With Radiotherapy in Patients With Nonmetastatic Prostate Cancer

PURPOSE To estimate the safety and tolerability of daily administration of 250 mg of gefitinib given concurrently with three-dimensional conformal radiotherapy for patients with nonmetastatic prostate cancer. METHODS AND MATERIALS A total of 42 patients with T2-T3N0M0 tumors were treated in a nonrandomized single-center study. A prostate-specific antigen (PSA) level of <20 and a good performance status (WHO, 0-1) were required. Adjuvant or neoadjuvant hormone treatments were not allowed. A daily regimen of 250 mg of gefitinib was started 1 week before radiation therapy began and lasted for the duration of radiation therapy. A dose of 50.4 Gy (1.8 Gy/day) was administered to the tumor, prostate, and seminal vesicles, followed by a 22-Gy booster (2 Gy/day) for a total dose of 72.4 Gy. Correlative studies included analysis of epidermal growth factor receptor (EGFR), EGFRvIII, and phosphorylated EGFR in tumors and tumor necrosis factor, interleukin-1alpha (IL-1alpha), and IL-6 in serum. RESULTS Maximum tolerated dose was not reached in phase I (12 patients), and 30 additional patients were treated in phase II. Thirty (71.4%) patients completed trial medication. Dose-limiting toxicities were recorded for 16 (38.1%) patients, the most common of which was a grade 3 to 4 increase in transaminase (6 patients). After a median follow-up of 38 months, there were no deaths due to prostate cancer. The estimated PSA relapse-free survival rate at 4 years (Kaplan-Meier) was 97%, the salvage therapy-free survival rate was 91%, and the overall survival rate was 87%. These figures compared favorably with those of matched patients treated with radiation only at higher doses. CONCLUSIONS The combination of gefitinib and radiation is reasonably well tolerated and has promising activity against nonmetastatic prostate cancer.

Implementation of adaptive radiation therapy for urinary bladder carcinoma: Imaging, planning and image guidance

Abstract Background. Adaptive radiation therapy (ART) for urinary bladder cancer has emerged as a promising alternative to conventional RT with potential to minimize radiation-induced toxicity to healthy tissues. In this work we have studied bladder volume variations and their effect on healthy bladder dose sparing and intrafractional margins, in order to refine our ART strategy. Material and methods. An online ART treatment strategy was followed for five patients with urinary bladder cancer with the tumors demarcated using Lipiodol®. A library of 3–4 predefined treatment plans for each patient was created based on four successive computed tomography (CT) scans. Cone beam CT (CBCT) images were acquired before each treatment fraction and after the treatment at least weekly. In partial bladder treatment the sparing of the healthy part of the bladder was investigated. The bladder wall displacements due to bladder filling were determined in three orthogonal directions (CC, AP, DEX-SIN) using the treatment planning CT scans. An ellipsoidal model was applied in order to find the theoretical maximum values for the bladder wall displacements. Moreover, the actual bladder filling rate during treatment was evaluated using the CBCT images. Results. In partial bladder treatment the volume of the bladder receiving high absorbed doses was generally smaller with a full than empty bladder. The estimation of the bladder volume and the upper limit for the intrafractional movement of the bladder wall could be represented with an ellipsoidal model with a reasonable accuracy. Observed maximum growth of bladder dimensions was less than 10 mm in all three orthogonal directions during 15 minute interval. Conclusion. The use of Lipiodol contrast agent enables partial bladder treatment with reduced irradiation of the healthy bladder volume. The ellipsoidal bladder model can be used for the estimation of the bladder volume changes and the upper limit of the bladder wall movement during the treatment fraction.

Patterns of relapse following definitive treatment of head and neck squamous cell cancer by intensity modulated radiotherapy and weekly cisplatin

Eighty-three patients with oropharyngeal, hypopharyngeal or laryngeal cancer were treated with concomitant cisplatin 40 mg/m(2) once a week during the radiotherapy and IMRT up to a total dose of 70 Gy. The 2-year rate of local control, overall survival and disease specific survival were 84%, 82% and 89%, respectively. The corresponding 5-year Kaplan-Meier estimates were 79%, 69% and 76%.

Submandibular gland-sparing intensity modulated radiotherapy in the treatment of head and neck cancer: Sites of locoregional relapse and survival

Abstract Background and purpose. To evaluate the patterns of locoregional relapse and survival following submandibular gland (SMG)-sparing intensity modulated radiotherapy (IMRT). Patients and methods. Eighty patients with laryngeal (n = 15), oropharyngeal (n = 50), hypopharyngeal (n = 11) or nasopharyngeal cancer (n = 4) were treated by submandibular gland-sparing IMRT for head and neck squamous cell cancer between July 2000 and December 2008. All patients were treated by bilateral IMRT. Thirty-nine (49%) received definitive radiotherapy (RT) and 41 (51%) postoperative RT. The contralateral parotid gland (PG) and SMG were included in the dose optimization planning program with intent to keep the mean doses for PG and SMG below 23 Gy and 28–30 Gy, respectively. The ipsilateral glands were also spared when considered feasible. Results. During a median follow-up time of 51 months (range, 24–117 months) nine local recurrent tumors were observed. Four of these nine patients were salvaged by surgery with no further recurrence. All local recurrences were located within the high-dose CTVs. None of the locally recurrent cancers were located at the vicinity of the spared PGs or SMGs. No recurrent tumors were observed in the contralateral neck. The Kaplan-Meier estimate for local control at five years following IMRT was 88% for the whole cohort and the corresponding figure for local control following salvage surgery was 94%. The estimates for five-year overall survival and disease-specific survival were 85% and 90%, respectively. Conclusion. In selected head and neck cancer patients who are estimated to have a low risk of cancer recurrence at the nodal levels I–II and who are treated with SMG-sparing IMRT the risk of cancer recurrence at the vicinity of the spared salivary glands is low.

Radiotherapy for GIST progressing during or after tyrosine kinase inhibitor therapy: A prospective study

PURPOSE Gastrointestinal stromal tumor (GIST) has been considered radiation-resistant, and radiotherapy is recommended only for palliation of bone metastases in current treatment guidelines. No registered prospective trial has evaluated GIST responsiveness to radiotherapy. PATIENTS AND METHODS Patients with GIST progressing at intra-abdominal sites or the liver were entered to this prospective Phase II multicenter study (identifier NCT00515931). Metastases were treated with external beam radiotherapy using either conformal 3D planning or intensity modulated radiotherapy and conventional fractionation to a cumulative planning target volume dose of approximately 40 Gy. Systemic therapy was maintained unaltered during the study. RESULTS Of the 25 patients entered, 19 were on concomitant tyrosine kinase inhibitor therapy, most often imatinib. Two (8%) patients achieved partial remission, 20 (80%) had stable target lesion size for ⩾3 months after radiotherapy with a median duration of stabilization of 16 months, and 3 (12%) progressed. The median time to radiotherapy target lesion progression was 4-fold longer than the median time to GIST progression at any site (16 versus 4 months). Radiotherapy was generally well tolerated. CONCLUSIONS Responses to radiotherapy were infrequent, but most patients had durable stabilization of the target lesions. GIST patients with soft tissue metastases benefit frequently from radiotherapy.