Maarten C. C. M. Hulshof

Randomised trial of hyperthermia as adjuvant to radiotherapy for recurrent or metastatic malignant melanoma

The value of hyperthermia as an adjuvant to radiotherapy in patients with malignant melanoma was studied in a European multicentre trial. 134 metastatic or recurrent lesions of malignant melanoma in 70 patients were randomly assigned to receive radiotherapy (three fractions of 8 Gy or 9 Gy in 8 days) alone or followed by hyperthermia (43 degrees C for 60 min). Overall, the 2-year actuarial local tumour control was 37 (SE 5)%. Univariate analysis showed a beneficial effect of hyperthermia (radiation alone 28% vs combined treatment 46%, p = 0.008) and radiation dose (24 Gy 25% vs 27 Gy 56%, p = 0.02), but no effect of tumour size (< or = 4 cm 42% vs > 4 cm 29%, p = 0.21). Cox multivariate regression analysis showed the most important prognostic variables to be hyperthermia (odds ratio for 2-year local control 1.73 [95% CI 1.07-2.78], p = 0.023), tumour size (0.91 [0.85-0.99], p = 0.05), and radiation dose (1.17 [1.01-1.36], p = 0.05). Addition of heat did not significantly increase acute or late radiation reactions. Heating was well tolerated, but because of difficulties with equipment only 14% of treatments achieved the protocol objective. The overall 5-year survival rate was 19%, but 38% of the patients for whom all known disease was controlled survived 5 years. Adjuvant hyperthermia significantly improved local tumour control when applied in association with radiation in treatment of malignant melanoma. Successful local treatment of patients with a single or a few metastatic malignant melanoma lesions has significant curative potential.

Patterns of Recurrence After Surgery Alone Versus Preoperative Chemoradiotherapy and Surgery in the CROSS Trials

PURPOSE To analyze recurrence patterns in patients with cancer of the esophagus or gastroesophageal junction treated with either preoperative chemoradiotherapy (CRT) plus surgery or surgery alone. PATIENTS AND METHODS Recurrence pattern was analyzed in patients from the previously published CROSS I and II trials in relation to radiation target volumes. CRT consisted of five weekly courses of paclitaxel and carboplatin combined with a concurrent radiation dose of 41.4 Gy in 1.8-Gy fractions to the tumor and pathologic lymph nodes with margin. RESULTS Of the 422 patients included from 2001 to 2008, 418 were available for analysis. Histology was mostly adenocarcinoma (75%). Of the 374 patients who underwent resection, 86% were allocated to surgery and 92% to CRT plus surgery. On January 1, 2011, after a minimum follow-up of 24 months (median, 45 months), the overall recurrence rate in the surgery arm was 58% versus 35% in the CRT plus surgery arm. Preoperative CRT reduced locoregional recurrence (LRR) from 34% to 14% (P < .001) and peritoneal carcinomatosis from 14% to 4% (P < .001). There was a small but significant effect on hematogenous dissemination in favor of the CRT group (35% v 29%; P = .025). LRR occurred in 5% within the target volume, in 2% in the margins, and in 6% outside the radiation target volume. In 1%, the exact site in relation to the target volume was unclear. Only 1% had an isolated infield recurrence after CRT plus surgery. CONCLUSION Preoperative CRT in patients with esophageal cancer reduced LRR and peritoneal carcinomatosis. Recurrence within the radiation target volume occurred in only 5%, mostly combined with outfield failures.

INFLUENCE OF BLADDER AND RECTAL VOLUME ON SPATIAL VARIABILITY OF A BLADDER TUMOR DURING RADICAL RADIOTHERAPY

PURPOSE To assess the spatial variability of a bladder tumor relative to the planning target volume boundaries during radical radiotherapy, and furthermore to develop strategies to reduce spatial variability. METHODS AND MATERIALS Seventeen patients with solitary T2-T4N0M0 bladder cancer were treated with a technique delivering 40 Gy/2 Gy in 20 fractions to the whole bladder with a concomitant boost to the bladder tumor of 20 Gy in 1 Gy fractions in an overall time of 4 weeks. CT scans were made weekly, immediately after treatment, and matched with the planning CT scan. Spatial variability of the tumor, as well as bladder volume and rectal diameter, were scored for each patient each week. RESULTS In 65% of patients, a part of the tumor appeared outside the planning target volume boundaries at least one time during the course of radiotherapy. No consistent relation of this variability with time was found. Bladder volumes and rectal diameters showed marked variability during the course of treatment. A large initial bladder volume and rectal diameter predicted a large volume variation and a large tumor spatial variability. CONCLUSION In this study, a margin of 1.5 to 2 cm seemed to be inadequate in 65% of the patients with respect to spatial variability. Bladder volume and rectal diameter were found to be predictive for spatial variability of a bladder tumor during concomitant boost radiotherapy.

Fluorodeoxyglucose Positron Emission Tomography for Evaluating Early Response During Neoadjuvant Chemoradiotherapy in Patients With Potentially Curable Esophageal Cancer

Background:Neoadjuvant chemoradiotherapy before surgery can improve survival in patients with potentially curable esophageal cancer, but not all patients respond. Fluorodeoxyglucose positron emission tomography (FDG-PET) has been proposed to identify nonresponders early during neoadjuvant chemoradiotherapy. The aim of the present study was to determine whether FDG-PET could differentiate between responding and nonresponding esophageal tumors early in the course of neoadjuvant chemoradiotherapy. Methods:This clinical trial comprised serial FDG-PET before and 14 days after start of chemoradiotherapy in patients with potentially curable esophageal carcinoma. Histopathologic responders were defined as patients with no or less than 10% viable tumor cells (Mandard score on resection specimen). PET response was measured using the standardized uptake value (SUV). Receiver operating characteristic analysis was used to evaluate the ability of SUV in distinguishing between histopathologic responders and nonresponders. Results:In 100 included patients, 64 were histopathologic responders. The median SUV decrease 14 days after the start of therapy was 30.9% for histopathologic responders and 1.7% for nonresponders (P = 0.001). In receiver operating characteristic analysis, the area under the curve was 0.71 (95% CI = 0.60–0.82). Using a 0% SUV decrease cutoff value, PET correctly identified 58 of 64 responders (sensitivity 91%) and 18 of 36 nonresponders (specificity 50%). The corresponding positive and negative predictive values were 76% and 75%, respectively. Conclusions:SUV decrease 14 days after the start of chemoradiotherapy was significantly associated with histopathologic tumor response, but its accuracy in detecting nonresponders was too low to justify the clinical use of FDG-PET for early discontinuation of neoadjuvant chemoradiotherapy in patients with potentially curable esophageal cancer.

Accelerated Radiotherapy, Carbogen, and Nicotinamide in Glioblastoma Multiforme: Report of European Organization for Research and Treatment of Cancer Trial 22933

PURPOSE A three-step phase I/II trial associating accelerated radiotherapy with carbogen (step 1, ARCO), with nicotinamide (step 2, ARN), or with both (step 3, ARCON) was conducted, the aim of which was to overcome the effects of proliferation and hypoxia as potential causes of tumor radioresistance in glioblastoma multiforme. PATIENTS AND METHODS Radiotherapy consisted of 60 Gy delivered over 4 weeks in 1.5-Gy fractions twice daily, 5 days a week. Carbogen breathing was started 5 minutes before each fraction and continued until the end of each treatment session. Nicotinamide was given daily as a single oral dose of 85 mg/kg. RESULTS A total of 115 patients with a median age of 55 years were registered. Of 107 eligible patients, 23 were registered in step 1, 28 in step 2, and 56 in step 3. The planned treatment was administered without any interruption in 72% of patients (86% in ARCO but 68% in ARN and ARCON). The incidence and severity of acute skin and mucous membrane toxicity were higher in patients who received nicotinamide (ie, the ARN and ARCON groups). Grade 1 to 2 gastrointestinal toxicity was observed in 44% of patients in the ARN group and 32% of patients in the ARCON group, but only in 8% of patients in the ARCO group. Eight percent of evaluated patients presented with abnormal liver test results at treatment completion. The dose of corticosteroids had to be increased in 44% of patients. Late neurologic side effects were similar in all treatment steps and were observed mostly in patients with disease progression. Median survival times for patients treated with ARCO, ARN, and ARCON were 10.1, 9.7, and 11.1 months, respectively. CONCLUSION Feasibility of ARCO treatment was good but that of ARN and ARCON was only fair. This probably reflected the higher acute toxicity rate, particularly gastrointestinal, for patients receiving nicotinamide. The dose of corticosteroids had to be increased frequently during treatment, suggesting a higher than expected acute neurologic toxicity. Overall survival was similar in the three treatment steps and not different when compared with results of other series that used radiotherapy alone.

Hypofractionation in glioblastoma multiforme.

PURPOSE To compare conventional fractionation with hypofractionation in patients with a glioblastoma multiforme. Endpoints of the analysis are overall survival and palliative effect. MATERIALS AND METHODS From 1988 to 1998, 155 patients with pathologically confirmed glioblastoma multiforme were prospectively analysed. Patients without irradiation and patients receiving an interstitial boost were excluded from this analysis. Three different radiation schemes were used in subsequent periods; 33x2, 8x5 and 4x7 Gy. In the last 5 years a scheme of 4x7 Gy conformal irradiation was given to poor prognosis patients. The more favourable group received the conventionally fractionated scheme up to 66 Gy. RESULTS Median survival was 7, 5.6 and 6.6 months for the 33x2, 8x5 and 4x7 Gy, respectively. In general, patients in the hypofractionation group had far worse prognostic factors compared with patients treated with the conventional scheme. The period of neurological improvement or stabilisation was similar between the 4x7 and 33x2 Gy group. CONCLUSION An extreme hypofractionation scheme of 4x7 Gy conformal irradiation in poor prognostic glioblastoma patients is well tolerated, convenient for the patient and provides equal palliation without negative effects on survival compared with conventional fractionation.

Prognostic Factors in Glioblastoma Multiforme 10 Years Experience of a Single Institution

Background: To analyze prognostic factors in patients with a glioblastoma multiforme treated in an academic institute over the last 10 years. Patients and Method: From 1988 to 1998, 198 patients with pathologically confirmed glioblastoma multiforme were analyzed. Five radiation schedules were used mainly based on pretreatment selection criteria: 1. 60 Gy in 30 fractions followed by an interstitial iridium-192 (Ir-192) boost for selected patients with a good performance and a small circumscribed tumor, 2. 66 Gy in 33 fractions for good performance patients, 3. 40 Gy in eight fractions or 4. 28 Gy in four fractions for poor prognostic patients and 5. no irradiation. Results: Median survival was 16 months, 7 months, 5.6 months, 6.6 months and 1.8 months for the groups treated with Ir-192, 66 Gy, 40 Gy, 28 Gy and the group without treatment, respectively. No significant improvement in survival was encountered over the last 10 years. At multivariate analysis patients treated with a hypofractional scheme showed a similar survival probability and duration of palliative effect compared to the conventionally fractionated group. The poor prognostic groups receiving radiotherapy had a highly significant better survival compared to the no-treatment group. Patients treated with an Ir-192 boost had a better median survival compared to a historical group matched on selection criteria but without boost treatment (16 vs 9.7 months, n. s.). However, survival at 2 years was similar. Analysis on pretreatment characteristics at multivariate analysis revealed age, neurological performance, addition of radiotherapy, total resection, tumor size post surgery and deterioration before start of radiotherapy (borderline) as significant prognostic factors for survival. Conclusion: Despite technical developments in surgery and radiotherapy over the last 10 years, survival of patients with a glioblastoma multiforme has not improved in our institution. The analysis of prognostic factors corresponded well with data from the literature. A short hypofractionated scheme seems to be a more appropriate treatment for patients with intermediate or poor prognosis as compared to a conventional scheme. The benefit in median survival for patients treated with an interstitial boost is partly explained by patient selection. Since there were no long-term survivors with this boost treatment, its clinical value, if there is one, is still limited.Hintergrund: Es wurden Prognosefaktoren bei Patienten mit Glioblastoma multiforme ermittelt, die über einen Zeitraum von 10 Jahren in einer Institution behandelt wurden. Patienten und Methoden: Die Analyse beruht auf 198 Patienten, die von 1988 bis 1998 nach histologischer Sicherung fünf verschiedenen Bestrahlungsschemata zugeführt wurden: 1. 60 Gy in 30 Fraktionen gefolgt von einem Ir-192-(LDR-)Boost bei selektierten Patienten mit gutem Performance-Status und kleinen Tumoren, 2. 66 Gy in 33 Fraktionen bei Patienten mit gutem Performance-Status, 3. 40 Gy in acht Fraktionen oder 4. 28 Gy in vier Fraktionen bei Patienten in schlechtem Allgemeinzustand, 5. keine Bestrahlung. Ergebnisse: Das mediane Überleben betrug 16 Monate für die Ir-192-Boost-Gruppe, 7 Monate nach 66 Gy, 5,6 Monate nach 40 Gy, 6,6 Monate nach 28 Gy und 1,8 Monate für unbehandelte Patienten. Über den Behandlungszeitraum von 10 Jahren waren keine signifikanten Verbesserungen der Überlebensraten zu verzeichnen. In der Multivarianzanalyse wiesen Patienten, die hypofraktioniert bestrahlt wurden, ähnliche Überlebenswahrscheinlichkeiten und Palliativeffekte auf wie Patienten nach konventioneller Bestrahlung. Die Strahlentherapie führte bei Patienten mit schlechtem Allgemeinzustand zu signifikanten Überlebenszeitverbesserungen im Vergleich zu Patienten ohne Behandlung. Verglichen mit einer historischen Kontrollgruppe ohne Ir-192-Boost-Bestrahlung hatten Patienten nach Ir-192-Boost-Bestrahlung nicht signifikante Verbesserungen der medianen Überlebensraten (16 Monate v. 9,7 Monate), wobei sich jedoch die 2-Jahres-Überlebensraten wieder angeglichen. In der Multivarianzanalyse waren Alter, neurologischer Status, Radiotherapie, totale Resektion, Resttumorgröße nach Resektion und Verschlecherung vor Anfang der Strahlentherapie (Grenzwert) für das Überleben signifikante Prognosefaktoren. Schlussfolgerungen: Trotz technischer Entwicklungen sowohl im Bereich der Neurochirurgie als auch der Radiotherapie verbesserten sich die Überlebensraten von Patienten mit Glioblastoma multiforme in den letzten 10 Jahren in unserer Institution nicht. Die Analyse der Prognosefaktoren korreliert gut mit Angaben aus der Literatur. Für Patienten mit intermediärer oder schlechter Prognose ist ein abgekürztes hypofraktioniertes Bestrahlungsregime eine angemessene Therapieoption. Die beobachtete Verbesserung der medianen Überlebensraten nach Ir-192-Boost ist zumindest teilweise durch eine Patientenselektion erklärbar. Da diese Behandlungsform zu keinem Langzeitüberleben führt, ist der klinische Stellenwert weiterhin unklar.

Concomitant boost radiotherapy for muscle invasive bladder cancer

PURPOSE To evaluate the feasibility and efficacy of a concomitant partial bladder boost schedule in radiotherapy for invasive bladder cancer, coupling a limited boost volume with shortening of the overall treatment time. METHODS AND MATERIALS Between 1994 and 1999, 50 patients with a T2-T4 N0M0 transitional cell carcinoma of the bladder received radiotherapy delivered in a short overall treatment time with a concomitant boost technique. With this technique a dose of 40 Gy in 2-Gy fractions was administered to the small pelvis with a concomitant boost limited to the bladder tumor area plus margin of 15 Gy in fractions of 0.75 Gy. The total tumor dose was 55 Gy in 20 fractions in 4 weeks. Toxicity was scored according to EORTC/RTOG toxicity criteria. RESULTS The feasibility of the treatment was good. Severe acute toxicity >/=G3 was observed in seven patients (14%). Severe late toxicity >/=G3 was observed in six patients (13%). Thirty-seven patients (74%) showed a complete and five (10 %) a partial remission after treatment. The actuarial 3-year freedom of local progression was 55%. CONCLUSION In external radiotherapy for muscle invasive bladder cancer a concomitant boost technique coupling a partial bladder boost with shortening of the overall treatment time provides a high probability of local control with acceptable toxicity.

Improving locoregional hyperthermia delivery using the 3-D controlled AMC-8 phased array hyperthermia system: A preclinical study

Background: The aim of this study is preclinical evaluation of our newly developed regional hyperthermia system providing 3-D SAR control: the AMC-8 phased array consisting of two rings, each with four 70 MHz waveguides. It was designed to achieve higher tumour temperatures and improve the clinical effectiveness of locoregional hyperthermia. Methods: The performance of the AMC-8 system was evaluated with simulations and measurements aiming at heating a centrally located target region in rectangular (30 × 30 × 110 cm) and elliptical (36 × 24 × 80 cm) homogeneous tissue equivalent phantoms. Three properties were evaluated and compared to its predecessor, the 2-D AMC-4 single ring four waveguide array: (1) spatial control and (2) size of the SAR focus, (3) the ratio between maximum SAR outside the target region and SAR in the focus. Distance and phase difference between the two rings were varied. Results: (1) Phase steering provides 3-D SAR control for the AMC-8 system. (2) The SAR focus is more elongated compared to the AMC-4 system, yielding a lower SAR level in the focus when using the same total power. This is counter-balanced by (3) a superficial SAR deposition which is half of that in the AMC-4 system, yielding a more favourable ratio between normal tissue and target SAR and allowing higher total power and up to 30% more SAR in the focus for 3 cm ring distance. Conclusion: The AMC-8 system is capable of 3-D SAR control and its SAR distribution is more favourable than for the 2-D AMC-4 system. This result promises improvement in clinical tumour temperatures.

Monitoring of response to pre-operative chemoradiation in combination with hyperthermia in oesophageal cancer by FDG-PET

Purpose: To evaluate the use of positron emission tomography using 18F-fluorodeoxyglucose (FDG-PET) to assess early response to pre-operative chemoradiation therapy in combination with external locoregional hyperthermia in patients with oesophageal cancer by correlating the reduction of metabolic activity with histopathologic response. Material and methods: Twenty-six patients with histopathologically proven intra-thoracic oesophageal cancer (with ≤2 cm gastric involvement), scheduled to undergo a 5-week course of pre-operative chemoradiation therapy and hyperthermia, were included. FDG-PET was performed before (n = 26) and 2 weeks after initiation of therapy (n = 17). FDG uptake was quantitatively assessed by standardized uptake values. Results: After neoadjuvant therapy, 24 of the 26 patients underwent surgery. In 16 patients changes in FDG uptake were correlated to histopathologic response. In these patients, histopathologic evaluation revealed less than 10% viable tumour cells in eight patients (responders) and more than 10% viable tumour cells in eight patients (non-responders). In responders, FDG uptake decreased by a median −44% (−75 to 2); in non-responders, it decreased by a median of −15% (−46 to 40). At a threshold of 31% decrease of FDG uptake compared with baseline, sensitivity to detect response was 75%, with a corresponding specificity of 75%. The positive and negative predictive values were both 75%. Conclusion: FDG-PET is a promising tool for early response monitoring in patients undergoing chemoradiation therapy in combination with hyperthermia.