Marc W. Münter

Stereotactic single-dose radiotherapy of stage I non–small-cell lung cancer (NSCLC)

PURPOSE The treatment of early-stage lung cancers is a primary domain of thoracic surgery, leading to persuasive results. In patients with medical contraindications, radiotherapy is an alternative, although with considerably worse outcome. Radiotherapy is associated with the risk of severe acute side effects and a permanent decrease of lung function. By the introduction of an extracranial stereotactic treatment technique, the amount of normal tissue in the high-dose region can be reduced, allowing the performance of single-dose treatment with high, biologically effective doses. METHODS AND MATERIALS Between October 1998 and May 2001, 10 patients with histologically confirmed Stage I non-small-cell lung cancer were treated with stereotactic single-dose radiotherapy. A self-developed stereotactic frame was used for patient positioning and navigation. Total doses applied ranged from 19 to 26 Gy. After treatment, regular CT-based follow-up was performed. RESULTS During a median follow-up period of 14.9 months, the tumors in 8 of 10 patients were locally controlled. The actuarial overall survival was 80% and 64%, respectively, 12 and 24 months after therapy. Actuarial local recurrence-free survival reached 88.9% and 71.1%, respectively. Therapy-related perifocal normal-tissue reaction occurred in 70% of all treated patients, although no major clinical symptoms were seen. In 5 patients, systemic metastases were found during follow-up; 1 patient developed suspect mediastinal lymph nodes. CONCLUSION Stereotactic single-fraction radiotherapy is a feasible, safe, and effective procedure for the treatment of Stage I non-small-cell lung cancer. It promises high local control with a reduced overall treatment time. However, further investigation in a larger patient collective with extended follow-up is necessary.

Evaluation of salivary gland function after treatment of head-and-neck tumors with intensity-modulated radiotherapy by quantitative pertechnetate scintigraphy

PURPOSE To evaluate salivary gland function after inversely planned stereotactic intensity-modulated radiotherapy (IMRT) for tumors of the head-and-neck region using quantitative pertechnetate scintigraphy. METHODS AND MATERIALS Since January 2000, 18 patients undergoing IMRT for cancer of the head and neck underwent pre- and posttherapeutic scintigraphy to examine salivary gland function. The mean dose to the primary planning target volume was 61.5 Gy (range 50.4-73.2), and the median follow-up was 23 months. In all cases, the parotid glands were directly adjacent to the planning target volume. The treatment planning goal was for at least one parotid gland to receive a mean dose of <26 Gy. Two quantitative parameters (change in maximal uptake and change in the relative excretion rate before and after IMRT) characterizing the change in salivary gland function after radiotherapy were determined. These parameters were compared with respect to the dose thresholds of 26 and 30 Gy for the mean dose. In addition, dose-response curves were calculated. RESULTS Using IMRT, it was possible in 16 patients to reduce the dose for at least one parotid gland to < or =26 Gy. In 7 patients, protection of both parotid glands was possible. No recurrent disease adjacent to the protected parotid glands was observed. Using the Radiation Therapy Oncology Group/European Organization for the Research and Treatment of Cancer scoring system, only 3 patients had Grade 2 xerostomia. No greater toxicity was seen for the salivary glands. The change in the relative excretion rate was significantly greater, if the parotid glands received a mean dose of > or =26 Gy or > or =30 Gy. For the change in maximal uptake, a statistically significant difference was seen only for the parotid glands and a dose threshold of 30 Gy. For the end point of a reduction in the parotid excretion rate of >50% and 75%, the dose-response curves yielded a dose at 50% complication probability of 34.8 +/- 3.6 and 40.8 +/- 5.3 Gy, respectively. CONCLUSION Using IMRT, it is possible to protect the parotid glands and reduce the incidence and severity of xerostomia in patients. Doses <26-30 Gy significantly preserve salivary gland function. The results support the hypothesis that application of IMRT does not lead to increased local failure rates.

The use of the multislice CT for the determination of respiratory lung tumor movement in stereotactic single-dose irradiation.

Background: In three-dimensional (3-D) precision high-dose radiation therapy of lung tumors, the exact definition of the planning target volume (PTV) is indispensable. Therefore, the feasibility of a 3-D determination of respiratory lung tumor movements by the use of a multislice CT scanner was investigated. Patients and Methods: The respiratory motion of 21 lung tumors in 20 consecutively treated patients was examined. An abdominal pressure device for the reduction of respiratory movement was used in 14 patients. Two regions of the tumor were each scanned repeatedly at the same table position, showing four simultaneously acquired slices for each cycle. Stereotactic coordinates were determined for one anatomic reference point in each tumor region (Figure 1). The 3-D differences of these coordinates between the sequentially obtained cycles were assessed (Figure 2), and a correlation with the tumor localization was performed. Results: In the craniocaudal (Z-)direction the mean tumor movement was 5.1 mm (standard deviation [SD] 2.4 mm, maximum 10 mm), in the ventrodorsal (Y-)direction 3.1 mm (SD 1.5 mm, maximum 6.7 mm), and in the lateral (X-)direction 2.6 mm (SD 1.4 mm, maximum 5.8 mm; Figures 3 to 5). Inter- and intraindividual differences were present in each direction. With an abdominal pressure device no clinically significant difference between tumors in different locations was seen. Conclusion: The 3-D assessment of lung tumor movements due to breathing is possible by the use of multislice CT. The determination, indispensable to the PTV definition, should be performed individually for several regions, because of the inter- and intraindividual deviations detected.Hintergrund: Die dreidimensionale Hochdosispräzisionsbestrahlung von Lungentumoren erfordert eine exakte Definition des Planungszielvolumens (PTV). Daher wurde die Möglichkeit des Einsatzes eines Mehrzeilen-CT-Geräts zur dreidimensionalen Bestimmung der Tumorbewegung in der Lunge untersucht. Patienten und Methodik: In 20 konsekutiv behandelten Patienten wurde die atembedingte Bewegung von 21 Tumoren untersucht. Eine Abdominalkompression zur Minimierung der Atembewegung kam bei 14 Patienten zum Einsatz. Zwei unterschiedliche Tumorregionen wurden jeweils wiederholt ohne Tischvorschub in einer Auflösung von vier simultan akquirierten Schichten über eine Distanz von 1 cm gescannt (sechs Wiederholungen, Scanzeit 0,75 s, Abstand 3 s, Schichtdicke 2,5 mm). Ein anatomischer Referenzpunkt in beiden Tumorregionen wurde festgelegt, und stereotaktische Koordinaten dieses Punkts wurden in jeder Wiederholung bestimmt (Abbildung 1). Die maximale Differenz dieser Koordinaten wurde in allen drei Raumrichtungen berechnet (Abbildung 2) und mit der Tumorlokalisation korreliert. Ergebnisse: Die mittlere Bewegung betrug in kraniokaudaler Richtung 5,1 mm (Standardabweichung [SD] 2,4 mm, Maximum 10 mm), in ventrodorsaler 3,5 mm (SD 1,5 mm, Maximum 6,7 mm) und in mediolateraler Richtung 2,6 mm (SD 1,4 mm, Maximum 5,8 mm; Abbildungen 3 bis 5). In jeder Raumrichtung gab es inter- und intraindividuelle Unterschiede. Unter Verwendung der Abdominalkompression war kein signifikanter Einfluss der Tumorlokalisation auf die Atembeweglichkeit nachzuweisen. Schlussfolgerung: Der Einsatz der Mehrzeilen-CT für die dreidimensionale Bestimmung von atembedingten Lungentumorbewegungen ist möglich. Die zur Definition des PTV notwendige Bestimmung sollte aufgrund der nachgewiesenen inter- und intraindividuellen Unterschiede individuell in mehreren Tumorregionen erfolgen.

Surgery for locally recurrent rectal cancer in the era of total mesorectal excision: is there still a chance for cure?

Objective:To evaluate the perioperative outcome and long-term survival of patients who underwent surgical resection for recurrent rectal cancer within a multimodal approach in the era of total mesorectal excision (TME). Background:Introduction of TME has reduced local recurrence and improved oncological outcome of patients with rectal cancer. Local recurrence after TME still occurs in 2% to 8% of patients and presents a challenge to surgical and medical oncologists. However, there has been very limited data on the perioperative and long-term outcome of patients who are operated for local recurrence in the era of TME. Methods:A total of 107 patients who were identified from a prospective rectal cancer database underwent surgical exploration for recurrent rectal cancer after previous TME between October 2001 and April 2009. Risk factors of perioperative morbidity were analyzed using a multivariate logistic regression model. Independent predictors of disease-specific survival were identified by a Cox proportional hazards regression model, as were those of local recurrence and disease recurrence at any site. Results:Surgical resection was performed in 92 patients and negative resection margins were achieved in 54 (58.7%) of these. Recurrent disease was located intraluminally and extraluminally in 35 (38.0%) patients and 57 (62.0%) patients, respectively. A total of 19 (20.6%) patients had metastatic extrapelvic disease at the time of surgery. Perioperative surgical morbidity and in-hospital mortality accounted for 42.4% and 3.3%, respectively. On multivariate analysis, partial sacrectomy was associated with surgical morbidity (P = 0.004). Three- and 5-year disease-specific survival rates were 61% and 47%. Three-year survival rate of patients with extrapelvic disease who underwent R0 resection was 42%. On multivariate analysis, surgical morbidity (P = 0.001), presence of extrapelvic disease (P = 0.006), and noncurative (R1; R2) resection (P < 0.0001) were identified as independent adverse predictors of disease-specific survival, whereas a transabdominal resection (as opposed to an abdominoperineal resection/pelvic exenteration) was associated with a more favorable prognosis (P = 0.04). Conclusions:Surgical resection of local recurrence from rectal cancer in the era TME can be carried out with acceptable morbidity and curative resection rates. Curative resection remains the major prognostic factor and may enable long-term survival even in patients with extrapelvic disease.

Evaluating target coverage and normal tissue sparing in the adjuvant radiotherapy of malignant pleural mesothelioma: Helical tomotherapy compared with step-and-shoot IMRT

PURPOSE To evaluate the potential of helical tomotherapy in the adjuvant treatment of malignant pleural mesothelioma and compare target homogeneity, conformity and normal tissue dose with step-and-shoot intensity-modulated radiotherapy. METHODS AND MATERIALS Ten patients with malignant pleural mesothelioma who had undergone neoadjuvant chemotherapy with cisplatin and permetrexed followed by extrapleural pneumonectomy (EPP) were treated in our department with 54 Gy to the hemithorax delivered by step-and-shoot IMRT. A planning comparison was performed by creating radiation plans for helical tomotherapy. The different plans were compared by analysing target homogeneity using the homogeneity indices HI(max) and HI(min) and target conformity by using the conformity index CI(95). To assess target coverage and normal tissue sparing TV(90), TV(95) and mean and maximum doses were compared. RESULTS Both modalities achieved excellent dose distributions while sparing organs at risk. Target coverage and homogeneity could be increased significantly with helical tomotherapy compared with step-and-shoot IMRT. Mean dose to the contralateral lung could be lowered beyond 5 Gy. CONCLUSIONS Our planning study showed that helical tomotherapy is an excellent option for the adjuvant intensity-modulated radiotherapy of MPM. It is capable of improving target coverage and homogeneity.

Intensity-modulated radiotherapy of nasopharyngeal carcinoma: a comparative treatment planning study of photons and protons

BackgroundThe aim of this treatment planning study was to investigate the potential advantages of intensity-modulated (IM) proton therapy (IMPT) compared with IM photon therapy (IMRT) in nasopharyngeal carcinoma (NPC).MethodsEight NPC patients were chosen. The dose prescriptions in cobalt Gray equivalent (GyE) for gross tumor volumes of the primary tumor (GTV-T), planning target volumes of GTV-T and metastatic (PTV-TN) and elective (PTV-N) lymph node stations were 72.6 GyE, 66 GyE, and 52.8 GyE, respectively. For each patient, nine coplanar fields IMRT with step-and-shoot technique and 3D spot-scanned three coplanar fields IMPT plans were prepared. Both modalities were planned in 33 fractions to be delivered with a simultaneous integrated boost technique. All plans were prepared and optimized by using the research version of the inverse treatment planning system KonRad (DKFZ, Heidelberg).ResultsBoth treatment techniques were equal in terms of averaged mean dose to target volumes. IMPT plans significantly improved the tumor coverage and conformation (P < 0.05) and they reduced the averaged mean dose to several organs at risk (OARs) by a factor of 2–3. The low-to-medium dose volumes (0.33–13.2 GyE) were more than doubled by IMRT plans.ConclusionIn radiotherapy of NPC patients, three-field IMPT has greater potential than nine-field IMRT with respect to tumor coverage and reduction of the integral dose to OARs and non-specific normal tissues. The practicality of IMPT in NPC deserves further exploration when this technique becomes available on wider clinical scale.

Combined treatment of nonsmall cell lung cancer NSCLC stage III with intensity‐modulated RT radiotherapy and cetuximab

The aim of this study was to evaluate efficacy and toxicity of radioimmunotherapy with intensity‐modulated radiation (IMRT) and cetuximab in stage III nonsmall cell lung cancer (NSCLC).

Radiobiological investigation of dose-rate effects in intensity-modulated radiation therapy.

Background and Purpose:Intensity-modulated radiation therapy (IMRT) has proven extraordinary capability in physical terms such as target conformity, dose escalation in the target volume, and sparing of neighboring organs at risk. The radiobiological consequences of the protracted dose delivery for cell survival and cell cycle progression are still unclear and shall be examined in this study.Material and Methods:Human lymphoblasts (TK6) and human melanoma cells (MeWo) were irradiated with protocols of increasing dose protraction. In addition, a new biophysical phantom was developed and used to transfer clinical IMRT plans to experimental cell irradiation. Clonogenic cell survival and cell cycle analysis were performed after various irradiation experiments.Results:In a first series of experiments, melanoma cells showed a highly significant increase of survival of 6.0% after protracted dose delivery of 2 Gy compared to conventional fast application with the same dose. Lymphoblastoid cells also showed a significant increase of survival of 2.2%. Experiments with patient plans in the phantom confirmed the trend of increased cell survival after protracted dose delivery. Cells were irradiated at 13 points in four different IMRT plans. In comparison to irradiation with application of the same dose in a classic four-field box, a significantly increased survival of 5.1% (mean value) was determined.Conclusion:Even at fraction times of 15–30 min the protracted dose delivery increases the survival rates in cell culture. The altered survival rates indicate the importance of the dose rate in the effectivity of IMRT. Besides physical parameters the consideration of biological factors might contribute to the optimization of IMRT in the future.Hintergrund und Ziel:Die intensitätsmodulierte Strahlentherapie (IMRT) ist ein modernes Radiotherapieverfahren, welches unter physikalischen Gesichtspunkten wie der Zielkonformität, Dosiseskalation und Schonung von Risikostrukturen hervorragende Ergebnisse erzielen kann. Doch die strahlenbiologischen Konsequenzen für Zellüberleben und Zellzyklusprogression, die sich aus der protrahierten Dosisapplikation ergeben könnten, sind noch unklar und sollen in dieser Arbeit untersucht werden.Material und Methodik:Humane Lymphoblasten (TK6) und humane Melanomzellen (MeWo) wurden mit Protokollen ansteigender Dosisprotrahierung bestrahlt. Zudem wurde ein neuartiges biophysikalisches Phantom entwickelt, welches die Übertragung klinischer IMRT-Pläne in ein vielseitiges experimentelles Setup ermöglicht. Klonogenes Zellüberleben sowie Zellzyklusprogression nach verschiedenen Bestrahlungsexperimenten wurden untersucht.Ergebnisse:In einer ersten Versuchsreihe zeigten die Melanomzellen ein signifikant um 6,0% erhöhtes Zellüberleben, wenn 2 Gy stark protrahiert appliziert wurden, verglichen mit schneller herkömmlicher Bestrahlung. Auch die Lymphoblasten zeigten ein um 2,2% signifikant erhöhtes Überleben. Die Experimente im Phantom mit Patientenplänen bestätigten den Trend des erhöhten Überlebens nach Dosisprotrahierung. Die Zellen wurden an 13 verschiedenen Punkten in vier IMRT-Plänen bestrahlt. Im Vergleich zur Bestrahlung mit der gleichen Dosis in einer konventionellen Vierfelderbox war das Überleben nach IMRT durchschnittlich um 5,1% erhöht.Schlussfolgerung:Selbst bei Fraktionszeiten von 15–30 min führt die protrahierte Dosisapplikation zu einem erhöhten Zellüberleben in Zellkultur. Die veränderten Überlebensraten zeigen die Bedeutung der Dosisrate für die Effektivität der IMRT. Neben physikalischen Parametern der Planbeurteilung müssen auch biologische Parameter zur weiteren Optimierung der IMRT herangezogen werden.

Influence of intra-fractional breathing movement in step-and-shoot IMRT

Efforts have been made to extend the application of intensity-modulated radiotherapy to a variety of organs. One of the unanswered questions is whether breathing-induced organ motion may lead to a relevant over- or underdosage, e.g., in treatment plans for the irradiation of lung cancer. Theoretical considerations have been made concerning the different kinds of IMRT but there is still a lack of experimental data. We examined 18 points in a fraction of a clinical treatment plan of a NSCLC delivered in static IMRT with a new phantom and nine ionization chambers. Measurements were performed at a speed of 12 and 16 breathing cycles per minute. The dose differences between static points and moving target points ranged between -2.4% and +5.5% (mean: +0.2%, median: -0.1%) when moving with 12 cycles min(-1) and between -3.6% and +5.0% (mean: -0.4%, median: -0.6%) when moving with 16 cycles min(-1). All differences of measurements with and without movements were below 5%, with one exception. In conclusion, our results underline that at least in static IMRT breathing effects (concerning target dose coverage) due to interplay effects between collimator leaf movement and target movement are of secondary importance and will not reduce the clinical value of IMRT in the step-and-shoot technique for irradiation of thoracic targets.

Carbon ion radiation therapy for high-risk meningiomas

BACKGROUND We analyzed outcome after a carbon ion boost in combination with precision photon radiation therapy in patients with meningiomas. PATIENTS AND METHODS Ten patients with meningiomas were treated with carbon ion RT as part of a Phase I/II trial. Carbon ion RT was conducted in conjunction with fractionated stereotactic RT (FSRT) or intensity-modulated RT (IMRT). Eight patients were treated as primary RT, in 2 patients carbon ion RT was performed as re-irradiation. Carbon ion RT was applied with a median dose of 18 GyE, and photon RT was applied with a median dose of 50.4 Gy. Two patients with a history of former irradiation received 18GyE of carbon ion RT and a reduced dose of photon treatment. RESULTS The median follow-up time was 77 months. Five patients died during follow-up, of which four died of tumor progression. In the group treated in the primary situation, actuarial survival rates after RT were 75% and 63% at 5 and 7 years. After re-irradiation, both patients died at 10 and 67 months, respectively. Actuarial local control rates after primary RT were 86% and 72% at 5 and 7 years. Two patients developed tumor recurrence after re-irradiation, 6 and 67 months after treatment. CONCLUSION In conclusion, carbon ion radiation shows promising results in patients with atypical or anaplastic meningiomas. Further evaluation in a larger, prospective study in comparison to proton RT or modern photon RT is needed to corroborate these results.