Rolf-Peter Mueller

Intensified hyperfractionated accelerated radiotherapy limits the additional benefit of simultaneous chemotherapy—results of a multicentric randomized German trial in advanced head-and-neck cancer

PURPOSE To demonstrate the efficacy of radiochemotherapy (RCT) as the first choice of treatment for advanced unresectable head-and-neck cancer. To prove an expected benefit of simultaneously given chemotherapy, a two-arm randomized study with hyperfractionated accelerated radiochemotherapy (HF-ACC-RCT) vs. hyperfractionated accelerated radiotherapy (HF-ACC-RT) was initiated. The primary endpoint was 1-year survival with local control (SLC). METHODS AND MATERIALS Patients with Stage III and IV (UICC) unresectable oro- and hypopharyngeal carcinomas were randomized for HF-ACC-RCT with 2 cycles of 5-FU (600 mg/m(2)/day)/carboplatinum (70 mg/m(2)) on days 1--5 and 29--33 (arm A) or HF-ACC-RT alone (arm B). In both arms, there was a second randomization for testing the effect of prophylactically given G-CSF (263 microg, days 15--19) on mucosal toxicity. Total RT dose in both arms was 69.9 Gy in 38 days, with a concomitant boost regimen (weeks 1--3: 1.8 Gy/day, weeks 4 and 5: b.i.d. RT with 1.8 Gy/1.5 Gy). Between July 1995 and May 1999, 263 patients were randomized (median age 56 years; 96% Stage IV tumors, 4% Stage III tumors). RESULTS This analysis is based on 240 patients: 113 patients with RCT and 127 patients with RT, qualified for protocol and starting treatment. There were 178 oropharyngeal and 62 hypopharyngeal carcinomas. Treatment was tolerable in both arms, with a higher mucosal toxicity after RCT. Restaging showed comparable nonsignificant different CR + PR rates of 92.4% after RCT and 87.9% after RT (p = 0.29). After a median observed time of 22.3 months, l- and 2-year local-regional control (LRC) rates were 69% and 51% after RCT and 58% and 45% after RT (p = 0.14). There was a significantly better 1-year SLC after RCT (58%) compared with RT (44%, p = 0.05). Patients with oropharyngeal carcinomas showed significantly better SLC after RCT (60%) vs. RT (40%, p = 0.01); the smaller group of hypopharyngeal carcinomas had no statistical benefit of RCT (p = 0.84). For both tumor locations, prophylactically given G-CSF was a poor prognostic factor (Cox regression), and resulted in reduced LRC (log-rank test: +/- G-CSF, p = 0.0072). CONCLUSION With accelerated radiotherapy, the efficiency of simultaneously given chemotherapy may be not as high as expected when compared to standard fractionated RT. Oropharyngeal carcinomas showed better LRC after HF-ACC-RCT vs. HF-ACC-RT; hypopharyngeal carcinomas did not. Prophylactic G-CSF resulted in an unexpected reduced local control and should be given in radiotherapy regimen only with strong hematologic indication.

Positron emission tomography has a high negative predictive value for progression or early relapse for patients with residual disease after first-line chemotherapy in advanced-stage Hodgkin lymphoma

In the HD15 trial of the German Hodgkin Study Group, the negative predictive value (NPV) of positron emission tomography (PET) using [(18)F]-fluorodeoxyglucose in advanced-stage Hodgkin lymphoma (HL) was evaluated. A total of 817 patients were enrolled and randomly assigned to receive BEACOPP-based chemotherapy. After completion of chemotherapy, residual disease measuring more than or equal to 2.5 cm in diameter was assessed by PET in 311 patients. The NPV of PET was defined as the proportion of PET(-) patients without progression, relapse, or irradiation within 12 months after PET review panel. The progression-free survival was 96% for PET(-) patients (95% confidence interval [CI], 94%-99%) and 86% for PET(+) patients (95% CI, 78%-95%, P = .011). The NPV for PET in this analysis was 94% (95% CI, 91%-97%). Thus, consolidation radiotherapy can be omitted in PET(-) patients with residual disease without increasing the risk for progression or early relapse compared with patients in complete remission. The impact of this finding on the overall survival at 5 years must be awaited. Until then, response adapted therapy guided by PET for HL patients seems to be a promising approach that should be further evaluated in clinical trials. This trial is registered at http://isrctn.org study as #ISRCTN32443041.

Randomized trial with early-stage Hodgkin's disease testing 30 Gy vs. 40 Gy extended field radiotherapy alone

PURPOSE To evaluate whether or not a total dose (TD) of 30 Gy is sufficient for treatment of assumed subclinical Hodgkins Disease compared to 40 Gy TD with early stage Hodgkins Disease (ESHD). METHODS AND MATERIALS In a prospective multicenter trial, 376 patients with laparotomy-proven ESHD stages PS IA to PS IIB without risk factors such as large mediastinum, massive splenic involvement, extranodal disease, elevated erythrocyte sedimentation rate (ESR), and/or three or more involved lymph node areas were randomly allocated either to receive (ARM A) 40 Gy TD extended field-radiotherapy (EF-RT) or (ARM B) 30 Gy TD EF-RT plus 10 Gy TD involved field-radiotherapy (IF-RT), both arms without any chemotherapy. Three hundred sixty-six of these patients were evaluable for early and long-term response, such as remission status, freedom from treatment failure (FFTF), and overall survival (OAS). For quality control, all planning and verification films as well as dose charts were prospectively reviewed by a panel of four experts, all heads of a radiotherapy department, where protocol violations (PV) were seen either with regard to errors in treatment technique, treatment volume, in TD and/or in dose/time-relationship. RESULTS Treatment resulted in a complete remission (CR) of 98%; in a 5-year FFTF of 76%, and a 5-year OAS of 97%. There was no difference between the two arms in favor of 40 Gy EF compared to 30 Gy EF regarding FFTF and OAS, without any in field relapse throughout the EF volumes. Expectedly, 5-years FFTF was significantly influenced by the quality of radiotherapeutical procedures: 70% with protocol violations (PV) vs. 82% without PV. CONCLUSION Subclinical involvement in ESHD without risk factors is sufficiently treated by a TD of 30 Gy without chemotherapy, leading to a 5-years FFTF of 82% and a 5-year OAS of 97% in a multicenter treatment setting, where quality assurance is mandatory.

Linear accelerator radiosurgery for recurrent malignant tumors of the skull base

The efficacy of linear accelerator-based radiosurgery for patients who have preirradiated recurrent nasopharyngeal carcinomas and unresectable recurrent sarcomas invading the base of skull was assessed. Thirteen patients were treated: 8 patients had carcinomas arising from the nasopharynx (lymphoepithelioma, 4; squamous cell carcinoma, 2; adenoid-cystic, 2); 5 patients had sarcomas (rhabdomyosarcoma, 1; chordoma, 1; chondrosarcoma, 1; hemangiopericytoma, 2). All patients had had repeated tumor resections or irradiation, hindering any further conventional fractionated radiotherapy or surgery. Convergent-beam irradiation was performed with a modified linear accelerator (8-MeV photons). Because of irregular tumor configuration, multiple (up to seven) isocenters had to be used in 10 of 13 patients to match the target volume with the reference isodose (60%-80%). Each isocenter was irradiated with 6 to 10 arcs. The median planning target volume was 33 mL (4-128 mL) and the median dose was 15 Gy (9-24 Gy). Median survival time was 9 months in 8 patients who had recurrent nasopharyngeal carcinomas. Three patients who had complete or partial tumor remission survived 1.5 to 3.5 years. All of the sarcoma patients responded to radiosurgery. After a follow-up of 28 to 67 months, 4 of 5 patients are alive. This investigation demonstrates that radiosurgery is an effective tool in palliative treatment for patients who have recurrent, extensively pretreated nasopharyngeal cancer. Patients who have recurrent sarcomas of the base of skull may be treated for long-term palliation or even for cure.

Radiotherapy for Early Mediastinal Hodgkin Lymphoma According to the German Hodgkin Study Group (GHSG): The Roles of Intensity-Modulated Radiotherapy and Involved-Node Radiotherapy

PURPOSE Cure rates of early Hodgkin lymphoma (HL) are high, and avoidance of late complications and second malignancies have become increasingly important. This comparative treatment planning study analyzes to what extent target volume reduction to involved-node (IN) and intensity-modulated (IM) radiotherapy (RT), compared with involved-field (IF) and three-dimensional (3D) RT, can reduce doses to organs at risk (OAR). METHODS AND MATERIALS Based on 20 computed tomography (CT) datasets of patients with early unfavorable mediastinal HL, we created treatment plans for 3D-RT and IMRT for both the IF and IN according to the guidelines of the German Hodgkin Study Group (GHSG). As OAR, we defined heart, lung, breasts, and spinal cord. Dose-volume histograms (DVHs) were evaluated for planning target volumes (PTVs) and OAR. RESULTS Average IF-PTV and IN-PTV were 1705 cm(3) and 1015 cm(3), respectively. Mean doses to the PTVs were almost identical for all plans. For IF-PTV/IN-PTV, conformity was better with IMRT and homogeneity was better with 3D-RT. Mean doses to the heart (17.94/9.19 Gy for 3D-RT and 13.76/7.42 Gy for IMRT) and spinal cord (23.93/13.78 Gy for 3D-RT and 19.16/11.55 Gy for IMRT) were reduced by IMRT, whereas mean doses to lung (10.62/8.57 Gy for 3D-RT and 12.77/9.64 Gy for IMRT) and breasts (left 4.37/3.42 Gy for 3D-RT and 6.04/4.59 Gy for IMRT, and right 2.30/1.63 Gy for 3D-RT and 5.37/3.53 Gy for IMRT) were increased. Volume exposed to high doses was smaller for IMRT, whereas volume exposed to low doses was smaller for 3D-RT. Pronounced benefits of IMRT were observed for patients with lymph nodes anterior to the heart. IN-RT achieved substantially better values than IF-RT for almost all OAR parameters, i.e., dose reduction of 20% to 50%, regardless of radiation technique. CONCLUSIONS Reduction of target volume to IN most effectively improves OAR sparing, but is still considered investigational. For the time being, IMRT should be considered for large PTVs especially when the anterior mediastinum is involved.

Patterns of lymph node spread and its influence on outcome in resectable parotid cancer

AIM To assess the metastatic topography of intraparotideal and neck lymph nodes in parotid cancer and its influence on tumour recurrence and survival. METHODS The lymph node spread of 142 patients with primary parotid carcinoma treated from 1986 to 2006 was analysed. Disease-free survival (DFS) and overall survival (OS) were calculated. The role of the metastatic pattern as prognostic factors were univariately and multivariately analysed. RESULTS A lateral, total or radical parotidectomy was performed in 19, 80 and 43 patients, respectively. A radical/radical-modified or selective neck dissection was performed in 68 and 74 patients, respectively. Eighty-seven neck dissection specimens were negative (pN0). Twelve patients had intraparotideal and cervical lymph node involvement (pPar+/pN+). In 24 patients only intraparotideal metastases were detected (pPar+/pN0). 19 patients only had cervical nodal involvement (pPar-/pN+). Twenty-five patients had occult locoregional lymph metastases (cN0/pN+). The median follow-up was 24.4 months. The disease-free survival rate was 81% at 5 years, and 62% at 10 years. By univariate analysis, R+ (p=0.001), pT (p=0.019), lymphangiosis carcinomatosa (p=0.019), pN+ (p=0.042), and extracapsular spread (p=0.046) were prognostic for disease-free survival. Multivariate analysis revealed R+ as independent risk factor (p=0.046). In pN+ patients, involvement of parotid lymph nodes (p=0.013), nodes in neck level I (p<0.0001) and IV (p=0.005) were univariate risk factors. Multivariate analysis showed lymph node metastases in level I as independent risk factor (p=0.022). CONCLUSION Total parotidectomy and radical-modified neck dissection is recommended as surgical treatment of parotid cancer and should be analysed in a prospective trial.

Diagnostic work-up and outcome of cervical metastases from an unknown primary.

Conclusions. An intensive diagnostic work-up including 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) detects many unknown primary tumours, leads to a low emergence rate of primary tumours, and selects carcinoma of unknown primary with much more favourable results after neck dissection and postoperative radiotherapy. Objective. To investigate the optimal diagnostic approach and best treatment modality for rare head and neck cancer of unknown primary. Patients and methods. In a retrospective study, 69 patients admitted from 1987 to 2002 with cervical lymph node metastases without apparent primary were reviewed. Test characteristics of all diagnostic procedures were calculated. Disease-free and overall survival rates were calculated. Major prognostic factors were analysed univariately. Results. At the primary site FDG-PET showed the best sensitivity with 69% and the highest negative predictive value with 87%. Computed tomography and magnetic resonance imaging had a better specificity with 87% and 95%, respectively. The primary tumour was detected in 23 cases (33%). Frequent primary tumour origin was the palatine tonsil (n=8, 35%), base of the tongue (n=6, 26%) and lung (n=4, 17%). All patients with unknown primary were treated by neck dissection. Adjuvant radiotherapy was performed in 26 patients (57%), concurrent radiochemotherapy was performed in 12 patients (26%). The primary emergence rate was 7%. The 5-year overall survival rate was inferior in patients with detected primary in comparison with patients with unknown primary (22% versus 52%). Significant prognostic factors in case of unknown primary were M stage, smoking, alcohol consumption and tonsillectomy. Radiotherapy but not chemotherapy with carboplatin influenced the overall survival.

Parotid Cancer : Impact of Changes From the 1997 to the 2002 American Joint Committee on Cancer Classification on Outcome Prediction

The TNM classification [American Joint Committee on Cancer (AJCC)] of salivary gland cancer was revised again in 2002. In the present study, the outcome prediction of the new TNM system was compared with the old 1997 TNM system in 202 patients with primary parotid cancer.

An Analysis of Surgical Complications, Morbidity, and Cost Calculation in Patients Undergoing Multimodal Treatment for Operable Oropharyngeal Carcinoma

Objective/Hypothesis: Tumor control and survival are considered the most important measures of treatment efficacy for patients with primary oropharyngeal squamous cell carcinoma. Furthermore, multimodal treatment protocols should be judged by their complication rates, morbidity, and therapy costs.

Novel radiotherapy techniques for involved-field and involved-node treatment of mediastinal Hodgkin lymphoma

PurposeHodgkin lymphoma (HL) is a highly curable disease. Reducing late complications and second malignancies has become increasingly important. Radiotherapy target paradigms are currently changing and radiotherapy techniques are evolving rapidly.DesignThis overview reports to what extent target volume reduction in involved-node (IN) and advanced radiotherapy techniques, such as intensity-modulated radiotherapy (IMRT) and proton therapy–compared with involved-field (IF) and 3D radiotherapy (3D-RT)– can reduce high doses to organs at risk (OAR) and examines the issues that still remain open.ResultsAlthough no comparison of all available techniques on identical patient datasets exists, clear patterns emerge. Advanced dose-calculation algorithms (e.g., convolution-superposition/Monte Carlo) should be used in mediastinal HL. INRT consistently reduces treated volumes when compared with IFRT with the exact amount depending on the INRT definition. The number of patients that might significantly benefit from highly conformal techniques such as IMRT over 3D-RT regarding high-dose exposure to organs at risk (OAR) is smaller with INRT. The impact of larger volumes treated with low doses in advanced techniques is unclear. The type of IMRT used (static/rotational) is of minor importance. All advanced photon techniques result in similar potential benefits and disadvantages, therefore only the degree-of-modulation should be chosen based on individual treatment goals. Treatment in deep inspiration breath hold is being evaluated. Protons theoretically provide both excellent high-dose conformality and reduced integral dose.ConclusionFurther reduction of treated volumes most effectively reduces OAR dose, most likely without disadvantages if the excellent control rates achieved currently are maintained. For both IFRT and INRT, the benefits of advanced radiotherapy techniques depend on the individual patient/target geometry. Their use should therefore be decided case by case with comparative treatment planning.ZusammenfassungHintergrund und ZielDas Hodgkin-Lymphom (HL) ist eine Erkrankung mit hohen Heilungsraten. Die Verringerung von Spätkomplikationen und Zweittumoren wird daher immer wichtiger. Zielvolumenkonzepte der Strahlentherapie (RT) verändern sich gegenwärtig und Strahlentherapietechniken entwickeln sich sehr schnell weiter.MethodenDiese Übersichtsarbeit stellt dar, inwiefern die Zielvolumenreduktion hin zum Involved-node(IN)-Konzept und hochentwickelte Strahlentherapietechniken wie die intensitätsmodulierte Strahlentherapie (IMRT) und Protonentherapie, im Vergleich zu Involved-field(IF)-Konzept und 3-D-konformaler Strahlentherapie (3D-RT), die Belastung von Risikoorganen (OAR) mit hohen Dosen reduzieren können und welche Fragen in diesem Kontext noch geklärt werden müssen.ErgebnisseObwohl kein Vergleich aller verfügbaren Techniken auf identischen Patientendatensätzen existiert, entsteht folgendes Bild: Fortgeschrittene Dosisberechnungsalgorithmen (z. B. convolution-superposition/Monte Carlo) sollten im Rahmen der Behandlung des mediastinalen HL zur Anwendung kommen. INRT reduziert unter allen Bedingungen die behandelten Volumina im Vergleich zur IFRT, wobei die Höhe des Vorteils von der jeweiligen INRT-Definition abhängt. Die Anzahl der Patienten, die deutlich von hochkonformalen Techniken wie IMRT gegenüber der 3D-RT hinsichtlich der OAR-Belastung profitiert, ist bei INRT geringer. Die Konsequenz größerer Volumina, die bei modernen Techniken mit eher isotroper Strahlanordnung mit niedrigen Dosen belastet werden, ist unklar. Die Art der verwendeten IMRT-Technik (statisch/Rotation) ist von geringer Relevanz. Alle fortgeschrittenen Photonentechniken resultieren in den gleichen Vorteilen und Nachteilen. Daher muss nur die Modulationstiefe abhängig von den individuellen Behandlungszielen gewählt werden. Die Bestrahlung in tiefer Inspiration wird gegenwärtig evaluiert. Protonentherapie kann theoretisch bei hervorragender Hochdosiskonformalität die applizierte Integraldosis reduzieren.SchlussfolgerungDie weitere Verkleinerung der behandelten Volumina reduziert die Risikoorganbelastung am effektivsten und ohne Nachteile, wenn die gegenwärtig exzellenten Kontrollraten weiterhin erreicht werden können. Sowohl für IFRT als auch INRT hängen Vor- und Nachteile der modernen Strahlentherapietechniken von der individuellen Patientengeometrie ab. Die Entscheidung für die jeweils anzuwendende Technik sollte daher Fall für Fall auf Basis einer vergleichenden Bestrahlungsplanung getroffen werden.