Piet van den Ende

Accelerated Radiotherapy With Carbogen and Nicotinamide for Laryngeal Cancer: Results of a Phase III Randomized Trial

PURPOSE To report the results from a randomized trial comparing accelerated radiotherapy (AR) with accelerated radiotherapy plus carbogen inhalation and nicotinamide (ARCON) in laryngeal cancer. PATIENTS AND METHODS Patients with cT2-4 squamous cell laryngeal cancer were randomly assigned to AR (68 Gy within 36 to 38 days) or ARCON. To limit the risk of laryngeal necrosis, ARCON patients received 64 Gy on the laryngeal cartilage. The primary end point was local control. Secondary end points were regional control, larynx preservation, toxicity, disease-free survival, and overall survival. In a translational side study, the hypoxia marker pimonidazole was used to assess the oxygenation status in tumor biopsies. RESULTS From April 2001 to February 2008, 345 patients were accrued. After a median follow-up of 44 months, local tumor control rate at 5 years was 78% for AR versus 79% for ARCON (P = .80), with larynx preservation rates of 84% and 87%, respectively (P = .48). The 5-year regional control was significantly better with ARCON (93%) compared with AR (86%, P = .04). The improvement in regional control was specifically observed in patients with hypoxic tumors and not in patients with well-oxygenated tumors (100% v 55%, respectively; P = .01). AR and ARCON produced equal levels of toxicity. CONCLUSION Despite lack of benefit in local tumor control for advanced laryngeal cancers, a significant gain in regional control rate, with equal levels of toxicity, was observed in favor of ARCON. The poor regional control of patients with hypoxic tumors is specifically countered by ARCON treatment.

The Use of FDG-PET to Target Tumors by Radiotherapy

Fluorodeoxyglucose positron emission tomography (FDG-PET) plays an increasingly important role in radiotherapy, beyond staging and selection of patients. Especially for non-small cell lung cancer, FDG-PET has, in the majority of the patients, led to the safe decrease of radiotherapy volumes, enabling radiation dose escalation and, experimentally, redistribution of radiation doses within the tumor. In limited-disease small cell lung cancer, the role of FDG-PET is emerging. For primary brain tumors, PET based on amino acid tracers is currently the best choice, including high-grade glioma. This is especially true for low-grade gliomas, where most data are available for the use of 11C-MET (methionine) in radiation treatment planning. For esophageal cancer, the main advantage of FDG-PET is the detection of otherwise unrecognized lymph node metastases. In Hodgkin’s disease, FDG-PET is essential for involved-node irradiation and leads to decreased irradiation volumes while also decreasing geographic miss. FDG-PET’s major role in the treatment of cervical cancer with radiation lies in the detection of para-aortic nodes that can be encompassed in radiation fields. Besides for staging purposes, FDG-PET is not recommended for routine radiotherapy delineation purposes. It should be emphasized that using PET is only safe when adhering to strictly standardized protocols.ZusammenfassungDie Fluordesoxyglucose-Positronenemissionstomographie (FDG-PET) spielt eine zunehmende Bedeutung in der Strahlentherapie, neben der bereits etablierten Bedeutung für Tumorstaging und Patientenselektion. Insbesondere bei nichtkleinzelligen Lungenkarzinomen führt der Einsatz der FDG-PET in der Mehrzahl der Fälle zu einer unbedenklichen Abnahme des Strahlenvolumens, wodurch Dosiseskalationen und auf experimenteller Ebene selbst Dosisumverteilungen der Strahlendosis im Zielvolumen möglich werden. Bei kleinzelligen Lungenkarzinomen nimmt die Bedeutung der FDG-PET ebenfalls zu. Bei primären Hirntumoren stellt die Aminosäure-PET derzeit die beste Wahl dar, auch bei den hochgradigen Gliomen. Für die niedriggradigen Gliome favorisieren die meisten Daten den Einsatz von 11C-MET (Methionin) in der Strahlentherapieplanung. Beim Ösophaguskarzinom liegt der wesentliche Vorteil der FDG-PET in der Detektion von unerkannten Lymphknotenmetastasen. Beim Morbus Hodgkin ist die FDG-PET essentiell für die „involved-field“-Bestrahlung und führt zu einem reduzierten Strahlenvolumen bei gleichzeitig vermindertem Risko der geographischen Fehlbehandlung. Die bedeutendste Rolle der FDG-PET bei der Behandlung des Zervixkarzinoms liegt in der Detektion von paraaortalen Lymphknoten, die in das Bestrahlungsgebiet mit aufgenommen werden. Zusammenfassend wird die FDG-PET neben dem Einsatz beim primären Tumorstaging derzeit nicht für den Routineeinsatz bei der Einzeichnung des Zielvolumens in der Strahlentherapie empfohlen. Der Einsatz der FDG-PET sollte nur nach streng standardisierten Protokollen erfolgen.

Systematic review and meta-analysis of radiotherapy in various head and neck cancers: Comparing photons, carbon-ions and protons

PURPOSE To synthesize and compare available evidence considering the effectiveness of carbon-ion, proton and photon radiotherapy for head and neck cancer. METHODS A systematic review and meta-analyses were performed to retrieve evidence on tumor control, survival and late treatment toxicity for carbon-ion, proton and the best available photon radiotherapy. RESULTS In total 86 observational studies (74 photon, 5 carbon-ion and 7 proton) and eight comparative in-silico studies were included. For mucosal malignant melanomas, 5-year survival was significantly higher after carbon-ion therapy compared to conventional photon therapy (44% versus 25%; P-value 0.007). Also, 5-year local control after proton therapy was significantly higher for paranasal and sinonasal cancer compared to intensity modulated photon therapy (88% versus 66%; P-value 0.035). No other statistically significant differences were observed. Although poorly reported, toxicity tended to be less frequent in carbon-ion and proton studies compared to photons. In-silico studies showed a lower dose to the organs at risk, independently of the tumor site. CONCLUSIONS For carbon-ion therapy, the increased survival in mucosal malignant melanomas might suggest an advantage in treating relatively radio-resistant tumors. Except for paranasal and sinonasal cancer, survival and tumor control for proton therapy were generally similar to the best available photon radiotherapy. In agreement with included in-silico studies, limited available clinical data indicates that toxicity tends to be lower for proton compared to photon radiotherapy. Since the overall quantity and quality of data regarding carbon-ion and proton therapy is poor, we recommend the construction of an international particle therapy register to facilitate definitive comparisons.

Predictive Value of Lymph Node Metastases and Extracapsular Extension for the Risk of Distant Metastases in Laryngeal Carcinoma

Objective: The objective of this retrospective chart analysis was to determine the prognostic value of the lymph node status and extracapsular lymph node extension (ECE) of the neck for the development of distant metastases in squamous cell carcinoma of the larynx.

IPSILATERAL IRRADIATION FOR ORAL AND OROPHARYNGEAL CARCINOMA TREATED WITH PRIMARY SURGERY AND POSTOPERATIVE RADIOTHERAPY

PURPOSE The purpose was to evaluate the contralateral nodal control (CLNC) in postoperative patients with oral and oropharyngeal cancer treated with ipsilateral irradiation of the neck and primary site. Late radiation-induced morbidity was also evaluated. METHODS AND MATERIALS The study included 123 patients with well-lateralized squamous cell carcinomas treated with surgery and unilateral postoperative irradiation. Most patients had tumors of the gingiva (41%) or buccal mucosa (21%). The majority of patients underwent surgery of the ipsilateral neck (n = 102 [83%]). The N classification was N0 in 73 cases (59%), N1 or N2a in 23 (19%), and N2b in 27 cases (22%). RESULTS Contralateral metastases developed in 7 patients (6%). The 5-year actuarial CLNC was 92%. The number of lymph node metastases was the only significant prognostic factor with regard to CLNC. The 5-year CLNC was 99% in N0 cases, 88% in N1 or N2a cases, and 73% in N2b cases (p = 0.008). Borderline significance (p = 0.06) was found for extranodal spread. Successful salvage could be performed in 71% of patients with contralateral metastases. The prevalence of Grade 2 or higher xerostomia was 2.6% at 5 years. CONCLUSIONS Selected patients with oral or oropharyngeal carcinoma treated with primary surgery and postoperative ipsilateral radiotherapy have a very high CLNC with a high probability of successful salvage in case of contralateral metastases. However, bilateral irradiation should be applied in case of multiple lymph node metastases in the ipsilateral neck, particularly in the presence of extranodal spread. The incidence of radiation-induced morbidity is considerably lower as observed after bilateral irradiation.

Customized computed tomography-based boost volumes in breast-conserving therapy: use of three-dimensional histologic information for clinical target volume margins

PURPOSE To determine the difference in size between computed tomography (CT)-based irradiated boost volumes and simulator-based irradiated volumes in patients treated with breast-conserving therapy and to analyze whether the use of anisotropic three-dimensional clinical target volume (CTV) margins using the histologically determined free resection margins allows for a significant reduction of the CT-based boost volumes. PATIENTS AND METHODS The CT data from 49 patients were used to delineate a planning target volume (PTV) with isotropic CTV margins and to delineate a PTV(sim) that mimicked the PTV as delineated in the era of conventional simulation. For 17 patients, a PTV with anisotropic CTV margins was defined by applying customized three-dimensional CTV margins, according to the free excision margins in six directions. Boost treatment plans consisted of conformal portals for the CT-based PTVs and rectangular fields for the PTV(sim). RESULTS The irradiated volume (volume receiving > or =95% of the prescribed dose [V(95)]) for the PTV with isotropic CTV margins was 1.6 times greater than that for the PTV(sim): 228 cm(3) vs. 147 cm(3) (p < .001). For the 17 patients with a PTV with anisotropic CTV margins, the V(95) was similar to the V(95) for the PTV(sim) (190 cm(3) vs. 162 cm(3); p = NS). The main determinant for the irradiated volume was the size of the excision cavity (p < .001), which was mainly related to the interval between surgery and the planning CT scan (p = .029). CONCLUSION CT-based PTVs with isotropic margins for the CTV yield much greater irradiated volumes than fluoroscopically based PTVs. Applying individualized anisotropic CTV margins allowed for a significant reduction of the irradiated boost volume.

Improved Recurrence-Free Survival with ARCON for Anemic Patients with Laryngeal Cancer

Purpose: Anemia is associated with poor tumor control. It was previously observed that accelerated radiotherapy combined with carbogen breathing and nicotinamide (ARCON) can correct this adverse outcome in patients with head and neck cancer. The purpose of this study was to validate this observation based on data from a randomized trial. Experimental Design: Of 345 patients with cT2-4 laryngeal cancer, 174 were randomly assigned to accelerated radiotherapy and 171 to ARCON. Hemoglobin levels, measured before treatment, were defined as low when <7.5 mmol/L for women and <8.5 mmol/L for men. The hypoxia marker pimonidazole was used to assess the oxygenation status in tumor biopsies. Data were analyzed 2 years after inclusion of the last patient. Results: Pretreatment hemoglobin levels were available and below normal in 27 of 173 (16%) accelerated radiotherapy and 27 of 167 (16%) ARCON patients. In patients with normal pretreatment, hemoglobin levels treatment with ARCON had no significant effect on 5-year loco-regional control (LRC, 79% versus 75%; P = 0.44) and disease-free survival (DFS, 75% vs. 70%; P = 0.46) compared with accelerated radiotherapy. However, in patients with low pretreatment, hemoglobin levels ARCON significantly improved 5-year LRC (79% vs. 53%; P = 0.03) and DFS (68% vs. 45%; P = 0.04). In multivariate analysis including other prognostic factors, pretreatment hemoglobin remained prognostic for LRC and DFS in the accelerated radiotherapy treatment arm. No correlation between pretreatment hemoglobin levels and pimonidazole uptake was observed. Conclusion: Results from the randomized phase III trial support previous observations that ARCON has the potential to correct the poor outcome of cancer patients with anemia (ClinicalTrials.gov number, NCT00147732). Clin Cancer Res; 20(5); 1345–54. ©2014 AACR.

Pattern of CAIX expression is prognostic for outcome and predicts response to ARCON in patients with laryngeal cancer treated in a phase III randomized trial

BACKGROUND AND PURPOSE In a phase III trial in patients with advanced stage laryngeal carcinoma comparing ARCON (accelerated radiotherapy with carbogen breathing and nicotinamide) to accelerated radiotherapy alone (AR) the prognostic and predictive value of CAIX, a hypoxia-associated protein, was investigated. MATERIAL AND METHODS 261 Paraffin embedded tumor biopsies and 79 fresh frozen biopsies from patients entered in the trial were immunohistochemically stained for CAIX. CAIX-fraction and CAIX expression pattern were related to tumor control and patient survival. RESULTS Low CAIX-fraction was prognostic for worse regional control and overall survival in patients treated with AR. Patients with a low CAIX-fraction treated with ARCON had better regional control and metastasis-free survival compared to AR (RC 97% vs 71%, p < 0.01 and MFS 92% vs 69%, p = 0.06). Patients with a perinecrotic CAIX staining pattern had a significantly worse local control, metastasis-free and overall survival compared to patients with a diffuse pattern (65% vs 84%, p = 0.01, 70% vs 96%, p < 0.01 and 42% vs 71%, p < 0.01 respectively), and this could not be improved with ARCON. After multivariate analysis CAIX pattern and N-stage emerged as significant predictors for metastasis-free survival and overall survival. CONCLUSIONS ARCON improves regional control and metastasis-free survival only in patients with low CAIX expression. The different patterns of CAIX expression suggest different mechanisms of upregulation and have important prognostic value.

ACUTE TOXICITY PROFILE AND COMPLIANCE TO ACCELERATED RADIOTHERAPY PLUS CARBOGEN AND NICOTINAMIDE FOR CLINICAL STAGE T2-4 LARYNGEAL CANCER: RESULTS OF A PHASE III RANDOMIZED TRIAL

PURPOSE To report the acute toxicity profile and compliance from a randomized Phase III trial comparing accelerated radiotherapy (AR) with accelerated radiotherapy plus carbogen and nicotinamide (ARCON) in laryngeal cancer. METHODS AND MATERIALS From April 2001 to February 2008, 345 patients with cT2-4 squamous cell laryngeal cancer were randomized to AR (n = 174) and ARCON (n = 171). Acute toxicity was scored weekly until Week 8 and every 2-4 weeks thereafter. Compliance to carbogen and nicotinamide was reported. RESULTS Between both treatment arms (AR vs. ARCON) no statistically significant difference was observed for incidence of acute skin reactions (moist desquamation: 56% vs. 58%, p = 0.80), acute mucosal reactions (confluent mucositis: 79% vs. 85%, p = 0.14), and symptoms related to acute mucositis (severe pain on swallowing: 53% vs. 58%, p = 0.37; nasogastric tube feeding: 28% vs. 28%, p = 0.98; narcotic medicines required: 58% vs. 58%, p = 0.97). There was a statistically significant difference in median duration of confluent mucositis in favor of AR (2.0 vs 3.0 weeks, p = 0.01). There was full compliance with carbogen breathing and nicotinamide in 86% and 80% of the patients, with discontinuation in 6% and 12%, respectively. Adjustment of antiemesis prophylaxis was needed in 42% of patients. CONCLUSION With the exception of a slight increase in median duration of acute confluent mucositis, the present data reveal a similar acute toxicity profile between both regimens and a good compliance with ARCON for clinical stage T2-4 laryngeal cancers. Treatment outcome and late morbidity will determine the real therapeutic benefit.

Forward Intensity-Modulated Radiotherapy Planning in Breast Cancer to Improve Dose Homogeneity: Feasibility of Class Solutions

PURPOSE To explore forward planning methods for breast cancer treatment to obtain homogeneous dose distributions (using International Commission on Radiation Units and Measurements criteria) within normal tissue constraints and to determine the feasibility of class solutions. METHODS AND MATERIALS Treatment plans were optimized in a stepwise procedure for 60 patients referred for postlumpectomy irradiation using strict dose constraints: planning target volume (PTV)(95%) of >99%; V(107%) of <1.8 cc; heart V(5 Gy) of <10% and V(10 Gy) of <5%; and mean lung dose of <7 Gy. Treatment planning started with classic tangential beams. Optimization was done by adding a maximum of four segments before adding beams, in a second step. A breath-hold technique was used for heart sparing if necessary. RESULTS Dose constraints were met for all 60 patients. The classic tangential beam setup was not sufficient for any of the patients; in one-third of patients, additional segments were required (<3), and in two-thirds of patients, additional beams (<2) were required. Logistic regression analyses revealed central breast diameter (CD) and central lung distance as independent predictors for transition from additional segments to additional beams, with a CD cut-off point at 23.6 cm. CONCLUSIONS Treatment plans fulfilling strict dose homogeneity criteria and normal tissue constraints could be obtained for all patients by stepwise dose intensity modification using limited numbers of segments and additional beams. In patients with a CD of >23.6 cm, additional beams were always required.