Local control and postponement of systemic therapy after modest dose radiotherapy in oligometastatic myxoid liposarcomas.

INTRODUCTION: Oligometastatic disease and/or oligoprogression in myxoid liposarcoma(oMLS) triggers discussions on local treatment options and delay of systemic treatments. We hypothesized that satisfactory local control and postponement of systemic therapy could be achieved with a modest radiotherapy(RT) dose in oMLS. METHODS: The DOREMY trial is a multicenter, phase 2 trial evaluating efficacy and toxicity of a modest RT dose in both localized and oMLS; this report presents the data of the oMLS cohort treated with 36 Gy in 12-18 fractions with optional subsequent metastasectomy. The primary endpoint was local progression free survival(LPFS). Secondary endpoints included postponement of systemic therapy, symptom reduction, radiological objective response, and toxicity. RESULTS: Nine patients with a total of 25 lesions were included, with a median follow-up of 23 months. The median number of lesions per patient was three and the trunk wall and bone were the most frequently affected sites. In lesions treated with definitive RT(n = 21), LPFS rates at 1, 2, and 3 years were respectively 73%, 61%, and 40%. Radiological objective response and clinical symptom reduction were achieved in 8/15(53%) and 9/10(90%) of the evaluable lesions, respectively. No local recurrences occurred in lesions treated with RT and metastasectomy(n = 4). For the entire study population, the median postponement of systemic therapy was 10 months. Grade ≥ 2 toxicity was observed in 2/9(22%) of patients. CONCLUSIONS: This trial suggests that 36 Gy could possibly be effective to achieve local control, postpone systemic therapy and reduce symptoms in oMLS. Given the minimal toxicity this treatment could be reasonably considered in oMLS.

Dose Reduction of Preoperative Radiotherapy in Myxoid Liposarcoma: A Nonrandomized Controlled Trial.

IMPORTANCE: Currently, preoperative radiotherapy for all soft-tissue sarcomas is identical at a 50-Gy dose level, which can be associated with morbidity, particularly wound complications. The observed clinical radiosensitivity of the myxoid liposarcoma subtype might offer the possibility to reduce morbidity. OBJECTIVE: To assess whether a dose reduction of preoperative radiotherapy for myxoid liposarcoma would result in comparable oncological outcome with less morbidity. DESIGN, SETTING, AND PARTICIPANTS: The Dose Reduction of Preoperative Radiotherapy in Myxoid Liposarcomas (DOREMY) trial is a prospective, single-group, phase 2 nonrandomized controlled trial being conducted in 9 tertiary sarcoma centers in Europe and the US. Participants include adults with nonmetastatic, biopsy-proven and translocation-confirmed myxoid liposarcoma of the extremity or trunk who were enrolled between November 24, 2010, and August 1, 2019. Data analyses, using both per-protocol and intention-to-treat approaches, were conducted from November 24, 2010, to January 31, 2020. INTERVENTIONS: The experimental preoperative radiotherapy regimen consisted of 36 Gy in once-daily 2-Gy fractions, with subsequent definitive surgical resection after an interval of 4 or more weeks. MAIN OUTCOMES AND MEASURES: As a short-term evaluable surrogate for local control, the primary end point was centrally reviewed pathologic treatment response. The experimental regimen was regarded as a success when 70% or more of the resection specimens showed extensive treatment response, defined as 50% or greater of the tumor volume containing treatment effects. Morbidity outcomes consisted of wound complications and late toxic effects. RESULTS: Among the 79 eligible patients, 44 (56%) were men and the median (interquartile range) age was 45 (39-56) years. Two patients did not undergo surgical resection because of intercurrent metastatic disease. Extensive pathological treatment response was observed in 70 of 77 patients (91%; posterior mean, 90.4%; 95% highest probability density interval, 83.8%-96.4%). The local control rate was 100%. The rate of wound complication requiring intervention was 17%, and the rate of grade 2 or higher toxic effects was 14%. CONCLUSIONS AND RELEVANCE: The findings of the DOREMY nonrandomized clinical trial suggest that deintensification of preoperative radiotherapy dose is effective and oncologically safe and is associated with less morbidity than historical controls, although differences in radiotherapy techniques and follow-up should be considered. A 36-Gy dose delivered in once-daily 2-Gy fractions is proposed as a dose-fractionation approach for myxoid liposarcoma, given that phase 3 trials are logistically impossible to execute in rare cancers. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02106312.

Multicenter validation of recursive partitioning analysis classification for patients with squamous cell head and neck carcinoma treated with surgery and postoperative radiotherapy.

PURPOSE: To validate the recursive partitioning analysis (RPA) classification system for squamous cell head and neck cancer as recently reported by the VU University Medical Center. METHODS AND MATERIALS: In eight Dutch head and neck cancer centers, data necessary to classify patients according to the RPA system were retrospectively collected from the charts of a group of 780 patients treated between 1989 and 2003. The patients in this validation group were classified according to the RPA classification system. For each endpoint, the 5-year values and hazard ratios were calculated and compared with the results of the VU University Medical Center. The RPA classification system was considered valid if the hazard ratio of the validation population was within the 95% confidence interval of the VU University Medical Center study population. RESULTS: The locoregional control rate was 82%, 75%, and 63% at 5 years for those with class I, II, and III, respectively (p < 0.0001). The hazard ratio for the locoregional control rate relative to class I was 1.44 (95% confidence interval, 0.97-2.16) for class II and 2.37 (95% confidence interval, 1.57-3.57) for class III. Similar results were found for the distant metastasis, overall survival, and disease-free survival rates. CONCLUSION: The RPA classification system for head and neck squamous cell carcinoma in the postoperative setting, which was originally designed at one center, proved to be valid in a multicenter setting among patients included in a national multicenter study. This validated RPA classification scheme can be used to assess standard treatment strategies for head and neck squamous cell carcinoma in the postoperative setting, as well as in the design of future prospective studies.

The role of radiotherapy in the treatment of malignant salivary gland tumors.

PURPOSE: We analyzed the role of primary and postoperative low linear energy transfer radiotherapy in 538 patients treated for salivary gland cancer in centers of the Dutch Head and Neck Oncology Cooperative Group, in search for prognostic factors and dose response. METHODS AND MATERIALS: The tumor was located in the parotid gland in 59%, submandibular gland in 14%, oral cavity in 23%, and elsewhere in 5%. In 386 of 498 patients surgery was combined with radiotherapy, with a median dose of 62 Gy. Median delay between surgery and radiotherapy was 6 weeks. In the postoperative radiotherapy group, adverse prognostic factors prevailed. Elective radiotherapy to the neck was given in 40%, with a median dose of 50 Gy. Primary radiotherapy (n = 40) was given for unresectable disease or M(1), with a dose range of 28-74 Gy. RESULTS: Postoperative radiotherapy improved 10-year local control significantly compared with surgery alone in T(3-4) tumors (84% vs. 18%), in patients with close (95% vs. 55%) and incomplete resection (82% vs. 44%), in bone invasion (86% vs. 54%), and perineural invasion (88% vs. 60%). Local control was not correlated with interval between surgery and radiotherapy. No dose-response relationship was shown. Postoperative radiotherapy significantly improved regional control in the pN(+) neck (86% vs. 62% for surgery alone). A rating scale for different sites, T stage, and histologic type may be applied to calculate the risk of disease in the neck at presentation, and so indicate the need for elective neck treatment. A marginal dose-response was seen, in favor of a dose > or =46 Gy. A clear dose-response relationship was shown for patients treated with primary radiotherapy. Five-year local control was 50% with a dose of 66-70 Gy. CONCLUSIONS: Postoperative radiotherapy with a dose of at least 60 Gy is indicated for patients with T(3-4) tumors, incomplete or close resection, bone invasion, perineural invasion, and pN(+). In unresectable tumors, a dose of at least 66 Gy is advisable.

Epidermal growth factor receptor expression in laryngeal cancer predicts the effect of hypoxia modification as an additive to accelerated radiotherapy in a randomised controlled trial.

Accelerated radiotherapy (AR) improves the poor prognosis associated with epidermal growth factor receptor (EGFR) overexpression frequently seen in head and neck carcinomas. Combining AR with carbogen and nicotinamide (ARCON) counteracts enhanced tumour cell proliferation- and hypoxia-related radioresistance. The purpose of this study was to investigate if EGFR expression levels are associated with response to ARCON in patients with carcinoma of the larynx. Patients (N=272) with advanced stage larynx carcinoma were randomised between AR alone and ARCON. Paraffin-embedded biopsies from these patients were processed for immunohistochemical staining of EGFR. EGFR fraction was quantitated by automated image analysis and related to clinical outcome. A large variation was observed in EGFR fraction between tumours with expression levels ranging from 0 to 0.93 (median fraction 0.4). No difference in 5-year locoregional control was found between low and high EGFR expressing tumours in the AR arm (69% versus 75%), which is in line with the established effect of AR in EGFR overexpressing tumours. There was, however, a significant association in the ARCON arm: patients with low EGFR levels had a better 5-year locoregional control (88% versus 72% p=0.02) and disease-specific survival (92% versus 77% p=0.01). ARCON improved locoregional control relative to AR only in patients with low EGFR expression (hazard ratio (HR) 0.34 p=0.009). In conclusion, only in tumours with a low EGFR fraction, adding hypoxia modification to AR has an additive beneficial effect on outcome. EGFR expression is a predictive biomarker for the selection of patients that will or will not respond to ARCON.

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.