Efficacy of nivolumab as second line treatment for recurrent or metastatic head and neck squamous cell carcinoma: a national DAHANCA cohort study.

INTRODUCTION: The aim of this study was to investigate phase IV efficacy, of the PD-1 inhibitor nivolumab among an unselected and unbiased national cohort of recurrent/metastatic Head and Neck Squamous Cell Carcinoma (rmHNSCC) patients. MATERIAL AND METHODS: Inclusion criteria included histologically confirmed rmHNSCC and nivolumab as a second-line palliative treatment. Data were collected from patient files at the five Danish head and neck cancer centers and from the DAHANCA database. The iRECIST criteria were used for treatment evaluation.Endpoints were response rate (RR), overall survival (OS), and progression-free survival (PFS), calculated from the start of treatment to the date of event/censoring by the KM-method. Descriptive statistics were used to describe patients and treatment. Analyses were two-sided, with p < .05 considered significant. RESULTS: A total of 146 patients were identified in the period 2017-2020. They had a RR of 14%, median OS of 10.2 months [95% CI: 8.2-12.2] and median PFS of 3.1 months [95% CI: 2.3-4.2]. Patient age (≥ 70 years) or comorbidity did not significantly affect outcome. WHO performance status (PS) =1 was associated with an increased risk of death (HR: 2.1 [95% CI: 1.2-4.0], p = .02) and progression (HR: 1.9 [95% CI: 1.2-3.2], p = .01). Concomitant glucocorticoid-treatment during immunotherapy (≥ 50% of treatment time) appeared important for risk of death (HR: 6.4 [95% CI: 2.3-17.8], p < .001) and risk of progression (HR: 4.8 [95% CI: 1.8-12.5], p = .001). PD-L1 expression ≥ 20% was associated with a lowered risk of progression (HR: 0.5 [95% CI: 0.3-0.7], p = .001), but not lowered risk of death. CONCLUSION: In this unselected national cohort, outcome of second-line treatment reflects data from the registration studies. Furthermore, the results suggest that immunotherapy should be used with great care in treatment of rmHNSCC in patients with poor performance.

Up-front PET/CT changes treatment intent in patients with head and neck squamous cell carcinoma.

PURPOSE: In patients with newly diagnosed head and neck squamous cell carcinoma (HNSCC), we wanted to examine the differences in overall treatment decisions, i.e. curative versus palliative treatment intent, reached by a multidisciplinary team conference (MDTC) based on 18F-fluoro-deoxy-glucose-positron emission tomography/computed tomography (PET/CT) or chest X-ray + MRI of the head and neck (CXR/MRI). PATIENTS AND METHODS: This was a prospective blinded cohort study based on paired data. Consecutive patients with histologically verified primary HNSCC were invited to participate. All included patients underwent CXR/MRI and PET/CT before diagnostic biopsy. An ordinary MDTC using all available imaging was conducted as per standard practice. After at least 3 months (to eliminate recall bias in the team), the first project MDTC was conducted, based on either CXR/MRI or PET/CT, and the tumor board drew conclusions regarding treatment. After an additional 3 months, a second project MDTC was conducted using the complementary imaging modality. RESULTS: A total of 307 patients were included. Based on CXR/MRI, 303 patients (99%) were recommended for curative treatment and only four patients (1%) for palliative treatment. Based on PET/CT, the MDTC concluded that 278 (91%) patients were suitable for curative treatment and 29 (9%) patients for palliative treatment. The absolute difference of 8% was statistically significant (95% CI: 4.8%-11.5%, p < 0.001). CONCLUSIONS: A PET/CT-based imaging strategy significantly changed the decisions regarding treatment intent made by a MDTC for patients diagnosed with HNSCC, when compared with the standard imaging strategy of CXR/MRI.

Contouring and dose calculation in head and neck cancer radiotherapy after reduction of metal artifacts in CT images.

BACKGROUND: Delineation accuracy of the gross tumor volume (GTV) in radiotherapy planning for head and neck (H&N) cancer is affected by computed tomography (CT) artifacts from metal implants which obscure identification of tumor as well as organs at risk (OAR). This study investigates the impact of metal artifact reduction (MAR) in H&N patients in terms of delineation consistency and dose calculation precision in radiation treatment planning. MATERIAL AND METHODS: Tumor and OAR delineations were evaluated in planning CT scans of eleven oropharynx patients with streaking artifacts in the tumor region preceding curative radiotherapy (RT). The GTV-tumor (GTV-T), GTV-node and parotid glands were contoured by four independent observers on standard CT images and MAR images. Dose calculation was evaluated on thirty H&N patients with dental implants near the treated volume. For each patient, the dose derived from the clinical treatment plan using the standard image set was compared with the recalculated dose on the MAR image dataset. RESULTS: Reduction of metal artifacts resulted in larger volumes of all delineated structures compared to standard reconstruction. The GTV-T and the parotids were on average 22% (p < 0.06) and 7% larger (p = 0.005), respectively, in the MAR image plan compared to the standard image plan. Dice index showed reduced inter-observer variations after reduction of metal artifacts for all structures. The average surface distance between contours of different observers improved using the MAR images for GTV and parotids (p = 0.04 and p = 0.01). The median volume receiving a dose difference larger than ±3% was 2.3 cm3 (range 0-32 cm3). CONCLUSIONS: Delineation of structures in the head and neck were affected by metal artifacts and volumes were generally larger and more consistent after reduction of metal artifacts, however, only small changes were observed in the dose calculations.

Trends in melanoma in the elderly in Denmark, 1980-2012.

BACKGROUND: The incidence of melanoma is rising in Denmark. In the present paper we describe incidence, mortality and survival in Denmark from 1980 to 2012 focusing on age, comparing persons aged 70 years or more with those aged less than 70 years. MATERIAL AND METHODS: Melanoma was defined as ICD-10 code C43. Data derived from the NORDCAN database with comparable data on incidence, mortality, survival in the Nordic countries, where the Danish data were delivered from the Danish Cancer Registry and the Danish Cause of Death Registry with follow-up until the end of 2013. RESULTS: In 1980, 21.4% of the patients diagnosed with melanoma were older than 70 years compared to 28.4% in 2012. In persons aged less than 70 years, the incidence rate was higher among women than in men, but men aged 70-89 years had an incidence rate almost twice that of women. Incidence rates were increasing, particularly among the elderly. In 1980, 32.6% of the patients who died from melanoma were older than 69 years compared to 56.2% in 2012. In 1980, the mortality rate was 121.4 per 100,000 person years, increasing to 353.1 in 2012. For the younger patients, the mortality rates are only slight increasing, but for the elder patients the mortality rates are increasing dramatically. In general the survival has increased for all age groups over the years. CONCLUSION: The incidence rates for all age groups are rising. The increase was mainly caused by a rising incidence among the elderly. Mortality among Danish patients with melanoma is increasing and especially the mortality in the elderly. This important knowledge must be kept in mind when future treatment strategies are planned.

Delineation uncertainties of tumour volumes on MRI of head and neck cancer patients.

Background: During the last decade, radiotherapy using MR Linac has gone from research to clinical implementation for different cancer locations. For head and neck cancer (HNC), target delineation based only on MR images is not yet standard, and the utilisation of MRI instead of PET/CT in radiotherapy planning is not well established. We aimed to analyse the inter-observer variation (IOV) in delineating GTV (gross tumour volume) on MR images only for patients with HNC. Material/methods: 32 HNC patients from two independent departments were included. Four clinical oncologists from Denmark and four radiation oncologists from Australia had independently contoured primary tumour GTVs (GTV-T) and nodal GTVs (GTV-N) on T2-weighted MR images obtained at the time of treatment planning. Observers were provided with sets of images, delineation guidelines and patient synopsis. Simultaneous truth and performance level estimation (STAPLE) reference volumes were generated for each structure using all observer contours. The IOV was assessed using the DICE Similarity Coefficient (DSC) and mean absolute surface distance (MASD). Results: 32 GTV-Ts and 68 GTV-Ns were contoured per observer. The median MASD for GTV-Ts and GTV-Ns across all patients was 0.17 cm (range 0.08-0.39 cm) and 0.07 cm (range 0.04-0.33 cm), respectively. Median DSC relative to a STAPLE volume for GTV-Ts and GTV-Ns across all patients were 0.73 and 0.76, respectively. A significant correlation was seen between median DSCs and median volumes of GTV-Ts (Spearman correlation coefficient 0.76, p < 0.001) and of GTV-Ns (Spearman correlation coefficient 0.55, p < 0.001). Conclusion: Contouring GTVs in patients with HNC on MRI showed that the median IOV for GTV-T and GTV-N was below 2 mm, based on observes from two separate radiation departments. However, there are still specific regions in tumours that are difficult to resolve as either malignant tissue or oedema that potentially could be improved by further training in MR-only delineation.

Upfront PET/CT affects management decisions in patients with recurrent head and neck squamous cell carcinoma.

PURPOSE: To compare multidisciplinary team conference (MDTC) decisions regarding treatment intent based on either chest X-ray + MRI of the head and neck (CXR/MRI) or 18F-FDG-PET/CT (PET/CT) in patients with recurrent head and neck squamous cell carcinoma (HNSCC). METHODS: Prospective blinded cohort study based on paired data. Consecutive patients with suspected recurrent HNSCC were invited to participate. All included patients underwent CXR/MRI and PET/CT before diagnostic biopsy. An ordinary MDTC using all available imaging data was conducted as per standard practice. After at least three months (to eliminate recall bias in the team), the first project MDTC, based on either CXR/MRI or PET/CT, was conducted, and the tumor board made conclusions regarding treatment. After an additional three months, a second project MDTC was conducted using the complementary imaging strategy. The separate treatment strategies were compared using McNemar's test. RESULTS: A total of 110 patients (90 males and 20 females, median age 66 years, range 40-87) were included. The initial primary tumor originated from the pharynx in 56 (51%) patients, oral cavity in 17 (15%) patients, and larynx in 37 (34%) patients. Based on CXR/MRI, 87 patients (79%) were recommended curative treatment and 23 (21%) palliative treatment. Based on PET/CT, the MDTC decided that 52 (47%) patients were suitable for curative treatment and 58 (53%) for palliative treatment. The absolute difference of 32% was statistically significant (95% CI: 22-42%, p < 0.001). CONCLUSIONS: PET/CT affected MDTC decisions in patients with recurrent HNSCC towards less curative and more palliative treatment.

Thymidylate synthase and methylenetetrahydrofolate reductase gene polymorphism in normal tissue as predictors of fluorouracil sensitivity.

PURPOSE: To analyze thymidylate synthase (TS) and methylenetetrahydrofolate reductase (MTHFR) gene polymorphism with respect to fluorouracil (FU) sensitivity. PATIENTS AND METHODS: The study included a retrospective analysis of 88 patients with metastatic colorectal cancer and a prospective trial with 51 patients also with measurable metastases. All patients were treated with FU and leucovorin. The analysis of gene polymorphism was performed on normal intestinal tissue and lymphocytes. RESULTS: The response rate was significantly higher in patients with TS 3R/3R or MTHFR 677 TT gene polymorphism compared with the other groups. The difference of response rate translated to a difference in time to progression. Similar results were observed in the retrospective analysis and the prospective confirmatory trial. CONCLUSION: The analysis of gene polymorphism allows delineation of a group of patients (30%) with a response rate to a single drug of approximately 50%. This information should be used in the design of tailored treatment.

Automatic treatment planning improves the clinical quality of head and neck cancer treatment plans.

BACKGROUND: Treatment plans for head and neck (H&N) cancer are highly complex due to multiple dose prescription levels and numerous organs at risk (OARs) close to the target. The plan quality is inter-planner dependent since it is dependent on the skills and experience of the dosimetrist. This study presents a blinded prospective clinical comparison of automatic (AU) and manually (MA) generated H&N VMAT plans made for clinical use. METHODS: MA and AU plans were generated for 30 consecutive patients in Pinnacle3 using the IMRT optimisation module and the new Autoplan module, respectively. The plan quality was blindedly compared by three senior oncologists and the best plan was selected for treatment of the patient. Planning time was measured as the active operator time used. The plan quality was analysed with DVH metrics and the dose delivery accuracy validated on the ArcCheck phantom. RESULTS: For twenty-nine out of the thirty patients the AU plan was chosen for treatment. Target doses were more homogenous with the AU plans and the OAR doses were significantly reduced, between 0.5 and 6.5 Gy. The average operator time spent on creating a manual plan was 64 min which was halved by Autoplan. The AU plans were more modulated as illustrated by an increase in MUs, which might cause the slightly lower pass rate of 97.7% in the ArcCheck measurements. CONCLUSIONS: Target doses were similar between MA and AU plan, while AU plans spared all OAR considerably better than the MA plans.

A phase II study of UFT and Leucovorin in combination with mitomycin C in patients with metastatic colorectal cancer.

The main objectives of this phase II study were to determine efficacy and safety of the combination of UFT with Leucovorin and mitomycin C in patients with metastatic colorectal cancer. Ninety-seven patients were treated with UFT (91 patients 300 mg/m2, 6 patients 250 mg/m2) + Leucovorin 90 mg days 1-28 q 5 weeks. During the first 4 cycles the patients also received mitomycin C 7 mg/m2 on day 1. At the end of 4 courses patients with benefit from the treatment could receive further courses of UFT and Leucovorin alone. Two patients had a complete response (2%), 20 (21%) had a partial response, 40 (41%) had no change, 19 (20%) had progression, and 16 (17%) were not evaluable for response. The overall response rate by intention to treat was 22/97 (23%). Median time to progression was 5 months and median survival 13 months. Severe (grade 3-4) toxicities included: anorexia 3%, nausea 6%, vomiting 7%, diarrhoea 7%, and fatigue 9%. Febrile neutropenia, renal failure, and thrombocytopenia were seen in 1% of the patients, respectively. The combination of UFT with Leucovorin and mitomycin C shows similar clinical activity with regard to overall response rate (23%) and survival (13 months) to other frontline 5-fluorouracil-based therapies in metastatic colorectal cancer patients. The results indicate that mitomycin C did not increase either efficacy or toxicity. Therefore, phase III trials with this regimen cannot be recommended.