Phase I Trial of Cemiplimab, Radiotherapy, Cyclophosphamide, and Granulocyte Macrophage Colony-Stimulating Factor in Patients with Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma.

LESSONS LEARNED: Cemiplimab in combination with radiation therapy, cyclophosphamide, and granulocyte macrophage colony-stimulating factor did not demonstrate efficacy above what can be achieved with other PD-1 inhibitor monotherapies in patients with refractory and metastatic head and neck squamous cell carcinoma. The safety profile of cemiplimab combination therapy was consistent with previously reported safety profiles of cemiplimab monotherapy. No new safety signal was observed. BACKGROUND: Refractory and metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) generally does not respond to PD-1 inhibitor monotherapy. Cemiplimab is a human anti-PD-1 monoclonal antibody. An expansion cohort enrolled patients with R/M HNSCC in a phase I study combining cemiplimab plus radiation therapy (RT), cyclophosphamide, and granulocyte macrophage colony-stimulating factor (GM-CSF). METHODS: Patients with R/M HNSCC refractory to at least first-line therapy and for whom palliative RT is clinically indicated received cemiplimab plus RT, cyclophosphamide, and GM-CSF. The co-primary objectives were the safety, tolerability, and efficacy of cemiplimab plus RT, cyclophosphamide, and GM-CSF in 15 patients with R/M HNSCC. RESULTS: Fifteen patients were enrolled. Patients discontinued treatment due to progression of disease. The most common treatment-emergent adverse events (TEAEs) of any grade were fatigue (40.0%), constipation (26.7%), and asthenia, dyspnea, maculo-papular rash, and pneumonia (each 20%). The only grade ≥3 TEAE that occurred in two patients was pneumonia (13.3%). By investigator assessment, there was one partial response (6.7%); disease control rate was 40.0% (95% confidence interval [CI], 16.3-67.7; five patients with stable disease); seven patients had progressive disease, and two were not evaluable. Median progression-free survival by investigator assessment was 1.8 months (95% CI, 1.7-4.7). CONCLUSION: The regimen demonstrated tolerability but not efficacy above that which can be achieved with anti-PD-1 inhibitor monotherapy for R/M HNSCC.

Does ITV vaginal procedure ensure dosimetric coverage during IMRT of post-operative gynaecological tumours without instructions concerning rectal filling?

AIM: To find out whether the internal target volume (ITV) vaginal procedure ensures dosimetric coverage during intensity-modulated radiation therapy (IMRT) of post-operative gynaecological tumours without instructions on rectal filling. BACKGROUND: The ITV vaginal procedure does not necessarily include all movements of the bladder, and does not include changes in the rectal volume. We should know if the vaginal ITV is a useful tool in maintaining CTV coverage during treatment. MATERIALS AND METHODS: A retrospective analysis of 24 patients treated between July 2012 and July 2014 with adjuvant IMRT for gynaecological cancer. All patients underwent empty and full bladder CT on simulation (CT-planning) and three weeks later (CT-control). ITV displacement was measured and the 3D vector was calculated. ITV coverage was then evaluated by comparing the volume covered by the prescription isodose on both CT's. Patients were asked to have full bladder but they did not follow recommendations for the rectum. RESULTS: The mean 3D vector was 0.64 ± 0.32 cm (0.09-1.30). The mean ITV coverage loss was 5.8 ± 5.7% (0-20.2). We found a significant positive correlation between the 3D vector and the loss of coverage (Pearson correlation, r = 0.493, 95% CI: 0.111-0.748, p = 0.0144). We did not find any significant correlation between the bladder and rectal parameters with the 3D vector and loss of dosimetric coverage. We found a trend between the maximum rectal diameter in CT-planning and 3D vector (r = 0.400, 95% CI: -0.004 to 0.692, p = 0.0529). CONCLUSION: ITV vaginal procedure contributed to ensuring a good dose coverage without instructions on rectal filling.

p16, HPV, and Cetuximab: What Is the Evidence?

Squamous cell carcinoma of the head and neck (SCCHN) is the sixth most common cancer worldwide. It has recently been appreciated that human papillomavirus (HPV) status (or p16 status, which is a frequently used surrogate for HPV status) is prognostic for oropharyngeal SCCHN. Here, we review and contextualize existing p16 and HPV data, focusing on the cetuximab registration trials in previously untreated, locoregionally advanced, nonmetastatic SCCHN (LA SCCHN) and in recurrent and/or metastatic SCCHN (R/M SCCHN): the IMCL-9815 and EXTREME clinical trials, respectively. Taken together, the available data suggest that, while p16 and HPV are prognostic biomarkers in patients with LA SCCHN and R/M SCCHN, it could not be shown that they are predictive for the outcomes of the described cetuximab-containing trial regimens. Consequently, although HPV status provides prognostic information, it is not shown to predict therapy response, and so is not helpful for assigning first-line therapy in patients with SCCHN. In addition, we discuss assays currently used to assess p16 and HPV status, as well as the differentiation between these two biomarkers. Ultimately, we believe HPV E6/E7 polymerase chain reaction-based mRNA testing may represent the most informative technique for assessing HPV status in patients with SCCHN. While p16 is a valid surrogate for HPV status in oropharyngeal carcinoma (OPC), there is a higher risk of discordance between p16 and HPV status in non-OPC SCCHN. Collectively, these discussions hold key implications for the clinical management of SCCHN. IMPLICATIONS FOR PRACTICE: Human papillomavirus (HPV) status (or its commonly utilized surrogate p16) is a known prognostic biomarker in oropharyngeal squamous-cell carcinoma of the head and neck (SCCHN). We evaluated implications of the available evidence, including cetuximab registration trials in previously untreated locoregionally advanced (LA) SCCHN and recurrent and/or metastatic (R/M) SCCHN. We conclude that, although p16 and HPV are prognostic biomarkers for both LA and R/M SCCHN, they have not been shown to be predictive of response to the described cetuximab-containing regimens for either indication. Thus, current evidence suggests that benefits of cetuximab are observed in both p16-/HPV-positive and -negative SCCHN.

Effectiveness of radiotherapy for metastatic spinal cord compression in patients with short life expectancy.

AIM: To analyze the effect of radiotherapy (RT) in patients with metastatic spinal cord compression (MSCC) and poor prognosis in our center. BACKGROUND: RT is an effective treatment for MSCC. MATERIALS AND METHODS: Prospective evaluation on patients with MSCC and limited survival (according to Rades' scale), and treated with single-dose 8 Gy RT (February 2013-August 2014). Pain, ambulatory status and sphincter control were recorded. Pain relief was evaluated following the International Bone Metastases Consensus Working Party Guidelines. Ambulatory status was evaluated with Frankel's scale. Spinal fracture and instability were recorded. Health aspects were evaluated via a short survey and measuring the time spent on RT. RESULTS: 35 patients were included. 51% had unfavorable histologies; 60% bone fracture and 17% spinal instability. Median Karnofsky score was 60; 100% were on high doses of opioids. Median survival was 1.5 months. 49% had a partial pain response at 2 weeks post-radiation, and 47% at one month. Significant reductions in pain intensity were present at 2 weeks (Visual analog scale, VAS score, from 8 ± 1.5 to 5 ± 1.9). Negligible effects were observed on motor and bladder function, along with side effects. KPS score was maintained during follow-up. 80% of patients spent ≤5% of their remaining lifetime on RT. A survey comparison between clinical judgment and the results according to treatment decision consider that these patients merit treatment evaluation. CONCLUSIONS: A moderate pain response tailored to life expectancy can be obtained in patients treated with radiation. 8-Gy single-dose is an option for patients with limited survival.

Panitumumab plus radiotherapy versus chemoradiotherapy in patients with unresected, locally advanced squamous-cell carcinoma of the head and neck (CONCERT-2): a randomised, controlled, open-label phase 2 trial.

BACKGROUND: We aimed to compare panitumumab, a fully human monoclonal antibody against EGFR, plus radiotherapy with chemoradiotherapy in patients with unresected, locally advanced squamous-cell carcinoma of the head and neck. METHODS: In this international, open-label, randomised, controlled, phase 2 trial, we recruited patients with locally advanced squamous-cell carcinoma of the head and neck from 22 sites in eight countries worldwide. Patients aged 18 years and older with stage III, IVa, or IVb, previously untreated, measurable (≥ 10 mm for at least one dimension), locally advanced squamous-cell carcinoma of the head and neck (non-nasopharygeal) and an Eastern Cooperative Oncology Group performance status of 0-1 were randomly assigned (2:3) by an independent vendor to open-label chemoradiotherapy (two cycles of cisplatin 100 mg/m(2) during radiotherapy) or to radiotherapy plus panitumumab (three cycles of panitumumab 9 mg/kg every 3 weeks administered with radiotherapy) using a stratified randomisation with a block size of five. All patients received 70-72 Gy to gross tumour and 54 Gy to areas of subclinical disease with accelerated fractionation radiotherapy. The primary endpoint was local-regional control at 2 years, analysed in all randomly assigned patients who received at least one dose of their assigned protocol-specific treatment (chemotherapy, radiation, or panitumumab). The trial is closed and this is the final analysis. This study is registered with ClinicalTrials.gov, number NCT00547157. FINDINGS: Between Nov 30, 2007, and Nov 16, 2009, 152 patients were enrolled, and 151 received treatment (61 in the chemoradiotherapy group and 90 in the radiotherapy plus panitumumab group). Local-regional control at 2 years was 61% (95% CI 47-72) in the chemoradiotherapy group and 51% (40-62) in the radiotherapy plus panitumumab group. The most frequent grade 3-4 adverse events were mucosal inflammation (25 [40%] of 62 patients in the chemoradiotherapy group vs 37 [42%] of 89 patients in the radiotherapy plus panitumumab group), dysphagia (20 [32%] vs 36 [40%]), and radiation skin injury (seven [11%] vs 21 [24%]). Serious adverse events were reported in 25 (40%) of 62 patients in the chemoradiotherapy group and in 30 (34%) of 89 patients in the radiotherapy plus panitumumab group. INTERPRETATION: Panitumumab cannot replace cisplatin in the combined treatment with radiotherapy for unresected stage III-IVb squamous-cell carcinoma of the head and neck, and the role of EGFR inhibition in locally advanced squamous-cell carcinoma of the head and neck needs to be reassessed. FUNDING: Amgen.

Chemoradiotherapy with or without panitumumab in patients with unresected, locally advanced squamous-cell carcinoma of the head and neck (CONCERT-1): a randomised, controlled, open-label phase 2 trial.

BACKGROUND: Panitumumab is a fully human monoclonal antibody that targets EGFR. We aimed to compare chemoradiotherapy plus panitumumab with chemoradiotherapy alone in patients with unresected, locally advanced squamous-cell carcinoma of the head and neck. METHODS: In this international, open-label, randomised, controlled, phase 2 trial, we recruited patients with locally advanced squamous-cell carcinoma of the head and neck from 41 sites in nine countries worldwide. Patients aged 18 years and older with stage III, IVa, or IVb, previously untreated, measurable (≥ 10 mm for at least one dimension), locally advanced squamous-cell carcinoma of the head and neck (non-nasopharygeal) and an Eastern Cooperative Oncology Group performance status of 0-1 were randomly assigned (2:3) by an independent vendor to open-label chemoradiotherapy (three cycles of cisplatin 100 mg/m(2)) or panitumumab plus chemoradiotherapy (three cycles of intravenous panitumumab 9.0 mg/kg every 3 weeks plus cisplatin 75 mg/m(2)) using stratified randomisation with a block size of five. All patients received 70 Gy to gross tumour and 50 Gy to areas at risk for subclinical disease with standard fractionation. The primary endpoint was local-regional control at 2 years, analysed in all randomised patients who received at least one dose of their assigned protocol-specific treatment (chemotherapy, radiation, or panitumumab). The trial is closed and this is the final analysis. This trial is registered with ClinicalTrials.gov, number NCT00500760. FINDINGS: Between Oct 26, 2007, and March 26, 2009, 153 patients were enrolled and 150 received treatment (63 in the chemoradiotherapy group and 87 in the panitumumab plus chemoradiotherapy group). Local-regional control at 2 years was 68% (95% CI 54-78) in the chemoradiotherapy group and 61% (50-71) in the panitumumab plus chemoradiotherapy group. The most frequent grade 3-4 adverse events were dysphagia (17 [27%] of 63 patients in the chemoradiotherapy group vs 35 [40%] of 87 in the panitumumab plus chemoradiotherapy group), mucosal inflammation (15 [24%] vs 48 [55%]), and radiation skin injury (eight [13%] vs 27 [31%]). Serious adverse events were reported in 20 (32%) of 63 patients in the chemoradiotherapy group and in 37 (43%) of 87 patients in the panitumumab plus chemoradiotherapy group. INTERPRETATION: In patients with locally advanced squamous-cell carcinoma of the head and neck, the addition of panitumumab to standard fractionation radiotherapy and cisplatin did not confer any benefit, and the role of EGFR inhibition in these patients needs to be reassessed. FUNDING: Amgen.

Fluorouracil-based adjuvant chemotherapy after preoperative chemoradiotherapy in rectal cancer: long-term results of the EORTC 22921 randomised study.

BACKGROUND: EORTC trial 22921 examined the addition of preoperative or postoperative chemotherapy to preoperative radiotherapy in patients with rectal cancer. After a median follow-up of 5 years, chemotherapy-irrespective of timing-significantly improved local control. Adjuvant chemotherapy did not improve survival, but the Kaplan-Meier curves diverged, suggesting possible delayed benefit. Here, we report the updated long-term results. METHODS: We randomly assigned patients with clinical stage T3 or T4 resectable rectal cancer to receive preoperative radiotherapy with or without concomitant chemotherapy before surgery followed by either adjuvant chemotherapy or surveillance. Randomisation was done using minimisation with factors of institution, sex, T stage, and distance from the tumour to the anal verge. Study coordinators, clinicians, and patients were aware of assignment. Radiotherapy consisted of 45 Gy to the posterior pelvis in 25 fractions of 1·8 Gy over 5 weeks. Each course of chemotherapy consisted of fluorouracil (350 mg/m(2) per day intravenous bolus) and folinic acid (leucovorin; 20 mg/m(2) per day intravenous bolus). For preoperative chemotherapy, two courses were given (during weeks 1 and 5 of radiotherapy). Adjuvant chemotherapy was given in four cycles, every 3 weeks. The primary endpoint was overall survival. This analysis was done by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00002523. FINDINGS: 1011 patients were randomly assigned to treatment between April, 1993, and March, 2003 (252 to preoperative radiotherapy and 253 to each of the other three groups). After a median follow-up of 10·4 years (IQR 7·8-13·1), 10-year overall survival was 49·4% (95% CI 44·6-54·1) for the preoperative radiotherapy group and 50·7% (45·9-55·2) for the preoperative radiotherapy and chemotherapy group (HR 0·99, 95% CI 0·83-1·18; p=0·91). 10-year overall survival was 51·8% (95% CI 47·0-56·4) for the adjuvant chemotherapy group and 48·4% (43·6-53·0) for the surveillance group (HR 0·91, 95% CI 0·77-1·09, p=0·32). 10-year disease-free survival was 44·2% (95% CI 39·5-48·8) for the preoperative radiotherapy group and 46·4% (41·7-50·9) for the preoperative radiotherapy and chemotherapy group (HR 0·93, 95% CI 0·79-1·10; p=0·38). 10-year disease-free survival was 47·0% (95% CI 42·2-51·6) for the adjuvant chemotherapy group and 43·7% (39·1-48·2) for the surveillance group (HR 0·91, 95% CI 0·77-1·08, p=0·29). At 10 years, cumulative incidence of local relapse was 22·4% (95% CI 17·1-27·6) with radiotherapy alone, 11·8% (7·8-15·8) with neoadjuvant radiotherapy and chemotherapy, 14·5% (10·1-18·9) with radiotherapy and adjuvant chemotherapy and 11·7% (7·7-15·6) with both adjuvant and neoadjuvant chemotherapy (p=0·0017). There was no difference in cumulative incidence of distant metastases (p=0·52). The frequency of long-term side-effects did not differ between the four groups (p=0·22). INTERPRETATION: Adjuvant fluorouracil-based chemotherapy after preoperative radiotherapy (with or without chemotherapy) does not affect disease-free survival or overall survival. Our trial does not support the current practice of adjuvant chemotherapy after preoperative radiotherapy with or without chemotherapy. New treatment strategies incorporating neoadjuvant chemotherapy are required. FUNDING: EORTC, US National Cancer Institute, Programme Hospitalier de Recherche Clinique, Ligue contre le Cancer Comité du Doubs.

A multicentric randomized controlled phase III trial of adaptive and 18F-FDG-PET-guided dose-redistribution in locally advanced head and neck squamous cell carcinoma (ARTFORCE).

BACKGROUND AND PURPOSE: This multicenter randomized phase III trial evaluated whether locoregional control of patients with LAHNSCC could be improved by fluorodeoxyglucose-positron emission tomography (FDG-PET)-guided dose-escalation while minimizing the risk of increasing toxicity using a dose-redistribution and scheduled adaptation strategy. MATERIALS AND METHODS: Patients with T3-4-N0-3-M0 LAHNSCC were randomly assigned (1:1) to either receive a dose distribution ranging from 64-84 Gy/35 fractions with adaptation at the 10thfraction (rRT) or conventional 70 Gy/35 fractions (cRT). Both arms received concurrent three-cycle 100 mg/m2cisplatin. Primary endpoints were 2-year locoregional control (LRC) and toxicity. Primary analysis was based on the intention-to-treat principle. RESULTS: Due to slow accrual, the study was prematurely closed (at 84 %) after randomizing 221 eligible patients between 2012 and 2019 to receive rRT (N = 109) or cRT (N = 112). The 2-year LRC estimate difference of 81 % (95 %CI 74-89 %) vs. 74 % (66-83 %) in the rRT and cRT arm, respectively, was not found statistically significant (HR 0.75, 95 %CI 0.43-1.31,P=.31). Toxicity prevalence and incidence rates were similar between trial arms, with exception for a significant increased grade ≥ 3 pharyngolaryngeal stenoses incidence rate in the rRT arm (0 versus 4 %,P=.05). In post-hoc subgroup analyses, rRT improved LRC for patients with N0-1 disease (HR 0.21, 95 %CI 0.05-0.93) and oropharyngeal cancer (0.31, 0.10-0.95), regardless of HPV. CONCLUSION: Adaptive and dose redistributed radiotherapy enabled dose-escalation with similar toxicity rates compared to conventional radiotherapy. While FDG-PET-guided dose-escalation did overall not lead to significant tumor control or survival improvements, post-hoc results showed improved locoregional control for patients with N0-1 disease or oropharyngeal cancer treated with rRT.

International Recommendations on Postoperative Management for Potentially Resectable Locally Recurrent Nasopharyngeal Carcinoma.

PURPOSE: Locally recurrent nasopharyngeal carcinoma (NPC) presents substantial challenges in clinical management. While postoperative re-irradiation (re-RT) has been acknowledged as a potential treatment option, standardized guidelines and consensus regarding the use of re-RT in this context are lacking. This article provides a comprehensive review and summary of international recommendations on postoperative management for potentially resectable locally recurrent NPC, with a special focus on postoperative re-RT. METHODS AND MATERIALS: A thorough search was conducted to identify relevant studies on postoperative re-RT for locally recurrent NPC. Controversial issues, including resectability criteria, margin assessment, indications for postoperative re-RT, and the optimal dose and method of re-RT, were addressed through a Delphi consensus process. RESULTS: The consensus recommendations emphasize the need for a clearer and broader definition of resectability, highlighting the importance of achieving clear surgical margins, preferably through an en bloc approach with frozen section margin assessment. Furthermore, these guidelines suggest considering re-RT for patients with positive or close margins. Optimal postoperative re-RT doses typically range around 60Gy, and hyperfractionation has shown promise in reducing toxicity. CONCLUSION: These guidelines aim to assist clinicians in making evidence-based decisions and improving patient outcomes in the management of potentially resectable locally recurrent NPC. By addressing key areas of controversy and providing recommendations on resectability, margin assessment, and re-RT parameters, these guidelines serve as a valuable resource for the clinical experts involved in the treatment of locally recurrent NPC. SUMMARY: This article provides international recommendations on postoperative management for potentially resectable locally recurrent nasopharyngeal carcinoma (NPC), with a special focus on postoperative re-irradiation (re-RT). The consensus guidelines highlight the importance of achieving clear surgical margins, suggest considering re-RT for patients with positive or close margins, recommend an optimal re-RT dose of around 60Gy, and propose the use of hyperfractionation to reduce toxicity. The aim is to improve patient outcomes in the management of resectable locally recurrent NPC.

Adaptive and innovative Radiation Treatment FOR improving Cancer treatment outcomE (ARTFORCE); a randomized controlled phase II trial for individualized treatment of head and neck cancer.

BACKGROUND: Failure of locoregional control is the main cause of recurrence in advanced head and neck cancer. This multi-center trial aims to improve outcome in two ways. Firstly, by redistribution of the radiation dose to the metabolically most FDG-PET avid part of the tumour. Hereby, a biologically more effective dose distribution might be achieved while simultaneously sparing normal tissues. Secondly, by improving patient selection. Both cisplatin and Epidermal Growth Factor Receptor (EGFR) antibodies like Cetuximab in combination with Radiotherapy (RT) are effective in enhancing tumour response. However, it is unknown which patients will benefit from either agent in combination with irradiation. We will analyze the predictive value of biological markers and (89)Zr-Cetuximab uptake for treatment outcome of chemoradiation with Cetuximab or cisplatin to improve patient selection. METHODS: ARTFORCE is a randomized phase II trial for 268 patients with a factorial 2 by 2 design: cisplatin versus Cetuximab and standard RT versus redistributed RT. Cisplatin is dosed weekly 40 mg/m(2) for 6 weeks. Cetuximab is dosed 250 mg/m(2) weekly (loading dose 400 mg/m(2)) for 6 weeks. The standard RT regimen consists of elective RT up to 54.25 Gy with a simultaneous integrated boost (SIB) to 70 Gy in 35 fractions in 6 weeks. Redistributed adaptive RT consists of elective RT up to 54.25 Gy with a SIB between 64-80 Gy in 35 fractions in 6 weeks with redistributed dose to the gross tumour volume (GTV) and clinical target volume (CTV), and adaptation of treatment for anatomical changes in the third week of treatment.Patients with locally advanced, biopsy confirmed squamous cell carcinoma of the oropharynx, oral cavity or hypopharynx are eligible.Primary endpoints are: locoregional recurrence free survival at 2 years, correlation of the median (89)Zr-cetuximab uptake and biological markers with treatment specific outcome, and toxicity. Secondary endpoints are quality of life, swallowing function preservation, progression free and overall survival. DISCUSSION: The objective of the ARTFORCE Head and Neck trial is to determine the predictive value of biological markers and (89)Zr-Cetuximab uptake, as it is unknown how to select patients for the appropriate concurrent agent. Also we will determine if adaptive RT and dose redistribution improve locoregional control without increasing toxicity.ClinicalTrials.gov Identifier: NCT01504815.

Treatment time of image-guided radiotherapy with a Halcyon 2.0 system.

INTRODUCTION: The treatment fraction time is a key indicator of the external beam radiotherapy process. The Halcyon system was designed to improve the clinical workflow, according to the manufacturer (Varian Medical Systems). Few works studied the actual delivery efficiency of the Halcyon system. This work analyzed the treatment time on a Halcyon 2.0 unit for a variety of sites along a period of 9 months. MATERIALS AND METHODS: Treatment time included patient setup, image acquisition, image-guided online couch correction, and radiation delivery time. Data were extracted from the ARIA oncology information system and were studied as a function of the treatment site, the delivery modality, and the time from the first day of treatments with the Halcyon 2.0 system in our institution. RESULTS: A total of 8599 fractions were delivered during the analyzed period (69.5% from VMAT plans, and 30.5% from IMRT plans). The number of fractions by site ranged from 30 for anal canal to 1933 for prostate. Five sites (prostate, lung, pelvis with prostate, breast, and gynecological sites) accounted for the 84% of the fractions. After a 2-week adaptation period of the staff, the daily mean treatment time was reduced to less than 12 min. The mean treatment time of all the fractions amounted to 10.5 ± 3.8 min. CONCLUSIONS: The Halcyon 2.0 allowed delivering online image-guided radiation therapy in all fractions with total treatment time consistently below the 12-min standard time slot, for most of the analyzed treatment sites.

Nutritional status associates with immunotherapy clinical outcomes in recurrent or metastatic head and neck squamous cell carcinoma patients.

BACKGROUND: Beyond programmed death-ligand 1 (PD-L1) assessed by the combined positive score (CPS) and tumor mutational burden (TMB), no other biomarkers are approved for immunotherapy interventions. Here, we investigated whether additional clinical and pathological variables may impact on immunotherapy outcomes in recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) patients. METHODS: R/M HNSCC patients treated with immunotherapy were reviewed. Analyzed variables at baseline included: clinicopathological, laboratory, and variables reflecting the host nutritional status such as the prognostic nutritional index (PNI) and albumin. The primary endpoint was progression free survival (PFS). The secondary endpoints were overall survival (OS) and objective response rate (ORR). Univariable and multivariable Cox models were fitted and random forest algorithm was used to estimate the importance of each prognostic variable. RESULTS: A total of 100 patients were treated with immunotherapy; 50% with single agent and 50% with experimental immunotherapy combinations. In the multivariable analysis, both ECOG performance status (HR: 1.73; 95%CI 1.07-2.82; p = 0.03) and PNI levels (10-point increments, HR: 0.66; 0.46-0.95; p = 0.03) were significantly associated with PFS. However, the derived neutrophil to lymphocyte ratio (dNLR) and lactate dehydrogenase (LDH) were not significantly associated with PFS (p-values > 0.15). In the OS analysis, albumin and PNI were the only statistically significant factors in the multivariable model (p < 0.001). CONCLUSIONS: In our cohort, PNI and ECOG performance status were most strongly associated with PFS in R/M HNSCC patients treated with immunotherapy. These results suggest that parameters informative of nutritional status should be considered before immunotherapy.

Dose variations in tumor volumes and organs at risk during IMRT for head-and-neck cancer.

Many head-and-neck cancer (HNC) patients treated with radiotherapy suffer significant anatomical changes due to tumor shrinkage or weight loss. The purpose of this study was to assess dose changes over target volumes and organs at risk during intensity-modulated radiotherapy for HNC patients. Sixteen HNC IMRT patients, all requiring bilateral neck irradiation, were enrolled in the study. A CTplan was performed and the initial dose distribution was calculated. During the treatment, two subsequent CTs at the 15th (CT15) and 25th (CT25) fractions were acquired. The initial plan was calculated on the CT15 and CT25, and dose-volume differences related to the CTplan were assessed. For target volumes, mean values of near-maximun absorbed dose (D2%) increased at the 25th fraction, and doses covering 95% and 98% of volume decreased significantly at the 15th fraction. Contralateral and ipsilateral parotid gland mean doses increased by 6.1% (range: -5.4, 23.5%) and 4.7% (range: -9.1, 22.3%), respectively, at CT25. The D2% in the spinal cord increased by 1.8 Gy at CT15. Mean absorbed dose increases at CT15 and CT25 were observed in: the lips, 3.8% and 5.3%; the oral cavity, 3.5% and 2.5%; and lower middle neck structure, 1.9% and 1.6%. Anatomical changes during treatment of HNC patients affect dose distribution and induce a loss of dose coverage to target volumes and an overdosage to critical structures. Appropriate organs at risk have to be contoured and monitored in order to know if the initial plan remains suitable during the course of the treatment. Reported dosimetric data can help to identify patients who could benefit from adaptive radiotherapy.

Cell Senescence-Related Pathways Are Enriched in Breast Cancer Patients With Late Toxicity After Radiotherapy and Low Radiation-Induced Lymphocyte Apoptosis.

Background: Radiation-induced late effects are a common cause of morbidity among cancer survivors. The biomarker with the best evidence as a predictive test of late reactions is the radiation-induced lymphocyte apoptosis (RILA) assay. We aimed to investigate the molecular basis underlying the distinctive RILA levels by using gene expression analysis in patients with and without late effects and in whom we had also first identified differences in RILA levels. Patients and Methods: Peripheral blood mononuclear cells of 10 patients with late severe skin complications and 10 patients without symptoms, selected from those receiving radiotherapy from 1993 to 2007, were mock-irradiated or irradiated with 8 Gy. The 48-h response was analyzed in parallel by RILA assay and gene expression profiling with Affymetrix microarrays. Irradiated and non-irradiated gene expression profiles were compared between both groups. Gene set enrichment analysis was performed to identify differentially expressed biological processes. Results: Although differentially expressed mRNAs did not reach a significant adjusted p-value between patients suffering and not suffering clinical toxicity, the enriched pathways indicated significant differences between the two groups, either in irradiated or non-irradiated cells. In basal conditions, the main differentially expressed pathways between the toxicity and non-toxicity groups were the transport of small molecules, interferon signaling, and transcription. After 8 Gy, the differences lay in pathways highly related to cell senescence like cell cycle/NF-κB, G-protein-coupled receptors, and interferon signaling. Conclusion: Patients at risk of developing late toxicity have a distinctive pathway signature driven by deregulation of immune and cell cycle pathways related to senescence, which in turn may underlie their low RILA phenotype.

Radiographic-anatomy, natural history and extension pathways of parotid and submandibular gland cancers.

Intensity-modulated radiotherapy has been widely used routinely in recent past years for post-operative radiotherapy of salivary gland cancers Because of the sharp dose fall off outside of target volumes with IMRT, each volume must be strictly and rigorously defined, as the areas not specifically included in the target volume will not be treated to a therapeutic dose. The selection and delineation of these volumes is complex and requires extensive knowledge of parotid and submandibular gland cancer radiographic-anatomy, natural history and extension pathways (including local tumor spread, PNI risks and regional spread), which are detailed in the present article.

Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 randomised trial, and relation between cetuximab-induced rash and survival.

BACKGROUND: Previous results from our phase 3 randomised trial showed that adding cetuximab to primary radiotherapy increased overall survival in patients with locoregionally advanced squamous-cell carcinoma of the head and neck (LASCCHN) at 3 years. Here we report the 5-year survival data, and investigate the relation between cetuximab-induced rash and survival. METHODS: Patients with LASCCHN of the oropharynx, hypopharynx, or larynx with measurable disease were randomly allocated in a 1:1 ratio to receive either comprehensive head and neck radiotherapy alone for 6-7 weeks or radiotherapy plus weekly doses of cetuximab: 400 mg/m(2) initial dose, followed by seven weekly doses at 250 mg/m(2). Randomisation was done with an adaptive minimisation technique to balance assignments across stratification factors of Karnofsky performance score, T stage, N stage, and radiation fractionation. The trial was un-blinded. The primary endpoint was locoregional control, with a secondary endpoint of survival. Following discussions with the US Food and Drug Administration, the dataset was locked, except for queries to the sites about overall survival, before our previous report in 2006, so that an independent review could be done. Analyses were done on an intention-to-treat basis. Following completion of treatment, patients underwent physical examination and radiographic imaging every 4 months for 2 years, and then every 6 months thereafter. The trial is registered at www.ClinicalTrials.gov, number NCT00004227. FINDINGS: Patients were randomly assigned to receive radiotherapy with (n=211) or without (n=213) cetuximab, and all patients were followed for survival. Updated median overall survival for patients treated with cetuximab and radiotherapy was 49.0 months (95% CI 32.8-69.5) versus 29.3 months (20.6-41.4) in the radiotherapy-alone group (hazard ratio [HR] 0.73, 95% CI 0.56-0.95; p=0.018). 5-year overall survival was 45.6% in the cetuximab-plus-radiotherapy group and 36.4% in the radiotherapy-alone group. Additionally, for the patients treated with cetuximab, overall survival was significantly improved in those who experienced an acneiform rash of at least grade 2 severity compared with patients with no rash or grade 1 rash (HR 0.49, 0.34-0.72; p=0.002). INTERPRETATION: For patients with LASCCHN, cetuximab plus radiotherapy significantly improves overall survival at 5 years compared with radiotherapy alone, confirming cetuximab plus radiotherapy as an important treatment option in this group of patients. Cetuximab-treated patients with prominent cetuximab-induced rash (grade 2 or above) have better survival than patients with no or grade 1 rash. FUNDING: ImClone Systems, Merck KGaA, and Bristol-Myers Squibb.

30-Day Mortality Following Palliative Radiotherapy.

PURPOSE: 30-day mortality (30-DM) is a parameter with widespread use as an indicator of avoidance of harm used in medicine. Our objective is to determine the 30-DM followed by palliative radiation therapy (RT) in our department and to identify potential prognosis factors. MATERIAL/METHODS: We conducted a retrospective cohort study including patients treated with palliative RT in our center during 2018 and 2019. Data related to clinical and treatment characteristics were collected. RESULTS: We treated 708 patients to whom 992 palliative irradiations were delivered. The most frequent primary tumor sites were lung (31%), breast (14.8%), and gastrointestinal (14.8%). Bone was the predominant location of the treatment (56%), and the use of single doses was the preferred treatment schedule (34.4%). The 30-DM was 17.5%. For those who died in the first month the median survival was 17 days. Factors with a significant impact on 30-DM were: male gender (p < 0.0001); Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 2-3 (p = 0.0001); visceral metastases (p = 0.0353); lung, gastrointestinal or urinary tract primary tumors (p = 0.016); and single dose RT (p = <0.0001). In the multivariate analysis, male gender, ECOG PS 2-3, gastrointestinal and lung cancer were found to be independent factors related to 30-DM. CONCLUSION: Our 30-DM is similar to previous studies. We have found four clinical factors related to 30-DM of which ECOG was the most strongly associated. This data may help to identify terminally ill patients with poor prognosis in order to avoid unnecessary treatments.

Defining a Standard Set of Health Outcomes for Patients With Squamous Cell Carcinoma of the Head and Neck in Spain.

PURPOSE: A systematic, standardized collection of health outcomes during patient treatment and follow-up, relevant from the perspective of all stakeholders, is a crucial step toward effective and efficient disease management. This project aimed to define a standard set of health outcomes for patients with squamous cell carcinoma of the head and neck (SCCHN). METHODS: The project was led and coordinated by a scientific committee (SC). It comprised: (1) a literature review (to identify variables used during SCCHN management); (2) 1st-SC meeting (to select the variables for presentation during nominal groups-NG); (3) five NG (n=42 experts) and four interviews with patients (to reach consensus on the variables for inclusion); and (4) final-SC meeting (to review the results of NG ensuring consensus on the variables where consensus was not reached). RESULTS: Experts agreed to include the following variables in the standard set: treatment-related (treatment intent and type, response to treatment, treatment toxicity/complication, treatment completion), degree of health (performance status, patient-reported health status, pain, dysphonia, feeding and speech limitations, body image alteration, tracheotomy), survival (overall and progression-free survival, cause of death), nutritional (weight, nutritional intervention), other variables (smoking status, alcohol consumption, patient satisfaction with aftermath care, employment status), and case-mix variables (demographic, tumor-related, clinical and nutritional factors). CONCLUSIONS: This project may pave the way to standardizing the collection of health outcomes in SCCHN and promote the incorporation of patients' perspective in its management. The information provided through the systematic compilation of this standard set may define strategies to achieve high-quality, patient-centered care.

Radical radiotherapy for paediatric solid tumour metastases: An overview of current European protocols and outcomes of a SIOPE multicenter survey.

PURPOSE/OBJECTIVE: About 20% of children with solid tumours (ST) present with distant metastases (DM). Evidence regarding the use of radical radiotherapy of these DM is sparse and open for personal interpretation. The aim of this survey was to review European protocols and to map current practice regarding the irradiation of DM across SIOPE-affiliated countries. MATERIALS/METHODS: Radiotherapy guidelines for metastatic sites (bone, brain, distant lymph nodes, lung and liver) in eight European protocols for rhabdomyosarcoma, non-rhabdomyosarcoma soft-tissue sarcoma, Ewing sarcoma, neuroblastoma and renal tumours were reviewed. SIOPE centres irradiating ≥50 children annually were invited to participate in an online survey. RESULTS: Radiotherapy to at least one metastatic site was recommended in all protocols, except for high-risk neuroblastoma. Per protocol, dose prescription varied per site, and information on delineation and treatment planning/delivery was generally missing. Between July and September 2019, 20/27 centres completed the survey. Around 14% of patients were deemed to have DM from ST at diagnosis, of which half were treated with curative intent. A clear cut-off for a maximum number of DM was not used in half of the centres. Regardless of the tumour type and site, conventional radiotherapy regimens were most commonly used to treat DM. When stereotactic radiotherapy was used, a wide range of fractionation regimens were applied. CONCLUSION: Current radiotherapy guidelines for DM do not allow a consistent approach in a multicentre setting. Prospective (randomised) trials are needed to define the role of radical irradiation of DM from paediatric ST.

Early Toxicities After High Dose Rate Proton Therapy in Cancer Treatments.

BACKGROUND: The conventional dose rate of radiation therapy is 0.01-0.05 Gy per second. According to preclinical studies, an increased dose rate may offer similar anti-tumoral effect while dramatically improving normal tissue protection. This study aims at evaluating the early toxicities for patients irradiated with high dose rate pulsed proton therapy (PT). MATERIALS AND METHODS: A single institution retrospective chart review was performed for patients treated with high dose rate (10 Gy per second) pulsed proton therapy, from September 2016 to April 2020. This included both benign and malignant tumors with ≥3 months follow-up, evaluated for acute (≤2 months) and subacute (>2 months) toxicity after the completion of PT. RESULTS: There were 127 patients identified, with a median follow up of 14.8 months (3-42.9 months). The median age was 55 years (1.6-89). The cohort most commonly consisted of benign disease (55.1%), cranial targets (95.1%), and were treated with surgery prior to PT (56.7%). There was a median total PT dose of 56 Gy (30-74 Gy), dose per fraction of 2 Gy (1-3 Gy), and CTV size of 47.6 ml (5.6-2,106.1 ml). Maximum acute grade ≥2 toxicity were observed in 49 (38.6%) patients, of which 8 (6.3%) experienced grade 3 toxicity. No acute grade 4 or 5 toxicity was observed. Maximum subacute grade 2, 3, and 4 toxicity were discovered in 25 (19.7%), 12 (9.4%), and 1 (0.8%) patient(s), respectively. CONCLUSION: In this cohort, utilizing high dose rate proton therapy (10 Gy per second) did not result in a major decrease in acute and subacute toxicity. Longer follow-up and comparative studies with conventional dose rate are required to evaluate whether this approach offers a toxicity benefit.