Maintenance durvalumab after first-line chemotherapy in patients with HER2-negative advanced oesophago-gastric adenocarcinoma: results from the randomised PLATFORM study.

BACKGROUND: PLAnning Treatment For Oesophago-gastric Cancer: a Randomised Maintenance Therapy Trial (PLATFORM) is an adaptive phase II study assessing the role of maintenance therapies in advanced oesophago-gastric (OG) adenocarcinoma. We evaluated the role of the anti-programmed death-ligand 1 (PD-L1) inhibitor durvalumab in these patients. PATIENTS AND METHODS: Patients with human epidermal growth factor receptor 2-negative locally advanced or metastatic OG adenocarcinoma with disease control or response to 18 weeks of platinum-based first-line chemotherapy were randomised to active surveillance or maintenance durvalumab. The primary endpoint was progression-free survival (PFS). Safety was assessed in all patients who had commenced surveillance visits or received at least one dose of durvalumab. Exploratory survival analyses according to PD-L1 Combined Positive Score (CPS) and immune (biomarker-positive) or angiogenesis dominant (biomarker-negative) tumour microenvironment (TME) phenotypes were conducted. RESULTS: Between March 2015 and April 2020, 205 patients were randomised to surveillance (n = 100) and durvalumab (n = 105). No significant differences were seen in PFS [hazard ratio (HR) 0.84, P = 0.13] and overall survival (OS; HR 0.98, P = 0.45) between surveillance and durvalumab. Five patients randomised to durvalumab demonstrated incremental radiological responses compared with none with surveillance. Treatment-related adverse events occurred in 77 (76.2%) durvalumab-assigned patients. A favourable effect in OS with durvalumab over surveillance in CPS ≥5 and immune biomarker-positive patients was observed compared with CPS <5 and biomarker-negative subgroups, respectively: CPS ≥5 versus <5: HR 0.63, 95% confidence interval (CI) 0.32-1.22 versus HR 0.93, 95% CI 0.44-1.96; biomarker-positive versus negative: HR 0.60, 95% CI 0.29-1.23 versus HR 0.84, 95% CI 0.42-1.65. CONCLUSION: Maintenance durvalumab does not improve PFS in patients with OG adenocarcinoma who respond to first-line chemotherapy but induced incremental radiological responses in a subset of patients. TME characterisation could refine patient selection for anti-PD-L1 therapy above PD-L1 CPS alone.

How Long Does Contouring Really Take? Results of the Royal College of Radiologists Contouring Surveys.

AIMS: The success and safety of modern radiotherapy relies on accurate contouring. Understanding the time taken to complete radiotherapy contours is critical to informing workforce planning and, in the context of a workforce shortfall, advocating for investment in technology and multi-professional skills mix. We aimed to quantify the time taken to delineate target volumes for radical radiotherapy. MATERIALS AND METHODS: The Royal College of Radiologists circulated two electronic surveys via email to all clinical oncology consultants in the UK. The individual case survey requested anonymous data regarding the next five patients contoured for radical radiotherapy. The second survey collected data on respondents' usual practice in radiotherapy contouring. RESULTS: The median time to contour one radiotherapy case was 85 minutes (IQR = 50-131 minutes). Marked variability between and within tumour sites was evident: paediatric cancers took the most time (median = 210 minutes, IQR = 87.5 minutes), followed by head and neck and gynaecological cancers (median = 120 minutes, IQR = 71 and 72.5 minutes respectively). Breast cancer contouring required the least time (median = 43 minutes, IQR = 60 minutes). Radiotherapy technique, inclusion of nodes and 4D CT planning were associated with longer contouring times. A non-medical professional was involved in contouring in 65% of cases, but clinical oncology consultants were involved in target volume delineation in 90% of cases, and OARs in 74%. Peer review took place in 46% of cases with 56% of consultants reporting no time for peer review in their job plan. CONCLUSION: Contouring for radical radiotherapy is complex and time-consuming, and despite increasing involvement of non-medical professionals, clinical oncology consultants remain the primary practitioners. Peer review practice is variable and time is often a limiting factor. Many factors influence the time required for contouring, and departments should take these factors and the need for peer-review into account when developing job plans.

Global Health System Resilience during Encounters with Stressors - Lessons Learnt from Cancer Services during the COVID-19 Pandemic.

AIMS: The protracted COVID-19 pandemic has overwhelmed health systems globally, including many aspects of cancer control. This has underscored the multidimensional nature of cancer control, which requires a more comprehensive approach involving taking a wider perspective of health systems. Here, we investigated aspects of health system resilience in maintaining cancer services globally during the COVID-19 pandemic. This will allow for health systems to be resilient to different types of system stressors/shocks in the future, to allow cancer care to be maintained optimally. MATERIALS AND METHODS: Using the World Health Organization health system framework (capturing aspects of service delivery, health workforce, information, medical products, vaccines and technologies, financing and governance and leadership), we carried out a comparative analysis of the impact of COVID-19 and the synthesis of the findings in responses in cancer care in 10 countries/jurisdictions across four continents comprising a wide diversity of health systems, geographical regions and socioeconomic status (China, Colombia, Egypt, Hong Kong SAR, Indonesia, India, Singapore, Sri Lanka, UK and Zambia). A combination of literature and document reviews and interviews with experts was used. RESULTS: Our study revealed that: (i) underlying weaknesses of health systems before the pandemic were exacerbated by the pandemic (e.g. economic issues in low- and middle-income countries led to greater shortage of medication and resource constraints compounded by inadequacies of public financing and issues of engagement with stakeholders and leadership/governance); (ii) no universal adaptive strategies were applicable to all the systems, highlighting the need for health systems to design emergency plans based on local context; (iii) despite the many differences between health systems, common issues were identified, such as the lack of contingency plan for pandemics, inadequate financial policies for cancer patients and lack of evidence-based approaches for competing priorities of cancer care/pandemic control. CONCLUSION: We identified four key points/recommendations to enhance the resilient capacity of cancer care during the COVID-19 pandemic and other system stressors: (i) effective pandemic control approaches in general are essential to maintain the continuity of cancer care during the emergency health crises; (ii) strong health systems (with sufficient cancer care resources, e.g. health workforce, and universal health coverage) are fundamental to maintain quality care; (iii) the ability to develop response strategies and adapt to evolving evidence/circumstances is critical for health system resilience (including introducing systematic, consistent and evidence-based changes, national support and guidance in policy development and implementation); (iv) preparedness and contingency plans for future public health emergencies, engaging the whole of society, to achieve health system resilience for future crises and to transform healthcare delivery beyond the pandemic.

Improvement in Dysphagia Outcomes Following Clinical Target Volume Reduction in the De-ESCALaTE Study.

AIMS: The De-ESCALaTE study showed an overall survival advantage for the administration of synchronous cisplatin chemotherapy with radiotherapy in low-risk oropharyngeal cancer when compared with synchronous cetuximab. During the trial, a radiotherapy quality assurance protocol amendment permitted centres to swap from the original radiotherapy contouring protocol (incorporating the whole oropharynx into the high-dose clinical target volume (CTV); anatomical protocol) to a protocol that incorporated the gross tumour volume with a 10 mm margin into the CTV (volumetric protocol). The purpose of this study was to examine both toxicity and tumour control related to this protocol amendment. MATERIALS AND METHODS: Overall survival and recurrence at 2 years were used to compare tumour control in the two contouring cohorts. For toxicity, the cohorts were compared by both the number of severe (grades 3-5) and all grades acute and late toxicities. In addition, quality of life and swallowing were compared using EORTC-C30 and MD Anderson Dysphagia Inventory, respectively. RESULTS: Of 327 patients included in this study, 185 were contoured according to the anatomical protocol and 142 by the volumetric protocol. The two cohorts were well balanced, with the exception of significantly more patients in the anatomical cohort undergoing prophylactic feeding tube insertion (P < 0.001). With a minimum of 2 years of follow-up there was no significant difference in overall survival or recurrence between the two contouring protocols. Similarly, there was no significant difference in the rate of reported severe or all grades acute or late toxicity and no sustained significant difference in quality of life. However, there was a significant difference in favour of volumetric contouring in several domains of the MD Anderson Dysphagia Inventory questionnaire at 1 year, which persisted to 2 years in the dysphagia functional (P = 0.002), dysphagia physical (P = 0.009) and dysphagia overall function (P = 0.008) domains. CONCLUSION: In the context of the unplanned post-hoc analysis of a randomised trial, measurable improvement in long-term dysphagia has been shown following a reduction in the CTV. Further reductions in the CTV should be subject to similar scrutiny within the confines of a prospective study.

Oral cavity and lip cancer: United Kingdom National Multidisciplinary Guidelines.

This is the official guideline endorsed by the specialty associations involved in the care of head and neck cancer patients in the UK. It provides recommendations on the assessment and management of patients with cancer of the oral cavity and the lip. Recommendations • Surgery remains the mainstay of management for oral cavity tumours. (R) • Tumour resection should be performed with a clinical clearance of 1 cm vital structures permitting. (R) • Elective neck treatment should be offered for all oral cavity tumours. (R) • Adjuvant radiochemotherapy in the presence of advanced neck disease or positive margins improves control rates. (R) • Early stage lip cancer can be treated equally well by surgery or radiation therapy. (R).

Management of neck metastases in head and neck cancer: United Kingdom National Multidisciplinary Guidelines.

This is the official guideline endorsed by the specialty associations involved in the care of head and neck cancer patients in the UK. A rational plan to manage the neck is necessary for all head and neck primaries. With the emergence of new level 1 evidence across several domains of neck metastases, this guideline will identify the evidence-based recommendations for management. Recommendations • Computed tomographic or magnetic resonance imaging is mandatory for staging neck disease, with choice of modality dependant on imaging modality used for the primary site, local availability and expertise. (R) • Patients with a clinically N0 neck, with more than 15-20 per cent risk of occult nodal metastases, should be offered prophylactic treatment of the neck. (R) • The treatment choice of for the N0 and N+ neck should be guided by the treatment to the primary site. (G) • If observation is planned for the N0 neck, this should be supplemented by regular ultrasonograms to ensure early detection. (R) • All patients with T1 and T2 oral cavity cancer and N0 neck should receive prophylactic neck treatment. (R) • Selective neck dissection (SND) is as effective as modified radical neck dissection for controlling regional disease in N0 necks for all primary sites. (R) • SND alone is adequate treatment for pN1 neck disease without adverse histological features. (R) • Post-operative radiation for adverse histologic features following SND confers control rates comparable with more extensive procedures. (R) • Adjuvant radiation following surgery for patients with adverse histological features improves regional control rates. (R) • Post-operative chemoradiation improves regional control in patients with extracapsular spread and/or microscopically involved surgical margins. (R) • Following chemoradiation therapy, complete responders who do not show evidence of active disease on co-registered positron emission tomography-computed tomography (PET-CT) scans performed at 10-12 weeks, do not need salvage neck dissection. (R) • Salvage surgery should be considered for those with incomplete or equivocal response of nodal disease on PET-CT. (R).

Functional organ preservation in locally advanced laryngeal squamous cell carcinoma: is there a role for induction chemotherapy?

Concurrent chemoradiation (CRT) is currently the most effective strategy for organ preservation in locally advanced laryngeal squamous cell carcinoma (SCC) unsuitable for function-preserving surgery. The larynx preservation approach of induction chemotherapy followed by radiotherapy in responders is based on the hypothesis that tumours that show a satisfactory response to induction chemotherapy are more likely to respond to radiation-based treatment. This enables the use of chemotherapy response to identify patients who are more likely to achieve long-term disease control with organ-preserving therapies. An induction chemotherapy response allows prognostication, outcome prediction and treatment selection in patients with locally advanced laryngeal SCC. Excellent survival outcomes have been achieved with induction chemotherapy followed by CRT as definitive therapy in responders. The addition of docetaxel to cisplatin and 5-fluorouracil induction chemotherapy has also resulted in higher larynx preservation rates. Future organ preservation studies should assess whether induction chemotherapy with docetaxel, cisplatin and 5-fluorouracil followed by CRT in responders improves survival compared with an unselected approach of primary CRT in all eligible patients with T2 or T3 laryngeal SCC. The primary end point of such studies should be laryngo-oesophageal dysfunction-free survival, which focuses on the treatment goals of survival, disease control and laryngeal-oesophageal function after therapy. In addition, the inclusion of patients with N2 or N3 disease will help to determine whether the addition of docetaxel, cisplatin and 5-fluorouracil to CRT reduces the incidence of distant relapse in advanced laryngeal SCC. Other areas of interest include the use of concurrent cetuximab in place of platinum-based chemotherapy with radiotherapy in larynx preservation and the search for better predictive markers of successful larynx preservation than induction chemotherapy response.

Target volume definition for intensity-modulated radiotherapy after induction chemotherapy and patterns of treatment failure after sequential chemoradiotherapy in locoregionally advanced oropharyngeal squamous cell carcinoma.

AIMS: To validate our approach to target volume definition for intensity-modulated radiotherapy (IMRT) after induction chemotherapy and to analyse the pattern of treatment failure in patients with locoregionally advanced oropharyngeal squamous cell carcinoma (SCC) after sequential chemoradiotherapy (SCRT). MATERIALS AND METHODS: We studied all patients with locoregionally advanced oropharyngeal SCC treated with SCRT, definitive IMRT and no prior surgery between December 2004 and February 2010. SCRT consisted of three cycles of induction chemotherapy followed by IMRT with concurrent weekly chemotherapy. Our approach to IMRT tumour volume definition after induction chemotherapy was similar to recommendations from published clinical practice guidelines. Volumetric expansion was used to create the high-dose clinical target volume with a margin of 10 mm. The high-dose planning target volume (PTV) was treated to 65 Gy, whereas the prophylactic-dose PTV received 54 Gy over 30 fractions using the simultaneous integrated boost technique. The location and extent of each treatment failure was recorded, reconstructed on the planning computed tomography images and analysed using the dose distribution of the IMRT plan. RESULTS: Fifty-two patients were included. The median follow-up was 32.2 months (range 5.0-67.1 months). There were seven local failures, no regional recurrences and one with distant disease. None of the patients required post-treatment neck dissection. All local failures were in-field and occurred within the high-dose PTV. There were no marginal recurrences. Actuarial recurrence-free, disease-specific and overall survival rates at 3 years were 83.9, 85.9 and 79.7%, respectively. CONCLUSIONS: The absence of marginal recurrences validated the approach to IMRT target volume definition after induction chemotherapy proposed by clinical practice guidelines and practised at our institution. It suggested a lack of benefit with the use of larger geometric margins and additional anatomical expansion for the high-dose clinical target volume. SCRT resulted in excellent regional and distant disease control in patients with locoregionally advanced oropharyngeal SCC.

Feasibility and tolerance of sequential chemoradiotherapy in squamous cell carcinoma of the head and neck.

This paper evaluates the feasibility and tolerance of sequential chemoradiotherapy in patients with squamous cell carcinoma of the head and neck and ascertains whether the use of induction chemotherapy compromises delivery of subsequent radiotherapy with or without concurrent chemotherapy. We also compared sequential chemoradiotherapy treatment adherence between the elderly and younger patients with squamous cell carcinoma of the head and neck. One hundred and ninety-four patients with head and neck squamous cell carcinoma who received induction chemotherapy with cisplatin and 5-fluorouracil were included in this study. Treatment-related death rate from induction chemotherapy was 1.5%. One hundred and ninety-one patients (98.5%) proceeded to radical radiotherapy, with 90.1% also receiving planned concomitant chemotherapy. One hundred and seventy-eight patients (93.2%) completed radiotherapy with no prolongation of the treatment duration. There were no statistical differences in sequential chemoradiotherapy treatment adherence and tolerance between the elderly and younger patients apart from the proportion who required hospitalisation during radiotherapy. Induction chemotherapy in head and neck squamous cell carcinoma does not compromise delivery of definitive radiotherapy with or without concurrent chemotherapy. Elderly patients with head and neck squamous cell carcinoma are able to tolerate aggressive treatments such as sequential chemoradiotherapy. Treatment 'deintensification' based solely on chronological age is not recommended.

Interobserver variation in parotid gland delineation: a study of its impact on intensity-modulated radiotherapy solutions with a systematic review of the literature.

OBJECTIVES: This study evaluates the interobserver variation in parotid gland delineation and its impact on intensity-modulated radiotherapy (IMRT) solutions. METHODS: The CT volumetric data sets of 10 patients with oropharyngeal squamous cell carcinoma who had been treated with parotid-sparing IMRT were used. Four radiation oncologists and three radiologists delineated the parotid gland that had been spared using IMRT. The dose-volume histogram (DVH) for each study contour was calculated using the IMRT plan actually delivered for that patient. This was compared with the original DVH obtained when the plan was used clinically. RESULTS: 70 study contours were analysed. The mean parotid dose achieved during the actual treatment was within 10% of 24 Gy for all cases. Using the study contours, the mean parotid dose obtained was within 10% of 24 Gy for only 53% of volumes by radiation oncologists and 55% of volumes by radiologists. The parotid DVHs of 46% of the study contours were sufficiently different from those used clinically, such that a different IMRT plan would have been produced. CONCLUSION: Interobserver variation in parotid gland delineation is significant. Further studies are required to determine ways of improving the interobserver consistency in parotid gland definition.

Interobserver variation in clinical target volume and organs at risk segmentation in post-parotidectomy radiotherapy: can segmentation protocols help?

OBJECTIVE: A study of interobserver variation in the segmentation of the post-operative clinical target volume (CTV) and organs at risk (OARs) for parotid tumours was undertaken. The segmentation exercise was performed as a baseline, and repeated after 3 months using a segmentation protocol to assess whether CTV conformity improved. METHODS: Four head and neck oncologists independently segmented CTVs and OARs (contralateral parotid, spinal cord and brain stem) on CT data sets of five patients post parotidectomy. For each CTV or OAR delineation, total volume was calculated. The conformity level (CL) between different clinicians' outlines was measured using a validated outline analysis tool. The data for CTVs were re-analysed after using the cochlear sparing therapy and conventional radiation segmentation protocol. RESULTS: Significant differences in CTV morphology were observed at baseline, yielding a mean CL of 30% (range 25-39%). The CL improved after using the segmentation protocol with a mean CL of 54% (range 50-65%). For OARs, the mean CL was 60% (range 53-68%) for the contralateral parotid gland, 23% (range 13-27%) for the brain stem and 25% (range 22-31%) for the spinal cord. CONCLUSIONS: There was low conformity for CTVs and OARs between different clinicians. The CL for CTVs improved with use of a segmentation protocol, but the CLs remained lower than expected. This study supports the need for clear guidelines for segmentation of target and OARs to compare and interpret the results of head and neck cancer radiation studies.

Neck dissection can be avoided after sequential chemoradiotherapy and negative post-treatment positron emission tomography-computed tomography in N2 head and neck squamous cell carcinoma.

AIMS: This study assessed neck control in patients with N2 head and neck squamous cell carcinoma (HNSCC) treated with sequential chemoradiotherapy (SCRT) and the incidence of neck recurrence when neck dissection was withheld in those with negative post-treatment fluorine-18 fluorodeoxyglucose positron emission tomography (FDG PET). MATERIALS AND METHODS: Thirty-four consecutive patients with N2 HNSCC who were treated with radical intent using SCRT were included. Twenty-seven patients received concomitant platinum-based chemotherapy with their radiotherapy. Nineteen patients were treated with intensity-modulated radiotherapy. PET-computed tomography (PET-CT) was obtained 3 months after the completion of radical radiotherapy. Neck dissection was carried out only in those with increased FDG uptake in the neck. RESULTS: The median follow-up was 39.1 months. One patient had increased FDG uptake in the neck post-treatment, which was false positive for malignancy. The remaining 33 patients were observed without neck dissection. No regional recurrence occurred. The negative predictive value (NPV) of post-treatment PET-CT was 100%. CONCLUSIONS: Good disease control in the neck can be achieved in patients with N2 HNSCC with SCRT. Post-treatment PET-CT has a high NPV. Neck dissection can be avoided if post-treatment PET-CT is negative.

General practitioner assessment of stage and performance status in lung cancer patients at a population level: implications for prognosis and radiotherapy needs analyses.

BACKGROUND: Stage, weight loss, and performance status (PS) are important prognostic factors and eligibility factors for curative intent therapy for lung cancer patients. Details of stage, weight loss, and PS are often not collected until referral to a cancer specialist, and since not all patients are referred to cancer specialists these important variables are not well defined at a population level. PATIENTS AND METHODS: Data on stage, weight loss, PS and referral pattern were requested from general practitioners (GPs) on all lung cancer patients diagnosed between May and June of 2002 in the province of British Columbia, Canada. Outcomes were analyzed in relation to survival and referral to a cancer centre. RESULTS: 395 patients were identified, and GP questionnaires were returned on 85% of the cases. Patients referred to a cancer centre shortly after diagnosis differed from those who were not referred. Patients who were not referred to a cancer centre consisted of two groups-patients with localized disease and good PS who tended to have a better survival than those who were referred, and patients with advanced disease and poor performance status who tended to have a worse survival than those who were referred. GP assessed stage and PS are prognostic factors for survival. CONCLUSIONS: GP assessed stage and PS are prognostic factors for survival in lung cancer patients. The case mix of patients who are not referred to a cancer centre shortly after their diagnosis differs from those that are referred.

High remission rate in T-cell prolymphocytic leukemia with CAMPATH-1H.

T-cell prolymphocytic leukemia (T-PLL) is a chemotherapy-resistant malignancy with a median survival of 7.5 months. Preliminary results indicated a high remission induction rate with the human CD52 antibody, CAMPATH-1H. This study reports results in 39 patients with T-PLL treated with CAMPATH-1H between March 1993 and May 2000. All but 2 patients had received prior therapy with a variety of agents, including 30 with pentostatin; none achieved complete remission (CR). CAMPATH-1H (30 mg) was administered intravenously 3 times weekly until maximal response. The overall response rate was 76% with 60% CR and 16% partial remission (PR). These responses were durable with a median disease-free interval of 7 months (range, 4-45 months). Survival was significantly prolonged in patients achieving CR compared to PR or no response (NR), including one patient who survived 54 months. Nine patients remain alive up to 29 months after completing therapy. Seven patients received high-dose therapy with autologous stem cell support, 3 of whom remain alive in CR 5, 7, and 15 months after autograft. Stem cell harvests in these patients were uncontaminated with T-PLL cells as demonstrated by dual-color flow cytometry and polymerase chain reaction. Four patients had allogeneic stem cell transplants, 3 from siblings and 1 from a matched unrelated donor. Two had nonmyeloablative conditioning. Three are alive in CR up to 24 months after allograft. The conclusion is that CAMPATH-1H is an effective therapy in T-PLL, producing remissions in more than two thirds of patients. The use of stem cell transplantation to consolidate responses merits further study.