Search

Gemcitabine-cisplatin (GP) chemotherapy is the standard first-line systemic treatment for recurrent or metastatic nasopharyngeal carcinoma (RM-NPC). In this international, double-blind, phase 3 trial (ClinicalTrials.gov identifier: NCT03581786), 289 patients with RM-NPC and no previous chemotherapy for recurrent or metastatic disease were randomized (1/1) to receive either toripalimab, a monoclonal antibody against human programmed death-1 (PD-1), or placebo in combination with GP every 3 weeks for up to six cycles, followed by monotherapy with toripalimab or placebo. The primary endpoint was progression-free survival (PFS) as assessed by a blinded independent review committee according to RECIST v.1.1. At the prespecified interim PFS analysis, a significant improvement in PFS was detected in the toripalimab arm compared to the placebo arm: median PFS of 11.7 versus 8.0 months, hazard ratio (HR) = 0.52 (95% confidence interval (CI): 0.36–0.74), P = 0.0003. An improvement in PFS was observed across key subgroups, including PD-L1 expression. As of 18 February 2021, a 40% reduction in risk of death was observed in the toripalimab arm compared to the placebo arm (HR = 0.603 (95% CI: 0.364–0.997)). The incidence of grade ≥3 adverse events (AEs) (89.0 versus 89.5%), AEs leading to discontinuation of toripalimab/placebo (7.5 versus 4.9%) and fatal AEs (2.7 versus 2.8%) was similar between the two arms; however, immune-related AEs (39.7 versus 18.9%) and grade ≥3 infusion reactions (7.5 versus 0.7%) were more frequent in the toripalimab arm. In conclusion, the addition of toripalimab to GP chemotherapy as a first-line treatment for patients with RM-NPC provided superior PFS compared to GP alone, and with a manageable safety profile. Interim analysis from the randomized phase 3 JUPITER-02 trial shows that the addition of anti-PD-1 toripalimab to standard gemcitabine/cisplatin as a first-line treatment for patients with recurrent or metastatic nasopharyngeal carcinoma has manageable toxicity and improves progression-free survival, suggesting a potential new treatment standard in this setting.

Gemcitabine-cisplatin (GP) chemotherapy is the standard first-line systemic treatment for recurrent or metastatic nasopharyngeal carcinoma (RM-NPC). In this international, double-blind, phase 3 trial (ClinicalTrials.gov identifier: NCT03581786), 289 patients with RM-NPC and no previous chemotherapy for recurrent or metastatic disease were randomized (1/1) to receive either toripalimab, a monoclonal antibody against human programmed death-1 (PD-1), or placebo in combination with GP every 3 weeks for up to six cycles, followed by monotherapy with toripalimab or placebo. The primary endpoint was progression-free survival (PFS) as assessed by a blinded independent review committee according to RECIST v.1.1. At the prespecified interim PFS analysis, a significant improvement in PFS was detected in the toripalimab arm compared to the placebo arm: median PFS of 11.7 versus 8.0 months, hazard ratio (HR) = 0.52 (95% confidence interval (CI): 0.36-0.74), P = 0.0003. An improvement in PFS was observed across key subgroups, including PD-L1 expression. As of 18 February 2021, a 40% reduction in risk of death was observed in the toripalimab arm compared to the placebo arm (HR = 0.603 (95% CI: 0.364-0.997)). The incidence of grade ≥3 adverse events (AEs) (89.0 versus 89.5%), AEs leading to discontinuation of toripalimab/placebo (7.5 versus 4.9%) and fatal AEs (2.7 versus 2.8%) was similar between the two arms; however, immune-related AEs (39.7 versus 18.9%) and grade ≥3 infusion reactions (7.5 versus 0.7%) were more frequent in the toripalimab arm. In conclusion, the addition of toripalimab to GP chemotherapy as a first-line treatment for patients with RM-NPC provided superior PFS compared to GP alone, and with a manageable safety profile.

Background: Primary lymphoepithelioma-like carcinoma (LELC) of the lung is a rare histological type of lung cancer with a relatively better prognosis. It is common in Chinese population, is associated with Epstein Barr Virus (EBV), and has morphological similarities to nasopharyngeal carcinoma. Methods: We retrospectively analysed medical records of patients with LELC at Tan Tock Seng Hospital, Singapore from November 2010 to January 2016 and evaluated baseline characteristics, staging, therapeutic interventions and survival. Results: Ten patients were diagnosed with pulmonary LELC, all were Chinese. The median age (range) at diagnosis was 62 (42-88) years, with a female preponderance ratio of 4:1. All had Epstein-Barr virus encoded small non-polyadenylated ribonucleic acid positive status. Six (60%) patients had stage IV, 3 (30%) stage IIIA, and 1 (10%) stage IIA disease. The median overall survival was 24.2 (4.7-59.4) months; in stage II, IIIA, and IV it was 27.6, 20.7 (19.8-48.9), and 26.6 (4.7-59.4) months respectively. The 1-year, 2-year, 3-year, and 5-year survival rate was 90%, 50%, 30%, and 10% in the whole group, but 100%, 43%, 28.6%, and 14.3% in 7 patients who received chemotherapy. Gemcitabine/carboplatin was the most commonly used 1st line chemotherapy. Conclusion: LELC is associated with Chinese ethnicity, younger age of onset, EBV, lack of smoking, advanced stage, and better prognosis than other subtypes of lung cancers. For improving outcomes, future efforts should focus on increased awareness, early diagnosis, development of an ASEAN registry and international collaboration. Options such as EBV-directed adopted immunotherapy or the role of EBV vaccine also merit evaluation.

Background: Gemcitabine-Cisplatin (GP) chemotherapy is the standard first-line treatment for recurrent or metastatic (RM) Nasopharyngeal Carcinoma (NPC). Toripalimab, a humanized monoclonal antibody specific for human programmed death-1 (PD-1), provided durable responses in patients with RM-NPC in the second line+ setting. Methods: In this international phase III trial, 289 patients with RM-NPC with no prior chemotherapy in the RM setting were randomized (1:1) to receive either toripalimab or placebo in combination with GP every 3 weeks for up to 6 cycles, followed by monotherapy with toripalimab or placebo until disease progression or intolerable toxicity. The primary endpoint was progression-free survival (PFS) as assessed by a blinded independent review committee per RECIST v1.1.RESULTSAt interim analysis, a significant improvement in PFS was detected in the toripalimab arm than the placebo arm, median PFS 11.7 vs. 8.0 months, HR=0.52 (95% CI: 0.36-0.74), p=0.0003. As of February 18, 2021, a 40% reduction in risk of death was observed in the toripalimab arm than the placebo arm, HR=0.603 (95% CI: 0.364 to 0.997). The incidence of Grade ≥3 adverse events (AEs) (89.0% vs 89.5%), AEs leading to discontinuation of toripalimab/placebo (7.5% vs 4.9%), and fatal AEs (2.7% vs 2.8%) were similar between two arms; however, immune-related (irAEs) (39.7% vs. 18.9%) and Grade ≥3 irAEs (7.5% vs. 0.7%) were more frequent in the toripalimab arm. Conclusions: The addition of toripalimab to GP chemotherapy as a first-line treatment for patients with RM-NPC provided superior PFS and OS than GP alone with a manageable safety profile. Trial Registration: NCT number NCT03581786. Funding: Shanghai Junshi Biosciences Co., LTD, Shanghai, China. Declaration of Interest: Hui Feng and Sheng Yao are employed by Shanghai Junshi Bioscience and TopAlliance Biosciences. Patricia Keegan is employed by TopAlliance Biosciences. Rui-hua Xu has served in a consulting or an advisory role for Bristol-Myers Squibb, Merck Serono, Roche, Astellas, AstraZeneca. The rest of authors have no disclosures of potential conflicts of interests. Ethical Approval: This trial was conducted in full conformance with the ICH E6 guideline for Good Clinical Practice (GCP) and the principles of the Declaration of Helsinki.

A 71-year-old lady with Stage IV Epidermal Growth Factor Receptor (EGFR) exon 19 deletion adenocarcinoma of the lung presented with de novo metastasis to the bone, lung, liver, and lymph nodes and developed subsequent T790 mutation and pleomorphic transformation at different disease sites. She was treated with a combination of pembrolizumab and osimertinib successfully after progression on both agents when previously used as monotherapy highlighting the importance of biopsy at the time of progression looking for tumor heterogeneity.

Introduction There is limited diversity in current hereditary multi-gene testing data-sets, leading to greater challenges in accurate variant classification. To address this, a collaboration between 3 Singapore-based healthcare organizations (Tan Tock Seng Hospital, National Cancer Centre Singapore and Lucence Diagnostics) pooled results from patients of East Asian, Southeast Asian and South Asian ancestry, representing over 60% of the world's population. We hypothesized that a multi-ethnic collaboration would provide deeper understanding of cancer predisposition genes, particularly in terms of novel variants. Methods A total of 704 cancer patients of multi-ethnic Asian (SE Asian, East Asian and South Asian) ethnicity with either a history of breast, ovarian, pancreatic or prostate cancer, were tested with multi-gene panels. All patients were tested by multi-gene testing, including but not limited to BRCA1/2, PALB2 and ATM. In addition to genetic testing, the family histories of the patients were collected. All variants were classified by ACMG criteria. Chi-square testing was used for statistical analysis. Results Three sites (TTSH, NCCS, and Lucence) pooled patients selected for breast (n=458), ovarian (n=176), pancreatic (n=61) and prostate cancer (n=25). The mean and median ages were 44.9 years and 43 years, respectively. Of the 704 patients, 209 had a history of cancer in their first degree relatives, 432 did not and 63 patients did not know of any cancers in their first degree relatives. 122 of 704 patients (17.33%) had pathogenic/likely pathogenic variants in any tested risk-related gene, of which 86 were in BRCA1/2, 11 in PALB2 and 4 in ATM. Some variants were detected in more than one patient. 212 of 704 patients (30.1%) had VUSs detected in any tested risk-related gene, with 32.1% in BRCA1/2. There was a positive association between multiple-cancer status and pathogenic variants (9/22 vs 113/682, p = 0.007). Most notably, among the unique pathogenic/likely pathogenic variants in BRCA1, BRCA2, PALB2 and ATM, 10.64% (5/47), 12.9% (4/31), 30% (3/10) and 25% (1/4) respectively were novel variants, not previously reported in ClinVar (Dec 2019). Conclusion To our knowledge, this is the largest regional multi-ethnic cohort of patients with breast, ovarian, pancreatic and prostate cancer undergoing comprehensive genetic testing. Only one third of patients reported a first-degree family history suggesting that testing ought to be performed if clinical suspicion is high. Notably, 14.1% of BRCA1/BRCA2/PALB2/ATM pathogenic/likely pathogenic variants detected in our cohort were novel variants, not hitherto published in ClinVar. In conclusion, this collaboration demonstrates that testing of Asian patients can enrich global understanding of cancer predisposition gene mutations. This will improve cancer prevention, surveillance, and treatment selection for cancer patients, such as the use of PARP inhibitors for genetic defects of DNA repair. Citation Format: Jens Samol, Wei Lim Chia, Liuh Ling Goh, Matthew Myint, Min-Han Tan, Ru Jin Tay, Hao Chen, Yukti Choudhury, Ann SG Lee. Germline homologous recombination deficiency pathway defects in a multi-ethnic East Asian, Southeast Asian and South Asian cancer patient cohort [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4600.

Patients with central airway obstruction (CAO) from advanced lung cancer present with significant morbidity and are assumed to have lower survival. Hence, they are offered only palliative support. We asked if patients who have advanced lung cancer with CAO (recanalised and treated) will behave similarly to those with advanced lung cancer without CAO. This study was a retrospective review of the medical records of the patients managed for advanced lung cancer during 2010 and 2015 at our institution. 85 patients were studied. Median survival and 1-, 2- and 5-year survival were 5.8 months, 30.3%, 11.7% and 2.3% versus 9.3 months, 35.7%, 9.6% and 4.7%, respectively, in the CAO and no CAO groups (p=0.30). More patients presented with respiratory failure (15 (35%) versus none; p=0.0001) and required assisted mechanical ventilation (10 (23.3%) versus none; p=0.001) in the CAO group compared with the no CAO group. Fewer patients received chemotherapy in the CAO group (11 (25.5%)) compared with the no CAO group (23 (54.7%); p=0.008). There was no difference in survival among patients with advanced lung cancer whether they presented with CAO or without CAO. Survival was similar to those without CAO in patients with recanalised CAO despite greater morbidity and lesser use of chemotherapy, strongly advocating bronchoscopic recanalisation of CAO. These findings dispel the nihilism associated with such cases., Survival is similar among patients with advanced lung cancer whether they present with CAO or without CAO http://ow.ly/djRE30iDH6V

For over two decades, the prognosis of patients with metastatic or locally advanced non-resectable bladder cancer has remained poor, with no significant advances in life-prolonging treatment, especially following progression on platinum-based chemotherapy or for cisplatin-ineligible patients. In recent years, immunotherapy has changed the standard of care for an increasing number of tumour types, including bladder cancer. Here, we will review the current evidence of the clinical usage of immune checkpoint inhibitors with a focus on programmed cell death-1 (PD-1) and programmed death-ligand 1 (PD-L1) inhibitors, as well as their toxicities, potential biomarkers and predictors of response, and provide an outline of future directions in the treatment of patients with metastatic and/or non-surgically curable urothelial bladder cancer.

Background Clarity and accuracy of the pharmacy aspects of cancer clinical trial protocols is essential. Inconsistencies and ambiguities in such protocols have the potential to delay research and jeopardise both patient safety and collection of credible data. The Chemotherapy and Pharmacy Advisory Service was established by the UK National Cancer Research Network, currently known as National Institute for Health Research Clinical Research Network, to improve the quality of pharmacy-related content in cancer clinical research protocols. This article reports the scope of Chemotherapy and Pharmacy Advisory Service, its methodology of mandated protocol review and pharmacy-related guidance initiatives and its current impact. Methods Over a 6-year period (2008–2013) since the inception of Chemotherapy and Pharmacy Advisory Service, cancer clinical trial protocols were reviewed by the service, prior to implementation at clinical trial sites. A customised Review Checklist was developed and used by a panel of experts to standardise the review process and report back queries and inconsistencies to chief investigators. Based on common queries, a Standard Protocol Template comprising specific guidance on drug-related content and a Pharmacy Manual Template were developed. In addition, a guidance framework was established to address ‘ad hoc’ pharmacy-related queries. The most common remarks made at protocol review have been summarised and categorised through retrospective analysis. In order to evaluate the impact of the service, chief investigators were asked to respond to queries made at protocol review and make appropriate changes to their protocols. Responses from chief investigators have been collated and acceptance rates determined. Results A total of 176 protocols were reviewed. The median number of remarks per protocol was 26, of which 20 were deemed clinically relevant and mainly concerned the drug regimen, support medication, frequency and type of monitoring and drug supply aspects. Further analysis revealed that 62% of chief investigators responded to the review. All responses were positive with an overall acceptance rate of 89% of the proposed protocol changes. Conclusion Review of pharmacy content of cancer clinical trial protocols is feasible and exposes many undetected clinically relevant issues that could hinder efficient trial conduct. Our service audit revealed that the majority of suggestions were effectively incorporated in the final protocols. The refinement of existing and development of new pharmacy-related guidance documents by Chemotherapy and Pharmacy Advisory Service might aid in better and safer clinical research.

Variable proportions of Hodgkin's disease (HD) cases are associated with the Epstein–Barr virus (EBV), but the role of EBV in HD is not entirely clear. Hodgkin and Reed–Sternberg (HRS) cells of EBV-associated HD are characterized by expression of the EBV gene product LMP1. In other cellular environments, LMP1 has been shown to induce interleukin (IL)-6. In this study, 105 HD cases were tested for differences in IL-6 expression among LMP1-positive and -negative cases. Isotopic in situ hybridization and correlation with the presence of EBV gene products revealed significantly higher proportions of cases with IL-6-expressing tumour cells in LMP1-positive (31 of 37, 84 per cent) as compared with LMP1-negative HD cases (35 of 68, 51 per cent). Thus, although not exclusive to EBV-positive HRS cells, IL-6 expression appears to be upregulated in EBV-associated HD. IL-6 receptor (CD126) expression was tested by in situ hybridization and found in a broad spectrum of cell types, regularly including HRS cells. Superinduction of IL-6 expression may be among the mechanisms by which EBV confers a growth advantage on virus-infected HRS cells and by which the virus may contribute to the morphological and clinical peculiarities of HD. © 1997 John Wiley & Sons, Ltd.

A lady in her seventies with a history of breast cancer and left mastectomy presented in summer 2000 with weight loss, hepatosplenomegaly and abnormal liver functions. Her chest x ray at that time revealed enlargement of the azygous node and evidence of left mastectomy, in addition to a well known calcified opacity in the left lower lobe (fig 1A). A CT scan confirmed mediastinal lymphadenopathy (fig 1B) and hepatosplenomegaly (fig 1C). Figure 1 A. Chest x ray showing left mastectomy, azygos node and calcified opacity in left lower lobe. B. CT showing mediastinal lymphadenopathy. C. CT showing hepatosplenomegaly. On mediastinal lymph node biopsy a …

Background The aim of this phase I study was to determine the safety and tolerability and to establish the maximum tolerated dose (MTD) of orally administered olaparib (AZD2281) in combination with topotecan in patients with advanced solid tumors. Patients and methods Patients aged ≥18 years with histologically or cytologically diagnosed advanced solid tumors for whom no suitable effective therapy exists were included. Patients in four cohorts received topotecan (0.5 mg/m2/day × 3 days or 1.0 mg/m2/day × 3 days) intravenously in combination with oral olaparib 50, 100 or 200 mg bid for six cycles. The primary objectives were to determine the safety and tolerability and to establish the MTD of olaparib in combination with topotecan. Results Twenty-one patients were enrolled and 19 received treatment. Dose-limiting toxicities were neutropenia and thrombocytopenia. The MTD was established as topotecan 1.0 mg/m2/day × 3 days plus olaparib 100 mg bid. The most common adverse events (AEs) included fatigue and gastrointestinal events. There was an olaparib and topotecan dose-related increase in neutropenia which was dose limiting. Conclusions Further development of olaparib and topotecan in combination was not explored due to dose-limiting hematological AEs and the resulting sub-therapeutic MTD.

Aim: The Chemotherapy and Pharmacy Advisory Service (CPAS) was established in 2007 by the UK National Cancer Research Network (NCRN) to improve the quality of pharmacy-related issues in clinical research protocols. We report the scope and methodology of the CPAS, and its impact on the quality of clinical research protocols. Methods: All clinical research protocols were independently reviewed by a minimum of three health professionals including at least one oncology pharmacist, using a customised protocol review checklist (assessing 12 areas of clinical oncology/pharmacy). A collated review was subsequently drafted by the CPAS pharmacy advisor and returned to the chief investigators. A working party performed a systematic review of all protocol reviews conducted by CPAS during the 6-year period since its inception (2008-2013) and categorised the remarks. A service evaluation audit was conducted to check response rate and acceptance rate of the proposed changes with chief investigators. Results: During the 6 year systematic review period a total of 176 clinical research protocols were reviewed. The median number of remarks per protocol was 26 of which 20 were deemed clinically relevant. The majority of clinically relevant remarks concerned the drug regimen, guidelines concerning support medication, frequency and type of monitoring and drug supply aspects. Further analysis of the 176 protocols reviewed revealed that 62% of chief investigators responded to the review. All responses were positive with an overall acceptance rate of 89% of the proposed protocol changes. Conclusions: Review of pharmacy aspects regarding clinical cancer research protocols is feasible and reveals many undetected clinically relevant issues that could hinder efficient trial conduct. Our service audit revealed that the very large majority of suggestions were effectively incorporated in the final protocols. Disclosure: All authors have declared no conflicts of interest.

We present a 21-year-old HIV-negative Somalian male who was diagnosed with an immunohistochemically proven human herpes virus 8 (HHV8)-positive primary penile Karposi’s Sarcoma (KS). He was treated with local surgery and remained in complete clinical remission for 18 months. This is the first case of a heterosexual teenage and young adult (TYA) patient diagnosed with a primary penile KS without a history of sexual intercourse. This case provides clinical evidence that KS may be transmitted through routes other than sexual transmission.

A 51-year-old patient was treated with chemotherapy for two synchronous colon cancers and was diagnosed with Lynch syndrome. The patient also suffered a cardiac arrest and was also diagnosed with a long QT syndrome (LQTS) subsequently. This is the first case of a co-existence of Lynch syndrome and LQTS.

We present a case of a 64-year-old man who was diagnosed with a primary anaplastic large cell lymphoma of the central nervous system (PCNSAL). He had received radical chemotherapy and radiotherapy for a non-small cell lung cancer (NSCLC) in the past. There is no known association between NSCLC and PCNSAL. We describe the diagnostic and therapeutic challenges associated with these rare intracranial lymphomas and highlight the potential role of newer biological agents in patients with anaplastic lymphoma kinase (ALK-1) positive PCNSAL.

A 67-year-old woman with metastatic colorectal cancer was given her first oxaliplatin infusion as part of the XELOX protocol. She developed chest pain with ECG changes leading subsequently to a diagnosis of coronary artery spasm. To our knowledge, this is the first report of oxaliplatin-induced coronary artery spasm.

Tumor cells of Epstein-Barr virus (EBV)-associated Hodgkin's disease (HD) express the viral protein, latent infection membrane protein-1 (LMP1), but evade cytotoxic responses normally directed at this antigen. We tested whether local production of the immunoregulatory interleukins (IL)-4 and -10 may have a role in this process. IL-4 RNA was not detectable in any of the HD cases. By contrast, isotopic in situ hybridization and correlation with the presence of EBV gene products showed significantly higher proportions of cases with IL-10 expressing tumor cells in LMP1-positive (17 of 26, 66%) as compared with LMP1-negative HD cases (six of 37, 16%). Absence of EBV BCRF1 RNA indicated that the transcripts originated from the cellular IL-10 gene. Similarly, an association between IL-10 expression and EBV-infection of tumor cells was found in AIDS-related malignant non-Hodgkin lymphomas (ARL). Very small proportions of EBV-infected cells, mainly blasts, expressed IL-10 in infectious mononucleosis tonsils. Thus, although not entirely exclusive to EBV-positive cases, IL-10 expression is frequently associated with EBV-infection in HD and ARL and appears to be upregulated by EBV, most likely through LMP1. In view of the established inhibitory effects of IL-10 on cell mediated immunity, it is suggested that IL-10 expression may contribute to evasion of LMP1- positive cells from cytotoxicity directed at viral antigens.