Curative Setting Research Articles

The impact of the COVID-19 pandemic on the diagnosis, stage, and treatment of esophagogastric cancer

BackgroundThe COVID-19 pandemic has affected the entire global healthcare system, including oncological care. This study investigated the effects of the COVID-19 pandemic on the diagnosis, stage, and treatment of esophagogastric cancer in the Netherlands.MethodsPatients diagnosed in 2020 were divided into 5 periods, based on the severity of the COVID-19 pandemic in the Netherlands, and compared to patients diagnosed in the same period in the years 2017–2019. Patient characteristics and treatments were evaluated for esophageal cancer (EC) and gastric cancer (GC) separately.ResultsThe number of esophagogastric cancer diagnoses decreased prominently during the first 2 months of the COVID-19 pandemic. During this period, a significantly higher percentage of GC patients was diagnosed with incurable disease (52.5% in 2017–2019 and 67.7% in 2020, p = 0.011). We observed a significant reduction in the percentage of patients with potentially curable EC treated with resection and neoadjuvant chemoradiotherapy (from 35.0% in 2017–2019 to 27.3% in 2020, p < 0.001). Also, patients diagnosed with incurable GC were treated less frequently with a resection (from 4.6% in 2017–2019 to 1.5% in 2020, p = 0.009) in the second half of 2020.ConclusionsCompared to previous years, the number of esophagogastric cancer diagnoses decreased in the first 2 months of the COVID-19 pandemic, while an increased percentage of patients was diagnosed with incurable disease. Both in the curative and palliative setting, patients were less likely to be treated with a surgical resection.

Caveolin-1 protein expression as a prognostic biomarker of gastrointestinal tumours: A systematic review and meta-analysis.

Gastrointestinal (GI) cancers remain a major threat worldwide, accounting for over 30% of cancer deaths. The identification of novel prognostic biomarkers remains a challenge despite significant advances in the field. The CAV1 gene, encoding the caveolin-1 protein, remains enigmatic in cancer and carcinogenesis, as it has been proposed to act as both a tumour promoter and a tumour suppressor. To analyse the differential role of caveolin-1 expression in both tumour cells and stroma in relation to prognosis in GI tumours, we performed a systematic review and meta-analysis according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines; PROSPERO registration number: CRD42022299148. Our analysis showed that high levels of caveolin-1 in tumour cells were associated with poor prognosis and inferior overall survival (OS) in oesophageal and pancreatic cancer and hepatocellular carcinoma (HCC), but not in gastric and colorectal cancer. Importantly, our study showed that higher stromal caveolin-1 expression was associated with significantly longer OS and disease-free survival in colorectal cancer. Analysis of stromal caveolin-1 expression in the remaining tumours showed a similar trend, although it did not reach statistical significance. The data suggest that caveolin-1 expression in the tumour cells of oesophageal, pancreatic cancer and HCC and in the stroma of colorectal cancer may be an important novel predictive biomarker for the clinical management of these diseases in a curative setting. However, the main conclusion of our analysis is that caveolin-1 expression should always be assessed separately in stroma and tumour cells.

A phase 2 study of neoadjuvant chemotherapy plus durvalumab in resectable locally advanced head and neck squamous cell carcinoma.

Patients with locally advanced head and neck squamous cell cancer (HNSCC) are treated with surgery followed by adjuvant (chemo) radiotherapy or definitive chemoradiation, but recurrence rates are high. Immune checkpoint blockade improves survival in patients with recurrent/metastatic HNSCC; however, the role of chemo-immunotherapy in the curative setting is not established. This phase 2, single-arm, multicenter study evaluated neoadjuvant chemo-immunotherapy with carboplatin, nab-paclitaxel, and durvalumab in patients with resectable locally advanced HNSCC. The primary end point was a hypothesized pathologic complete response rate of 50%. After chemo-immunotherapy and surgical resection, patients received study-defined, pathologic risk adapted adjuvant therapy consisting of either durvalumab alone (low risk), involved field radiation plus weekly cisplatin and durvalumab (intermediate risk), or standard chemoradiation plus durvalumab (high risk). Between December 2017 and November 2021, 39 subjects were enrolled at three centers. Oral cavity was the most common primary site (69%). A total of 35 of 39 subjects underwent planned surgical resection; one subject had a delay in surgery due to treatment-related toxicity. The most common treatment-related adverse events were cytopenias, fatigue, and nausea. Post treatment imaging demonstrated an objective response rate of 57%. Pathologic complete response and major pathologic response were achieved in 29% and 49% of subjects who underwent planned surgery, respectively. The 1-year progression-free survival was 83.8% (95% confidence interval, 67.4%-92.4%). Neoadjuvant carboplatin, nab-paclitaxel, and durvalumab before surgical resection of HNSCC were safe and feasible. Although the primary end point was not met, encouraging rates of pathologic complete response and clinical to pathologic downstaging were observed.

The Dental Oncology Complication that Wouldn’t go Away

Background: Bone modifying agents are used throughout cancer care and their utilisation can optimise advanced stage cancer cases with bone metastases, by reducing skeletal-related events, treatment-induced bone loss and treatment hypercalcaemia. They are also used in patients with a curative intent such as early breast cancer, reducing recurrence and increasing survival rates. Medication-related osteonecrosis of the jaw (MRONJ) is a potential complication following bone modifying agents (BMAs). It represents exposed bone in the maxillofacial region which significantly compromises the quality of life for these patients. Dental disease is the most common initiating factor of MRONJ. We report a case in which MRONJ has dominated cancer care despite its successful treatment. Case presentation: A 69-year-old female was diagnosed with a breast cancer (grade 1, infiltrating ductal carcinoma, pT1c pN1mi(sc) Mx), for which she was treated with a wide local excision and axillary lymph-node clearance. Seven years after initial presentation, the patient presented with metastatic disease involving the left supraclavicular fossa, bone, peritoneum, and liver. Her BMA regime included zoledronic acid intravenous (IV) every month for 12 months and switched to oral zoledronic acid for a subsequent year due to poor venous access. Two years after her diagnosis of metastatic disease, the patient presented with exposed bone in her anterior maxilla, which represented advanced stage MRONJ (AAOMS 3). The exposed bone in the maxilla was treated surgically by sequestrectomy and fistula closure. Three years later (12 years after initial breast cancer diagnosis), the patient was re-admitted with a cervical fascial space infection involving the right mandible. The patient developed another site of advanced- stage MRONJ (AAOMS 3) in the right mandible associated with an orocutaneous fistula. The patient had a marginal resection of her mandible, fistula closure and extraction of the remaining teeth under general anesthetic. Conclusion: The practicing oncologist needs to be cognisant of the possibility of MRONJ in both the curative and palliative setting. Traditionally, oncology care has required a significant degree of self-reliance on patients to navigate dental treatment pathways. Integration of dental clinics into oncology pathways would help eliminate this need for self-reliance. MRONJ is an inevitable risk for a large cohort of oncology patients and active engagement of dental-oncology specialities will ensure optimal care for patients.

Treatment Algorithm for Patients With Gastric Adenocarcinoma: Austrian Consensus on Systemic Therapy - An Update.

Over the last decade, therapeutic options for patients with gastric cancer have improved significantly. However, despite these recent advances, mortality is still substantial. Surgery and chemotherapy represent the cornerstones of patient management. Immune checkpoint inhibitors as well as targeted treatments such as HER2-directed therapies and antiangiogenic agents contribute to improved patient prognosis. Herein, we present the updated version of an Austrian consensus on the systemic treatment of patients with gastric adenocarcinoma and adenocarcinoma of the lower gastroesophageal junction, including those with human epidermal growth receptor 2 (HER2) overexpression, microsatellite instability, programmed death-ligand 1 (PD-L1)-positive disease, and claudin 18.2 positivity. The consensus considers the curative setting as well as first-line and later-line systemic treatment options in advanced disease. For HER2-positive disease, HER2 testing is discussed in addition to a review of first-line and later-line therapies. Potential future therapies are also listed, with a focus on targeted [e.g., fibroblast growth factor receptor 2 (FGRF2)-directed] treatments that might provide a further step forward in the management of patients with gastric cancer.

Efgartigimod restores muscle function in a humanized mouse model of immune-mediated necrotizing myopathy.

Immune-mediated necrotizing myopathies (IMNMs) are severe forms of myositis often associated with pathogenic anti-3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) autoantibodies (aAbs). Efgartigimod is an engineered human IgG1 Fc fragment that antagonizes the neonatal Fc receptor (FcRn), thereby preventing recycling and promoting lysosomal degradation of IgG, including aAbs. We evaluated the therapeutic effects of IgG reduction by efgartigimod in a humanized murine model of IMNM. Disease was induced in C5-deficient (C5def) or Rag2-deficient (Rag2-/-) mice receiving co-injections of anti-HMGCR+ IgG from an IMNM patient and human complement. C5def mice were treated in a preventive setting with s.c. injections of efgartigimod and Rag2-/- mice in a curative setting after disease was induced by anti-HMGCR+ IgG injections. Anti-HMGCR aAbs levels were monitored in mouse serum and muscle tissue. Histological analysis was performed on muscle sections. Muscle force was assessed by grip test or measurement of gastrocnemius strength upon electrostimulation. Administration of efgartigimod rapidly reduced total IgG levels, including the level of pathogenic anti-HMGCR aAbs, in both serum (P < 0.0001) and muscle (P < 0.001). In the preventive setting, efgartigimod prevented myofibre necrosis (P < 0.05), thus precluding loss of muscle strength (P < 0.05). In the therapeutic setting, efgartigimod prevented further necrosis and allowed muscle fibre regeneration (P < 0.05). Hence, muscle strength returned to normal (P < 0.01). Efgartigimod reduces circulating IgG levels, including pathogenic anti-HMGCR+ IgG aAbs, in a humanized mouse model of IMNM, preventing further necrosis and allowing muscle fibre regeneration. These results support investigating the therapeutic efficacy of efgartigimod through a clinical trial in IMNM patients.

Challenges and Opportunities With the Use of Hypofractionated Radiation Therapy in Cancer Care: Regional Perspectives From South Korea, Japan, Singapore, and Australia

Hypofractionated radiotherapy schedules provide higher per-fraction radiation doses delivered in fewer fractions than conventional schedules. This novel delivery method is supported by a large body of clinical trial evidence across various cancer sites in both curative and palliative settings. Hypofractionation is associated with benefits such as lower costs, improved patient access and increased treatment precision, which has led to its inclusion in various treatment guidelines. Despite this, utilization is not uniform across cancer sites and geographic regions due to reasons such as reimbursement models, nuances in healthcare systems, and professional culture. Key factors to ensure patients benefit from access to high quality radiotherapy include publishing clinical evidence, cross-country collaboration to fill knowledge gaps, reviewing reimbursement models, and improving patient advocacy in treatment decision-making.

Optimizing the safety of antibody-drug conjugates for patients with solid tumours.

Over the past 5 years, improvements in the design of antibody-drug conjugates (ADCs) have enabled major advances that have reshaped the treatment of several advanced-stage solid tumours. Considering the intended rationale behind the design of ADCs, which is to achieve targeted delivery of cytotoxic molecules by linking them to antibodies targeting tumour-specific antigens, ADCs would be expected to be less toxic than conventional chemotherapy. However, most ADCs are still burdened by off-target toxicities that resemble those of the cytotoxic payload as well as on-target toxicities and other poorly understood and potentially life-threatening adverse effects. Given the rapid expansion in the clinical indications of ADCs, including use in curative settings and various combinations, extensive efforts are ongoing to improve their safety. Approaches currently being pursued include clinical trials optimizing the dose and treatment schedule, modifications of each ADC component, identification of predictive biomarkers for toxicities, and the development of innovative diagnostic tools. In this Review, we describe the determinants of the toxicities of ADCs in patients with solid tumours, highlighting key strategies that are expected to improve tolerability and enable improvements in the treatment outcomes of patients with advanced-stage and those with earlystage cancers in the years to come.

Effect of Conventional and Ultrahigh Dose Rate FLASH Irradiations on Preclinical Tumor Models: A Systematic Analysis

Compared with conventional dose rate irradiation (CONV), ultrahigh dose rate irradiation (UHDR) has shown superior normal tissue sparing. However, a clinically relevant widening of the therapeutic window by UHDR, termed "FLASH effect," also depends on the tumor toxicity obtained by UHDR. Based on a combined analysis of published literature, the current study examined the hypothesis of tumor isoefficacy for UHDR versus CONV and aimed to identify potential knowledge gaps to inspire future in vivo studies. A systematic literature search identified publications assessing in vivo tumor responses comparing UHDR and CONV. Qualitative and quantitative analyses were performed, including combined analyses of tumor growth and survival data. We identified 66 data sets from 15 publications that compared UHDR and CONV for tumor efficacy. The median number of animals per group was 9 (range 3-15) and the median follow-up period was 30.5 days (range 11-230) after the first irradiation. Tumor growth assays were the predominant model used. Combined statistical analyses of tumor growth and survival data are consistent with UHDR isoefficacy compared with CONV. Only 1 study determined tumor-controlling dose (TCD50) and reported statistically nonsignificant differences. The combined quantitative analyses of tumor responses support the assumption of UHDR isoefficacy compared with CONV. However, the comparisons are primarily based on heterogeneous tumor growth assays with limited numbers of animals and short follow-up, and most studies do not assess long-term tumor control probability. Therefore, the assays may be insensitive in resolving smaller response differences, such as responses of radioresistant tumor subclones. Hence, tumor cure experiments, including additional TCD50 experiments, are needed to confirm the assumption of isoeffectiveness in curative settings.

Evolution of HER2 scores after neoadjuvant systemic therapy in breast cancer.

3139 Background: Breast cancer (BC) is a malignancy with a wide array of histopathological characteristics and tumor heterogeneity leading to major clinical implications for management. With the recent approval of antibody-drug conjugates (ADCs) for human epidermal growth factor receptor 2 (HER2)-low advanced BC, there is increased significance for characterizing the spectrum of HER2 expression in the curative setting. Methods: We conducted a single institution retrospective review of patients with BC who received neoadjuvant systemic therapy (NAST) followed by definitive surgical resection from 2008 to 2022. The initial tumor biopsies were tested for estrogen receptor (ER), progesterone receptor (PR), and HER2 status per ASCO/CAP guidelines and repeated on the residual tumor tissue after NAST. HER2 status was categorized into HER2-negative (IHC 0), HER2-low (IHC 1 or IHC 2/ Fluorescence in situ hybridization [FISH] negative), and HER2-positive (IHC 2/ FISH positive or IHC 3). Concordance and discordance with HER2 status in the pre and post NAST tumor samples were analyzed using descriptive statistics. Results: Of 340 patients with BC who received NAST, 55 patients with residual disease had pre and post treatment biomarker data available for analysis. Prevalence of HER2-low was 70.9 % (39/55) in the pretreatment tumors while it was 58.2% (32/55) in the post treatment tumors. 40% of tumors (22/55) had HER2 discordance while 60% (33/55) demonstrated concordance with HER2 expression after NAST. Among the changes in HER2 status, a shift from HER2-low to HER2-negative status occurred most frequently in 18.2% of tumors (10/55). In tumors with HER2 discordance, 36.4% (8/22) were also noted to have changes in ER or PR status while this was seen in 48.5% (16/33) of tumors with HER2 concordance. For rates of recurrence, 22.7% (5/22) of patients in the HER2 discordant group had relapsed compared to 18.2% (6/33) patients in the HER2 concordant group. Conclusions: Dynamics of HER2 expression is increasingly important in the rapidly changing therapeutic landscape of BC. Our study shows high prevalence of HER2-low expression in tumors with residual disease after NAST and frequent conversion of HER2-low to HER2-negative status with NAST. Further studies are warranted to determine the clinical and therapeutic relevance of biomarker evolution and tumor heterogeneity in the curative setting. [Table: see text]

Rapid establishment of patient-derived organoids from treatment-naive head and neck cancer patients for drug and radiosensitivity screening.

e18043 Background: Patient-derived organoids (PDOs) have been shown to be powerful tools for modeling disease and patient-individualized drug sensitivity screening, opening a novel avenue to precision medicine. A major challenge for guidance of clinical decisions is the extended time frame for establishing these models. Here, we report the feasibility of a refined protocol for PDO generation from head neck squamous cell carcinoma (HNSCC) tumors, suitable to guide personalized treatment decisions in the curative setting. Methods: After informed consent, tumor tissue specimens from 145 newly diagnosed HNSCC patients were collected during diagnostic biopsy or curative surgery. Following mechanic / enzymatic dissociation and initial expansion in 2D cultures, tumor cells were seeded in extracellular matrix (Matrigel) to form PDOs. Primary endpoint of the study was the PDO engraftment rate. In additio, the time needed for ex vivo expansion of PDO cultures for personalized drug/radiosensitivity testing was determined. Interference of patient and tumor characteristics with PDO engraftment was analyzed using SPSS version 27. Results: The PDO engraftment rate in the entire cohort was 51% (n = 74 of 145 patients). Neither tumor stage, grading, anatomical sublocalisation, HPV status nor sample type (biopsy vs. surgical specimen) were significantly associated with PDO establishment. Of note, Kaplan-Meier analysis revealed a trend between successful ex vivo engraftment and reduced overall survival (log-rank: p = 0.09), suggesting preferential engraftment of aggressive poor prognosis tumors. Engraftment rate in the subgroup of patients with recommendation for adjuvant chemoradiation was 58%. Time for expansion of PDO cultures for subsequent drug/radiation screening was 18.5 ± 9.6 days (median ± SD). Expansion was completed before start of adjuvant chemoradiation in all but one cases. Conclusions: Our study suggests feasibility of PDO generation for locally advanced aggressive HNSCC within a timeframe suitable for guiding treatment decisions for adjuvant therapy. Planned future directions include clinical validation of drug testing results for individual patients and clinical study cohorts.

Real-world experience of checkpoint inhibitors across India: CRSF 2020-01.

e18862 Background: There are limited data available from India on the real-world use of checkpoint inhibitors. Hence we did this analysis across India to study the pattern of use and outcomes with checkpoint inhibitors. Methods: This was a retrospective multicentric protocol. Patients who received immunotherapy from January 2016 to October 2021 were included. The baseline demographic, previous treatment, response, date of progression, date of death and status were noted. SPSS version 20 was used for analysis. Descriptive statistics were performed. Kaplan Meier method was used for estimation of progression-free survival (PFS) and overall survival (OS). COX regression model was used to identify factors impacting OS. Results: We identified 308 patients in the study. The median age was 58.5 years (Interquartile range 51-66 years) and there was a male preponderance (249, 80.8%). The 3 commonest sites of use were head and neck cancer in 144 patients (46.8%), lung cancer in 81 (26.3%) and renal cell carcinoma in 31(10.1) patients. The ECOG PS was 0-1 in 215 (70%), 2 in 71 (23.1), 3-4 in 21(6.8%) and not documented in 1(0.3%) patient. The two most common checkpoint inhibitors used were nivolumab and pembrolizumab 255 (82.8%) and 37(12%) patients respectively. These were used in curative setting in 6 patients (1.9%) and palliative in rest all. 43(14%) patients received them as first-line in, 129 (41.9) as second-line and beyond the second line in 130 (42.2%) patients. The response rate was 24% (n = 74). The median PFS was 4.067 (95%CI 3.45-4.67) and the median OS was 10.0 months (95%CI 6.2-13.8). Among the factors tested for impact on OS the ECOG PS 0-1 ( HR-0.493 95%CI 0.324-0.749; P = 0.001), non head and neck site of the disease (HR-2.134 95%CI 1.164-3.911) and reception of immunotherapy in first line setting (HR -0.533 95%CI 0.295-0.963: P = 0.037) had an favorable impact on OS. Conclusions: Checkpoint inhibitors provide similar efficacy as those seen in pivotal studies in real-world settings.

Hypofractionation Adoption in Prostate Cancer Radiotherapy: Results of an International Survey.

Hypofractionation is noninferior to conventional fractionation in the treatment of localized prostate cancer. Using results from the European Society of Radiation Oncology's (ESTRO) Global Impact of Radiotherapy in Oncology (GIRO) initiative survey on hypofractionation, this study identifies rates of adoption, facilitating factors, and barriers to adoption of hypofractionation in prostate cancer across World Bank income groups. The ESTRO-GIRO initiative administered an international, anonymous, electronic survey to radiation oncologists from 2018 to 2019. Physician demographics, clinical practice characteristics, and hypofractionation regimen use (if any) for several prostate cancer scenarios were collected. Responders were asked about specific justifications and barriers to adopting hypofractionation, and responses were stratified by World Bank income group. Multivariate logistic regression models were used to analyze variables associated with hypofractionation preference. A total of 1,157 physician responses were included. Most respondents (60%) were from high-income countries (HICs). In the curative setting, hypofractionation was most often preferred in low- and intermediate-risk prostate cancers, with 52% and 47% of respondents reporting hypofractionation use in ≥50% of patients, respectively. These rates drop to 35% and 20% in high-risk prostate cancer and where pelvic irradiation is indicated. Most respondents (89%) preferred hypofractionation in the palliative setting. Overall, respondents from upper-middle-income countries and lower-middle- and low-income countries were significantly less likely to prefer hypofractionation than those from HICs (P < .001). The most frequently cited justification and barrier were availability of published evidence and fear of worse late toxicity, respectively. Hypofractionation preference varies by indication and World Bank income group, with greater acceptance among providers in HICs for all indications. These results provide a basis for targeted interventions to increase provider acceptance of this treatment modality.

Apollo: A randomized phase II double-blind study of olaparib versus placebo following curative intent therapy in patients with resected pancreatic cancer and a pathogenic BRCA1, BRCA2, or PALB2 mutation—ECOG-ACRIN EA2192.

TPS4202 Background: A meaningful subset of PDAC is characterized by a homologous recombination deficiency (HRD). The most well-defined patients within this group are those with pathogenic variants in BRCA1, BRCA2 and PALB2. In the metastatic setting, PARP inhibitor maintenance provides a progression-free survival benefit after a period of platinum based chemotherapy1,2, but the role of PARP inhibitors in the curative intent setting is undefined. The OlympiA study established one year of olaparib as the standard of care for patients with BRCA-related, early stage breast cancer who completed all other curative-intent treatment3. Therefore, we have designed a randomized, phase II double-blind study of one year of olaparib vs placebo in patients with pancreatic cancer and a germline or somatic variant in BRCA or PALB2 who have completed all curative intent therapy. Methods: We have enrolled and treated 29 of 152 planned patients on study NCT 04858334/EA2192. Eligibility criteria include: a pathogenic germline or somatic variant in BRCA1, BRCA2 or PALB2 as determined by local laboratory (central review required); completion of curative-intent resection and ≥ three months of multi-agent chemotherapy; no evidence of recurrent disease. At enrollment, patients must be within 12 weeks of their last anti-cancer intervention. Patients are randomized 2:1 to receive oral olaparib 300 mg twice daily or placebo for 12 28-day cycles. The primary endpoint is relapse-free survival. Overall survival is a secondary endpoint. Tumor tissue, fecal material (for microbiome analysis) and serial ctDNA samples are being collected. 1) Golan T, Locker GY, Kindler HL: Maintenance Olaparib for Metastatic Pancreatic Cancer. Reply. N Engl J Med 381:1492-1493, 2019. 2) Reiss KA, Mick R, O'Hara MH, et al: Phase II Study of Maintenance Rucaparib in Patients With Platinum-Sensitive Advanced Pancreatic Cancer and a Pathogenic Germline or Somatic Variant in BRCA1, BRCA2, or PALB2. J Clin Oncol 39:2497-2505, 2021. 3) Tutt ANJ, Garber JE, Geyer CE, Jr.: Adjuvant Olaparib in BRCA-Mutated Breast Cancer. Reply. N Engl J Med 385:1440, 2021. Clinical trial information: NCT04858334 .

Profile of toxicities and quality of life in long-term survivors treated with immunotherapy: A prospective cross sectional trial.

6569 Background: Long-term cancer survivors (LTS) patients (pts) treated with immunotherapy (IT) represent a relatively new population whose characteristics, such as long-term toxicities, quality of life (QoL), and financial toxicities, need to be elucidated in a real-world setting. The aim of this study is to evaluate long-term toxicities in patients free of disease progression and treated with IT. Methods: This is a cross-sectional, multicentric study, involving ten Italian centres. Pts should have started IT (as monotherapy or combination, either in curative or adjuvant setting) more than 2 years before accrual and they needed to be progression free at last follow up (fup). Subjects who discontinued IT for disease progression or who started any subsequent line of systemic treatment were excluded. We retrieved baseline demographic and clinical characteristics of the pts, as well as haematological and biochemical exams at the start of IT (baseline) and at the last fup. We also assessed the patient's toxicities (according to CTCAE v5.0) at last fup and we submitted to each patient three questionnaires: PRO-CTCAE (selection of questions), EORTC QLQ C30, and FITALY (for financial toxicities), which were analysed according to subdomains. Results: We enrolled 141 LTS pts treated with IT from 2013 to 2022. Median age was 69 years (35-88), most were male (72%), and still receiving IT at time of last fup (72%). Primary tumour was in lung (43%), genito-urinary tract (26%), or melanoma (14%). IT included pembrolizumab and nivolumab in 40% and 32% of cases, respectively. The median global health status of QoL was 83 (IQR 25). Any toxicities &gt; G2 negatively impacted on individual functional scales (physical, p=0.02; role, p= 0.06; and social p=0.08). A higher baseline Charlson Comorbidity Index was associated with worse global health status (p=0.02) at last fup. Most frequent low grade adverse events were fatigue, dyspnoea, and insomnia; younger age (&lt; 65 years) was associated with higher pain (p=0.04). PRO-CTCAE questionnaires showed that the prevalent complained symptoms were rheumatological and cutaneous, regardless of tumor site. The most affected domain of financial toxicities was financial stress, including costs for out of pocket medications and transports. Pts with melanoma (p=0.01), with skin toxicities (p=0.04), and younger than 65 years (p=0.01) were at higher risk of financial toxicities (global score). Conclusions: Overall QoL is well preserved in LTS treated with IT. At long term fup, the pts complained mostly about rheumatological and skin adverse events. Financial stress due to out of pocket costs was the most affected financial toxicity domain. Baseline comorbidities predicted a worse long-term global health status, while young age, skin toxicities and melanoma predicted higher financial toxicities.

HELP — Heidelberg decision aid for lung cancer patients: a randomized controlled clinical trial

BackgroundShared decision-making (SDM), which increases the patient’s well-being, adherence, and success of treatment, is becoming increasingly important in medicine and especially in oncology. To empower patients to participate more actively in consultations with their physicians decision aids have been developed. In non-curative settings, such as the treatment of advanced lung cancer, decisions differ substantially from the curative setting, as uncertain gains in terms of survival outcomes and quality of life have to be weighed against the severe side effects of treatment regimens. There is still a lack of tools developed and implemented for such specific settings in cancer therapy that support shared decision-making. The aim of our study is to evaluate the effectiveness of the HELP decision aid.MethodsThe HELP-study is designed as a randomized, controlled, open monocenter trial with two parallel groups. The intervention consists of the use of the HELP decision aid brochure, accompanied by a decision coaching session. The primary endpoint is clarity of personal attitude as operationalized by the Decisional Conflict Scale (DCS) after the decision coaching. Randomization will be performed as stratified block randomization according to the characteristic of preferred decision-making at baseline with a 1:1 allocation.The participants in the control group get usual care, i.e., the doctor-patient conversation takes place without preliminary coaching and deliberation about their preferences and goals.DiscussionDeveloping decision aids (DA) for (lung) cancer patients with limited prognosis should empower patients to address these aspects and include information about “Best Supportive Care” as a treatment option. Using and implementing the decision aid HELP can not only give patients the possibility to include their personal wishes and values in the decision-making process, but also raise the awareness of shared decision-making itself among these patients and their physicians.Trial registrationGerman Clinical Trial Register DRKS00028023. Registered on 8 February 2022.

Immunotherapies in non-metastatic gastrointestinal cancers.

Over the last decade, immune checkpoint inhibitors (ICI) have emerged as cornerstone in the treatment of many metastatic tumour types, including gastrointestinal cancers. In many solid tumours, the effective therapies in the metastatic field are progressively brought into the curative setting. Consequently, earlier tumoural settings have become a field of experiment for immunotherapies. In melanoma, lung, and bladder cancers, excellent results were recorded, possibly explained by differences in the tumour microenvironment between metastatic and non-metastatic settings. In gastrointestinal (GI) Oncology, nivolumab is the first immune checkpoint inhibitor to become a standard-of-care adjuvant treatment after curative surgery for oesophagal or gastroesophageal junction cancer. We herein discuss the results of a selection of the most relevant studies presented/published over the last 18 months testing immunotherapies in non-metastatic GI cancers. Among immunotherapies, ICI have been investigated in pre-, peri- and postoperative setting across tumour types, alone or in combination with chemo- and/or radiotherapy. Vaccines are also a new field of investigation. Promising results from two studies (NCT04165772 and NICHE-2 study) demonstrating never-seen-before responses to neoadjuvant immunotherapy in MMR deficient (dMMR) colorectal cancers raise hope for improving the patients' outcome and developing organ-sparing strategies in this situation.

Perioperative therapy with FLOT4 significantly increases survival in patients with gastroesophageal and gastric cancer in a large real-world cohort.

In 2019, the FLOT4 protocol was established as the new standard for perioperative therapy in patients with locally advanced gastroesophageal and gastric cancer. Whether this protocol is beneficial in a real-world setting remains a question with limited answers to date. In our study, a large cohort of unselected patients treated with FLOT4 was analyzed and compared to protocols based on 5-FU/platinum derivative. This retrospective analysis included patients with locally advanced gastroesophageal and gastric cancer treated with perioperative FLOT or 5-FU/platinum derivative at University Hospital, Bonn between 2010 and 2022 in a curative setting (n=99). Overall survival, disease-free survival, therapy response and therapy complications were analyzed. Patients treated with FLOT showed a statistically significant longer median overall survival of 57.8 vs 28.9 months (HR: 0.554, 95% CI: 0.317-0.969, P=.036). Moreover, pathological tumor regression (pTR) was significantly higher in the FLOT group compared to the 5-FU/platinum group (P=.001). Subgroup analysis showed a favorable survival benefit for the FLOT vs 5-FU/platinum derivate in patients with AEG and non-signet cell carcinoma. Overall, FLOT was tolerated well but CTCAE ≥3 grade neutropenia and diarrhea occurred more often within the FLOT group. Similar to the prospective phase II/III trials, FLOT4 was the best protocol for patients with locally advanced gastroesophageal and gastric cancer as perioperative therapy in terms of overall survival and pathological response rate compared to 5-FU/platinum derivative protocols. Interestingly, patients with gastroesophageal cancer benefitted more from this therapy. In contrast, patients with signet ring cells appear not to benefit from addition of docetaxel.

Role of microsatellite instability and HER2 positivity in locally advanced esophago-gastric cancer patients treated with peri-operative chemotherapy.

Neoadjuvant chemotherapy (NAC) significantly improved the prognosis of patients with locally advanced gastric cancer (LAGC). Several biomarkers, including HER2 and MMR/MSI are crucial for treatment decisions in the advanced stage but, currently, no biomarkers can guide the choice of NAC in clinical practice. Our aim was to evaluate the role of MSI and HER2 status on clinical outcomes. We retrospectively collected LAGC patients treated with NAC and surgery +/- adjuvant chemotherapy from 2006 to 2018. HER2 and MSI were assessed on endoscopic and surgical samples. Pathologic complete response (pCR) rate, overall survival (OS), and event-free survival (EFS) were estimated and evaluated for association with downstaging and MSI. We included 76 patients, 8% were classified as MSI-H, entirely consistent between endoscopic and surgical samples. Six percent of patients were HER2 positive on endoscopic and 4% on surgical samples. Tumor downstaging was observed in 52.5% of cases, with three pCR (5.1%), none in MSI-H cancers. According to MSI status, event-free survival (EFS) and overall survival (OS) were higher for MSI-H patients to MSS [EFS not reached vs 30.0 months, p=0.08; OS not reached vs 39.6 months, p=0.10]. Our work confirms the positive prognostic effect of MSI-H in the curative setting of LAGC, not correlated with pathologic tumor downstaging. Prospective ad-hoc trial and tumor molecular profiling are eagerly needed.

Pharmacoeconomics of novel pharmacotherapies in triple-negative breast cancer

ABSTRACT Introduction Triple-negative breast cancer (TNBC) represents the most aggressive breast cancer subtype carrying unfavorable clinical outcomes. Although traditionally chemotherapy has represented the only systemic treatment option available, novel drugs have changed the treatment landscape, granting approval by regulatory agencies worldwide, while determining new economic struggles on health systems for their high prices. Areas covered In this review, we provided a comprehensive analysis of pharmacoeconomic studies of drugs recently approved in the early and advanced settings of TNBC. Expert opinion Novel systemic treatment options redefined the therapeutic algorithms for TNBC by establishing new paradigms, based on substantial clinical benefits. Pembrolizumab and olaparib in the curative setting portend high value, as shown with the use of value frameworks, resulting in cost-effective interventions. In the metastatic setting, new drugs have demonstrated mixed improvements in patient-centric end-points, resulting often in interventions unlikely to have good value for money. We believe that cost-effectiveness alone is not a metric to inform the opportunity to invest on new interventions, while the intrinsic value of medicines should be the driver of the decisions. We endorse a patient-centric priority setting that can ensure health system sustainability, to timely deliver innovative cancer care to all in need and positively impact on population health.