Months Of Adjuvant Chemotherapy Research Articles

Early detection of occupational cholangiocarcinoma in a high-risk patient under intensive surveillance: a case study

BackgroundOccupational cholangiocarcinoma is associated with exposure to organic solvents, such as dichloromethane (DCM) and 1,2-dichloropropane (DCP). This report describes a case of occupational cholangiocarcinoma detected through regularly imaging following the discovery of elevated serum γ-glutamyl trans peptidase (γ-GTP) levels revealed during regular checkup.Case presentationA 43-year-old man who had been working in a printing company with 15 years of exposure to organic solvents presented to our hospital owing to abnormalities found during a routine checkup. Ultrasound (US) imaging revealed thickening of the gallbladder wall accompanied by gallstones, although in the blood tests, γ-GTP levels were within normal range. Given the high risk of cholangiocarcinoma development, the patient underwent regular monitoring with abdominal US and blood tests at a local doctor's office. At the age of 48, his serum γ-GTP level mildly elevated for the first time, prompting the initiation of semi-annual magnetic resonance cholangiopancreatography (MRCP). By the age of 50 years, dilation in B8 was detected, and one and a half years later, a tumor on the central side of the B8 dilation appeared. The patient was diagnosed with intrahepatic cholangiocarcinoma, which was treated with anterior sectionectomy. Pathological examination revealed an adenocarcinoma with a papillary glandular ductal structure at the root of the B8. In addition, biliary intraepithelial neoplasia (BilIN) and dysplasia have been identified around the tumor and periphery bile ducts and in noncancerous bile ducts. Postoperatively, the patient received 6 months of adjuvant chemotherapy with S-1monotherapy. Eight months after surgery, the patient remained under observation with no signs of recurrence.ConclusionsWe report a case of occupational cholangiocarcinoma detected during a prolonged period of regular follow-up after exposure to DCM and DCP. Given the delayed carcinogenesis process, occupational cholangiocarcinomas manifest long after exposure to organic solvents, therefore, ongoing screening is extremely important. Vigilance is essential to avoid underdiagnosis, particularly for individuals who are at an increased risk of developing this form of cancer. Continuous monitoring is key to the early detection and effective management of occupational cholangiocarcinoma.

An expatiate review on adjuvant chemotherapy of colorectal cancer

Colorectal cancer is the second leading cause of cancer-related death and the third most common cancer globally. For loco regional colon cancer, surgery is the sole curative option. Adjuvant chemotherapy aims to eliminate micro metastases and increase survival. It has been most convincingly proven in stage III illness, even though there is ongoing debate on the usefulness of adjuvant chemotherapy for stage II illness. For the past fifteen years, six months of adjuvant chemotherapy with an oxaliplatin-based chemotherapy has been the accepted standard of care for stage III colon cancer. It is still advised to use 6 months of adjuvant chemotherapy for individuals with stage II illness and high clinicopathological risk. Chemo radiation therapy (CRT) is frequently used as neoadjuvant or adjuvant therapy in the treatment of stage II and stage III rectal cancers because this cancer type has a higher risk of local recurrence than other cancer types.

Personalized treatment in localized pancreatic cancer

SummaryThe treatment elements used for pancreatic ductal adenocarcinoma (PDAC) include surgical resection, systemic cytotoxic agents, and targeted drugs. For second- and third-line therapies in PDAC, approximately 15% of patients have actionable mutations although only 2.5% receive matched targeted treatment but with a significant improvement in survival of around 16 months. For the majority of PDAC patients the current most effective strategy is surgical resection of the primary tumor and systemic combination chemotherapy. The chemotherapy regimens and the order of delivery relative to the resection reference point have been based to a large extent on randomized trials using a newly developed empirical staging (Em) system. Although the reductionist TNM based AJCC and UICC systems work well for pathology staging, they are less accurate and less manageable for treatment decision-making. This Em system defines locally resectable (EmR), borderline resectable (EmBR), and unresectable (EmUR) stages, plus the emerging entity of oligometastatic disease (EmOm). For EmR patients, 6 months of adjuvant chemotherapy achieves 5‑year survival rates of 30–50%. In EmBR short-course (2 months) neoadjuvant plus 6‑month adjuvant chemotherapy increases 12-month survival rates to around 77%, compared to 40% for upfront surgery, despite resection rates of 64–85% and 75%, respectively. Longer-course (4 months) neoadjuvant chemotherapy has also been shown to achieve an 18-month overall survival of 67%. In EmUR, induction therapy (3–6 months) may result in resections rates of 20–60% with significantly improved survival rates compared to no resection. For all stages including the polymetastatic (EmPm) setting, patients with good performance status receive combination chemotherapies based on either oxaliplatin (FOLFIRINOX or NALIRIFOX) or gemcitabine (GEM-CAP, or Gem-NabP). Molecular subtypes (Moffitt, Collisson, Bailey, and Cheng-Sen-Yue) are shown to be associated with treatment responses. Transcriptomic signatures have also been developed as classifiers for determining either oxaliplatin- or gemcitabine-based therapies (PurIST, Tiriac, GemPred+, and ESPAC) and are being evaluated in various studies. Most notably the ESPAC transcriptomic signature is being used as the treatment classifier in the experimental arms of the randomized ESPAC6 adjuvant trial in EmR patients and the ESPAC7 induction therapy trial in EmUR patients. Genomic and transcriptomic profiling at baseline and over time is an integral part of ESPAC6/7 to deepen our understanding of tumor plasticity during the course of therapy, identifying the intrinsic (persister cell) and acquired (genetic) tumor plasticity evolving over time and in reaction to different therapies in order to enable a scientific approach to overcoming clonal-resistance clades.

Impact of sarcopenia on S1 adjuvant chemotherapy and prognosis in pancreatic cancer patients.

Although the importance of adjuvant chemotherapy (AC) has been recognized in pancreatic cancer (PC) patients, there are few studies to address the underlying mechanisms of failure to complete AC. This study aims to investigate the relationship between nutritional state represented by sarcopenia and failure to complete AC in patients after curative-intent surgery for PC. This study included 110 patients who underwent pancreaticoduodenectomy for potentially resectable pancreatic cancers with intention of adjuvant S-1. Sarcopenia was defined using the psoas muscle mass index with cutoff values of 6.36 cm2/m2 for men and 3.92 cm2/m2 for women, which were calculated with a 3-D volumetric software. The relation between sarcopenia and successful AC and long-term survival were investigated. Twenty-nine (26%) patients were diagnosed as having sarcopenia (Sarcopenia group). Sarcopenia group comprised significantly older patients than Non-sarcopenia group (72 vs. 67 years old, p = 0.0087). AC was successfully completed in 14 patients (48%) in Sarcopenia group compared to 72 patients (89%) in Non-sarcopenia group (p < 0.0001). Multivariate analysis identified age ≥ 70 years and sarcopenia as significant risk factors for failure of AC. Among patients ≥ 70 years old, rate of successful AC was significantly higher in sarcopenia groups than non-sarcopenia group (17% vs. 78%, p < 0.001). In conclusions, age and sarcopenia were critical risk factors for the failure of 6 months of adjuvant chemotherapy. Among elderly patients, sarcopenia can predict the poor success rate of AC.

Changes in Prescribing Patterns in Stage III Colon Cancer.

For patients with resected stage III colon cancer, 6 months of adjuvant fluoropyrimidine-based chemotherapy has been the standard of care. The IDEA collaboration aimed to evaluate whether 3 months of adjuvant chemotherapy was noninferior to 6 months. Despite failing to meet its primary endpoint, the subgroup analyses demonstrated noninferiority based on regimen and treatment duration when a risk-stratified approach was used. To evaluate the impact of the results of the IDEA collaboration, we evaluated adjuvant chemotherapy prescribing practice patterns, including planned adjuvant treatment regimen and duration from January 1, 2016, to January 31, 2021. The time period was selected to evaluate chemotherapy prescribing patterns prior to the abstract presentation of the IDEA collaboration in June 2017 and after full manuscript publication in March 2018. A total of 399 patients with stage III colon cancer who received adjuvant chemotherapy were included in the analysis. A significant increasing trend for use of 3 months of adjuvant chemotherapy was observed after presentation of the IDEA abstract (P<.001). A significant change in CAPOX (capecitabine/oxaliplatin) prescribing was also observed, increasing from 14% of patients prior to presentation of the IDEA abstract to 48% after presentation (P<.001). Comparing 3 months of CAPOX with 6 months of FOLFOX (fluorouracil/leucovorin/oxaliplatin), 3 months of CAPOX use also steadily increased over time (adjusted odds ratio [aOR], 1.28; 95% CI, 1.20-1.37; P<.001). Among subgroups of interest, no differences in adoption of CAPOX were observed. The adoption of 3 months of CAPOX was similar in patients with low-risk cancer (aOR, 1.27; 95% CI, 1.17-1.37) and those with high-risk cancer (aOR, 1.31; 95% CI, 1.16-1.47). Despite the IDEA collaboration failing to demonstrate noninferiority of 3 months' duration of adjuvant therapy compared with 6 months, the findings have influenced practice prescribing patterns, favoring CAPOX and a shorter duration of planned adjuvant treatment.

Lessons from the COVID-19 Pandemic: A New Paradigm in Treating Patients with Colorectal Cancer

Starting in 2020 and continuing for 2 years thereafter, the COVID-19 pandemic has greatly affected routine clinical practice, particularly in treating patients with gastrointestinal cancer. Delay, postponement or refusal to continue multimodal treatment have increased the number of emergency cases, and consequently patient morbidity and mortality. Many recommendations have been announced to guide the adaptation of clinical practice during and after the COVID-19 pandemic. Although early diagnosis and screening should proceed as usual before the pandemic, adjuvant treatment for patients with gastrointestinal cancer should be evaluated in the future. For example, during the pandemic, most recommendations state that adjuvant treatment for patients with colorectal cancer is still required, and many adaptations have been suggested according to local conditions. In some instances, 6 months of adjuvant chemotherapy has been modified to an optional 3 month duration. A common challenge is that most patients remain unsure about the decreased chemotherapy duration, although many guidelines recommend this modified treatment strategy. Short term follow up has already indicated promising clinical outcomes of this modified adjuvant duration, but the long-term outcomes remain to be evaluated.

440TiP TRESBIEN (OGSG 2101): Encorafenib, binimetinib and cetuximab for early relapse stage II/III BRAF V600E-mutated CRC

The BRAF V600E mutation accounts for approximately 5% of colorectal cancer (CRC) cases and is an extremely poor prognostic factor. There are no clear recommendations for patients with early recurrent BRAF V600E-mutated CRC, during or after adjuvant chemotherapy. Recently, triplet therapy of encorafenib, binimetinib, and cetuximab, resulted in significantly longer overall survival and a higher response rate than standard chemotherapy in patients with previously treated metastatic CRC with the BRAF V600E mutation (Kopetz S, N Engl J Med. 2019.). Furthermore, in first-line treatment for BRAF V600E-mutated CRC, triplet therapy showed a promising response rate and disease control rate (Cutsem EV, Ann Oncol. 2021). These results suggest that triplet therapy may be effective even in early recurrent BRAF V600E-mutated CRC during or after adjuvant chemotherapy. The TRESBIEN study is an open-label, multicenter, single-arm phase II study designed to evaluate whether encorafenib, binimetinib, and cetuximab are effective for patients with early recurrent BRAF V600E-mutated CRC during or after adjuvant chemotherapy (jRCTs051210152). The main inclusion criteria were BRAF V600E- mutated stage II/III colorectal adenocarcinoma after radical resection, recurrence during or within six months of adjuvant chemotherapy with measurable lesions, no prior treatment with encorafenib, binimetinib, or cetuximab, age ≥ 20 years, ECOG PS 0 to 2, with adequate organ function. Patients will receive encorafenib, binimetinib, and cetuximab. The primary endpoint was objective response rate. To achieve 90% power to show a significant response benefit with a one-sided alpha level of 0.05, assuming a threshold objective response rate of 6.0% and an expected value of at least 26.0%, we estimated that 25 patients were required. The secondary endpoints included overall survival, progression-free survival, disease control rate, duration of response, time to treatment failure, and safety. This is the first study to investigate whether triplet therapy combined with encorafenib, binimetinib, and cetuximab is effective for the treatment of early recurrent BRAF V600E-mutated CRC. The first patient was enrolled in January 2022. jRCTs051210152. Osaka Gastrointestinal cancer chemotherapy Study Group (OGSG).

Perioperative chemotherapy with mFOLFOX6 or CAPOX for patients with locally advanced colon cancer (OPTICAL): A multicenter, randomized, phase 3 trial.

3500 Background: Adjuvant chemotherapy is the recommended standard treatment for resected stage III and high-risk stage II colon cancer, but disease recurrence remain common. Perioperative chemotherapy has proved effective in several tumors, but not in colon cancer. We aimed to assess whether perioperative chemotherapy could improve outcomes in patients with locally advanced colon cancer. Methods: In this multicenter, randomized, phase 3 trial, participants were recruited from 28 hospitals in China. Eligible patients were aged 18-75 years, had a colon adenocarcinoma, with radiologically staged locally advanced (T3 with ≥5 mm invasion beyond the muscularis propria or T4 assessed by CT). Patients were randomly assigned (1:1) to either the experimental group or standard of care group, stratified by center, cT stage, and cN stage. The experimental group received 3 months of neoadjuvant chemotherapy with mFOLFOX6 or CAPOX, then surgery, then 3 months of adjuvant chemotherapy. The standard of care group received immediate surgery, and optional adjuvant chemotherapy (per physician’s discretion according to pathological stage ). The primary endpoint was disease-free survival assessed in the intention-to-treat population at 3 years. Results: Between January 6, 2016, and April 3, 2021, 752 patients were enrolled and randomly assigned to a treatment, of whom 744 were eligible (371 in the experimental group; 373 in the standard of care group). At a median follow-up of 32.5 months (IQR 19.2-45.7), 3-year disease-free survival rates were 78.7% (95%CI 73.8-83.5) in the experimental group and 76.6% (95%CI 71.8-81.4) in the standard of care group (stratified HR 0.83, 95%CI 0.60-1.15; p = 0.138). A pathological complete response was achieved in 26 (7%) of 371 patients in the experimental group. 69 (19%) patients in the experimental group had low pathological disease stage (pT0-2N0) compared with 16 (4%) of 373 in the standard of care group (p &lt; 0.0001). 3-year overall survival rates were 94.9% (95%CI 92.1-97.7) in the experimental group and 88.6% (95%CI 84.6-92.5) in the standard of care group (stratified HR 0.47, 95%CI 0.25-0.87; p = 0.012). The post hoc subgroup analyses revealed perioperative chemotherapy induced an increase in disease-free survival in female patients (HR 0.54, 95%CI 0.31-0.83; p = 0.025). Conclusions: In patients with locally advanced colon cancer, perioperative chemotherapy with mFOLFOX6/CAPOX increased chance of pathological downstaging, but did not improve disease-free survival compared with standard of care. Clinical trial information: NCT02572141. [Table: see text]

Revised Nodal Staging Integrating Tumor Deposit Counts With Positive Lymph Nodes in Patients With Stage III Colon Cancer.

We evaluated the prognostic value of tumor deposit (TD) counts and incorporated them with the number of positive lymph nodes to develop a revised nodal staging. The current American Joint Committee on Cancer (AJCC) staging on colon cancer includes the TDs only for nodenegative patients, as N1c, and their counts are not considered. We included consecutive patients with stage III colorectal cancer who underwent curative resections between January 2010 and December 2019. The patients were grouped as TD 0, TD 1, TD 2, or TD ≥3 based on their TD counts. Disease-free survival and overall survival were compared. Of 2446 eligible stage III patients, 658 (26.9%) had TDs. Among them, 500 (76.0%) patients concurrently had positive lymph nodes (LNs). TD counts were significantly related to worse disease-free survival (DFS) and overall survival regardless of pT stages or the number of positive LNs. The patients were restaged based on the integrated number of TD counts and positive LNs. The N3 stage, which had ≥10 integrated TDs and positive LNs, was newly classified. Among the patients who completed 6 months of adjuvant chemotherapy, those upstaged to N2 from an initial stage of N1 experienced significantly worse DFS than those confirmed as N1 in the revised N staging. The newly N3-staged patients showed significantly worse DFS than the patients initially staged as N2. Revised N staging using the integrated number of TD counts and positive LNs could predict DFS more accurately than current staging. It would also draw greater attention to the patients with high-risk stage III colon cancer staged as N3.

A Novel Nutrition-Based Nomogram to Predict Prognosis After Curative Resection of Gastric Cancer.

Objective: We sought to investigate the prognostic significance of body composition and weight change during the first 6 months of adjuvant chemotherapy after R0 resection and develop novel nomograms to accurately predict relapse-free survival (RFS) and overall survival (OS).Methods: This retrospective study included 190 patients who underwent curative radical gastrectomy for gastric cancer and received adjuvant chemotherapy. The changes in weight and body composition including skeletal muscle index (SMI), subcutaneous adipose tissue (SAT), and visceral adipose tissue (VAT) were analyzed for 6 months. LASSO Cox regression and multivariate Cox regression were conducted to evaluate other clinical characteristics, which were used to construct a nomogram for the prediction of 3- and 5-year RFS and OS. The constructed nomogram was subjected to 1,000 resamples bootstrap for internal validation. The Concordance index (C-index) and time-dependent receiver operating characteristic (t-ROC) curves were used to evaluate and compare the discriminative abilities of the new nomograms, non-nutritional nomograms, and pTNM stage.Results: The median follow-up duration was 42.0 (25.2–55.1) months. Factors included in the newly-built nomogram for RFS were pT stage, pN stage, tumor site, tumor size, nerve invasion or not, surgery type, and change of L3SMI, while factors included in the nomogram for OS were pT stage, pN stage, tumor size, nerve invasion or not, surgery type, and change of L3SMI. The C-index and t-ROC indicated that our newly-built nomograms had greater potential to accurately predict prognosis than the non-nutritional nomograms and pTNM stage system. Besides, oral nutritional supplements can reduce the degree of weight and L3SMI loss.Conclusion: Change in skeletal muscle mass during adjuvant chemotherapy can be incorporated into predictive prognostic nomograms for RFS and OS in GC patients after radical resection. Dynamic changes in body composition and weight during adjuvant chemotherapy contribute to the early detection of poor outcomes.

GRECO-2: A Randomized, Phase 2 Study of Stereotactic Body Radiation Therapy (SBRT) in Combination with GC4711 in the Treatment of Unresectable or Borderline Resectable Nonmetastatic Pancreatic Cancer (PC)

New therapeutic approaches are needed to improve survival in PC. The GRECO-2 study is designed to examine survival benefit of adding GC4711 to multi-modality treatment in selected patients, responsive to first line (m)FOLFIRINOX. While systemic treatment of PC has improved, rates of surgical resection - considered optimum treatment - remain low due to toxicity and disease progression during induction chemotherapy. SBRT is practiced enhancing resection rates and has shifted to higher dose delivery (Mellon 2015, Colbert 2018), but timing and appropriate patient selection are under constant debate. SBRT delivery over 50Gy exhibits superior cell killing compared to conventionally RT but carries potential GI toxicity risk (Zhong 2017). GC4711 is a selective superoxide dismutase mimetic that converts superoxide to hydrogen peroxide. As radiation response modifiers, dismutase mimetics have the potential to increase tumor control without compromising radiation safety (Sishc, AACR 2019). GC4711 consistently augmented the anti-tumor activity of SBRT in PC experimental xenograft mouse models. In a pilot Phase 1/2 trial (GC4419-101), subjects with locally advanced PC were randomized to receive SBRT with a selective dismutase mimetic or placebo. This pilot trial has demonstrated acceptable safety with SBRT (5 × 10-11Gy), as well as apparent improvements in survival, surgical resection, locoregional control, and time to distant metastases. Altogether, these data support the hypothesis that GC4711 may improve tumor outcomes and the benefit-risk ratio of 5-fraction SBRT delivering 50Gy by improving efficacy without increasing GI toxicity.GRECO-2 is a Phase 2, multicenter, randomized, double-blind, placebo-controlled study (NCT04698915) to determine the effect on the overall survival of adding GC4711 to SBRT following 4 months of chemotherapy in subjects with unresectable or borderline nonmetastatic PC. Approximately 160 subjects will be randomized (20 sites) to receive GC4711 100 mg or placebo IV infusion over 15 min, prior to each SBRT (5×10Gy). All subjects will then complete 2 additional months of adjuvant chemotherapy. Subjects judged operable will be operated within 8 weeks after SBRT. Secondary endpoints address resection rates, local and distant disease progression, and safety, while exploratory studies include ctDNA, immune profiling, PRO-CTCAE, CA19.9 normalization, and radiomics.For trial progress, see NCT04698915.GC4711 may improve the benefit-risk ratio of 5-fraction SBRT and drive survival benefit of local treatment of chemotherapy responsive PC patients.

Identification of GPC3 mutation and upregulation in a multidrug resistant osteosarcoma and its spheroids as therapeutic target

BackgroundDrug resistance and the lack of molecular therapeutic target are the main challenges in the management of osteosarcomas (OSs). Identification of novel genetic alteration(s) related with OS recurrence and chemotherapeutic resistance would be of scientific and clinical significance. MethodsTo identify potential genetic alterations related with OS recurrence and chemotherapeutic resistance, the biopsies of a 20-year-old male osteosarcoma patient were collected at primary site (p-OS) and from its metastatic tumor (m-OS) formed after 5 months of adjuvant chemotherapy. Both OS specimens were subjected to cancer-targeted next generation sequencing (NGS) and their cell suspensions were cultured under three-dimensional condition to establish spheroid therapeutic model. Transcript-oriented Sanger sequencing for GPC3, the detected mutated gene, was performed on RNA samples of p-OS and m-OS tissues and spheroids. The effects of anti-GPC3 antibody and its combination with cisplatin on m-OS spheroids were elucidated. ResultsNGS revealed 4 mutations (GPC3, SOX10, MDM4 and MAPK8) and 6 amplifications (MDM2, CDK4, CCND3, RUNX2, GLI1 and FRS2) in p-OS, and 3 mutations (GPC3, SOX10 and EGF) and 10 amplifications (CDK4, CCND3, MDM2, RUNX2, GLI1, FRS2, CARD11, RAC1, SLC16A7 and PMS2) in m-OS. Among those alterations, the mutation abundance of GPC3 was the highest (56.49%) in p-OS and showed 1.54 times increase in m-OS. GPC3 transcript-oriented Sanger sequencing confirmed the mutation at 1046 in Exon 4, and immunohistochemical staining showed increased GPC3 production in m-OS tissues and its spheroids. EdU cell proliferation and Calcein/PI cell viability assays revealed that of the anti-OS first line drugs (doxorubicin, cisplatin, methotrexate, ifosfamide and carboplatin), 10 μM carboplatin exerted the best inhibitory effects on the p-OS but not the m-OS spheroids. 2 μg/mL anti-GPC3 antibody effectively committed m-OS spheroids to death by itself (76.43%) or in combination with cisplatin (92.93%). ConclusionThis study demonstrates increased abundance and up-regulated expression of mutant GPC3 in metastatic osteosarcoma and its spheroids with multidrug resistance. As GPC3-targeting therapy has been used to treat hepatocellular carcinomas and it is also effective to OS PDSs, GPC3 would be a novel prognostic parameter and therapeutic target of osteosarcomas.

401P Translation of the IDEA trial into clinical practice: Evaluation of implementation of a new guideline

The pivotal IDEA trial showed marginal differences in survival outcomes for 3 vs 6 months of adjuvant chemotherapy (ACT) in stage II and III colon cancer (CC). Severe treatment toxicity was substantially lower in the short treatment regimen. Therefore, in 2017 the Dutch colorectal cancer (CRC) guideline was revised and currently recommends 3 months of oxaliplatin (OX)-based ACT. In addition, the definition of high-risk stage II CC was restricted to include only pathological T4 (pT4) tumors (instead of presence of poor differentiation, lymph node harvest <10, lymphovascular invasion and perforation/obstruction at presentation).

Advances in the treatment of gastric cancer: 2020-2021.

To review studies from 2020 to 2021 in esophagogastric cancer. After up front D2 gastrectomy for lymph node-positive gastric cancer, 6 months of adjuvant chemotherapy with S-1 and oxaliplatin achieved superior disease-free survival (DFS) compared with 1 year of S-1. The addition of adjuvant radiotherapy, however, added no benefit. After chemoradiotherapy and surgery in esophageal and gastroesophageal junction cancer, in patients with residual disease found at surgery, 1 year of adjuvant nivolumab substantially improved DFS compared with observation alone, leading to regulatory approval for adjuvant nivolumab. In metastatic esophagogastric cancer, the addition of either pembrolizumab or nivolumab to first-line chemotherapy improved response, disease free, and overall survival with the greatest survival benefit dependent on programmed death receptor ligand, programmed death receptor ligand -1 status, leading to regulatory approval for these agents. A preliminary report of a phase 3 trial adding pembrolizumab to first-line chemotherapy with trastuzumab in HER2-positive gastric cancer reported a significant improvement in response, leading to regulatory approval for pembrolizumab. The fibroblast growth factor receptor appears to be a promising new target in gastroesophageal cancer based on phase 2 data for bemarituzumab. Optimal adjuvant chemotherapy after D2 resection of node-positive gastric cancer is 6 months of a fluorinated pyrimidine and oxaliplatin, with no benefit for adjuvant radiotherapy. Adjuvant nivolumab after resection of esophageal cancer after chemoradiotherapy improves DFS and is a new care standard. Pembrolizumab added to first-line chemotherapy in both HER2-positive and negative esophagogastric cancer improves outcome and is a new standard of care. Nivolumab added to first-line chemotherapy in HER2-negative gastric cancer improves treatment outcome and is a new care standard.

Niraparib for Advanced Breast Cancer with Germline BRCA1 and BRCA2 Mutations: the EORTC 1307-BCG/BIG5-13/TESARO PR-30-50-10-C BRAVO Study.

To investigate the activity of niraparib in patients with germline-mutated BRCA1/2 (gBRCAm) advanced breast cancer. BRAVO was a randomized, open-label phase III trial. Eligible patients had gBRCAm and HER2-negative advanced breast cancer previously treated with ≤2 prior lines of chemotherapy for advanced breast cancer or had relapsed within 12 months of adjuvant chemotherapy, and were randomized 2:1 between niraparib and physician's choice chemotherapy (PC; monotherapy with eribulin, capecitabine, vinorelbine, or gemcitabine). Patients with hormone receptor-positive tumors had to have received ≥1 line of endocrine therapy and progressed during this treatment in the metastatic setting or relapsed within 1 year of (neo)adjuvant treatment. The primary endpoint was centrally assessed progression-free survival (PFS). Secondary endpoints included overall survival (OS), PFS by local assessment (local-PFS), objective response rate (ORR), and safety. After the pre-planned interim analysis, recruitment was halted on the basis of futility, noting a high degree of discordance between local and central PFS assessment in the PC arm that resulted in informative censoring. At the final analysis (median follow-up, 19.9 months), median centrally assessed PFS was 4.1 months in the niraparib arm (n = 141) versus 3.1 months in the PC arm [n = 74; hazard ratio (HR), 0.96; 95% confidence interval (CI), 0.65-1.44; P = 0.86]. HRs for OS and local-PFS were 0.95 (95% CI, 0.63-1.42) and 0.65 (95% CI, 0.46-0.93), respectively. ORR was 35% (95% CI, 26-45) with niraparib and 31% (95% CI, 19-46) in the PC arm. Informative censoring in the control arm prevented accurate assessment of the trial hypothesis, although there was clear evidence of niraparib's activity in this patient population.

GRECO-2: A randomized, phase 2 study of stereotactic body radiation therapy (SBRT) in combination with GC4711 in the treatment of unresectable or borderline resectable nonmetastatic pancreatic cancer (PC).

TPS4175 Background: While systemic treatment of PC has improved, rates of surgical resection - considered optimum treatment - remain low. Patients with un-resectable or borderline PC still have poor outcomes, with both toxicity and disease progression during induction chemotherapy limiting the number eligible for surgery. SBRT practice to enhance margin negative resection or to provide local control, if inoperable after neoadjuvant therapy, has shifted to higher dose delivery (Mellon 2015, Colbert 2018), but timing and appropriate patient selection are under constant debate. SBRT delivery over 50Gy exhibits superior cell killing compared to conventionally fractionated RT but carries potential GI toxicity risk (Zhong 2017). GC4711 is a selective superoxide dismutase mimetic that converts superoxide to hydrogen peroxide. As radiation response modifiers, dismutase mimetics have the potential to increase tumor control without compromising radiation safety (Sishc, AACR 2019). GC4711 consistently augmented tumor control by SBRT in PC experimental xenograft mouse models. In a pilot phase 1/2 trial (GC4419-101), subjects with locally advanced PC were randomized to receive SBRT plus either the selective dismutase mimetic GC4419 or placebo. This pilot trial has demonstrated acceptable safety with SBRT (5 × 10-11Gy), as well as apparent improvements in survival, surgical resection, locoregional control, and time to distant metastases. Altogether, these data support the hypothesis that GC4711 may improve tumor outcomes and the benefit-risk ratio of 5-fraction SBRT delivering 50Gy by improving efficacy without increasing GI-toxicity. Methods: GRECO-2 is a phase 2, multicenter, randomized, double-blind, placebo-controlled study to determine the effect on overall survival of adding GC4711 to SBRT following 4 months of chemotherapy in subjects with un-resectable or borderline non-metastatic PC. Approximately 160 subjects will be enrolled at over 20 sites to receive GC4711 100 mg or placebo IV given as IV infusion over 15 min, prior to each of 5 SBRT fractions of 10Gy). Subjects judged operable will be explored within 8 weeks after SBRT. All subjects will complete 2 additional months of adjuvant chemotherapy. Primary end point is overall survival and secondary endpoints address resection rates, local and distant disease progression, and safety, while exploratory studies include ctDNA, tumor exome/transcriptome sequencing, and immune profiling, patient-reported symptoms (PRO-CTCAE), CA19.9 normalization, and radiomics. Colbert L, Rebueno N, Moningi S et al Advances in Radiation Oncology (2018) 3, 693-700 Mellon EA, Hoffe SE, Springett GM, et al Acta Oncologica, 2015;54:7 Zhong J, Patel K, Switchenko J, et al. Cancer. 2017 Sep 15;123(18):3486-3493. Sishc BJ, Saha D, Story MD. AACR PADC 2019 C52. Clinical trial information: NCT04698915.

Benefit of Oxaliplatin in Stage III Colon Cancer According to IDEA Risk Groups: Findings from the ACCENT Database of 4934 Patients

BackgroundThe International Duration Evaluation of Adjuvant Chemotherapy (IDEA) pooled analysis compared 3 to 6 months of adjuvant chemotherapy for stage III colon cancer. Patients were classified into low risk and high risk, suggesting low-risk patients may be offered only 3 months of treatment. In this study, we aimed to assess the benefit of oxaliplatin in the adjuvant setting per IDEA risk groups, using data from 3 large adjuvant phase III studies, namely Multicenter International Study of Oxaliplatin/Fluorouracil/ Leucovorin in the Adjuvant Treatment of Colon Cancer (MOSAIC), C-07, and XELOXA. MethodsUsing the MOSAIC, C-07, and XELOXA previously published studies, we identified 2810 low-risk and 2124 high-risk patients with stage III colon cancer. We used Cox regression model to evaluate the magnitude of survival differences between IDEA risk groups, according to oxaliplatin use. Based on design similarity and equivalent follow-up data, MOSAIC and C-07 were pooled, whereas XELOXA was analyzed separately. Subgroup analyses were also performed for T4 and/or N2 patients. ResultsIndividuals with IDEA low and high risk derived overall survival benefit from the addition of oxaliplatin to adjuvant chemotherapy, with adjusted hazard ratios of 0.79 (0.66-0.95) and 0.84 (0.71-0.99), respectively. Among individuals with IDEA high risk, those with T4 disease did not gain overall survival benefit from addition of oxaliplatin with hazard ratio of 0.95 (0.71-1.27). Similar results were demonstrated using data from the XELOXA study. ConclusionIDEA risk classification per se does not predict benefit from addition of oxaliplatin to adjuvant chemotherapy in stage III colon cancer. T4 disease may predict lack of benefit from oxaliplatin addition.

Three Months of CAPOX Acceptable in High-Risk Stage II Colon Cancer

The International Duration of Adjuvant Chemotherapy (IDEA) collaboration, which compared 3 versus 6 months of adjuvant chemotherapy in nearly 13,000

Adjuvant Chemotherapy After Neoadjuvant Chemotherapy for Pancreatic Cancer is Associated with Improved Survival for Patients with Low-Risk Pathology.

With limited evidence, the benefit of adjuvant chemotherapy (AT) after completion of neoadjuvant chemotherapy (NT) and surgical resection for patients with pancreatic adenocarcinoma is debated. Guidelines recommend 6 months of AT for patients receiving NT. However, the patient-derived benefit from additional AT remains unknown. The National Cancer Database from 2006 to 2015 was used to identify patients undergoing NT. The chi-square test and multivariable logistic regression were used to identify differences between those receiving only NT and those receiving NT and AT. Survival analysis using the Kaplan-Meier method and the Cox proportional hazard ratio model was applied to the entire cohort and to subgroups with differing lymph node ratios (LNRs), tumor sizes, grades, and surgical margin statuses. Of the 3897 patients who received NT, 36.7 % received additional AT. Analysis of the entire cohort showed that associated survival was significantly improved with NT and AT compared with NT alone (hazard ratio [HR], 0.83; p < 0.001). In the subgroup analysis, the survival benefit of additional AT remained significant for those with negative nodal disease, an LNR lower than 0.15, low-grade histology, and negative margin status. Overall survival did not differ between those receiving NT only and those receiving NT and AT in the group with an LNR of 0.15 or higher, high-grade histology, and positive margins. This study identified an increasing trend in the use of AT after NT and showed an associated survival benefit for subgroups with low-risk pathologic features. These results suggest that the addition of AT after NT likely beneficial for these subgroups.

Clinicopathological characteristics and impact on efficacy of three versus six months of adjuvant chemotherapy in early-onset colon cancer: ACHIEVE and ACHIEVE-2 trials.

60 Background: Colorectal cancer (CRC) incidence and mortality have decreased since the 1970s but several data such as the SEER CRC registry show that the incidence of early onset colon cancer (eoCC, age 20-49) and RC keep increasing. There is limited results suggesting eoCC may have different behaviors compared to traditional CC (tCC, age ≥ 50). Methods: Individual patient data of 1,805 high-risk stage II/III colon cancer (CC) patients (pts) as the modified ITT population in ACHIEVE and ACHIEVE-2 trials were investigated. Clinicopathological features and treatment-related data were assessed by age group. Disease-free survival (DFS) was assessed by Kaplan-Meier curves and Cox multivariable models adjusted by trials, regimen, T and N. Results: Of the 1,805 pts, eoCC were 155 pts (8.6%). Using 5% difference between age groups as clinically meaningful cutoff, eoCC had similar gender (female, 52 vs 48%), PS (PS = 1, 1 vs 4%), risk group (high-risk, 43 vs 42%) and T stage (T4, 30 vs 30%) as tCC, while eoCC were less likely right-sided colon primary (32 vs 39%), had N1 disease (48 vs 54%), and treated by FOLFOX (16 vs 23%). Overall, eoCC significantly had a worse DFS than tCC (3y-DFS, 75 vs 82%; Adjusted Hazard Ratio = 1.40: 95% Confidence Interval, 1.00-1.95: p= 0.0478); in addition, similar DFS were observed among tCC pts (age 50-69 vs &gt;70). eoCC experienced less neutropenia, thrombocytopenia and stomatitis, but had more diarrhea, nausea and/or vomiting. There were 38 and 297 pts with an initial relapse in eoCC and tCC, respectively. Of those, peritoneal metastases were more frequently seen in eoCC (n = 13, 34%) than in tCC (n = 63, 21%) (p = 0.097), whereas liver and lung metastases were similar between the two groups. Impact on DFS of 3 versus 6 months of adjuvant chemotherapy in eoCC (3y-DFS, 75% vs 76%) is similar to that in tCC (83% vs 81%). Conclusions: eoCC had unique characteristics; the difference in DFS between eoCC and tCC were potentially due to a different metastatic spread. eoCC had a different adverse event profile compared to tCC. No impact on DFS of treatment duration in eoCC was suggested. Clinical trial information: UMIN000013036.