ALLIANCE A022104/NRG-GI010: The Janus Rectal Cancer Trial: a randomized phase II/III trial testing the efficacy of triplet versus doublet chemotherapy regarding clinical complete response and disease-free survival in patients with locally advanced rectal cancer.

Background: Recent data have demonstrated that in locally advanced rectal cancer (LARC), a total neoadjuvant therapy (TNT) approach improves compliance with chemotherapy and increases rates of tumor response compared to neoadjuvant chemoradiation (CRT) alone. They further indicate that the optimal sequencing of TNT involves consolidation (rather than induction) chemotherapy to optimize complete response rates. Data, largely from retrospective studies, have also shown that patients with clinical complete response (cCR) after neoadjuvant therapy may be managed safely with the watch and wait approach (WW) instead of preemptive total mesorectal resection (TME). However, the optimal consolidation chemotherapy regimen to achieve cCR has not been established, and a randomized clinical trial has not robustly evaluated cCR as a primary endpoint. Collaborating with a multidisciplinary oncology team and patient groups, we designed this NCI-sponsored study of chemotherapy intensification to address these issues and to drive up cCR rates, to provide opportunity for organ preservation, improve quality of life for patients and improve survival outcomes. Methods: In this NCI-sponsored multi-group randomized, seamless phase II/III trial (1:1), up to 760 patients with LARC, T4N0, any T with node positive disease (any T, N+) or T3N0 requiring abdominoperineal resection or coloanal anastomosis and distal margin within 12 cm of anal verge will be enrolled. Stratification factors include tumor stage (T4 vs T1-3), nodal stage (N+ vs N0) and distance from anal verge (0-4; 4-8; 8-12 cm). Patients will be randomized to receive neoadjuvant long course chemoradiation (LCRT) followed by consolidation doublet (mFOLFOX6 or CAPOX) or triplet chemotherapy (mFOLFIRINOX) for 3-4 months. LCRT in both arms involves 4500 cGy in 25 fractions over 5 weeks + 900 cGy boost in 5 fractions with a fluoropyrimidine (capecitabine preferred). Patients will undergo assessment 8-12 (+/- 4) weeks post-TNT completion. The primary endpoint for the phase II portion will compare cCR between treatment arms. A total number of 296 evaluable patients (148 per arm) will provide statistical power of 90.5% to detect an 17% increase in cCR rate, at a one-sided alpha=0.048. The primary endpoint for the phase III portion will compare disease-free survival (DFS) between treatment arms. A total of 285 DFS events will provide 85% power to detect an effect size of hazard ratio 0.70 at a one-sided alpha of 0.025, requiring enrollment of 760 patients (380 per arm). Secondary objectives include time-to event outcomes (overall survival, organ preservation time and time to distant metastasis) and adverse effects. Biospecimens including archival tumor tissue, plasma and buffy coat in EDTA tubes, and serial rectal MRIs will be collected for exploratory correlative research. This study, activated in late 2022, is open across the NCTN and has a current accrual of 312. Support: U10CA180821, U10CA180882, U24 CA196171; https://acknowledgments.alliancefound.org . Discussion: Building off of data from modern day rectal cancer trials and patient input from national advocacy groups, we have designed the current trial studying chemotherapy intensification via a consolidation chemotherapy approach with the intent to enhance cCR and DFS rates, increase organ preservation rates, and improve quality of life for patients with rectal cancer. Trial Registration: Clinicaltrials.gov ID: NCT05610163 ; Support includes U10CA180868 (NRG) and U10CA180888 (SWOG).

Robotic lateral pelvic lymph node dissection after chemoradiation for rectal cancer: a Western perspective.

AIM: There are limited outcome data for lateral pelvic lymph node dissection (LPLND) following neoadjuvant chemoradiotherapy (nCRT), particularly in the West. Our aim was to evaluate the short-term perioperative and oncological outcomes of robotic LPLND at a single cancer centre. METHOD: A retrospective analysis of a prospective database of consecutive patients undergoing robotic LPLND for rectal cancer between November 2012 and February 2020 was performed. The main outcomes were short-term perioperative and oncological outcomes. Major morbidity was defined as Clavien-Dindo grade 3 or above. RESULTS: Forty patients underwent robotic LPLND during the study period. The mean age was 54 years (SD ± 15 years) and 13 (31.0%) were female. The median body mass index was 28.6 kg/m2 (IQR 25.5-32.6 kg/m2 ). Neoadjuvant CRT was performed in all patients. Resection of the primary rectal cancer and concurrent LPLND occurred in 36 (90.0%) patients, whilst the remaining 4 (10.0%) patients had subsequent LPLND after prior rectal resection. The median operating time was 420 min (IQR 313-540 min), estimated blood loss was 150 ml (IQR 55-200 ml) and length of hospital stay was 4 days (IQR 3-6 days). The major morbidity rate was 10.0% (n = 4). The median lymph node harvest from the LPLND was 6 (IQR 3-9) and 13 (32.5%) patients had one or more positive LPLNs. The median follow-up was 16 months (IQR 5-33 months), with 1 (2.5%) local central recurrence and 7 (17.5%) patients developing distant disease, resulting in 3 (7.5%) deaths. CONCLUSION: Robotic LPLND for rectal cancer can be performed in Western patients to completely resect extra-mesorectal LPLNs and is associated with acceptable perioperative morbidity.

Robotic rectal cancer surgery: comparative study of the impact of obesity on early outcomes.

The aim of this study was to compare the outcomes of robotic total mesorectal excision (TME) in obese versus non-obese patients. A total of 533 patients, of whom 161 were obese (30·2 per cent) underwent robotic proctectomy during the study interval. Patient obesity was not associated with adverse short-term clinical outcomes after robotic rectal cancer surgery. Indicated in the obese perhaps?

Digital health for optimal supportive care in oncology: benefits, limits, and future perspectives.

BACKGROUND: Digital health provides solutions that capture patient-reported outcomes (PROs) and allows symptom monitoring and patient management. Digital therapeutics is the provision to patients of evidence-based therapeutic interventions through software applications aimed at prevention, monitoring, management, and treatment of symptoms and diseases or for treatment optimization. The digital health solutions collecting PROs address many unmet needs, including access to care and reassurance, increase in adherence and treatment efficacy, and decrease in hospitalizations. With current developments in oncology including increased availability of oral drugs and reduced availability of healthcare professionals, these solutions offer an innovative approach to optimize healthcare resource utilization. DESIGN: This scoping review clarifies the role and impact of the digital health solutions in oncology supportive care, with a view of the current segmentation according to their technical features (connection to sensors, PRO collection, remote monitoring, self-management in real time…), and identifies evidence from clinical studies published about their benefits and limitations and drivers and barriers to adoption. A qualitative summary is presented. RESULTS: Sixty-six studies were identified and included in the qualitative synthesis. Studies supported the use of 38 digital health solutions collecting ePROs and allowing remote monitoring, with benefits to patients regarding symptom reporting and management, reduction in symptom distress, decrease in unplanned hospitalizations and related costs and improved quality of life and survival. Among those 38 solutions 21 provided patient self-management with impactful symptom support, improvement of QoL, usefulness and reassurance. Principal challenges are in developing and implementing digital solutions to suit most patients, while ensuring patient compliance and adaptability for use in different healthcare systems and living environments. CONCLUSIONS: There is growing evidence that digital health collecting ePROs provide benefits to patients related to clinical and health economic endpoints. These digital solutions can be integrated into routine supportive care in oncology practice to provide improved patient-centered care.

Anti-EGFR-resistant clones decay exponentially after progression: implications for anti-EGFR re-challenge.

BACKGROUND: Colorectal cancer (CRC) has been shown to acquire RAS and EGFR ectodomain mutations as mechanisms of resistance to epidermal growth factor receptor (EGFR) inhibition (anti-EGFR). After anti-EGFR withdrawal, RAS and EGFR mutant clones lack a growth advantage relative to other clones and decay; however, the kinetics of decay remain unclear. We sought to determine the kinetics of acquired RAS/EGFR mutations after discontinuation of anti-EGFR therapy. PATIENTS AND METHODS: We present the post-progression circulating tumor DNA (ctDNA) profiles of 135 patients with RAS/BRAF wild-type metastatic CRC treated with anti-EGFR who acquired RAS and/or EGFR mutations during therapy. Our validation cohort consisted of an external dataset of 73 patients with a ctDNA profile suggestive of prior anti-EGFR exposure and serial sampling. A separate retrospective cohort of 80 patients was used to evaluate overall response rate and progression free survival during re-challenge therapies. RESULTS: Our analysis showed that RAS and EGFR relative mutant allele frequency decays exponentially (r2=0.93 for RAS; r2=0.94 for EGFR) with a cumulative half-life of 4.4 months. We validated our findings using an external dataset of 73 patients with a ctDNA profile suggestive of prior anti-EGFR exposure and serial sampling, confirming exponential decay with an estimated half-life of 4.3 months. A separate retrospective cohort of 80 patients showed that patients had a higher overall response rate during re-challenge therapies after increasing time intervals, as predicted by our model. CONCLUSION: These results provide scientific support for anti-EGFR re-challenge and guide the optimal timing of re-challenge initiation.

Pre-existing Symptoms and Healthcare Utilization Prior to Diagnosis of Neuroendocrine Tumors: A SEER-Medicare Database Study.

The incidence and prevalence of neuroendocrine tumors (NETs) are continually increasing. While it is known that NET symptoms often predate diagnosis, their prevalence and impact on resource utilization and costs are largely unknown. We identified 9,319 elderly patients diagnosed with NETs between 1/2003 and 12/2011 from the Surveillance, Epidemiology and End Results (SEER)-Medicare. We examined the patients' conditions potentially associated with NET, resource utilization and costs during the year before diagnosis. We found that NET patients were more likely to have diagnoses of hypertension (63.8% vs. 53.3%), abdominal pain (22.2% vs. 7.6%), heart failure (11.7% vs. 8.0%), diarrhea (5.8% vs. 1.8%), peripheral edema (5.4% vs. 3.8%) and irritable bowel syndrome (1.2% vs. 0.5%) compared to the non-cancer control group. They also had much higher resource utilization including number of outpatient visits (mean: 22.1 vs. 17.2), percentage with ER visits (20.9% vs. 11.6%), and hospitalizations (28.4% vs. 17.0%). Similarly, NET patients incurred significantly higher total (mean: $14602 vs. $9464), outpatient (mean: $5987 vs. $4253), and inpatient costs (mean: $8615 vs. $5211). This first population-based study on the pre-diagnosis symptoms and healthcare utilization found that NET patients were more likely to have certain conditions and incur higher resource utilizations and costs.

Phase II study of nab-paclitaxel in refractory small bowel adenocarcinoma and CpG island methylator phenotype (CIMP)-high colorectal cancer.

Background: Hypermethylation of promoter CpG islands [CpG island methylator phenotype (CIMP)] represents a unique pathway for the development of colorectal cancer (CRC), characterized by lack of chromosomal instability and a low rate of adenomatous polyposis coli (APC) mutations, which have both been correlated with taxane resistance. Similarly, small bowel adenocarcinoma (SBA), a rare tumor, also has a low rate of APC mutations. This phase II study evaluated taxane sensitivity in SBA and CIMP-high CRC. Patients and methods: The primary objective was Response Evaluation Criteria in Solid Tumors version 1.1 response rate. Eligibility included Eastern Cooperative Oncology Group performance status 0/1, refractory disease, and SBA or CIMP-high metastatic CRC. Nab-paclitaxel was initially administered at a dose of 260 mg/m2 every 3 weeks but was reduced to 220 mg/m2 owing to toxicity. Results: A total of 21 patients with CIMP-high CRC and 13 with SBA were enrolled from November 2012 to October 2014. The efficacy-assessable population (patients who received at least three doses of the treatment) comprised 15 CIMP-high CRC patients and 10 SBA patients. Common grade 3 or 4 toxicities were fatigue (12%), neutropenia (9%), febrile neutropenia (9%), dehydration (6%), and thrombocytopenia (6%). No responses were seen in the CIMP-high CRC cohort and two partial responses were seen in the SBA cohort. Median progression-free survival was significantly greater in the SBA cohort than in the CIMP-high CRC cohort (3.2 months compared with 2.1 months, P = 0.03). Neither APC mutation status nor CHFR methylation status correlated with efficacy in the CIMP-high CRC cohort. In vivo testing of paclitaxel in an SBA patient-derived xenograft validated the activity of taxanes in this disease type. Conclusion: Although preclinical studies suggested taxane sensitivity was associated with chromosomal stability and wild-type APC, we found that nab-paclitaxel was inactive in CIMP-high metastatic CRC. Nab-paclitaxel may represent a novel therapeutic option for SBA.

Clinical, pathological, and demographic factors associated with development of recurrences after surgical resection in elderly patients with neuroendocrine tumors.

BACKGROUND: Incidence of locoregional neuroendocrine tumors (NETs) is rising. However, after curative resection, the patterns and risk factors associated with recurrence remain unknown. Consensus guidelines recommend surveillance every 6-12 months for up to 10 years after surgery for resected, well-differentiated NETs irrespective of patient demographics, site, grade or stage of tumor with few exceptions. PATIENTS AND METHODS: From the Surveillance, Epidemiology, and End Results (SEER)-Medicare database, we identified localized and regional stage NET patients who underwent surgical resection between January 2002 and December 2011. Development of recurrence was identified by capturing at least two claims indicative of metastatic disease until 31 December 2013. RESULTS: Of the 2366 identified patients (median age 73 years), 369 (16%) developed metastatic disease within 5 years and only an additional 1% developed metastases between years 5 and 10 with the majority dying due to unrelated causes. The 5-year risk of developing metastases (hazard ratio, HR) varied significantly (log-rank P < 0.001) by grade: 9.9% versus 25.9% (2.2) versus 48.1% (4.4) for grades 1, 2, and ≥ 3, respectively; stage: 10.3% versus 31.1% (2.8) for localized versus regional; primary tumor size: 7.6% versus 15% (1.3) versus 26.6% (1.5) for <1, 1-2, and > 2 cm, respectively; and site: ranging from 11.3% for colon to 23.9% for pancreas. CONCLUSIONS: Contrary to current guidelines, our study suggests that surveillance recommendations should be tailored according to patient and tumor characteristics. Surveillance past 5 years may be avoided in elderly patients with competing morbidities or low risk of recurrence. Pancreatic, lung, higher grade, and regional NETs have a higher risk of recurrence and may be considered for future adjuvant trials.

Utility of a molecular prescreening program in advanced colorectal cancer for enrollment on biomarker-selected clinical trials.

BACKGROUND: Incorporation of multiple enrichment biomarkers into prospective clinical trials is an active area of investigation, but the factors that determine clinical trial enrollment following a molecular prescreening program have not been assessed. PATIENTS AND METHODS: Patients with 5-fluorouracil-refractory metastatic colorectal cancer at the MD Anderson Cancer Center were offered screening in the Assessment of Targeted Therapies Against Colorectal Cancer (ATTACC) program to identify eligibility for companion phase I or II clinical trials with a therapy targeted to an aberration detected in the patient, based on testing by immunohistochemistry, targeted gene sequencing panels, and CpG island methylation phenotype assays. RESULTS: Between August 2010 and December 2013, 484 patients were enrolled, 458 (95%) had a biomarker result, and 157 (32%) were enrolled on a clinical trial (92 on biomarker-selected and 65 on nonbiomarker selected). Of the 458 patients with a biomarker result, enrollment on biomarker-selected clinical trials was ninefold higher for predefined ATTACC-companion clinical trials as opposed to nonpredefined biomarker-selected clinical trials, 17.9% versus 2%, P < 0.001. Factors that correlated positively with trial enrollment in multivariate analysis were higher performance status, older age, lack of standard of care therapy, established patient at MD Anderson, and the presence of an eligible biomarker for an ATTACC-companion study. Early molecular screening did result in a higher rate of patients with remaining standard of care therapy enrolling on ATTACC-companion clinical trials, 45.1%, in contrast to nonpredefined clinical trials, 22.7%; odds ratio 3.1, P = 0.002. CONCLUSIONS: Though early molecular prescreening for predefined clinical trials resulted in an increase rate of trial enrollment of nonrefractory patients, the majority of patients enrolled on clinical trials were refractory to standard of care therapy. Within molecular prescreening programs, tailoring screening for preidentified and open clinical trials, temporally linking screening to treatment and optimizing both patient and physician engagement are efforts likely to improve enrollment on biomarker-selected clinical trials. CLINICAL TRIALS NUMBER: The study NCT number is NCT01196130.

Characterizing the patterns of clonal selection in circulating tumor DNA from patients with colorectal cancer refractory to anti-EGFR treatment.

INTRODUCTION: KRAS and EGFR ectodomain-acquired mutations in patients with metastatic colorectal cancer (mCRC) have been correlated with acquired resistance to anti-EGFR monoclonal antibodies (mAbs). We investigated the frequency, co-occurrence, and distribution of acquired KRAS and EGFR mutations in patients with mCRC refractory to anti-EGFR mAbs using circulating tumor DNA (ctDNA). PATIENTS AND METHODS: Sixty-two post-treatment plasma and 20 matching pretreatment archival tissue samples from KRAS (wt) mCRC patients refractory to anti-EGFR mAbs were evaluated by high-sensitivity emulsion polymerase chain reaction for KRAS codon 12, 13, 61, and 146 and EGFR 492 mutations. RESULTS: Plasma analyses showed newly detectable EGFR and KRAS mutations in 5/62 [8%; 95% confidence interval (CI) 0.02-0.18] and 27/62 (44%; 95% CI 0.3-0.56) samples, respectively. KRAS codon 61 and 146 mutations were predominant (33% and 11%, respectively), and multiple EGFR and/or KRAS mutations were detected in 11/27 (41%) cases. The percentage of mutant allele reads was inversely correlated with time since last treatment with EGFR mAbs (P = 0.038). In the matching archival tissue, these mutations were detectable as low-allele-frequency clones in 35% of patients with plasma mutations after treatment with anti-EGFR mAbs and correlated with shorter progression-free survival (PFS) compared with the cases with no new mutations (3.0 versus 8.0 months, P = 0.0004). CONCLUSION: Newly detected KRAS and/or EGFR mutations in plasma ctDNA from patients refractory to anti-EGFR treatment appear to derive from rare, pre-existing clones in the primary tumors. These rare clones were associated with shorter PFS in patients receiving anti-EGFR treatment. Multiple simultaneous mutations in KRAS and EGFR in the ctDNA and the decline in allele frequency after discontinuation of anti-EGFR therapy in a subset of patients suggest that several resistance mechanisms can co-exist and that relative clonal burdens may change over time. Monitoring treatment-induced genetic alterations by sequencing ctDNA could identify biomarkers for treatment screening in anti-EGFR-refractory patients.

A phase I study of sorafenib and vorinostat in patients with advanced solid tumors with expanded cohorts in renal cell carcinoma and non-small cell lung cancer.

BACKGROUND: This phase I study evaluated the safety, tolerability and preliminary efficacy of sorafenib combined with vorinostat in patients with solid tumors. PATIENTS AND METHODS: Patients were treated with sorafenib 400 mg po bid daily and vorinostat 200-400 mg po days 1-14 of a 21 day cycle to establish the recommended phase II dose (RP2D). The tolerability and efficacy of the RP2D was further tested in two cohorts of 6-12 patients each with advanced RCC and NSCLC. RESULTS: 17 patients were treated in the dose escalation phase that established the RP2D at sorafenib 400 mg po bid daily, vorinostat 300 mg po days 1-14. Dose limiting toxicities (DLT) included intolerable grade 2 hand-foot syndrome and multiple grade 1 toxicities causing dose interruption for more than 14 days. Despite good tolerance in the all-comers population, the RP2D was poorly tolerated in the RCC and NSCLC cohorts with the majority being unable to finish 2 full cycles of therapy. Although there were no confirmed responses, 1 patient each with NSCLC adenocarcinoma and renal sarcoma had unconfirmed partial responses and 5 of 8 patients with RCC having durable minor responses (11-26 %), including 2 who were on treatment for nearly a year. CONCLUSIONS: Although tolerable in other tumor types, sorafenib 400 mg po bid with vorinostat 300 mg po daily days 1-14 of a 21-day cycle is not tolerable without dose reductions/delays in RCC and NSCLC patients. These patients may require lower doses than the RP2D explored within this study. No confirmed responses were seen but minor responses particularly in RCC were observed.

Medullary thyroid cancer and pseudocirrhosis: case report and literature review.

Pseudocirrhosis is a rare form of liver disease that can cause clinical symptoms and radiographic signs of cirrhosis; however, its histologic features suggest a distinct pathologic process. In the setting of cancer, hepatic metastases and systemic chemotherapy are suspected causes of pseudocirrhosis. Here, we present a patient with medullary thyroid carcinoma metastatic to the liver who developed pseudocirrhosis while on maintenance sunitinib after receiving 5-fluorouracil, leucovorin, and oxaliplatin (folfox) in combination with sunitinib. Cirrhotic change in liver morphology was accompanied by diffusely infiltrative carcinomatous disease resembling the primary tumor. We discuss the diagnosis of pseudocirrhosis in this case and review the literature regarding pseudocirrhosis in cancer.