Complete Clinical Response Research Articles

Expression of c-erb-B2 oncoprotein as a neoantigen strategy to repurpose anti-neu antibody therapy in a model of melanoma.

In this study, we tested a novel approach of "repurposing" a biomarker typically associated with breast cancer for use in melanoma. HER2/neu is a well characterized biomarker in breast cancer for which effective anti-HER2/neu therapies are readily available. We constructed a lentivirus encoding c-erb-B2, an animal (rat) homolog to HER2/neu. This was used to transfect B16 melanoma in vitro for use in an orthotopic preclinical mouse model, which resulted in expression of rat c-erb-B2 as a neoantigen target for anti-c-erb-B2 monoclonal antibody (7.16.4). The c-erb-B2-expressing melanoma was designated B16/neu. 7.16.4 produced statistically significant in vivo anti-tumor responses against B16/neu. This effect was mediated by NK-cell antibody-dependent cell-mediated cytotoxicity. To further model human melanoma (which expresses < 5% HER2/neu), our c-erb-B2 encoding lentivirus was used to inoculate naïve (wild-type) B16 tumors in vivo, resulting in successful c-erb-B2 expression. When combined with 7.16.4, anti-tumor responses were again demonstrated where approximately 40% of mice treated with c-erb-B2 lentivirus and 7.16.4 achieved complete clinical response and long-term survival. For the first time, we demonstrated a novel strategy to repurpose c-erb-B2 as a neoantigen target for melanoma. Our findings are particularly significant in the contemporary setting where newer anti-HER2/neu antibody-drug therapies have shown increased efficacy.

Total Neoadjuvant Therapy in Locally Advanced Rectal Cancer: Insights from the Western Australian Context.

Recent studies have associated total neoadjuvant therapy (TNT) with better treatment adherence, decreased toxicity, improved complete clinical response and anal sphincter preservation rates in patients with locally advanced rectal cancer (LARC). However, real-world experience with TNT in the management of LARC remains limited. This study aimed to evaluate the efficacy and safety outcomes of TNT for LARC in Western Australia. Patients with LARC (cT2-4 and/or cN1-2) who underwent induction chemotherapy followed by neoadjuvant chemoradiotherapy or neoadjuvant chemoradiotherapy followed by consolidation chemotherapy, followed by surgery were recruited from two hospitals in Western Australia. Efficacy outcomes assessed included clinical response (complete, partial, no response), and pathologic complete response (pCR) rate, R0 resection rate, and R1 resection rate were evaluated. Those patients who achieved clinical complete response following TNT were given the option of active surveillance. The safety and tolerability of TNT were assessed. 32 patients with LARC were treated with TNT. In total, 17 patients (53%) received chemoradiotherapy followed by consolidation chemotherapy and 15 patients (47%) received induction chemotherapy followed by chemoradiotherapy. Nine (28%) of the patients with LARC treated with TNT had a complete clinical response, twenty-one (66%) patients had a partial clinical response, and two (6%) patients had no response to TNT. Of the 32 patients, 27 (84%) underwent surgery. There was a 100% R0 resection rate. The pCR rate was 15%. pCR, clinical response, and the R0 resection rate were similar between the two TNT regimens. TNT was well tolerated, with the majority of patients (88%) completing the chemotherapy course with grade 1 and 2 adverse effects. In conclusion, TNT emerges as a promising approach for the management of LARC. However, further research is warranted to refine the optimal TNT protocols, determine its long-term outcomes, and identify patient populations who would benefit the most from this innovative therapeutic strategy.

Efficacy and safety of bevacizumab in neoadjuvant and concurrent chemoradiotherapy for refractory cervical cancer patients.

A platinum-based concurrent chemoradiotherapy (CCRT) is the standard treatment for refractory cervical cancer (CC). However, the recurrence of disease and the occurrence of metastasis remain prevalent. We observed the long-term efficacy and safety of bevacizumab combined with neoadjuvant chemotherapy (NACT) and CCRT in refractory CC. A total of 62 patients with refractory CC were enrolled in this study from January 2016 to December 2019. The NACT regimen included bevacizumab (7.5 mg/kg), docetaxel (75 mg/m2), and cisplatin (75 mg/m2), administered tri-weekly for 2 cycles. The CCRT regimen included bevacizumab (7.5 mg/kg) and cisplatin (75 mg/m2), administered tri-weekly for 2 cycles. A dose of 45-50 Gy was prescribed for external beam radiotherapy (EBRT), while 30-35 Gy in 4-5 fractions was prescribed for brachytherapy (BT). Among the patients, 21 patients (33.9%) were at stages IIB-IIIB, 8 patients (12.9%) were at stage IIIC1, 19 patients (30.6%) were at stage IIIC2, and 14 patients (22.6%) were at stage IVB. Pelvic, para-aortic, supraclavicular, and inguinal lymph node metastases were discovered in 41 patients (66.1%). The median follow-up was 49.8 months (12.3-82.7 months). The median tumor volumes pre-treatment, after NACT, and before BT were 84.64 ± 53.15 cm3, 1.64 ± 13.15 cm3, and 0 ± 1.5 cm3, respectively. Complete clinical response (cCR) rates after NACT and EBRT were 35.5% and 66.1%, respectively. Four years after the diagnosis, the overall survival (OS) rate was 78.6%, the local region-free survival (LRFS) rate was 91.3%, the disease-free survival (DFS) rate was 70.6%, and the distant metastasis-free survival (DMFS) rate was 81.4%. A total of 29 patients (46.8%) experienced grade 3/4 hematological toxicity, 3 patients (4.8%) experienced grade 3 gastrointestinal toxicities, and none experienced grade 5 adverse events. Bevacizumab combined with NACT and CCRT significantly improved cCR and OS in refractory CC with acceptable toxicity.

Prediction of Pathologic Complete Response in Esophageal Squamous Cell Carcinoma Using Preoperative Serum Small Ribonucleic Acid Obtained After Neoadjuvant Chemoradiotherapy.

The authors hypothesized that small ribonucleic acid (sRNA) obtained from blood samples after neoadjuvant therapy from patients treated with neoadjuvant chemoradiation therapy (NACRT) could serve as a novel biomarker for predicting pathologic complete response (pCR). This study included 99 patients treated with esophagectomy after NACRT between March 2010 and October 2021 whose blood samples were collected between the end of NACRT and surgery. Next-generation sequencing (NGS) was used to analyze sRNAs from the blood samples. A predictive model for pCR comprising micro-RNA isoforms (isomiR), transfer RNA (tRNA)-derived sRNAs (tsRNAs), and clinical factors was constructed using cross-validation. Of the 99 patients, pCR was diagnosed for 30 and non-pCR for 69 of the patients. Among sRNAs, the isomiRs of let-7b and miR-93 and the tsRNA group derived from tRNA-Gly-CCC/GCC were identified as predictive factors. The clinical factors included a decrease in the maximum standardized uptake value (SUVmax) at the primary site, clinical complete response post-NACRT, preoperative biopsy, and post-NACRT carcinoembryonic antigen levels. The combined predictive model for pCR (C-PM) was established using the three sRNAs and four clinical factors. The area under the curve for the C-PM was 0.84, which was a significant factor in the multivariate analysis (odds ratio, 89.41; 95 % confidence interval 8.1-987.5; p < 0.001). Pathologic complete response after NACRT can be predicted by a predictive model constructed from preoperative clinical factors obtained via minimally invasive procedures and sRNA identified by NGS. Preoperative pCR prediction may influence treatment decision-making after NACRT.

A Rare Case of Acute Promyelocytic Leukemia with Concomitant PML-RARA Fusion and TP53 Loss/ider(17)(q10)t(15;17) Showing Complete Clinical and Molecular response: A Case Report

Abstract Introduction/Objective To report a case with rare cytogenetic abnormality: a patient with newly diagnosed acute promyelocytic leukemia (APL) with cytogenetic findings of t(15;17)(q24;q21), trisomy 8 and ider(17)(q10)t(15;17)-TP53 loss. The presence of isochromosome 17q may indicate the possibility of an unfavorable outcome. However, the case showed complete clinical and molecular response. Methods/Case Report A case of a 53-year-old female with history of ITP post-splenectomy presented with persistent hematuria, easy bruising, and worsening fatigue. She had mild microcytic anemia, moderate thrombocytopenia, 3% promyelocytes, and 14% blasts on differential CBC count. With increased PT, PTT, LDH, Uric acid and decreased fibrinogen level, APL was clinically suspected. The patient was initiated on all-trans retinoic acid (ATRA), allopurinol, and IV fluids. Bone marrow (BM) biopsy confirmed the diagnosis with unusual cytogenetic findings. The patient underwent induction and consolidation therapies (4 weeks each) with ATRA plus Arsenic Trioxide (ATO) and followed- up with a series of marrow biopsies, cytogenetic and molecular studies. Results (if a Case Study enter NA) The patient demonstrated complete clinical, histological, and molecular response. She tolerated the treatment without major side effects, showing improvement in CBC counts, coagulation profile and tumor lysis labs. Initial BM exam revealed hypercellularity with infiltrating sheets of atypical hypergranular promyelocytes (~80%) and minimal residual left trilineage hematopoiesis. Flow cytometry revealed a CD34 negative, CD117 variable abnormal promyelocyte population (~67% of total events). FISH was positive for PML/RARA translocation (15; 17) and TP53 loss. Karyotype showed 46,XX,der(15)t(15;17)(q24;q21),ider(17)(q10)t(15;17)[12]/47,idem,+8[9]. By the end of treatment, BM biopsy was normocellular with trilineage hematopoiesis and no definitive evidence of acute leukemia or increase in blasts. The Karyotype was normal. Quantitative PCR for PML-RARA was negative, indicating complete molecular remission. Conclusion In this unique case of APL with unusual cytogenetic abnormalities the literature demonstrates controversial data. The patient achieved complete clinical and molecular remission following standard treatment. This may indicate the limited prognostic significance of these additional cytogenetic abnormalities in this case.

Short-Course TNT Improves Rectal Tumor Downstaging in a Retrospective Study of the US Rectal Cancer Consortium.

The RAPIDO trial showed promising rates of pathologic complete response (pCR) after neoadjuvant short-course radiation with consolidation chemotherapy (total neoadjuvant therapy [SC TNT]) for rectal cancer. Only single-center reviews comparing tumor downstaging between SC TNT and long-course chemoradiation (LCRT) have been published in the United States. We reviewed our multi-institutional experience with both. The US Rectal Cancer Consortium database (2007-2018) including data from six high-volume rectal cancer care centers was reviewed. Patients with nonmetastatic, rectal adenocarcinoma who had neoadjuvant LCRT alone or SC TNT before excision or definitive nonoperative management were included. The primary outcome was the rate of complete response (CR), including pCR or durable (12 month) clinical complete response. Of 857 included patients, 175 (20%) received SC TNT and 682 (80%) received LCRT. The LCRT group had more low tumors (51.8% vs. 37.1%, p < 0.0001) and more clinically node-negative disease (31.8% vs. 22.3%, p < 0.0001). The CR rate was higher after SC TNT (34.1% vs. 20.3%, p = 0.0001). SC TNT was a predictor of CR (OR: 2.52, CI: 1.68-3.78). SC TNT patients completing 5-6 months of consolidation chemotherapy had a CR rate of 42.9%. There was no difference in 3-year PFS. SC TNT increases CR rate when compared to LCRT. For patients seeking nonoperative options or fewer radiation treatments, SC TRT should be preferred over LCRT alone.

Outcomes of Distal Rectal Cancer Patients Who Did Not Qualify for Watch-and-Wait: Comparison of Intersphincteric Resection Versus Abdominoperineal Resection.

Total mesorectal excision (TME) with intersphincteric resection and handsewn coloanal anastomosis (ISR-CAA) has been shown to be oncologically safe in patients with distal rectal cancer treated with preoperative chemoradiation. The introduction of the watch-and-wait (WW) strategy for rectal cancer patients with a clinical complete response to neoadjuvant therapy is changing the profile of patients undergoing TME surgery immediately following neoadjuvant treatment. The outcomes of ISR-CAA for patients with locally advanced rectal cancers not qualifying for WW have not been investigated. We conducted a retrospective analysis comparing the outcomes of ISR-CAA and abdominoperineal resection (APR) in patients with distal rectal cancer treated with neoadjuvant therapy and not qualifying for WW, at a comprehensive cancer center with an established WW program. The primary outcome was local recurrence-free survival. Sixty-seven patients had ISR-CAA and 79 had APR. Median follow-up was 61.1 months. The two groups were similar in sex, tumor stage, grade, and distance from the anal verge, but patients in the APR group were older on average. An R0 resection was achieved in 94% of ISR-CAA patients and 91% of APR patients. Patients in the ISR-CAA group had a lower 5-year rate of local recurrence-free survival (79% vs. 93%; p = 0.038) compared with the APR group; however, 5-year disease-free survival did not differ significantly between groups (67% for ISR-CAA and 64% for APR; p = 0.19). The local recurrence rate after ISR-CAA may be higher than after APR for patients without a clinical complete response to neoadjuvant therapy requiring TME surgery.

Local excision versus total mesorectal excision for rectal cancer patients with clinical complete or near-complete response after neoadjuvant chemoradiotherapy

PurposeLocal excision is an effective approach for managing rectal cancer exhibiting substantial regression after neoadjuvant chemoradiotherapy. The purpose of this study is to compare the outcomes between local excision and total mesorectal excision in rectal cancer patients achieving clinical complete or near-complete response after neoadjuvant chemoradiotherapy.MethodsThis is a retrospective cohort study that includes a consecutive series of rectal cancer patients who responded well to neoadjuvant chemoradiotherapy followed by surgery. A total of 180 rectal cancer patients at a single institution during a 12-year period are included. The main outcomes include short-term outcomes, oncological outcomes, and functional outcomes between the two groups.ResultsA total of 180 patients were included in the study. Sixty-one (33.9%) received local excision and 119 (66.1%) received total mesorectal excision. The baseline characteristics were generally balanced between the two groups. The local excision group demonstrated a significantly shorter operative time, less blood loss, and shorter hospital stay (p < 0.001). 3-year overall survival rates were 97.5% (95% CI, 0.93–1.00) and 95.5% (95% CI, 0.91–1.00) between the two groups (p = 0.38). The local excision group exhibited significantly higher 3-year local recurrence rates 15.7% (95% CI, 0.74–0.97) vs 4.2% (95% CI, 0.92–1.00) (p = 0.017), yet lower 3-year distant metastasis rates 9.6% (95% CI, 0.82–1.00) vs 12.6% (95% CI, 0.81–0.94) (p = 0.33) and lower 3-year disease-free survival rates 76.8% (95% CI, 0.64–0.92) vs 84.7% (95% CI, 0.78–0.92) (p = 0.56) comparing with the total mesorectal excision group. The local excision group demonstrated significantly better functional outcomes compared with the total mesorectal excision group (p < 0.001).ConclusionPatients who achieve either clinical complete or near-complete response after neoadjuvant chemoradiotherapy are suitable candidates for local excision. The local excision group demonstrated superior short-term and functional outcomes, and the oncological outcomes were not compromised.

7787 Primary Aldosteronism Medical Treatment Outcomes (PAMO): An International Consensus on Outcome Assessment Criteria and Multicentre Study

Abstract Disclosure: J. Yang: None. J. Burrello: None. J. Goi: None. T.A. Williams: None. W.F. Young: Consulting Fee; Self; Arena Pharmaceuticals, Inc.. Other; Self; Crinetics Pharmaceuticals. P.J. Fuller: None. P. Investigators: None. Primary aldosteronism (PA) is the most common endocrine cause of hypertension. Mineralocorticoid receptor antagonists, at adequate doses, lower blood pressure and cardiovascular risk in patients with PA. However, there is a lack of a standardized approach to medical therapy and subsequent outcomes assessment. We aimed to: 1) establish criteria for assessing outcomes of targeted medical treatment of PA, and 2) evaluate outcomes using these criteria across an international cohort. A panel of 31 PA experts from 31 centres across four continents used the Delphi method, including three rounds of online questionnaires, to reach consensus. Clinical data were then collected from consecutive patients with PA who started targeted medical treatment between 2016 and 2021 at the participating centres. Consensus was reached for six outcomes, including complete, partial, or absent biochemical response, and complete, partial, or absent clinical response. “Complete biochemical response” was defined as “correction of hypokalemia without potassium supplementation, and normalization of plasma renin activity or concentration”; while “absent biochemical response” was defined as “persistent hypokalemia and/or persistently suppressed or low plasma renin activity or concentration without change from baseline”. “Complete clinical response” was defined as “normal blood pressure without additional antihypertensive medications”; while “absent clinical response” was defined as “the same or increased blood pressure compared to before targeted treatment with same or more antihypertensive medications, not counting targeted therapy”. Of 1483 patients (mean age 52y, 48% female) from 28 centers, 232 (16%) had a complete clinical response, and 719 (49%) had a complete biochemical response at the most recent follow-up (median 29 months after treatment initiation). Compared to those with partial or absent clinical response, patients with complete clinical response had a significantly higher proportion of women and lower proportion with diabetes, stroke or left ventricular hypertrophy. They also had a significantly shorter duration of hypertension, lower BMI, higher eGFR and lower defined daily dose of antihypertensives at baseline. In contrast, these differences were not observed in those with a complete, partial or absent biochemical response. The defined daily dose of targeted therapy did not differ across the various response categories. In conclusion, we have established an international expert consensus for standardized criteria to evaluate the response to targeted medical treatment of PA, facilitate comparisons of outcome data and guide clinicians who manage PA. In a retrospective international cohort, less than half of medically-treated patients reached the established biochemical treatment targets. Further work is needed to increase the rate of complete response. Presentation: 6/3/2024

7815 Pembrolizumab-Induced Autoimmune Hypophysitis with “Isolated” ACTH Deficiency: Need for Heightened Awareness and Action Among Medical Fraternity

Abstract Disclosure: S. Shankar: None. S.S. Sundar: None. M.S. Vaishnav: None. L. Lekkala: None. K. Thummala: None. S. Srikanta: None. T. Deepak: None. R.B. Vijay: None. K. Muniraj: None. V. Nath: None. C. Siddlingappa: None. P. Ravikumar: None. M.D. Chitra: None. Introduction: Autoimmune hypophysitis caused by immune checkpoint inhibitors [ICIs; anti-CTLA-4 (Ipilimumab alone 7.9%), anti-PD-1 (Pembrolizumab alone 1.7%; nivolumab alone 0%)] are being increasingly documented, with anterior hypopituitarism affecting corticotrophs more commonly than thyrotrophs and gonadotrophs (large time span of onset; different recovery patterns). Clinical Case 2021 Sep Age 65 years (type 2 diabetes, hypertension). Renal Cell Carcinoma S/P radical nephrectomy. 2023 Jul PET-CT= Metastatic pleuropulmonary nodules. Four admissions to Specialist Oncology Hospital [Four 2 weekly cycles of Inj Pembrolizumab 200 mg (with Tab Axitinib 10 mg/day)]. After first cycle: progressive fatigue, body aches, drowsiness. S Sodium= Pre-pembrolizumab= 137 mEq/L (135-145); Post-pembrolizumab= 124, 134, 132, 124; T3= 1.63 to 0.60 to 1.24 to 1.35 ng/mL (0.97-1.69); T4= 6.83 to 4.93 to 10.44 to 11.44 mcg/dL (5.53-11); TSH= 10.46 to 6.28 to 5.39 to 9.48 mIU/mL (0.46-4.68); S Cortisol 8 am= 1.54 mcg/dL (5-25); S Potassium= 4.59 mEq/dL (3.5-5.1)]. One episode of loss of consciousness; EEG= abnormal; MRI Brain= normal. During every hospital admission, oncology, medical, endocrinology and nephrology teams attributed the same to “illness” (no specific diagnosis) and provided symptomatic treatment (IV 3% saline, tolvaptan and sodium bicarbonate tablets).2023 Nov Medicine: Very severe nausea, anorexia, generalised weakness, myalgia, hiccoughs, and inability to walk. Frustrated family members sought admission in “new” General Hospital. S Sodium= 119, 120; S Potassium= 4.8; S Creatinine= 1.67 mg/dL (0.7-1.3); S Uric acid= 4.5 mg/dL (4.40-7.60); Urine spot Sodium= 84 mmol/L; ESR= 144 mm. Endocrinology: S Cortisol 8 am= 0.09 mcg/dL;S Cortisol post 250 mcg Inj Synacthen= 3.76 (&amp;gt;20);Plasma ACTH= 5.4 pg/ml (9-52). S T3= 1.35; S T4= 11.44; S TSH= 9.48; LH= 3.61mIU/mL (1.5-9.3); FSH= 1.4mIU/mL (1.4-18.1); PRL= 30.1 (2.6-13.3); Testosterone total= 314 ng/dL (241-827); TPO antibodies negative. MRI-Pituitary: Partial empty sella; infundibulum neurohypophysis normal; mild asymmetric enhancement (5.5 mm) left cavernous sinus. Treatment: Tab Hydrocortisone 25 mg/day, with complete clinical and biochemical response [Suggestion of gonadotroph dysfunction and partial recovery of thyrotrope dysfunction/ injury. Hence, not on thyroxine replacement]. Clinical Lessons: Mechanisms for differential cellular vulnerability for ICI induced autoimmune pathologies [thyroid (destructive versus stimulatory), islet beta cells, adrenal cortical cells, various anterior pituitary cells (corticotrophs vs thyrotrophs and gonadotrophs] need elucidation. Specific molecular and cellular immunopathogenic pathways in different autoimmune endocrinopathies appear distinct and disparate. Presentation: 6/2/2024

Assessment of Radiotherapy as a Standalone Treatment Following Neoadjuvant Chemotherapy in Nonmetastatic Breast Cancer: A SEER Database Analysis.

Traditional breast cancer management involves surgery followed by systemic therapies. However, advancements in neoadjuvant chemotherapy (NACT) raise questions about the necessity of surgery in cases with an excellent response to NACT. This study investigates the outcomes of radiotherapy without surgery in selected patients with nonmetastatic breast cancer after a complete or substantial response to NACT. A retrospective study was conducted using the SEER database, reviewing records from 2010 to 2020 for patients with nonmetastatic breast cancer who received NACT, associated with a clinical response, followed by radiotherapy alone. The population included 123 patients, stratified into complete clinical response (cCR) and non-cCR (partial or unspecified clinical response) cohorts. Overall survival (OS) and cancer-specific survival (CSS) were analyzed using Kaplan-Meier and Cox proportional hazards models. The median follow-up was 41 months. Among the patients, 17 (13.82%) achieved cCR. The 5-year OS and CSS for the entire cohort were 65.8% and 71%, respectively, with the cCR group achieving 100% rates for both. Age above 60 and larger tumor size (T3 to T4) were associated with lower OS. The non-cCR group showed a 5-year OS of 61.5% and CSS of 67.1%. This study indicates that omitting surgery in patients with a cCR to NACT may be feasible, as evidenced by this subgroup's 100% OS and CSS rates at 5 and 10 years. These promising results support further research into less invasive breast cancer management. However, prospective studies must validate these findings and identify suitable patients for nonsurgical approaches.

Is an Electronic Nose Able to Predict Clinical Response following Neoadjuvant Treatment of Rectal Cancer? A Prospective Pilot Study.

Introduction: A watch-and-wait strategy for patients with rectal cancer who achieve a clinical complete response after neoadjuvant (chemo) radiotherapy is a valuable alternative to rectal resection. In this pilot study, we explored the use of an electronic nose to predict response to neoadjuvant therapy by analyzing breath-derived volatile organic compounds. Materials and Methods: A pilot study was performed between 2020 and 2022 on patients diagnosed with intermediate- or high-risk rectal cancer who were scheduled for neoadjuvant therapy. Breath samples were collected before and after (chemo) radiotherapy. A machine-learning model was developed to predict clinical response using curatively treated rectal cancer patients as controls. Results: For developing the machine-learning model, a total of 99 patients were included: 45 patients with rectal cancer and 54 controls. In the training set, the model successfully discriminated between patients with and without rectal cancer, with a sensitivity and specificity of 0.80 and 0.65, respectively, and an accuracy of 0.72. In the test set, the model predicted partial or (near) complete response with a sensitivity and specificity of 0.64 and 0.47, respectively, and an accuracy of 0.58. The AUC of the ROC curve was 0.63. Conclusions: The prediction model developed in this pilot study lacks the ability to accurately differentiate between partial and (near) complete responders with an electronic nose. Machine-learning studies demand a substantial number of patients and operate in a rapidly evolving field. Therefore, the prevalence of disease and duration of a study are crucial considerations for future research.

Patient-reported outcomes (PROs) in NRG Oncology RTOG 0436: a phase III trial evaluating the addition of cetuximab to paclitaxel, cisplatin, and radiation for esophageal cancer treated without surgery.

NRG/RTOG 0436 evaluated cetuximab added to chemoradiation (CRT) for non-operative esophageal cancer management. PRO objectives assessed improvement in the FACT-Esophageal cancer subscale (ECS), version 4, with cetuximab, and if improved ECS correlated with clinical complete response (cCR). Patients were randomized to cisplatin/paclitaxel/radiation ± cetuximab. Overall survival (OS) was the primary endpoint, with a 420 patient target, which also provided 82% power to detect ≥ 15 increase in the proportion of cetuximab patients with ECS improvement from baseline to 6-8weeks post-CRT; α = 0.05, using a χ2 test. Improvement in ECS and its Swallowing and Eating Indices (SI, EI) was defined as 5, 4 and 2 point increases, respectively, from baseline to 6-8weeks post-CRT. Univariate logistic regression assessed if cCR was associated with improved ECS. This study was stopped early for not meeting a pre-specified OS endpoint and did not show survival benefit. Of 420 planned patients, 344 enrolled and 281 consented to PROs. ECS was completed by 261 (93%) at baseline, 173 (66%) 6-8weeks post-CRT, and 117 (64%) at 1year. At 6-8weeks, patients receiving CRT + Cetuximab didn't have improved ECS; they experienced a lower proportion of improvement compared to standard CRT (37% vs. 53%; P = 0.04). The proportion of CRT patients with improvement in SI was 9% higher than with cetuximab, but not statistically significant (39% vs. 30%, P = 0.22). There was no association between treatment and EI. When examining ECS scores at 1year by cCR vs. residual disease, a higher proportion of cCR patients improved, but not statistically significant (48% vs. 45%, P = 0.74). The addition of cetuximab to CRT for the nonoperative management of esophageal cancer did not improve PROs.

Impact of Sarcopenia on Treatment Outcomes and Toxicity in Locally Advanced Rectal Cancer

Background and Objectives: Sarcopenia, a condition characterized by muscle mass loss, is prevalent in up to 68% of rectal cancer patients and has been described as a negative prognostic factor, impacting overall survival and tumor response. While there are extensive data on rectal cancer globally, only a handful of studies have evaluated the role of sarcopenia in locally advanced rectal cancer (LARC). Our study aimed to investigate the relationship between sarcopenia, overall response rate, and toxicity in patients who underwent total neoadjuvant treatment (TNT) for LARC. Materials and Methods: We performed a retrospective study of patients with rectal cancer treated with TNT and surgery with curative intent between 2021 and 2023 at Prof. Dr. Ion Chiricuta Institute of Oncology, Cluj-Napoca. Sarcopenia was assessed on MRI images by measuring the psoas muscle area (PMA) at the level of the L4 vertebra before and after neoadjuvant therapy. The primary endpoints were the overall complete response rate (oCR) and acute toxicity. Results: This study included 50 patients with LARC. The oCR rate was 18% and was significantly associated with post-treatment sarcopenia (OR 0.08, p = 0.043). Patients who did not achieve a clinical or pathologic complete response had, on average, an 8% muscle loss during neoadjuvant therapy (p = 0.022). Cystitis and thrombocytopenia were significantly associated with post-treatment sarcopenia (p = 0.05 and p = 0.049). Conclusions: Sarcopenia and loss of psoas muscle during neoadjuvant therapy were negatively associated with tumor response in locally advanced rectal cancer. Thrombocytopenia and cystitis are more frequent in sarcopenic than non-sarcopenic patients undergoing neoadjuvant chemoradiation for rectal cancer.

Safety, Efficacy and Biomarker Analysis of Crizotinib in MET Mutated Non-Small Cell Lung Cancer - Results from the Drug Rediscovery Protocol.

MET mutations occur in 3-4% of advanced non-small cell lung cancer (aNSCLC), correlating with poor survival. Despite known sensitivity of MET mutated (METmut) aNSCLC to c-MET-inhibition, no approved therapies existed until 2022. In the Drug Rediscovery Protocol (NCT0295234), patients with an actionable molecular profile are treated with off-label registered drugs. Both treated and untreated patients with aNSCLC harboring MET exon 14 skipping (METex14) or other METmuts received crizotinib 250 mg BID until disease progression or intolerable toxicity. Primary endpoints were clinical benefit (CB: RECIST v1.1 confirmed partial response (PR), complete response (CR) or stable disease (SD) ≥16 weeks) and safety. Patients were enrolled using a Simon-like two-stage design, with eight patients in stage 1 and if ≥1/8 patients had CB, 24 patients in stage 2. Whole genome and RNA-sequencing were performed on baseline biopsies. Between 09/2018 and 10/2022, 30 patients started treatment, and 24 were response-evaluable after completing ≥1 full treatment cycle. Two patients (8.3%) achieved CR, thirteen (54.2%) PR and two (8.3%) SD. The CB-rate was 70.8% (95%CI 48.9-87.4) and the objective response rate was 62.5% (95%CI 40.6-81.2). After 21.2 months median follow-up, median duration of response, progression-free and overall survival were 9.3 (95%CI 6.5-NA), 10.2 (95%CI 6.0-20.1) and 13.0 months (95%CI 9.0-NA), respectively. Twenty-three treatment-related grade ≥3 adverse events occurred in 12/30 patients (40%), causing treatment-discontinuation in three (10%). One patient (achieving CR) had a tyrosine kinase domain mutation (p.H1094Y), all other patients had METex14. Crizotinib is a valuable treatment option in METmut aNSCLC.

Management of Locally Advanced Rectal Cancer: ASCO Guideline.

ASCO Guidelines provide recommendations with comprehensive review and analyses of the relevant literature for each recommendation, following the guideline development process as outlined in the ASCO Guidelines Methodology Manual. ASCO Guidelines follow the ASCO Conflict of Interest Policy for Clinical Practice Guidelines.Clinical Practice Guidelines and other guidance ("Guidance") provided by ASCO is not a comprehensive or definitive guide to treatment options. It is intended for voluntary use by providers and should be used in conjunction with independent professional judgment. Guidance may not be applicable to all patients, interventions, diseases or stages of diseases. Guidance is based on review and analysis of relevant literature, and is not intended as a statement of the standard of care. ASCO does not endorse third-party drugs, devices, services, or therapies and assumes no responsibility for any harm arising from or related to the use of this information. See complete disclaimer in Appendix 1 and 2 (online only) for more.PURPOSETo provide evidence-based guidance for clinicians who treat patients with locally advanced rectal cancer.METHODSA systematic review of the literature published from 2013 to 2023 was conducted to identify relevant systematic reviews, phase II and III randomized controlled trials (RCTs), and observational studies where applicable.RESULTSTwelve RCTs, two systematic reviews, and one nonrandomized study met the inclusion criteria for this systematic review. Expert Panel members used available evidence and informal consensus to develop evidence-based guideline recommendations.RECOMMENDATIONSFollowing assessment with magnetic resonance imaging, for patients with microsatellite stable or proficient mismatch repair locally advanced rectal cancer, total neoadjuvant therapy (TNT; ie chemoradiation [CRT] and chemotherapy) should be offered as initial treatment for patients with tumors located in the lower rectum and/or patients who are at higher risk for local and/or distant metastases. Patients without higher-risk factors may discuss chemotherapy with selective CRT depending on extent of response, TNT, or neoadjuvant long-course CRT or short-course radiation. For patients who are candidates for TNT, the preferred timing for chemotherapy is after radiation, and neoadjuvant long-course CRT is preferred over short-course radiation therapy (RT), however short-course RT may also be a viable treatment option depending on circumstances. Nonoperative management may be discussed as an alternative to total mesorectal excision for patients who have a clinical complete response to neoadjuvant therapy. For patients whose tumors are microsatellite instability-high or mismatch repair deficient, immunotherapy is recommended.Additional information is available at http://www.asco.org/gastrointestinal-cancer-guidelines.

Neoadjuvant Treatment With Regorafenib and Capecitabine Combined With Radiotherapy in Locally Advanced Rectal Cancer: A Multicenter Phase Ib Trial (RECAP)–SAKK 41/16

BackgroundThe multi tyrosine kinase inhibitor regorafenib is active in metastatic colorectal cancer. Improvement in clinical outcome by adding regorafenib to long-course chemoradiotherapy (LcCRT) was investigated in molecularly undefined LARC. MethodsPatients with T3-4 and/or N+ but M0 rectal cancer were included. Neoadjuvant LcRCT consisted in capecitabine (C) 825mg/m2 d1-d38 and 28 fractions of 1.8Gy (50.4Gy). Regorafenib was added d1-14 and d22-35 in 3 dose escalation (DE) cohorts (40mg/80mg/120mg). The recommended dose (RD) was used for the expansion (EXP) cohort. Primary endpoints were dose-limiting toxicity (DLT) for DE and pathological response (near-complete regression [npCR] or complete regression [pCR]) for EXP. ResultsOverall, 25 patients were included. Two DLTs occurred at the regorafenib dose level of 120 mg, thereby establishing the RD at 80mg daily. Among the 19 patients who were treated at the RD, 8 (42.1%; 1-sided 80% confidence interval [CI] (lower bound): 30.7%; 95% CI, 20.3%-66.5%) reached the primary endpoint (5 [26.3%] had npCR and 3 [15.8%] pCR). One additional patient received no surgery due to clinical complete response. All patients had R0 resections and clear circumferential margins. Postoperative complications occurred in 6 patients (35.3%). The most common grade ≥ 3 treatment-related adverse event in the EXP cohort was diarrhea (2 patients). ConclusionAdding regorafenib 80 mg to LcCRT in LARC resulted in both primary endpoints being met and yielded an expectedpathological response rate. Toxicity was manageable, and postoperative complications were as expected.

Assessment of clinical and pathological response to neoadjuvant chemotherapy in breast cancer according to molecular subtypes

Background. Breast cancer (BC) is the commonest tumor in women. It is the leading malignancy in world, and representing an emerging oncologic issue in all countries. In Iraq, BC cases reached 7246 in 2021by Iraqi Cancer Registry reports. Objectives. The study conducted for assessment the clinical and pathological responses to neoadjuvant chemotherapy in BC among molecular subtypes and for description the clinico-pathologic features, and patterns of BC according to molecular subtypes. Methods. A prospective study of 60 females with breast cancer histologically confirmed were enrolled. All women received neoadjuvant chemotherapy. Then all patients underwent definitive surgery including MRM+AC or BCS+AC. The patients’ demographic, the pathologic and molecular subtypes date of the primary tumor were recorded. Results. The mostly distributed age group was belong to group 46-55 yrs in 22, 36.7%. The mean age was 49.7±10.8 yrs. The IDC represented the most common histopathological types of BC. The most of cases seen in upper-outer quadrant (UOQ). The results post-chemotherapy as followed: ypTx stage reported in 32 (53.3%), ypT1 in 15 (25.0%), ypT2 in 10 (16.7%) and ypT3 in 3 (5.0%). ypN0 stage in 40 patients (66.7%), ypN1 in 11 (18.3%), ypN2 in 6 (10.0%), and ypN3 in 3 (5.0%). There was a high statistical difference between cT and ypT in pre and post-chemotherapy (P&lt;0.0001), between cN and ypN in pre and post-chemotherapy (P=0.001) and between M and ypM in pre and post-chemotherapy (P=0.002). The mass location (P=0.005) and tumor size (P = 0.011) had significantly impacted on BC responses post NACT. 18(30.0%) had clinical complete response (cCR), 32 women (53.3%) had partial response (cPR), six cases (10.0%) had stable disease, and four cases (6.7%) had progressive disease. The cCR was better seen in T1 (77.8%) than T2 (22.2%), with statistical significant difference (P=0.002). The cCR was better seen in N0 (61.1%) than N1 (38.9%), with a high statistical significant difference (P&lt;0.0001). Conclusions. The commonest age breast cancer is four to five decade. The IDC and mass situated at UOQ are the most common features of BC. Approximately, 30.0% of women have clinical complete response (cCR), 53.3% have partial response (cPR), 10.0% have stable disease, and 6.7% have progressive disease post NACT. The ER positive, PR positive, and HER2neu negative are the mostly frequent subtype recorded in this study. The cCR is better seen in T1 and N0 stages. ER+ and PR+ are more reported after NACT whereas HER2neu- is more post NACT.

Outcomes of Locally Advanced Rectal Cancer Patients Following Complete Clinical Response After Neoadjuvant Treatment.

Background Watchful waiting and non-operative management of patients with complete clinical response to neoadjuvant treatment in locally advanced rectal cancers is an emerging practice now, especially in patients whose surgery would require permanent stoma. Methodology This is a retrospective study of patients presenting to the National Cancer Institute, Cairo University, Egypt from January 2005 to December 2019 with pathologically proven locally advanced rectal cancer who had a complete clinical response after neoadjuvant treatment. Patients who underwent surgery after achieving complete clinical response and patients who were kept under watchful waiting were compared in terms of overall survival (OS), disease-free survival (DFS), metastasis-free survival (MFS), and local recurrence-free survival (LRFS). Results Of the 51 patients identified, 31 (61%) went to surgery, and 20 (39%) were kept under watchful waiting. There was no difference in five-year OS between both groups (65% for both, p = 0.57). Five-year DFS for the watchful waiting group was 68% versus 62% for the surgery group (p = 0.75). Five-year LRFS was 100% in the watchful waiting group versus 83% in the surgery group (p = 0.15). Conclusions Watchful waiting after a complete clinical response to neoadjuvant treatment in locally advanced rectal cancer is feasible without compromising disease-related outcomes, especially in patients with distal rectal cancers requiring permanent stoma after surgery. However, further prospective validation is needed.

Clinical response and on-treatment clinical remission with tezepelumab in a broad population of patients with severe, uncontrolled asthma: results over 2 years from the NAVIGATOR and DESTINATION studies.

In asthma, clinical response is characterized by disease improvement with treatment, whereas clinical remission is characterized by long-term disease stabilization with or without ongoing treatment. The proportion of patients receiving tezepelumab who responded to treatment and those who achieved on-treatment clinical remission was assessed in the NAVIGATOR (NCT03347279) and DESTINATION (NCT03706079) studies of severe, uncontrolled asthma. NAVIGATOR and DESTINATION were phase 3, randomized, double-blind, placebo-controlled studies; DESTINATION was an extension of NAVIGATOR. Complete clinical response was defined as achieving all of the following: ≥50% reduction in exacerbations versus the previous year, improvements in pre-bronchodilator (BD) forced expiratory volume in 1 s (FEV1) of ≥100 mL or ≥5%, improvements in Asthma Control Questionnaire (ACQ)-6 score of ≥0.5 and physicians' assessment of asthma improvement. On-treatment clinical remission was defined as an ACQ-6 total score ≤1.5, stable lung function (pre-BD FEV1 >95% of baseline) and no exacerbations or use of oral corticosteroids during the time periods assessed. Higher proportions of tezepelumab than placebo recipients achieved complete clinical response over weeks 0-52 (46% versus 24%; OR: 2.83 [95% CI: 2.10-3.82]), and on-treatment clinical remission over weeks 0-52 (28.5% versus 21.9%; OR: 1.44 [95% CI: 0.95-2.19]) and weeks >52-104 (33.5% versus 26.7%; OR: 1.44 [95% CI: 0.97-2.14]). Tezepelumab recipients who achieved on-treatment clinical remission versus complete clinical response at week 52 had better preserved lung function and lower inflammatory biomarkers at baseline, and fewer exacerbations in the 12 months before the study. Among patients with severe, uncontrolled asthma, tezepelumab treatment was associated with an increased likelihood of achieving complete clinical response and on-treatment clinical remission compared with placebo. Both are clinically important outcomes but may be driven by different patient characteristics.