Near-complete Response Research Articles

Phase II trial of rosuvastatin combined with chemoradiation therapy (CRT) in the treatment of high-risk locally advanced rectal cancer (STARC trial).

131 Background: Pre-clinical evidence suggest that statins have antiproliferative, proapoptotic, and anti-invasive properties. Also, statins can sensitize cancer tissues and protect normal tissues to the effects of radiation. A standard treatment of locally advanced rectal cancer (LARC) involves neoadjuvant CRT followed by surgery and adjuvant chemotherapy. Retrospective analyses of statin use in rectal cancer patients receiving CRT suggest a higher pathological complete response rate (pCRr). Methods: Patients with clinical stage II-III rectal adenocarcinoma, within 5 cm of the anal verge (AV) or less than 12cm from the AV with threatened circumferential resection margin were treated with rosuvastatin 40 mg daily starting 2 weeks prior to the start and until 4 weeks after the end of CRT. The primary objective of the study was pCRr. Secondary objectives included, near-CRr, Ro resection rate (RR), sphincter preservation, 3-year relapse free survival (RFS), 3-year overall survival (OS), toxicity and safety. A Simon’s minimax two-stage design was used to determine significance. A pCRr of ≥25% was required to reject the null hypothesis. RFS and OS rates were calculated using the Kaplan-Meier product-limit method. Results: Forty-five patients were enrolled from 2016 to 2021. Sixty-seven percent were male with a median age of 54 (IQR 37- 61), 97.8% (44/45) had ECOG PS of 0-1, 15.6% (7/45) were cT4, 73.3% (33/45) were cN+. Of the 38 evaluable patients, 9 had a pCR (23.7%), an additional 9 had a near-pCR (23.7%). With a median follow-up of 3.26 years, the 3-year OS rate was 96.3% (95% CI (0.765, 0.995)) and the 3-year DFS rate was 77.9% (95% CI (0.604, 0.883)) in the evaluable patients. One patient elected for non-operative management and has an on-going clinical CR for the last 15 months. Surgery was sphincter sparing in 17 patients (43.6%) and an 87.2% Ro RR was observed. Toxicities attributable to rosuvastatin included: two patients with elevations in liver enzymes, grade 3. Remaining toxicities were grade 2 or less, with the most common toxicities being fatigue (n = 5) and pain (n = 3). Only 2 patients experienced CPK elevations, both grade 2. Conclusions: The addition of rosuvastatin to nCRT resulted in a considerable complete and near-complete response rate with an acceptable toxicity profile. Rosuvastatin treatment should be studied further in the total neoadjuvant and non-operative management settings for locally advanced rectal cancer. Clinical trial information: NCT02569645 .

The definition of a near-complete response after neoadjuvant (chemo)radiotherapy for rectal cancer: preliminary results of a systemic review and international expert based consensus

The definition of a near-complete response after neoadjuvant (chemo)radiotherapy for rectal cancer: preliminary results of a systemic review and international expert based consensus

Rectal Sparing Approaches after Neoadjuvant Treatment for Rectal Cancer: A Systematic Review and Meta-Analysis Comparing Local Excision and Watch and Wait.

Local Excision (LE) or Watch and Wait (WW) for patients with complete clinical response or near-complete clinical response after neoadjuvant chemoradiotherapy (nCRT) were proposed to avoid morbidity and impairment of quality of life after rectal resection. The aim of this study is to perform a systematic review of the literature, and to compare rectal-sparing approaches, in terms of rectum-preservation rate, local control, and distant recurrences. A systematic review and meta-analysis were performed of studies published until July 2022 (PROSPERO, registration CRD42022341480), and the quality of evidence was assessed using a GRADE approach. Seven retrospective studies and one prospective trial were included. In six studies, patients were treated with standard long-course nCRT, and in two with Total Neoadjuvant Therapy (TNT). Overall, there were 213 and 188 patients in WW and LE group, respectively, and no difference was found between WW and LE when considering rectum-preservation rate (OR 0.80 95%CI 0.31-2.01, p = 0.63), local disease (OR 1.60 95%CI 0.75-3.42, p = 0.22), locoregional failure (OR 0.85 95%CI 0.20-3.66, p = 0.83) and distant recurrence (OR 0.76 95%CI 0.37-1.55, p = 0.45). Studies directly comparing WW and LE are still lacking, even though no differences between WW and LE in terms of rectum-preservation, local control, and distant recurrences have been found.

The Oncologic Safety of Sentinel Lymph Node Biopsy in Patients with Node-Positive Breast Cancer with Complete Response to Neoadjuvant Chemotherapy: A Single-Center Experience.

To evaluate the efficiency and safety of sentinel lymph node biopsy (SLNB) in patients with breast cancer with complete response to neoadjuvant chemotherapy (NAC). Ninety-two consecutive (T1-4 and N1-2) patients with breast cancer who had pathologic and/or clinical and radiologic axillary lymph node involvement were included. All patients received NAC. Patients with a clinical and radiologic complete response in the axilla after NAC underwent SLNB. Pathologic complete response (ypCR) was defined as the absence of residual invasive and in situ cancer, and near-complete response (ypNCR) represented in situ and/or ≤ 1 mm residual tumor in the breast and/or presence of malignant cell clusters (≤0.2 mm) and/or micrometastases (≤2.0 mm) in the axillary lymph nodes (ALN) (ypTis/T1mi, ypN0i+/pN1mi). The mean age of the 92 patients was 49.6 ± 10.3 years and the mean follow-up was 34.0 ± 17.8 months. With respect to breast tumors, 23 (25.0%) patients had complete and 14 (15.2%) had a near-complete response to NAC. Complete response in ALN was obtained in 39 (42.4%) patients and near-complete in six (6.5%) patients. The overall survival of the 33 patients who achieved ypCR and ypNCR was 100% and the remaining 59 patients with partial or no response to NAC was 83.1% at a mean follow-up of 34 months (p=0.063). In this study, no event developed in cases with ypCR and ypNCR in the breast and axilla. The persistence of the same results in long-termfollow-ups may enable the use of ypNCR as a positive prognostic marker in addition to ypCR.

Efficacy of MEK Inhibitors in Erdheim Chester Disease

Background Erdheim Chester disease (ECD) is a rare histiocytosis with variable clinical behavior known to be driven by recurrent activating mutations in the MAP kinase pathway. BRAF inhibitors were the first targeted therapy used in this neoplastic disorder given the presence of the BRAFV600E mutation in 50-60% of patients. Increased understanding of additional driver mutations within this pathway resulted in a study of MEK inhibitors (MEKi) in cases not harboring this mutation, ultimately leading to the FDA breakthrough designation of cobimetinib for BRAFV600E negative histiocytic neoplasms. Herein, we present data from our institution on MEKi treatment of ECD, the largest cohort to date. Methods We included all patients with ECD consecutively seen at Mayo Clinic and treated with one of the 3 available MEKi (cobimetinib, trametinib, or binimetinib) between 2019-2021. Tumor MAPK pathway mutation status was determined with next-generation sequencing (NGS) via the Tempus-xT® assay (Chicago, IL). If NGS data was unavailable, immunohistochemistry (IHC) or allele-specific PCR was used to determine BRAF-specific mutation status. Time-to-event analyses were calculated from the time of MEKi initiation to progression, therapy discontinuation due to intolerant side effects, or initiation of systemic non-MEKi therapies. Response assessment was done based on the established positron emission radiography (PET)-response criteria used for clinical trials of targeted therapies in histiocytosis. Adverse events (AEs) were graded using the National Cancer Institute Common Toxicity Criteria v5.0 Results A total of 22 patients with ECD underwent treatment with a MEKi and were included. Median follow up was 19 months (95% CI 10 - 28 months) and 55% (n=12) were female. Median age at diagnosis of ECD was 54 years (IQR 36.8 - 70.8 years). Most common system involvement included osseous (68%), retroperitoneal soft tissue (46%), central nervous system (41%), and cardiovascular (41%). Mutational assessment studies included NGS in 82% (n=18). The four remaining patients had assessment of BRAFV600E by IHC or PCR. Tumor genomic profile included non-BRAFV600E mutations in 15 patients (68%). BRAFV600E was identified by IHC in one patient. All other patients did not have successful NGS (n=2) or had no pathogenic variants identified (n=3). Additional details presented in Table 1. Median time on a MEKi was 6.5 months (IQR 3 - 15 months). It was used as first-line therapy in 72.7% (n=16) of cases. Within the 22 patients, 28 instances of MEKi initiation were observed in our cohort, as 5 patients (23%) received 2 different MEKi throughout follow up and one patient had cobimetinib rechallenge after first progression. MEKi used included: cobimetinib (n=23, 82%), trametinib (n=3, 11%), and binimetinib (n=2, 7%). Response assessment after initiation of first MEKi was not available in 1 patient. In the remaining 21 cases, overall response rate was 81% including complete or near-complete response (CR/nCR) in 5 (24%), partial response (PR) in 12 (57%), stable disease (SD) in 2 (10%), and progressive disease (PD) in 2 (10%). Median EFS was 36 months (95%CI 9 - not reached), respectively. Intolerable AEs with MEKi included G3/4 diarrhea (n=2), G3 lower extremity edema (n=2), G3 acneiform rash (n=1), G2 pericardial effusion (n=1), and "dropped-head syndrome” (n=1). Of the 6 patients who were treated with a second MEKi (Figure 1), five had data for response assessment and had CR/nCR (n=2) or a PR (n=3) as best responses. At time of last follow-up, 21 patients (96%) were alive and one died due to progression of ECD. Of the 22 patients, 10 patients (46%) remained on MEKi at the time of last follow-up. Reasons for therapy discontinuation included intolerable side effects (n=4), drug holiday after response achievement (n=4), disease progression on therapy (n=3), and change to other kinase inhibitors (n=1). Additional details regarding patient follow-up are presented in Figure 1. Conclusion Our study suggests that MEK inhibitors are a highly efficacious treatment in patients with ECD. Main limitation of our study includes its retrospective nature and sample size. While treatment discontinuation due to severe toxicities / intolerance was common, this did not preclude from maintenance of tumor response for extended periods of time. Not all patients will respond to MEKi and further research to guide individualized therapies is required. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

RF11 | PMON26 A Lump By Any Other Name: A Case of Diffuse Large B Cell Lymphoma of the Thyroid

Abstract Patient is a 49-year-old female with a past medical history of hypothyroidism who presented to the endocrinology office for evaluation of a neck mass. A thyroid ultrasound in 2020 had shown significantly enlarged and diffusely heterogenous thyroid gland compatible with diffuse thyroid goiter without nodules. Her neck swelling worsened and therefore a thyroid ultrasound was repeated and showed a large hypoechoic nodule in the left thyroid gland. She had no symptoms such as night sweats, fevers, or weight loss. A computed tomography (CT) scan of the neck with contrast was obtained on 7/20/2020 showing a markedly enlarged thyroid gland with multiple >1 centimeter (cm) thyroid nodules, with a suspected exophytic extension nodule medial to the left lobe. Multiple adenopathy was present with an enlarged left lower cervical lymph node and a right-sided level 4 lymph node concerning for thyroid malignancy with local metastatic disease. She underwent a fine needle aspiration (FNA) with flow cytometry of the lymph node on 9/2/2020 which was benign. Her goiter continued to increase in size and she was referred to endocrine surgery for fine needle core biopsy of the left thyroid nodule which was favorable for diffuse large B cell lymphoma (DLBCL) with a germinal center phenotype on 4/5/2021. Flow cytometry was positive for CD-10 mature B cells. FNA biopsy of the left lower cervical lymph node showed polymorphic lymphocytes and rare macrophages. She was staged IIE. She underwent 4 cycles of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) and received 18 rounds of consolidation radiation after completion of chemotherapy. She had near-complete response to treatment and is now monitored through routine follow-ups. Primary thyroid lymphoma is a rare condition characterized as a lymphomatous process involving the thyroid gland without any contiguous spread or distant metastasis at the time of diagnosis. It comprises nearly 1% to 5% of all thyroid malignancies and is more common in women. DLBCL is the most common histiotype and accounts for 50% to 70% of all cases. Patients may notice a unilateral or bilateral rapidly enlarging neck mass with compressive symptoms, but B symptoms are less common. Nearly 30% to 40% of patients carry a diagnosis of hypothyroidism at the time of diagnosis as the lymphomatous process replaces the normal thyroid parenchyma. Diagnosis is made usually via core needle biopsy and flow cytometry since FNA biopsy is frequently inconclusive. Treatment is with chemotherapy, usually R-CHOP, and radiation therapy with an overall 5-year prognosis of 34.5%. Surgical decompression may be necessary if compressive symptoms are present. While this is a rare disease, providers should be cognizant of DBLCL especially when faced with a presentation such as the one summarized in this report. Presentation: No date and time listed

Immune-mediated pneumonitis: A clinical conundrum in a patient with stage IV lung adenocarcinoma with a dramatic and durable response to checkpoint inhibitor case report

Immune checkpoint blockade with pembrolizumab has demonstrated both progression-free survival and overall survival benefit for patients with NSCLC regardless of PD-L1 expression. However, immune-related adverse events, and in particular checkpoint inhibitor pneumonitis (CIP), are common and can complicate the treatment course, duration of response, as well as overall survival. Here we present a patient with stage IV lung adenocarcinoma who experienced a dramatic response following treatment with pembrolizumab, followed by the development of biopsy-proven organizing pneumonia and immune-mediated pneumonitis requiring early treatment discontinuation. The patient has now achieved a near-complete response over 13 months after treatment discontinuation, highlighting the importance of early recognition and management of immune-related adverse events as well as the possibility of durable response despite treatment discontinuation.

33597 Checkpoint inhibitor–induced vitiligo in nonmelanoma patients

Checkpoint inhibitors (ICIs) are anticancer therapies with a well-known association of vitiligo induction in melanoma patients. ICI-induced vitiligo is typically rapidly progressive and associated with increased tumor response, possibly because it indicates the body’s heightened immune response to melanocytes. Previously, ICI-induced vitiligo in nonmelanoma cancers had only been described in scattered case reports. Here we describe a cohort of melanoma and nonmelanoma patients with ICI-induced vitiligo. This is a retrospective cohort study from a single institution’s electronic medical record for cancer patients treated with CPIs who subsequently developed vitiligo. We identified 151 patients with ICI-induced vitiligo, 19 (12.6%) nonmelanoma and 132 (77.4%) melanoma patients. Time to onset of vitiligo was nearly doubled in the nonmelanoma cohort, however, this is confounded by possible delayed diagnosis or underreporting of this asymptomatic condition in patients who do not regularly receive skin exams. The majority of patients had a stable course of vitiligo with 91.4% receiving no treatment in this largely Caucasian cohort. Two patients with nonmelanoma cancers and Fitzpatrick type IV or above skin received treatment with narrowband ultraviolet B light therapy and topical steroids with near-complete response. This study highlights the occurrence of CPI-induced vitiligo in a variety of nonmelanoma cancers, where skin of color patients will be more prevalent and the need for treatment will potentially be more urgent. Further study is needed to elucidate the mechanism of CPI-induced vitiligo and determine if nonmelanoma cancers have the same association between vitiligo and increased tumor response.

584P Mutation analysis of ovarian carcinoma patients presenting optimal response to neoadjuvant chemotherapy

Neoadjuvant chemotherapy (NAC) followed by interval debulking does not present inferior results to those of primary cytoreduction and offers the opportunity to evaluate chemo-sensitivity in vivo. Chemotherapy response score (CRS) have been shown to correlate with outcome with a complete or near-complete (CRS3) response predicting improved progression-free survival (PFS). Our proposal is to determine the prevalence of BRCA1/2 mutations and to search for other molecular mechanisms of HR inactivation which could explain the great sensitivity to platinum salts.

Rates of homologous recombination deficiency across different subtypes of ovarian cancer and in pre- and post-neoadjuvant chemotherapy tumor samples (139.5)

Objectives: Homologous recombination deficiency (HRD) is defined as a pathogenic mutation in BRCA1/2 and/or a positive Genomic Instability Status score (GIS). The GIS assay is a custom hybridization capture panel that targets SNPs distributed across the genome. Patients who have ovarian cancer with HRD may benefit from treatment with therapies that exploit HR deficiency. To date, the majority of HRD studies in ovarian cancer have focused on high-grade serous carcinoma and have not directly compared the subtypes or surgical samples (i.e., biopsy or resection). Here, we compared the rate of HRD across chemotherapy response scores (CRS 1-no or minimal response, 2-some response, 3-complete or near-complete response), as well as across different ovarian cancer subtypes. Methods: Pathology reports were reviewed for a consecutive set of deidentified ovarian cancer samples analyzed between September 9, 2020, and January 8, 2021. BRCA1/2 mutation analysis captured both sequence variants and large rearrangements. Scores ≥42 were considered GIS-status positive. Descriptive statistics were used for data presentation. Results: Of 1351 patients, there were 1165 resections, 141 biopsies, and 45 cytology specimens. Total 327 resections were known to be post-neoadjuvant chemotherapy; of these, 274 were given a CRS (CRS 1, n=87; CRS 2, n=150; CRS 3, n=37). HRD was observed at a higher rate in tumors with CRS 2 (33.9%) and CRS 3 (50.0%), compared to those with CRS 1 (21.3%). Low tumor DNA percentage was observed in a higher percentage of post-neoadjuvant resection samples with CRS 2 (23.3%) and CRS 3 (21.6%), compared to those with CRS 1 (5.7%). As a result, low tumor DNA percentages in post-neoadjuvant resection samples with CRS 2-3 led to a 3- to 4-fold higher inconclusive rate (test failure) compared to resection samples with CRS 1, diagnostic biopsies, and resections without neoadjuvant chemotherapy. Mixed histology carcinomas had the highest percentage of HRD, followed by high-grade serous carcinoma and carcinosarcoma (Table 1). HRD was detected in all major carcinoma subtypes; however, endometrioid, mucinous, low-grade serous, and clear cell carcinoma had comparatively low rates of HRD. Conclusions: These data suggest that HRD testing is appropriate for all major ovarian cancer subtypes. Patients with certain tumor characteristics (e.g., CRS 2-3, mixed histology, high-grade serous carcinoma, and carcinosarcoma) have higher rates of HRD. Importantly, due to the relatively low tumor DNA percentage in post-neoadjuvant chemotherapy resections with CRS 2-3, submission of pre-chemotherapy biopsies is optimal. Objectives: Homologous recombination deficiency (HRD) is defined as a pathogenic mutation in BRCA1/2 and/or a positive Genomic Instability Status score (GIS). The GIS assay is a custom hybridization capture panel that targets SNPs distributed across the genome. Patients who have ovarian cancer with HRD may benefit from treatment with therapies that exploit HR deficiency. To date, the majority of HRD studies in ovarian cancer have focused on high-grade serous carcinoma and have not directly compared the subtypes or surgical samples (i.e., biopsy or resection). Here, we compared the rate of HRD across chemotherapy response scores (CRS 1-no or minimal response, 2-some response, 3-complete or near-complete response), as well as across different ovarian cancer subtypes. Methods: Pathology reports were reviewed for a consecutive set of deidentified ovarian cancer samples analyzed between September 9, 2020, and January 8, 2021. BRCA1/2 mutation analysis captured both sequence variants and large rearrangements. Scores ≥42 were considered GIS-status positive. Descriptive statistics were used for data presentation. Results: Of 1351 patients, there were 1165 resections, 141 biopsies, and 45 cytology specimens. Total 327 resections were known to be post-neoadjuvant chemotherapy; of these, 274 were given a CRS (CRS 1, n=87; CRS 2, n=150; CRS 3, n=37). HRD was observed at a higher rate in tumors with CRS 2 (33.9%) and CRS 3 (50.0%), compared to those with CRS 1 (21.3%). Low tumor DNA percentage was observed in a higher percentage of post-neoadjuvant resection samples with CRS 2 (23.3%) and CRS 3 (21.6%), compared to those with CRS 1 (5.7%). As a result, low tumor DNA percentages in post-neoadjuvant resection samples with CRS 2-3 led to a 3- to 4-fold higher inconclusive rate (test failure) compared to resection samples with CRS 1, diagnostic biopsies, and resections without neoadjuvant chemotherapy. Mixed histology carcinomas had the highest percentage of HRD, followed by high-grade serous carcinoma and carcinosarcoma (Table 1). HRD was detected in all major carcinoma subtypes; however, endometrioid, mucinous, low-grade serous, and clear cell carcinoma had comparatively low rates of HRD. Conclusions: These data suggest that HRD testing is appropriate for all major ovarian cancer subtypes. Patients with certain tumor characteristics (e.g., CRS 2-3, mixed histology, high-grade serous carcinoma, and carcinosarcoma) have higher rates of HRD. Importantly, due to the relatively low tumor DNA percentage in post-neoadjuvant chemotherapy resections with CRS 2-3, submission of pre-chemotherapy biopsies is optimal.

The prognostic value of the chemotherapy response score in tubo-ovarian or primary peritoneal high-grade serous carcinoma (466)

<b>Objectives:</b> The purpose of the study was to evaluate the prognostic value of a two-tiered chemotherapy response score (CRS) system on progression-free and overall survival in high-grade serous ovarian cancer patients using traditional survival type analysis. <b>Methods:</b> Retrospective chart data were collected from all patients aged 18 and older with FIGO stage III or IV tubo-ovarian high-grade serous carcinoma undergoing neoadjuvant chemotherapy (NACT) at a single institution from January 2017 to January 2021. A two-tier scoring system was used in which patients were stratified to either CRS 1-2 (no or minimal response to neoadjuvant chemotherapy) or CRS 3 (appreciable or near-complete response). These data were used to compare progression-free and overall survival between the patients in each subgroup using survival analysis (log-rank test). Survival data were adjusted for covariates as appropriate with a Cox regression model. <b>Results:</b> We identified 80 women who met the inclusion criteria above; 97% (<i>n</i>=78) were Caucasian, and the mean age was 66 years (range: 25-87). Baseline demographic data were similar between patients with CRS 1-2 (<i>n</i>=58) and patients with CRS 3 (<i>n</i>=22). More women with CRS 3 underwent an aborted attempt at cytoreduction or surgery for bowel obstruction at the time of diagnosis (<i>n</i>=3 compared to none in the CRS 1-2 cohort). Overall, 74% (<i>n</i>=58) of patients achieved a partial response on platinum-based NACT. About 23% (<i>n</i>=5) of patients with CRS 3 had a complete response compared to only 12.5% (<i>n</i>=7) of CRS 1-2. Overall a greater percentage of patients in the CRS 3 group (95%, <i>n</i>=21) achieved optimal cytoreduction compared with patients in CRS 1-2 (74%, <i>n</i>=43). <i>BRCA1</i> or <i>2</i> mutation frequencies were similar in both CRS subgroups. The majority of women recurred (73%, <i>n</i>=59) regardless of the CRS subgroup. Ultimately five patients were excluded from the analysis of progression-free and overall survival due to pertinent missing information such as documented CRS or missing vital statistics. The mean time from diagnosis to recurrence was 16 months versus 19 months for CRS 1-2 compared to CRS 3, but this difference was not significant. Median time from interval debulking to recurrence was not different between groups (11 months for CRS 1-2 vs 13 months for CRS 3, p=0.21). There was no difference in overall survival between the two groups; mean survival was 35 months in CRS 1-2 versus 34 months in CRS 3 (p=0.86). <b>Conclusions:</b> Previous studies have suggested a difference in progression-free survival for women who had CRS 1-2 versus CRS 3, indicating that this scoring system can inform disease prognosis and may help to guide adjuvant treatment strategies. Our preliminary analysis revealed no statistically significant difference in progression-free or overall survival for patients with CRS 1-2 versus CRS 3 and did not replicate the findings of other studies, a discrepancy that warrants further investigation.

Survival impact of histological response to neoadjuvant chemotherapy according to number of cycles in patients with advanced ovarian cancer

ObjectiveWe sought to evaluate the impact of chemotherapy response score according to the number of cycles of neoadjuvant chemotherapy, on disease-free survival and overall survival, in patients with advanced epithelial...

A Comparison Between Neoadjuvant Chemotherapy and Neoadjuvant Chemoradiotherapy in Treating Esophageal Carcinoma: A Study at a Tertiary Care Cancer Center in Suburban India.

Background and objectiveEsophageal carcinoma remains a disease associated with high mortality rates among patients even after receiving treatment. Management with surgery alone offers a five-year survival of only 20%. Hence adjuvant and neoadjuvant therapies were instituted to treat this condition along with surgery. Neoadjuvant chemoradiotherapy (NACRT) followed by surgery is currently the standard of care. Neoadjuvant chemotherapy (NACT) is also recommended by some authors as a method of adequate care. There is a scarcity of studies in the literature comparing NACRT with NACT. In light of this, we employed the criteria of pathological response as a primary endpoint to compare the effectiveness of NACT and NACRT in treating esophageal carcinoma.Materials and methodsA total of 50 patients with esophageal cancer having Eastern Cooperative Oncology Group (ECOG) scores 0-2 with cancer stages cT2-T4a, cN0-N1, and cM0 were enrolled. The patients were further classified into two groups of 25 each. While one group received chemotherapy using inj. paclitaxel and carboplatin (NACT group), the other was managed with inj paclitaxel and carboplatin as well as 42 Gy of fractionated irradiation (NACRT group). Six weeks after the last dose of radiation or three weeks after chemotherapy, they were evaluated and offered transthoracic esophagectomy (TTE).ResultsSquamous cell carcinoma was found in 39 (78%) cases and 11 (22%) cases had adenocarcinoma. Pathologically complete or near-complete responses were seen in 42% of patients in the NACRT group and 22% in the NACT group.ConclusionWhile NACT and NACRT are both effective therapies for esophageal cancers, NACRT offers better tumor regression compared to NACT. Given the higher rates of complete or near-complete response in the NACRT group, NACRT is likely to offer higher overall survival rates than NACT.

Magnetic Resonance Imaging Downstaging, Pathological Response, and Microsatellite Instability Status in Patients with Signet-Ring Cell Carcinoma Rectum Undergoing Preoperative Long-course Chemoradiation

Aim and Objective: To assess the magnetic resonance imaging (MRI) downstaging, pathological response, and the relationship between microsatellite instability (MSI) and radiotherapy response in signet-ring cell carcinoma rectum. Materials and Methods: Twenty two patients were recruited prospectively and retrospectively in this observational study. Six weeks following radiotherapy, the response was assessed using an MRI pelvis, and patients who were operable underwent total mesorectal excision followed by adjuvant chemotherapy. The outcome of radiotherapy was correlated with post radiation MRI downstaging, pathological response, and MSI status. Results: The post radiotherapy response assessment MRI showed tumor regression grading (TRG) 5 in 5 patients. TRG 4 seen in 12, TRG 3 in 3, and TRG 2 in 1 patient. Fifteen patients were operable and post-operativ histopathology showed that 40% had pathological complete response (pCR) and 26.7% had near-complete response. Even those who had no response in MRI had pCR. MSI done 17 patients were stable. Of the 6 patients who had complete pathological response, two were MRI TRG 5, three were MRI TRG 4, and one was MRI TRG 3. The median survival was 23 months. The 2-year and 3-year disease-free survival was 46% and 38%, respectively. Conclusion: The predictive value of MRI downstaging in these tumors following neoadjuvant long-course chemoradiation therapy is not often in concurrence with the histopathological response and needs to be interpreted carefully. Even though the pCR rate seen in this cohort is encouraging, this needs to be evaluated in studies with large cohorts.

Adaptive Dynamic Therapy and Survivorship for Operable Pancreatic Cancer

Neoadjuvant therapy is increasingly used in localized pancreatic carcinoma, and survival is correlated with carbohydrate antigen 19-9 (CA19-9) levels and histopathologic response following neoadjuvant therapy. With several regimens now available, the choice of chemotherapy could be best dictated by response to neoadjuvant therapy (as measured by CA19-9 levels and/or pathologic response), a strategy defined herein as adaptive dynamic therapy. To evaluate the association of adaptive dynamic therapy with oncologic outcomes in patients with surgically resected pancreatic cancer. This retrospective cohort study included patients with localized pancreatic cancer who were treated with either gemcitabine/nab-paclitaxel or fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) preoperatively between 2010 and 2019 at a high-volume tertiary care academic center. Participants were identified from a prospectively maintained database and had a median follow-up of 49 months. Data were analyzed from October 17 to November 24, 2020. The adaptive dynamic therapy group included 219 patients who remained on or switched to an alternative regimen as dictated by CA19-9 response and for whom the adjuvant regimen was selected based on CA19-9 and/or pathologic response. The nonadaptive dynamic therapy group included 103 patients who had their chemotherapeutic regimen selected independent of CA19-9 and/or tumoral response. Prognostic implications of dynamic perioperative therapy assessed through Kaplan-Meier analysis, Cox regression, and inverse probability weighted estimators. A total of 322 consecutive patients (mean [SD] age, 65.1 [9] years; 162 [50%] women) were identified. The adaptive dynamic therapy group, compared with the nonadaptive dynamic therapy group, had a more pronounced median (IQR) decrease in CA19-9 levels (-80% [-92% to -56%] vs -45% [-81% to -13%]; P < .001), higher incidence of complete or near-complete tumoral response (25 [12%] vs 2 [2%]; P = .007), and lower median (IQR) number of lymph node metastasis (1 [0 to 4] vs 2 [0 to 4]; P = .046). Overall survival was significantly improved in the dynamic group compared with the nondynamic group (38.7 months [95% CI, 34.0 to 46.7 months] vs 26.5 months [95% CI, 23.5 to 32.9 months]; P = .03), and on adjusted analysis, dynamic therapy was independently associated with improved survival (hazard ratio, 0.73; 95% CI, 0.53 to 0.99; P = .04). On inverse probability weighted analysis of 320 matched patients, the average treatment effect of dynamic therapy was to increase overall survival by 11.1 months (95% CI, 1.5 to 20.7 months; P = .02). In this cohort study that sought to evaluate the role of adaptive dynamic therapy in localized pancreatic cancer, selecting a chemotherapeutic regimen based on response to preoperative therapy was associated with improved survival. These findings support an individualized and in vivo assessment of response to perioperative therapy in pancreatic cancer.

Triplet Chemotherapy with Cisplatin versus Oxaliplatin in the CRITICS Trial: Treatment Compliance, Toxicity, Outcomes and Quality of Life in Patients with Resectable Gastric Cancer.

Simple SummaryPerioperative chemotherapy is the current standard treatment for patients with resectable gastric cancer. Either cisplatin or oxaliplatin could be part of the chemotherapy regimen, of which oxaliplatin is currently most used in the standard treatment. Evidence to choose oxaliplatin over cisplatin in the curative setting is limited. In this study, we compared cisplatin versus oxaliplatin in patients with resectable gastric cancer treated with pre- and postoperative chemotherapy. Adverse events were not different for patients who received cisplatin versus those who received oxaliplatin, nor was compliance with the treatment regimen. We could not detect survival differences between patients treated with cisplatin versus oxaliplatin. Diarrhea more frequently impacted patients treated with oxaliplatin than patients treated with cisplatin. As hydration is not needed for oxaliplatin, it is more practical to use in daily care. In conclusion, both cisplatin and oxaliplatin are legitimate options as part of systemic treatment in patients with resectable gastric cancer.(1) Background: Perioperative chemotherapy is the current standard treatment for patients with resectable gastric cancer. Based on studies in patients with metastatic gastric cancer, oxaliplatin has replaced cisplatin in the curative setting as well. However, evidence to prefer oxaliplatin over cisplatin in the curative setting is limited. (2) Methods: We compared patient-related and tumor-related outcomes for cisplatin versus oxaliplatin in patients with resectable gastric cancer treated with perioperative chemotherapy in the CRITICS trial. (3) Results: Preoperatively, 632 patients received cisplatin and 149 patients received oxaliplatin. Preoperative severe toxicity was encountered in 422 (67%) patients who received cisplatin versus 89 (60%) patients who received oxaliplatin (p = 0.105). Severe neuropathy was observed in 5 (1%) versus 6 (4%; p = 0.009) patients, respectively. Postoperative severe toxicity occurred in 109 (60%) versus 26 (51%) (p = 0.266) patients; severe neuropathy in 2 (1%) versus 2 (4%; p = 0.209) for patients who received cisplatin or oxaliplatin, respectively. Diarrhea impacted the quality of life more frequently in patients who received oxaliplatin compared to cisplatin. Complete or near-complete pathological response was achieved in 94 (21%) versus 16 (15%; p = 0.126) patients who received cisplatin or oxaliplatin, respectively. Overall survival was not significantly different in both groups (p = 0.300). (4) Conclusions: Both cisplatin and oxaliplatin are legitimate options as part of systemic treatment in patients with resectable gastric cancer.

The tumor immune microenvironment correlates with neoadjuvant chemotherapy response in high-grade serous ovarian cancer.

e17605 Background: Platinum-based neoadjuvant chemotherapy (NACT) plus interval debulking surgery (IDS) and adjuvant chemotherapy has been an established alternative for advanced epithelial ovarian cancer (EOC). The chemotherapy response score (CRS) has been applied to assess the efficacy of NACT in high-grade serous ovarian cancer (HGSOC). The purpose of this study was to assess the effect of NACT on tumor immune microenvironment (TIME) of HGSOC, and the correlation between the TIME and CRS. Methods: All patients underwent NACT with IDS. Formalin-fixed paraffin-embedded tissue samples were collected from pretreatment biopsy specimens and the corresponding post-NACT surgical specimens. The densities and percentage of various cell populations within the TIME were analyzed by multiplex immunohistochemistry (3DMedcines Inc.), including specific tumor infiltrating lymphocytes (TILs) (CD8+T cell, FOXP3+CD4+Treg cell and CD20+B cell), tumor associated macrophages (TAMs), NK cells (CD56 dim and CD56 bright). Patients were divided into three groups according to CRS based on pathological reaction of surgical specimens: CRS1 shows no or minimal response, CRS2 shows moderate response and CRS3 usually shows complete or near-complete response. Statistical analyses were performed using GraphPad Prism 7.0. P &lt; 0.05 was considered statistically significant. Results: A total of 25 HGSOC patients were enrolled in this study, 32% (8/25) of patients with CRS 1, 64% (16/25) with CRS 2, and 4% (1/25) with CRS 3. After NACT, patients with CRS 2 or 3 had a significant increase of the densities of CD20+B cells in stroma (pre-NACT 15.71/mm3 vs. post-NACT 87.82/mm3, p = 0.048). We also observed borderline significant increases of percentage of CD20+B cells, the densities and percentage of CD8+T cells in stroma after NACT (pre-NACT vs. post-NACT, 0.32% vs.1.54%, 56.35/mm3 vs. 311.35/mm3, 0.95% vs. 5.48%, respectively). Meanwhile, no significant change in CD4+T, TAMs and NK cells. In patients with CRS 1, we observed a significant increase of the densities and percentage of CD4+FOXP3+Treg in stroma (pre-NACT vs. post-NACT, 1.38/mm3 vs. 19.75/mm3, p = 0.01; 0.04% vs. 0.41%, p = 0.017, respectively), while CD8+T, CD20+B, TAMs and NK cells did not change significantly. Additionally, we found a significant difference in CD56 bright NK infiltration when comparing CRS 2 or 3 group with CRS1 group in post-NACT (0.5/mm3 vs.12/mm3, p = 0.049; 0.005% vs. 0.23%, p = 0.048). Conclusions: These data suggest immune infiltrate in TIME may serve as a biomarker to predict response to NACT in HGSOC. The infiltration of CD8+ T and CD20+ B cell was more pronounced in CRS2 or 3, while the enhanced infiltration of FOXP3+CD4+Treg cells is associated with immunosuppressive TIME and poor response (CRS1). The mechanism of lymphocyte regulation is not completely understood, thereby deserving further investigation.

Neo-adjuvant T-VEC plus nivolumab combination therapy for resectable early-stage or metastatic (IIIB-IVM1a) melanoma with injectable disease: The NIVEC trial.

TPS9607 Background: The prognosis of patients with melanoma is significantly correlated with disease stage and has greatly improved with the introduction of the currently approved therapies. Trials investigating neo-adjuvant treatment with immune checkpoint inhibitors (ICI) have shown high pathologic response rates up to 25-80%, however, still a large group of patients derive no (durable) clinical benefit. Treatment with talimogene laherparepvec (T-VEC), a modified herpes simplex virus type-1, is approved for patients with unresectable stage IIIB-IVM1a melanoma, with high and durable response rates and a mild toxicity profile. Earlier trials have suggested that T-VEC has the capacity to heighten the immune response and to elicit an abscopal effect in melanoma when given in combination with ICI. Combination ICI and intralesional T-VEC has already been investigated in patients with unresectable stage IIIB-IV disease, however, no data is available yet on the potential benefit of this combination therapy in neo-adjuvant setting. This is the first trial investigating the efficacy and safety of neo-adjuvant treatment of T-VEC in combination with nivolumab (anti-PD-1 antibody), followed by surgical resection in patients with resectable stage IIIB-IVM1a melanoma, with the potential of high pathologic response rates and acceptable toxicity. Methods: In this single center, single arm, phase II study, a total of 24 patients ≥18 years of age and a good clinical performance score with treatment naïve, stage IIIB-IVM1a melanoma (AJCC 8th edition) with injectable disease and resectable (sub)cutaneous satellite or in-transit metastases and/or tumor positive lymph nodes, will be included. Patients will receive four courses of T-VEC up to 4mL (first dose as seroconversion dose) and three doses of nivolumab (240mg flatdose) every two weeks, followed by surgical resection in week nine. The primary endpoint of this trial is pathologic response rate, with the aim to show a high major pathologic (near-complete or complete) response rate up to 45%. Secondary endpoints are safety according to CTCAE v5.0, the rate of delay of surgery and event free survival. Additionally, prognostic and predictive biomarker research and health-related quality of life evaluation will be performed. Enrollment started in June 2020 in the Netherlands Cancer Institute, with currently 13 of the 24 planned patients treated. Clinical trial information: NCT04330430.

MRI-Based Radiomics Features to Predict Treatment Response to Neoadjuvant Chemotherapy in Locally Advanced Rectal Cancer: A Single Center, Prospective Study.

This is a prospective, single center study aimed to evaluate the predictive power of peritumor and intratumor radiomics features assessed using T2 weight image (T2WI) of baseline magnetic resonance imaging (MRI) in evaluating pathological good response to NAC in patients with LARC (including Tany N+ or T3/4a Nany but not T4b). In total, 137 patients with LARC received NAC between April 2014 and August 2020. All patients were undergoing contrast-enhanced MRI and 129 patients contained small field of view (sFOV) sequence which were performed prior to treatment. The tumor regression grade standard was based on pathological response. The training and validation sets (n=91 vs. n=46) were established by random allocation of the patients. Receiver operating characteristic curve (ROC) analysis was applied to estimate the performance of different models based on clinical characteristics and radiomics features obtained from MRI, including peritumor and intratumor features, in predicting treatment response; these effects were calculated using the area under the curve (AUC). The performance and agreement of the nomogram were estimated using calibration plots. In total, 24 patients (17.52%) achieved a complete or near-complete response. For the individual radiomics model in the validation set, the performance of peritumor radiomics model in predicting treatment response yield an AUC of 0.838, while that of intratumor radiomics model is 0.805, which show no statically significant difference between then(P>0.05). The traditional and selective clinical features model shows a poor predictive ability in treatment response (AUC=0.596 and 0.521) in validation set. The AUC of combined radiomics model was improved compared to that of the individual radiomics models in the validation sets (AUC=0.844). The combined clinic-radiomics model yield the highest AUC (0.871) in the validation set, although it did not improve the performance of the radiomics model for predicting treatment response statically (P>0.05). Good agreement and discrimination were observed in the nomogram predictions. Both peritumor and intratumor radiomics features performed similarly in predicting a good response to NAC in patients with LARC. The clinic-radiomics model showed the best performance in predicting treatment response.

18F-FDG PET/CT During Neoadjuvant Targeted Therapy in Prior Unresectable Stage III Melanoma Patients: Can (Early) Metabolic Imaging Predict Histopathologic Response or Recurrence?

The aim of this study was to investigate whether 18F-FDG PET/CT can predict histopathological response or recurrence in BRAF-mutated unresectable locally advanced stage III melanoma treated with neoadjuvant BRAF/MEK inhibition followed by resection and the value of PET in detecting early recurrence after resection. Twenty BRAF-mutated, unresectable stage III melanoma patients received BRAF/MEK inhibitors before surgery. 18F-FDG PET/CT was performed at baseline and 2 and 8 weeks after initiation of therapy. After resection, PET/CT was performed at specific time points during 5 years of follow-up. Pathological response was assessed on the dissection specimen. Response monitoring was measured with SUVmax, SUVpeak, MATV, and TLG and according to EORTC and PERCIST criteria. Pathological response was assessed in 18 patients. Nine patients (50%) had a pathologic complete or near-complete response, and 9 (50%) had a pathologic partial or no response. EORTC or PERCIST response measurements did not correspond with pathologic outcome. SUVmax, SUVpeak, MATV, and TLG at all time points and absolute or percentage change among the 3 initial time points did not differ between the groups.During follow-up, 8 of 17 patients with R0 resection developed a recurrence, 6 recurrences were detected with imaging only, 4 of which with PET/CT in less than 6 months after surgery. PET parameters before surgery did not predict recurrence. Baseline 18F-FDG PET or PET response in previous unresectable stage III melanoma patients seems not useful to predict pathologic response after neoadjuvant BRAF/MEK inhibitors treatment. However, PET/CT seems valuable in detecting recurrence early after R0 resection.