Unresectable Disease Research Articles

HPB SO07 - Update to the role of staging laparoscopies in stratifying patients by operability in perihilar cholangiocarcinoma

Abstract Background Radical resection of perihilar cholangiocarcinoma (pCCA) is only an option for the minority presenting at an early stage. Sensitivity of radiological imaging to detect liver and peritoneal metastases is insufficient. Our published 2017 cohort study demonstrated over a quarter of patients with no radiologically detectable metastatic disease were subsequently found to have unresectable disease by staging laparoscopy. However, less than 3% of these patients had preoperative PET-CT, which is now strongly recommended in new national guidance.Advances in CT and MRI sensitivity and increased PET-CT use demanded a reassessment of the need for staging laparoscopy in diagnostic assessment of resectability. Method All patients referred to a tertiary UK hepatobiliary centre with a new diagnosis of radiologically suspected or biopsy-proven pCCA from January 2020 to January 2024 were included (n=305). Patients were identified through a prospectively maintained cancer database. Electronic health records were interrogated for demographic data, preoperative radiological imaging, and details related to operative procedures. Those referred with, or subsequently found to have, any of the following conditions were excluded: recurrent pCCA, intrahepatic or distal cholangiocarcinoma, gallbladder cancer or benign hepatobiliary disease. Results All patients underwent CT chest, abdomen and pelvis. 194 (64%) received contrast MRI liver or MRCP. Based on these, 242 (79%) had locally advanced or metastatic cancer, comorbidities precluding resection or otherwise declined surgery. PET-CT was employed to investigate all remaining 63 patients, which discovered metastatic disease in 16 patients (25%). 47 patients proceeded to staging laparoscopy. This yielded metastatic or locally advanced disease in five patients (11%); a near-statistically significant drop compared to our previously published yield of 27.2% (p=0.060). Two (5%) had open-and-close laparotomies for irresectable disease, compared to 16 of 114 (14%) in our 2017 publication (p=0.14). Conclusion Technological advances of CT and MRI and use of PET-CT have vastly improved detection of irresectable pCCA. This study reinforces the merits of PET-CT in identifying occult disease, and we would encourage units that undertake these resections to utilise this imaging modality prior to undertaking staging laparoscopy. Nevertheless, peritoneal spread remains challenging to exclude radiologically, and diagnostic laparoscopy endures as a vital tool in the prevention of open-and-close laparotomies.

In brief: A new non-small cell lung cancer indication for osimertinib (Tagrisso).

The oral kinase inhibitor osimertinib (Tagrisso – AstraZeneca), which has been available for years for treatment of non-small cell lung cancer (NSCLC) in adults with epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 L858R mutations, has now been approved for treatment of unresectable stage III EGFR-mutated NSCLC.1 About 20-30% of patients with NSCLC have locally advanced stage III NSCLC, and 60-90% of these patients have unresectable disease. Osimertinib is the first targeted therapy to be approved for the new indication.

The role of external-beam radiotherapy for differentiated thyroid cancer.

The treatment options for differentiated thyroid cancer (DTC) are surgery, thyroid stimulating hormone suppression, radioactive iodine, and multitargeted tyrosine kinase inhibitors. The role of external-beam radiotherapy (EBRT) for DTC is controversial because of the lack of randomized controlled trials, but prospective single-arm studies and propensity score matching analyses have shown its efficacy and safety. This review discusses the role of EBRT after resection of gross disease, when there is a high risk of locoregional failure, as well as its role for locoregionally gross recurrent and unresectable disease. As in other tumor sites, EBRT has an important role in the palliative management and local control of patients with metastatic DTC, especially with bone and brain metastases.

Efficacy and Safety of KH903 Plus FOLFIRI as A Second-line Treatment In Unresectable Recurrent or Metastatic Colorectal Cancer: A Randomized Phase 2 Study

BackgroundPatients with recurrent or metastatic advanced colorectal cancer (mCRC) often face the clinical dilemma as this unresectable disease is continuously progressing and endangering the patients’ lives. In the current study, we explored the clinical feasibility of KH903 in combination with FOLFIRI chemotherapy as a new clinical indication for mCRC. MethodsPatients (N=122) were randomized 1:1 to 4mg/kg q1w KH903 or 5mg/kg q2w KH903, and both groups of patients were treated with the fixed regimen of FOLFIRI (every 2 weeks) along with the KH903 therapy. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were Overall Survival (OS), objective response rate (ORR), and disease control rate (DCR). ResultsAs of December 30, 2020, median (m)PFS was 5.68 months (95% CI,4.67-7.13) with 4mg/kg q1w vs. 5.19 months (95% CI, 4.04, 5.78) with 5mg/kg q2w (HR, 0.76; 95% CI, 0.50-1.16),and mOS was 13.14 months (95% CI, 10.61-19.52) vs. 16.03 months (95% CI, 10.28- NE), respectively (HR, 1.11; 95% CI, 0.65-1.89), The ORR was 15.9% and 11.9% for both groups, respectively, and The DCR for both groups was 85.7% and 83.1%, respectively. Grade 3 or higher treatment-related adverse event rates for both groups were 68.3% vs.52.5%, respectively. ConclusionsKH903 in combination with FORFIRI in second-line treatment of patients with mCRC showed prolonged mPFS and mOS, comparing to the similar agents (Avastin®, ZALTRAP®, Cyramza®) and no new safety signals were observed. Micro AbstractIn the current study, we explored the clinical feasibility of KH903 in combination with FOLFIRI chemotherapy as a new clinical indication for mCRC. We demonstrated that KH903 in combination with FORFIRI in second-line treatment of patients with mCRC showed prolonged mPFS and mOS, comparing to the similar agents. It was suggested that KH903 in combination with FOLFIRI has shown further clinical development value, and its efficacy and safety can be further confirmed in later clinical trials, providing more options for second-line treatment of metastatic colorectal cancer patients.

Patterns of loco-regional progression and patient outcomes after definitive-dose radiation therapy for anaplastic thyroid cancer

BackgroundThe aim of this study is to characterize the patterns of loco-regional progression (LRP) and outcomes after definitive-dose intensity modulated radiation therapy (IMRT) for anaplastic thyroid cancer (ATC) with macroscopic neck disease at the time of IMRT. MethodsDisease/treatment characteristics and outcomes for patients with unresected or incompletely resected ATC who received IMRT (≥45 Gy) were retrospectively reviewed. For those with LRP after IMRT, progressive/recurrent gross tumor volumes (rGTV) were contoured on diagnostic CTs and co-registered with initial planning CTs using deformable image registration. rGTVs were classified based on established spatial/dosimetric criteria. ResultsForty patients treated between 2010–2020 formed the cohort. Median IMRT dose was 66 Gy (45–70 Gy); altered fractionation (AF) was used in 24 (60 %). All received concurrent chemotherapy. In addition to areas of gross disease, target volumes (TVs) commonly included: central compartment/upper mediastinum (levels VI/VII), neck levels II-V in an involved, and levels III-IV in an uninvolved lateral neck. Median overall survival was 7.1 m. Median progression free survival was 7.4 m for patients with locoregional disease and 1.8 m for patients with distant metastasis at the time of IMRT. Twenty-one patients (53 %) developed LRP at median of 10.9 m; freedom from LRP at 3 m and 12 m was 71 % (95 %CI 58–87 %) and 47 % (95 %CI 32–68 %). Forty-one individual rGTVs were identified and most occurred within the high dose (HD) TVs: Type A/central HD (n = 29, 71 %) and B/peripheral HD (n = 3, 7 %). ConclusionsDespite an intensive treatment schedule, including AF and concurrent chemotherapy, classic radio-resistant and rapid Type A failures predominated; isolated extraneous dose failures were rare. While these findings support the IMRT and TV delineation strategies described herein, they highlight the importance of identifying novel strategies to further improve LRC for patients with unresectable disease without targetable mutations for contemporary neo-adjuvant strategies.

S-1-based concurrent chemoradiotherapy plus nimotuzumab in patients with locally advanced esophageal squamous cell carcinoma who failed neoadjuvant therapy: a real-world prospective study

ABSTRACT Purpose This prospective study in a real-world setting investigated the feasibility and safety of S-1 plus nimotuzumab (S-1-Nimo) based concurrent chemoradiotherapy (CCRT) in locally advanced esophageal squamous cell carcinoma (LA-ESCC) patients who failed to neoadjuvant chemotherapy or chemoimmunotherapy. Methods LA-ESCC patients who failed to converse to resectable disease after neoadjuvant chemotherapy or chemoimmunotherapy were enrolled to receive the 4-week S-1-Nimo regimen of radiotherapy (40 Gy in 20 fractions, 5 days per week), S-1 chemotherapy, and nimotuzumab. Then, after surgical assessments, patients evaluated as resectable disease received surgery; patients with unresectable disease continued to receive definitive radiotherapy (50–60 Gy in 25–30 fractions, 5 days per week) concurrently with S-1-Nimo. The primary endpoint was event-free survival (EFS). Results Sixty-four patients were enrolled and evaluated. The median follow-up time was 23.2 months. Median EFS was 9.6 (95% confidence interval [CI], 7.1–14.0) months, with an estimated 2-year EFS rate of 24.2%. The median overall survival (OS) and the estimated OS rate at 2 years were 13.4 (95% CI, 10.3–17.5) months and 31.2%, respectively. Twelve underwent surgery, with a surgical conversion rate of 18.8% and an R0 resection rate of 100.0%. Subgroup analysis identified the significantly prolonged EFS and OS in patients who experienced radical surgery (median EFS, not reached vs. 8.7 months; p = .0117. median OS, 24.9 vs. 10.6 months; p = .0205) as compared to those treated with CCRT. Of 64 patients, grade 3 adverse events mainly included radiation esophagitis (4.7%), anemia (1.6%), and thrombocytopenia (1.6%). Conclusion The study demonstrated the reasonable efficacy and promising safety of the S-1-Nimo-based CCRT in LA-ESCC patients with failure to neoadjuvant chemotherapy or chemoimmunotherapy.

Feasibility of neoadjuvant chemotherapy for bulky early stage to stage IIIB cervical cancer in Uganda

IntroductionExternal beam radiotherapy (EBRT) became unavailable in Uganda from February 2016 to November 2017. Following resource stratification guidelines, an alternative treatment strategy was developed. MethodsBulky early stage to Stage IIIB patients received at least 3 cycles of neoadjuvant chemotherapy (NAC). Surgery was performed if adequate response was achieved and adjuvant therapy given for high risk factors. Chemotherapy versus supportive care was advised in unresectable disease. NAC protocol completion was defined as receiving at least 3 cycles of NAC followed by either surgery, chemotherapy and/or radiation, or best supportive care. The purpose of this study was to determine the completion rate of NAC and assess the adverse events associated with treatment. Data were collected through retrospective chart review. ResultsFrom February 2016 to November 2018, 53 evaluable patients were identified. 86.8% (46/53) of patients presented in Stage IIB or higher. The completion rate of the NAC protocol was 75.5% (40/53). 94.3% (50/53) received platinum-taxane combination. 7.6% (4/52) grade 3 adverse events occurred related to chemotherapy, all hematologic. 18.8% (10/53) patients underwent surgery with 2 aborted cases due to metastatic or inoperable disease. No adverse events related to surgery were reported. 5 patients underwent adjuvant therapy after surgery due to high risk factors or incomplete pathology findings. 26 patients received adjuvant radiation (3 brachytherapy, 23 EBRT after it became available). Reported side effects related to radiation included vaginal fibrosis and skin reactions. ConclusionIn this limited-resource setting, majority of patients completed a NAC treatment strategy for cervical cancer with acceptable toxicities.

Evaluating Combinations of Biological and Clinicopathologic Factors Linked to Poor Outcomes in Resected Colorectal Liver Metastasis: An External Validation Study.

Recent studies have suggested that certain combinations of KRAS or BRAF biomarkers with clinical factors are associated with poor outcomes and may indicate that surgery could be "biologically" futile in otherwise technically resectable colorectal liver metastasis (CRLM). However, these combinations have yet to be validated through external studies. We conducted a systematic search to identify these studies. The overall survival (OS) of patients with these combinations was evaluated in a cohort of patients treated at 11 tertiary centers. Additionally, the study investigated whether using high-risk KRAS point mutations in these combinations could be associated with particularly poor outcomes. The recommendations of four studies were validated in 1661 patients. The first three studies utilized KRAS, and their validation showed the following median and 5-year OS: (1) 30 months and 16.9%, (2) 24.3 months and 21.6%, and (3) 46.8 months and 44.4%, respectively. When analyzing only patients with high-risk KRAS mutations, median and 5-year OS decreased to: (1) 26.2 months and 0%, (2) 22.3 months and 15.1%, and (3) not reached and 44.9%, respectively. The fourth study utilized BRAF, and its validation showed a median OS of 10.4 months, with no survivors beyond 21 months. The combinations of biomarkers and clinical factors proposed to render surgery for CRLM futile, as presented in studies 1 (KRAS high-risk mutations) and 4, appear justified. In these studies, there were no long-term survivors, and survival was similar to that of historic cohorts with similar mutational profiles that received systemic therapies alone for unresectable disease.

Polymorphisms within autophagy-related genes as susceptibility biomarkers for pancreatic cancer: A meta-analysis of three large European cohorts and functional characterization.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers with patients having unresectable or metastatic disease at diagnosis, with poor prognosis and very short survival. Given that genetic variation within autophagy-related genes influences autophagic flux and susceptibility to solid cancers, we decided to investigate whether 55,583 single nucleotide polymorphisms (SNPs) within 234 autophagy-related genes could influence the risk of developing PDAC in three large independent cohorts of European ancestry including 12,754 PDAC cases and 324,926 controls. The meta-analysis of these populations identified, for the first time, the association of the BIDrs9604789 variant with an increased risk of developing the disease (ORMeta = 1.31, p = 9.67 × 10-6). We also confirmed the association of TP63rs1515496 and TP63rs35389543 variants with PDAC risk (OR = 0.89, p = 6.27 × 10-8 and OR = 1.16, p = 2.74 × 10-5). Although it is known that BID induces autophagy and TP63 promotes cell growth, cell motility and invasion, we also found that carriers of the TP63rs1515496G allele had increased numbers of FOXP3+ Helios+ T regulatory cells and CD45RA+ T regulatory cells (p = 7.67 × 10-4 and p = 1.56 × 10-3), but also decreased levels of CD4+ T regulatory cells (p = 7.86 × 10-4). These results were in agreement with research suggesting that the TP63rs1515496 variant alters binding sites for FOXA1 and CTCF, which are transcription factors involved in modulating specific subsets of regulatory T cells. In conclusion, this study identifies BID as new susceptibility locus for PDAC and confirms previous studies suggesting that the TP63 gene is involved in the development of PDAC. This study also suggests new pathogenic mechanisms of the TP63 locus in PDAC.

Treatment strategies for elderly patients with locally advanced esophageal cancer: a systematic review and meta-analysis

BackgroundNeoadjuvant chemoradiotherapy (nCRT) followed by surgery remains a standard of care for resectable esophageal cancer (EC), and definitive chemoradiotherapy (dCRT) is an alternative for unresectable diseases. However, it is controversial for the use of the two aggressive regimens in elderly patients.MethodsWe systematically searched multiple databases for studies comparing overall survival (OS) and/or progression-free survival (PFS) between dCRT and surgery (nCRT + surgery or surgery alone) or between dCRT and radiotherapy (RT) alone in elderly patients (age ≥ 65 years) until March 28, 2024. Statistical analysis was performed using random-effects model.ResultsFourty-five studies with 33,729 patients were included. dCRT significantly prolonged OS (hazard ratio [HR] = 0.64, 95% confidence interval [CI]: 0.58–0.70) and PFS (HR = 0.67, 95% CI: 0.60–0.76) compared to RT alone for unresectable EC, and resulted in a worse OS compared to surgery for resectable cases (HR = 1.34, 95% CI: 1.23–1.45). Similar results of OS were also observed when the multivariate-adjusted HRs were used as the measure of effect (dCRT vs. RT alone: HR = 0.65, 95% CI: 0.58–0.73; dCRT vs. surgery: HR = 1.49, 95% CI: 1.28–1.74). Subgroup analyses according to age group (≥ 70, ≥ 75, or ≥ 80 years), study design, study region, histological type, radiation field, chemotherapy regimen revealed comparable results.ConclusionsnCRT + surgery is likely a preferred strategy for elderly patients with good physiological conditions; and dCRT is a better alternative for unresectable cases. Advanced age alone does not appear to be a key predictor for the tolerability of the two aggressive treatments.

Mechanism, Potential, and Concerns of Immunotherapy for Hepatocellular Carcinoma and Liver Transplantation.

In the last decade, immunotherapy (IT) has revolutionized oncology and found indications in many cancers, including hepatocellular carcinoma (HCC). In HCC, IT has become the leading systemic therapy for advanced diseases. At the same time, it carries the promise of being a valuable therapy in other settings, including intermediate-stage and unresectable disease, as a downstaging or conversion modality. More controversial is the role of IT in relationship to liver transplantation (LT): on one side, it could be a helpful tool to control or downstage HCC before LT or to treat tumor recurrence after LT, while on the other, it carries the risk of graft rejection and graft loss. This review aims to cover these concerns in depth and unravel the current literature.

Definitive Radiation Therapy is a Viable Treatment for Locally Advanced Basal Cell Carcinoma Otherwise Requiring Radical or Disfiguring Resection

BackgroundStandard treatment for basal cell carcinoma (BCC) is surgical resection. However, a subset of locally advanced BCCs may be unresectable, or surgery would result in unacceptable functional or cosmetic defects. Outcomes after definitive radiotherapy for locally advanced BCC in the contemporary era are not well established. ObjectiveWe sought to determine locoregional control and disease specific survival after definitive radiotherapy for locally advanced BCC. MethodsPatients with locally advanced BCC treated with definitive radiotherapy between 2005-2020 from 4 academic tertiary care institutions were included. Locally advanced BCCs were defined as patients with unresectable disease, or locations where margin negative resection would lead to unacceptable cosmetic or functional deficit. Additionally, a set of 5 risk factors (size ≥4 cm, the presence of bone invasion, PNI, immunocompromised patient, and recurrent disease) was separately defined and outcomes were investigated. Results608 locally advanced BCC cases were identified, of which 140 were treated with definitive radiotherapy. Median follow up was 22.9 months (1.5-207.2 months). 101 (72.1%) tumors were treated with upfront definitive radiotherapy, while 39 (27.9%) were treated for a recurrence. 5-year Kaplan-Meier estimated locoregional control was 78%. The majority of locoregional failures were local recurrences (95.5%). Larger tumor diameter was a risk factor for locoregional failure (p=0.045), while recurrent disease was not (p=0.29). Cumulative incidence of BCC related mortality at 5 years was 9.5%. Patients with 0 risk factors had a 5-year FF-LRF of 92.4%, whereas those with 1+ risk factors had a 5-year FF-LRF of 68.5% (p=0.004). ConclusionDefinitive radiotherapy for locally advanced BCC has excellent locoregional control, with tumor size representing the only risk factor for recurrence in this study.

397. TREATMENT OUTCOMES OF IMMUNE CHECKPOINT INHIBITORS AS PRIMARY THERAPY FOR UNRESECTABLE OR RECURRENT ESOPHAGEAL CANCER

Abstract Background For the primary treatment of unresectable or recurrent esophageal cancer, combination therapy with immune checkpoint inhibitors (ICI) such as pembrolizumab (Pem) with CF (cisplatin and 5-fluorouracil), nivolumab (Nivo) with CF, and Nivo with ipilimumab (Ipi) has been shown the significantly improve prognosis compared to standard CF therapy in international collaborative phase III trials. As a result, these ICIs have been approved as primary treatment agents in Japan, with treatment guidelines strongly recommending therapies including ICIs. We evaluated the treatment outcomes at our institute and discussed their utility. Methods We examined the treatment outcomes of 26 esophageal cancer patients who underwent primary treatment with Pem+CF, Nivo+CF, or Nivo+Ipi from January 2018 to January 2023. The median observation period was 7.0 months. Results There were 20 male and 6 female patients, with a median age of 69 years. Histologically, there were 24 cases of squamous cell carcinoma and 2 cases of adenocarcinoma. Of the 26 patients, 9 were postoperative recurrences and 17 were unresectable diseases. They were treated with Pem+CF (12 cases), Nivo+CF (7 cases), or Nivo+Ipi (7 cases) as primary therapy. The initial response was complete response (CR) in 1 case, partial response (PR) in 14 cases, stable disease (SD) in 2 cases, and progressive disease (PD) in 9 cases, resulting in an overall response rate of 57.6%. The median progression-free survival was 5.0 months, and the median overall survival was 15.2 months. There was no significant difference in prognosis according to the regimens. Grade 3 or higher adverse events included neutropenia in 3 cases, pituitary insufficiency in 1 case, and adrenal insufficiency in 1 case. One case with lung metastasis and two cases with para-aortic lymph node metastasis showed disappearance of metastatic lesions after chemotherapy including ICIs, leading to conversion esophagectomy. One case had anastomotic failure, but no other postoperative complications were observed. All patients are currently under observation without recurrence. Conclusion ICIs for unresectable or recurrent esophageal cancer showed a prolongation of prognosis in real-world clinical practice, suggesting their significance as part of a multimodal treatment approach including conversion surgery.

249. OVERALL SURVIVAL OF PATIENTS WITH ESOPHAGEAL CANCER TREATED WITH DEFINITIVE CHEMORADIOTHERAPY: INSIGHTS FROM A RETROSPECTIVE STUDY

Abstract Background Neoadjuvant chemoradiotherapy followed by esophagectomy is the standard of care for patients with locally advanced esophageal cancer. However, definitive chemoradiotherapy (dCRT) may be considered as an alternative for those with unresectable disease, cervical location of the tumor or if a non-surgical approach is preferred based on the patient's condition. Heterogeneity in indications for dCRT makes it challenging to draw generalized conclusions regarding outcomes and survival. The aim of this study was to evaluate overall survival (OS) and recurrence patterns in patients with specified homogeneous indications for dCRT. Methods Patients with esophageal cancer treated with dCRT (50.4 Gy radiotherapy concomitant with 6 cycles of carboplatin/paclitaxel) between 2012-2022 in a tertiary referral center were identified from our institutional database. Primary endpoint was OS calculated from date of diagnosis until date of death or last day of follow-up, using the Kaplan Meier method. Secondary endpoints included the proportion of patients that completed the dCRT regimen, 30- and 90-day mortality following dCRT and disease recurrence. Results 162 patients were included, median follow-up was 74.6 months (IQR 46.2-99.3). The full dCRT regimen was completed by 116 (73.9%) patients. The 30- and 90-day mortality were 2.5% and 8.3%, respectively. The median OS was 23.7 months (95% CI 6.65-40.66) for cervical location of the tumor, 13.7 months (95% CI 7.92-29.8) for irresectable disease, 28.2 months (95% CI 12.10-44.22) for patients unfit for surgery and 20.6 months (95% CI 14.14-27.13) for those with preference for dCRT (p=0.15). Disease recurrence was observed in 74 patients (46%), located locoregional (46%), distant (19%) or both locoregional and distant (35%). Conclusion(s) Treatment with dCRT resulted in a 5-year OS of 35% and is associated with a high 90-day mortality. Disease recurrence was mostly locoregional located and was observed in 46% of patients. This emphasizes the critical necessity for enhanced treatment strategies centered on improving locoregional disease control.

291. CLINICAL OUTCOMES OF IMMUNOCHEMOTHERAPY FOR UNRESECTABLE OR RECURRENT ESOPHAGEAL SQUAMOUS CELL CARCIONOMA

Abstract Background/Aim KEYNOTE-590 and CheckMate 648 study showed significantly feasible clinical outcomes in patients with advanced esophageal carcinoma. Herein, we report our clinical results of immunochemotherapy for unresectable and recurrent esophageal squamous cell carcinoma. Patients and Methods 17 patients who received pembrolizumab plus 5-fluorouracil and cisplatin (IO+C) and 9 patients who received nivolumab plus ipilimumab (IO+IO) were enrolled. Results The median age of the IO+C group was 70 years, and all patients had unresectable disease. A median of 2 courses of treatment were performed, and the best overall response rate was 68.6% including CR in 2 patients, PR in 9 patients, SD in 4 patients, PD in 1 patient and NE in 1 patient. One-year progression-free survival rate (PFS) was 36.1% and one-year overall survival (OS) was 64.6%. Immune-related adverse events (irAE) included liver damage in 4 patients, skin damage in 4 patients, thyroid dysfunction in 2 patients and lung damage in 1 patient. The median age of the IO+IO group was 79 years, with 3 patients of unresectable disease and 6 patients of recurrence. A median of 2 courses of treatment were performed, and the best overall response rate was 71.4% including CR in 4 patients, PR in 1 patient, SD in 1 patient, PD in 1 patient, and NE in 2 patients. One-year PFS was 68.6% and one-year OS was 85.7%. irAE included liver damage in 3 patients, skin damage in 6 patients, thyroid dysfunction in 2 patients, rhabdomyolysis in 1 patient and hypopituitarism in 1 patient. Discussion/Conclusion Currently, in our institute, IO+C is the first choice for unresectable esophageal carcinoma, and IO+IO is selected for patients who are unresponsive or intolerant to FP, patients requiring outpatient treatment and patients with recurrent disease. Although long-term clinical outcomes will need to be examined, immunochemotherapy is very useful and it is necessary to examine the effective use of IO+C and IO+IO in the future.

Low to intermediate grade lung neuroendocrine tumours. A single centre real world experience

IntroductionLung neuroendocrine tumours (LNETs) are a rare heterogenous group of tumours whose incidence has been increasing. We investigated the diagnosis, treatment, and survival patterns of patients with low to intermediate grade LNETs. MethodsA retrospective chart review of patients with low to intermediate grade LNETs, treated at a Canadian tertiary-level cancer centre was performed. ResultsWe identified 59 patients. Most were G1or G2 and well or moderately differentiated. Forty-seven patients presented with local or locally advanced disease, of which 57.4 % received curative intent surgery. The rest were treated with definitive radiation, radical chemoradiation with platinum and etoposide, palliative chemotherapy with doxorubicin, or supportive care. The five-year overall survival (OS) for those treated surgically was 83 % versus 44 % in the non-surgical group. Metastatic disease was seen in 24/59 patients, with a five-year OS in patients with stage IV disease of 39 %. Of those with advanced or unresectable disease (n = 32), 21 received palliative systemic treatment with up to three lines of therapy. First-line treatment was most commonly chemotherapy with platinum/etoposide combination or somatostatin analogue therapy. Second-line treatment involved chemotherapy or targeted everolimus. PRRT was used once as a first-line and once as second-line therapy. Third-line included lanreotide or chemotherapy with capecitabine/temozolomide combination. ConclusionOverall, patients with surgically resectable disease had a good five-year OS. However, inoperable or more advanced disease was associated with a poorer OS. Despite many treatment options, the sequence of treatments is poorly established. This highlights the need for further development and dissemination of evidence-based guidelines for LNET patients.

Early circulating tumor DNA (ctDNA) changes during treatment with immune checkpoint inhibitors (ICI) as a predictor of clinical outcomes in patients (pts) with advanced stage melanoma/skin cancer.

225 Background: ctDNA monitoring has shown promising results in predicting relapse in resected solid tumors. Its role in treatment response assessment and predicting survival outcomes in the unresectable or metastatic disease setting merits further investigation. In our study, we attempt to assess the role of early ctDNA changes in predicting disease response, progression, and overall survival outcomes in pts with advanced stage melanoma/skin cancer treated with ICI therapy. Methods: A retrospective analysis using a personalized, tumor-informed ctDNA assay (Natera) on prospectively collected plasma samples from pts with unresectable stage III/IV melanoma/skin cancer treated with anti-PD-1 based therapy at the University of Wisconsin (Madison) was performed. Baseline ctDNA levels were assessed prior to the start of treatment and at 3-4 weeks (i.e. prior to the second treatment dose). A logistic regression model was used to evaluate the odds of overall disease control [complete response + partial response + stable disease, per RECIST version 1.1] based on the change in ctDNA levels (decrease vs increase) between both time points. Cox proportional hazard models were used to investigate the effects of ctDNA level change on progression free survival (PFS) and overall survival (OS). Results: 46 pts were evaluated. 82% melanoma, 14% Merkel cell carcinoma, 2% skin adenocarcinoma and 2% squamous cell carcinoma. 77% were treated with dual ICI (anti-PD-1 based) therapy and 23% with anti-PD-1 monotherapy. Median follow up was 12.1 months. Median change in ctDNA levels from baseline were -4.83 MTM/mL among pts with ctDNA decrease and +37.39 MTM/mL among pts with ctDNA increase. A qualitative decrease in ctDNA level was associated with overall disease control (OR 65.00, 95% CI 11.88-587.89, p<0.0001), longer PFS (HR 0.08, 95% CI 0.03-0.22, p<0.0001), and longer OS (HR 0.17, 95% CI 0.05-0.54, p=0.0008) compared to an increase in ctDNA level from baseline to 3-4 weeks after starting ICI therapy. Median PFS was not reached (NR) and 1.63 months; and median OS was NR and 5.57 months among pts with ctDNA decrease and ctDNA increase, respectively. Conclusions: We found that early ctDNA dynamics after 3-4 weeks of ICI initiation in pts with advanced melanoma/skin cancer appears to be a candidate strategy to predict treatment response, risk of progression, and potentially long-term survival. Larger prospective studies are warranted to validate the utility of ctDNA in treatment monitoring.

Systemic Management of Advanced Adrenocortical Carcinoma.

Adrenocortical cancer (ACC) is a rare and aggressive disease. Surgery has traditionally been the primary treatment for locally advanced disease with ongoing controversy around the optimal neoadjuvant and adjuvant treatment options. Unfortunately, local recurrence and the eventual development of metastatic disease is common and five-year survival rates are poor. While many trials have evaluated novel systemic agents to treat advanced adrenocortical cancer, only a few drugs have demonstrated any response at all. To date, only one drug, mitotane, is approved in the US for ACC and no regimen has clearly shown an increase in overall survival. In advanced metastatic or unresectable disease, data supports the first line regimen of EDP chemotherapy + mitotane as the primary treatment modality. In the second line, while data is limited, we would recommend consideration of immunotherapy using a PD(L)1 agent combined with a TKI/VEGF inhibitor or combination immunotherapy with PD1/CTLA-4 drugs. In all cases, we always prefer a clinical trial as available. This article reviews data from multiple studies evaluating novel systemic agents against ACC and discusses current systemic therapy combinations and ongoing clinical trials.

Conversion Therapy for Gastric Cancer with Peritoneal Metastasis

Peritoneal metastasis in gastric cancer has a poor prognosis and is increasing in prevalence. Neoadjuvant chemotherapy is used for advanced tumors; however, surgery is generally not considered for metastatic and unresectable diseases. Recently, conversion surgery, a treatment which aims for an R0 resection following chemotherapy, has become a novel therapeutic option with better survival rates. In addition to surgery, hyperthermic intraperitoneal chemotherapy (HIPEC) leads to significant tumor reduction, but it is limited by its morbidity. Pressurized intraperitoneal aerosol chemotherapy (PIPAC) delivers high concentrations of chemotherapy, but does not remove the tumor, making it useful mostly in palliative settings. Intraperitoneal (IP) therapy, known for its minimally invasive nature and repeatability, shows promise but requires further research. Ultimately, an integrated approach involving systemic chemotherapy, radical gastrectomy, HIPEC, PIPAC and IP chemotherapy can be used to optimize treatment outcomes of gastric cancer patients with peritoneal metastasis.

Reirradiation in head and neck squamous cell carcinoma; prognostic indicators, oncologic and functional outcomes

ObjectivesPatients with recurrent squamous cell carcinoma of the head and neck (HNSCC) have a poor prognosis and limited therapeutic alternatives. While reirradiation is feasible, it is usually associated with high treatment toxicity and is not yet considered the standard of care. Based on current NCCN guidelines, in the context of very advanced head and neck cancer (recurrent and/or persistent disease), surgical intervention is explored initially with/without adjuvants while unresectable disease is approached with radiation and/or systemic therapies. Specific and reliable prognostic indicators for both -oncologic and functional outcomes- have yet to be defined for this population. MethodsRetrospective chart review of 54 patients treated with reirradiation at a tertiary academic institution between January of 1998 and January of 2024. Only patients with non-metastatic recurrent, and second primary HNSCC were included in the series. Demographics, staging, radiation dose and technique, additional therapy, histopathologic variables, EORTC toxicity, pre- and post-treatment PEG/tracheotomy dependency and oncologic outcomes were retrieved. ResultsThe study cohort consisted of 54 patients (37 males, 17 females) with HNSCC, averaging 62.7 years in age. Initial tumors were locally advanced in over 42 % of cases, with 58 % being node-negative. The head and cutaneous regions (24.5 %) and tongue (20.8 %) were the most common tumor sites. Primary surgical resection and adjuvant radiation were performed in 47.2 % of cases, and concurrent chemotherapy was used in 40.7 %. Reirradiation was mainly for local or regional recurrence (88.9 %), often following salvage surgery (68.5 %), with a mean dose of 5623 Gy over 52.5 fractions. Positive surgical margins were present in 29.4 % of cases, and extracapsular spread in 59.5 %. No significant differences were found between the salvage surgery and definitive reirradiation groups except for tumor site (P = 0.022). Median follow-up was 52.6 months, with 27 deaths reported. Lymphovascular invasion was significantly correlated with overall survival (P = 0.017), while initial tumor T-stage and neck disease involvement were linked to local-regional control (P = 0.030 and P = 0.033, respectively). Reirradiation increased tracheotomy and PEG-tube dependency by 20 % (P = 0.011) and 23 % (P = 0.003), respectively. ConclusionsReirradiation is a feasible therapeutic alternative in recurrent head and neck SCC. Oncologic outcomes observed in this series compare favorably to most published reports. Complete response and perineural invasion were independent prognostic factors for survival and locoregional control. While no mortality directly associated with treatment was observed in this series, reirradiation had a significant impact in functional outcomes in terms of increased risk of tracheotomy and peg tube dependency. Further studies are required to define the role of this treatment in head and neck cancer.