HORMONET: a phase II trial of tamoxifen for estrogen/progesterone receptor-positive neuroendocrine tumors.

Background: Nearly 30% of neuroendocrine tumors (NETs) have evidence of immunohistochemical (IHC) expression of estrogen (ER) and/or progesterone (PR) receptors. Therefore, targeting ER/PR may offer an effective NET-directed treatment to select patients. Methods: We conducted a multicenter Simon two-stage single-arm phase II trial of tamoxifen in patients with metastatic, progressive NETs. Eligible patients had positive IHC expression of ER and/or PR ⩾ 1%. Prior therapy with somatostatin analogs was required for progressing/functioning cases. Main exclusion criterion was aggressive disease requiring cytotoxic therapy. The primary end point was disease control rate (DCR) at week 24 by Response Evaluation Criteria in Solid Tumors version 1.1. We planned to enroll 23 patients in the first stage, to reach a DCR at week 24 of 70% (versus 50%); if ⩾12 patients reached the primary end point, a total of 37 would be included. Results: From February 2019 to February 2022, 23 out of 59 patients were eligible and enrolled: 15 (65%) were females; the most common sites were pancreas (11; 48%) and small bowel (6; 26%). In all, 13 patients (56.5%) had G2 NETs. At a median follow-up of 27 months, 13 patients (56.5%) had stable disease at week 24 and median progression-free survival (PFS) was 7.9 months [interquartile range (IQR): 3.7-12.1]. The best response was stable disease in 13 patients, with most patients experiencing minor tumor growth. Median PFS times were not significantly different according to ER/PR < or ⩾30% (p = 0.49) or ER versus PR expression (p = 0.19). One patient experienced grade 2 constipation. Conclusion: Tamoxifen for ER-/PR-positive NETs patients is safe but offers modest antitumor effects. Trial registry name: Study of Tamoxifen in Well Differentiated Neuroendocrine Tumors and Hormone Receptor Positive Expression (HORMONET). URL: https://clinicaltrials.gov/ct2/show/NCT03870399?term=03870399&draw=2&rank=1. Registration number: NCT03870399.

Evaluation of prognostic factors in patients undergoing first-line chemotherapy for advanced biliary tract cancer: a retrospective analysis from a South American cancer centre.

INTRODUCTION: Biliary tract cancers (BTCs) are rare tumours with regional differences. Prognostic factors are poorly understood. Gemcitabine + platinum (GP) is the standard first-line chemotherapy in metastatic patients. We aimed to search for prognostic factors in patients with advanced disease in a cancer centre in South America. METHODS: We conducted a retrospective analysis of patients with advanced BTC treated with chemotherapy. Variables were age (< or ≥70 years), Eastern Cooperative Oncology Group (ECOG) performance status (0/1 versus 2/3), gender, primary site (intrahepatic (IHC), extrahepatic (EHC), gallbladder (GB)), staging (locally advanced versus metastatic), metastatic sites, albumin (>3.5 g/dL versus <3.5 g/dL), biliary obstruction and first-line chemotherapy (GP, 5FU-based or single-agent). Cox regression method was used to explore factors. RESULTS: From 2010 to 2017, 104 patients were included. Median age was 62 years (32-86) and 22.1% were older than 70 years. Most patients had ECOG performance status 0/1 (63.4%), were female (51.9%) and were metastatic (82.7%). Bone metastases were found in 19.2%. Primary IHC, EHC and GB were 54.8%, 36.5% and 8.7%, respectively. GP was used by 79.8%. Median follow-up was 32.4 months. Median overall survival (mOS) was 11.4 months. In univariate analysis, male (p = 0.007), albumin < 3.5 g/dL (p = 0.001), biliary obstruction (p = 0.006), 5FU-based (p = 0.006) and single-agent (p < 0.0001) were associated with worse OS. ECOG performance status 2/3 (p = 0.058) and bone metastases (p = 0.051) were marginally related. In multivariate analysis, male (p = 0.003), bone metastases (p = 0.023), biliary obstruction (p = 0.001), 5FU-based (p = 0.016) and single-agent (p = 0.023) were independently associated with inferior OS. CONCLUSION: In this retrospective study, we observed that male patients, bone metastases, biliary obstruction and regimens other than GP had worse survival. Larger studies should be conducted to confirm our findings.

Clinicopathological and molecular profile of grade 3 gastroenteropancreatic neuroendocrine neoplasms.

The 2019 Word Health Organization (WHO) subclassified grade 3 (G3) gastroenteropancreatic (GEP) neuroendocrine neoplasms (NEN) into neuroendocrine carcinoma (NEC) or tumours (G3 NET) based on morphology and proliferation. Yet, few data exist on molecular profiles for G3 NEN. We compared clinicopathological and molecular characteristics of these two groups. We retrospectively reviewed consecutive G3 GEP NEN patients and had their tumour tissues reviewed, reclassified as per the WHO 2019, and analyzed by a next-generation sequencing (NGS) panel. Between 2000 and 2019, 43 patients had pathology revision: 29 (67%) were NEC and 14 (33%) were G3 NET, with a 23% change in diagnosis. Median overal survival for G3 NET and NEC patients was 55.6 and 11.9 months, respectively (hazard ratio = 2.78 [95% confidence interval = 1.09-7.11], p = .042), which was confirmed by an adjusted analysis (hazard ratio = 2.90 NEC vs. G3 NET; p = .03). NGS was performed in 32 cases: 21 NEC and 11 G3 NET. Mutations in RB1 and PTEN were exclusively encountered in NEC. Median tumour mutational burden was 5 (0-67) mutations per megabase in NEC and 4.5 (0-9) among G3 NET. Microsatellite instability was found in 3 (14.3%) NEC cases. In conclusion, pathology revision is essential to estimate prognosis and therapeutic plan. G3 GEP NEN generally harbour low tumor mutation burden and fewer actionable mutations, but 14% of NEC cases were microsatellite unstable and could benefit from immune checkpoint inhibitors.

The Current and Evolving Role of Immunotherapy in Metastatic Colorectal Cancer.

Immunotherapy can be considered a therapeutic revolution in oncology, with great impact on many tumor types, such as melanoma and non-small cell lung cancer. However, in metastatic colorectal cancer, the benefits in terms of prolonged tumor control and high response rate are limited to the rare subgroup of tumors with high mutation burden - mostly tumors that harbor microsatellite instability (MSI) or a deficient mismatch repair system (dMMR), or tumor microsatellite stability and damaging mutations in the exonuclease domains of POLE or POLD. The KEYNOTE-028 uncontrolled phase II trial demonstrated an impressive antitumor activity of pembrolizumab in patients with treatmentrefractory Lynch-associated tumors, including colorectal cancer. Nivolumab with or without ipilimumab confirmed the efficacy of immune checkpoint inhibitors in patients with previously treated dMMR / MSI metastatic colorectal cancer. The recent KEYNOTE-177 phase III trial demonstrated that pembrolizumab significantly reduced the relative risk of disease progression or death and improved progression-free survival in patients with treatment-naive dMMR / MSI metastatic colorectal cancer in comparison with first-line chemotherapy with or without biologics. Unfortunately, current pharmacological strategies with immunotherapy have not been successful for most patients with microsatellite stable metastatic colorectal cancer. In this review, we critically appraise the applicability of immune checkpoint inhibitors in dMMR/MSI metastatic colorectal cancer. We also discuss the recent negative trials of immunotherapy combinations in microsatellite stabl.

Symptomatic Recurrence and Survival Outcomes After Curative Treatment of Gastric Cancer: Does Intensive Follow-up Evaluation Improve Survival?

BACKGROUND: Intensive surveillance after treatment of gastric cancer patients with curative intent may lead to an earlier diagnosis of disease recurrence, but its impact on survival is uncertain. This study aimed to evaluate whether early diagnosis of disease recurrence among asymptomatic patients was associated with long-term survival. METHODS: This retrospective study analyzed patients with stages 1 to 3C gastric adenocarcinoma treated between 1999 and 2018. All recurrence events were classified as symptomatic or asymptomatic (detected by follow-up tests), and their clinicopathologic characteristics, patterns of recurrence, and survival were analyzed. RESULTS: The cohort consisted of 669 patients treated with a total gastrectomy in 48.6% and a D2-lymphadenectomy in 88.8% of the cases. Most of the tumors were pT3-4 (46.5%), with 45.5% involving lymph node metastases and 42.3% manifesting a diffuse histology. During a median follow-up period of 80.1 months (95% confidence interval [CI], 75.3-84.8 months), 166 patients had recurrences (24.8%), 65.7% of which were symptomatic. The peritoneum was the main site of recurrence (37.2%), and peritoneal recurrence was associated with worse overall survival (OS) (hazard ratio, 1.69; 95%CI, 1.2-2.37). The median disease-free, post-recurrence survival, and OS periods in the asymptomatic and symptomatic groups were respectively 13.4 versus 17.2 months (p = 0.04), 11.9 versus 4.7 months (p < 0.001), and 29.9 versus 26.4 months (p = 0.21). When OS was analyzed among the patients with non-peritoneal recurrence, no difference was observed between the two groups (31.3 vs 31.1 months; p = 0.46). CONCLUSION: Early diagnosis of asymptomatic disease recurrence did not affect the OS of the gastric cancer patients treated with curative intent. The use of intensive surveillance strategies in this scenario still requires further evidence.

The prognostic influence of tumour budding in Western patients with stage II colorectal cancer.

BACKGROUND: Tumour budding (TB) refers to loss of tumour cohesiveness and is defined as isolated cells or a cell cluster of up to four tumour cells at the microscopic analysis. The International Tumour Budding Consensus Conference (ITBCC) in 2016 proposed a scoring system to standardise the pathology evaluation of TB in colorectal cancer (CRC) as high (H), intermediate (I) and low (L) TB. OBJECTIVE: To evaluate the recurrence-free survival (RFS) of stage II CRC patients as per the ITBCC 2016 classification and associations between TB and clinical pathological features. METHODS: Cases of stage II CRC undergoing surgery with available tumour tissue underwent central pathology review for TB. Prognostic factors, retrospectively retrieved from electronic medical charts, were evaluated in univariate and multivariate Cox regression analyses for RFS (primary end point). RESULTS: Among 137 patients included, L-TB was observed in 107 (78.1%), I-TB in 21 (15.3%) and H-TB in 9 (6.6%). In a median follow-up of 69 months, the median RFS was 134 months, with 14 patients (10.2%) presenting with tumour recurrence: 10 (9.3%) with L-TB, 2 (9.5%) with I-TB and 2 (22.2%) with H-TB. Perineural invasion was more commonly seen in the H-TB group. In multivariate analysis, TB (H and I versus L; HR = 2.6; p = 0.059) and not receiving adjuvant chemotherapy (HR 3.7; p = 0.020) were independently associated with RFS. Adjuvant chemotherapy was associated longer RFS (HR = 3.7; p = 0.022). CONCLUSION: In this series of Western patients, TB grade was associated with perineural invasion and increased risk of disease relapse.

Is there a role for rechallenge and reintroduction of anti-EGFR plus chemotherapy in later lines of therapy for metastatic colorectal carcinoma? A retrospective analysis.

BACKGROUND: Mechanisms of resistance have been described during disease progression (PD) for patients under treatment with anti-EGFR plus chemotherapy (CT). The aim of our study was to evaluate efficacy of anti-EGFR rechallenge (ReCH) and reintroduction (ReIn) in metastatic colorectal cancer (mCRC). MATERIALS AND METHODS: This is a retrospective analysis of patients with mCRC that previously received anti-EGFR + CT and interrupted therapy due to PD in the ReCH group and other reasons in the ReIn group. We aimed to describe progression-free survival (PFS), overall survival (OS) and response rate (RR) after re-exposure and to evaluate prognostic factors associated with PFS. RESULTS: Sixty-eight patients met the inclusion criteria. The median follow-up after re-exposure was 39.3 months. ReCH was adopted in 25% and ReIn in 75%. The median anti-EGFR free interval was at 10.5 months. At re-exposure, the main CT regimen was FOLFIRI in 58.8%. Cetuximab and Panitumumab were used in 59 and 9 patients, respectively. mPFS for ReCH and ReIn was 3.3 × 8.4 months, respectively (p 0.001). The objective response rate for ReCH and ReIn was 18% and 52%, respectively. In univariate analysis, adverse prognostic factors related to PFS were: stable disease or PD at first anti-EGFR exposure (HR: 2.12, CI:1.20-3.74; p = 0.009); ReCH (HR: 3.44, CI:1.88-6.29, p < 0.0001); rechallenge at fourth or later lines (HR: 2.51, CI:1.49-4.23, p = 0.001); panitumumab use (HR: 2.26 CI:1.18-5.54, p = 0.017). In the multivariate model, only ReCH remained statistically significant (HR = 2.63, CI: 1.14-6.03, p = 0.022). CONCLUSION: In our analysis, ReCH resulted in short PFS and low RR. However, reintroduction of anti-EGFR plus CT before complete resistance arose resulted in prolonged PFS. These data could be clinically useful to guide a treatment break due to side effects or patient decisions. Our data should be confirmed by larger and prospective trials.

Disease-Free Survival and Time to Complete Response After Definitive Chemoradiotherapy for Squamous-Cell Carcinoma of the Anus According to HIV Infection.

BACKGROUND: The standard treatment for localized squamous-cell carcinoma of the anal canal is definitive chemoradiotherapy. A meta-analysis of published studies conducted by our group showed significantly lower rates of disease-free survival (DFS) and overall survival at 3 years among HIV-positive patients. We aimed to compare detailed treatment outcomes between the groups of HIV-positive and -negative patients. PATIENTS AND METHODS: We performed a retrospective multicenter study of a comparative cohort of consecutive patients with histologic diagnosis of localized squamous-cell carcinoma of the anal canal who received definitive chemoradiotherapy. Patients' characteristics and outcomes were compared according to HIV status. The primary end points were time to complete response (CR) and DFS time. RESULTS: From June 2001 to September 2018, a total of 185 patients were included; 43 (30.2%) were HIV positive and 142 (69.8%) were HIV negative. The overall CR rates were 67.4% and 91.5% for HIV-positive and -negative patients, respectively (P < .001). The median follow-up was 47.8 months and the median time to experience CR was 7.8 months (95% confidence interval [CI], 5.7-10.5) for HIV-positive versus 4.89 months (95% CI, 4.54-5.25) for HIV-negative (P < .001) patients. The median DFS times were 79.7 months (95% CI, 56.8-102.6) and 127.9 months (95% CI, 112.6-143.2) for HIV-positive and -negative patients, respectively (P = .02). There was a trend toward greater grade 3/4 toxicity in the HIV-positive group. CONCLUSION: HIV-positive patients take longer to experience CR and present worse DFS. These findings have clinical implications because waiting longer to define CR among these patients may prevent unnecessary anorectal amputations.

Clinical factors related to severe enterocolitis after adjuvant CAPOX for colorectal cancer: a retrospective analysis.

BACKGROUND: CAPOX regimen is a standard option in stage III adjuvant colon cancer. Gastrointestinal toxicity is well described with fluoropyrimidine regimens and can be life-threatening. Identification of risk factors associated with severe gastrointestinal toxicity may help clinicians when choosing the adjuvant regimen. MATERIALS AND METHODS: We retrospectively analysed 61 patients treated with adjuvant CAPOX. Our primary objective was to estimate the incidence of severe chemotherapy-induced enterocolitis among patients treated with CAPOX. A secondary objective was to describe the main demographic and clinical characteristics of these patients. A univariate logistic regression was performed to estimate the odds ratio (OR) with a 95% CI to identify a predictor for severe enterocolitis. RESULTS: Grade 3 diarrhoea was reported in 10 patients (16.3%). Admissions to hospital due to toxicity occurred in nine cases. Reasons for hospitalisation were severe enterocolitis in eight cases (13.1%) and rectal bleeding plus thrombocytopenia in one case. Age > 70 years (OR 9.6; 95% CI 1.81-50.6; p = 0.008), primary surgery involving right/transverse colon (OR 16.8; 95% CI 2.88-98.8; p = 0.002) and Angiotensin II Receptor Blocker (ARB) use (OR 8.14; 95% CI 1.64-40.3; p = 0.010) were associated with severe enterocolitis. CONCLUSION: Our data showed that adjuvant CAPOX induced severe enterocolitis in 13.1% of patients. In addition, we found that advanced age, right colectomy and concurrent use of ARB were statistically associated with these events. Awareness of these factors could be easily incorporated into the treatment decision and patient orientation.

Does hipec improve outcomes in gastric cancer patients treated with perioperative chemotherapy and radical surgery? A propensity-score matched analysis.

BACKGROUND: Hyperthermic intraperitoneal chemotherapy (HIPEC) has been associated with improved survival when compared with surgery alone for non-metastatic gastric cancer patients in randomized trials and meta-analyses. However, little evidence is available regarding the use of HIPEC in nonmetastatic patients who are treated with perioperative chemotherapy and radical surgery. The aim of this study was to investigate the putative survival benefit of HIPEC in the subgroup of gastric cancer patients treated with perioperative chemotherapy and surgery. PATIENTS AND METHODS: This was a retrospective cohort study that included gastroesophageal junction and gastric cancer patients who were treated with perioperative chemotherapy and curative resection in a single cancer center in the period between 2006 and 2017. In this time period, younger patients with diffuse-type tumors and serosa invasion or positive lymph node disease were often offered an adjuvant HIPEC protocol. This study compared the survival outcomes of these patients to the ones of those who received only perioperative chemotherapy and resection. A 2:1 propensity-score matched analysis for the two groups was also performed, and variables used were postchemotherapy T (ypT) and N (ypN) stages, histology and tumor site. RESULTS: The study population comprised 269 subjects, 241 treated with chemotherapy and surgery and 28 who also received HIPEC. The mean age was 59 years old (standard deviation: 12.2) and 60% of all individuals were male. A total gastrectomy was performed in 137 patients and a distal resection in 132, with a D2-lymphadenectomy in 97.4% of the sample. Overall 60-day morbidity and mortality rates were 35.3% and 3.3%, respectively. In the HIPEC group, patients were younger, and more frequently had American Society of Anesthesiologists (ASA) 1 to 2 classification, tumors located in the gastric body, had diffuse histology, and ypN+ disease. Overall survival (OS; 5 years) results in the HIPEC and no HIPEC group were 59.5% vs 68.7% (P = .453), and disease-free survival (DFS) ones were 49.5% and 65.8% (P = .060), respectively. In the multivariable Cox regression model, ypT and ypN were independent overall and DFS predictors; also, ASA 3 to 4 classification and diffuse histology were associated with worse OS. In the matched analysis, HIPEC did not improve either overall (53.5% vs 59.5%; P = .517) or DFS (50.0% vs 49.5%; P = .993). CONCLUSION: Treatment with HIPEC in patients who received perioperative chemotherapy and a D2-resection did not improve survival outcomes. Both ypT and ypN stages remained as the most important survival predictors in this cohort.

Primary Tumor Location Is a Predictor of Poor Prognosis in Patients with Locally Advanced Esophagogastric Cancer Treated with Perioperative Chemotherapy.

BACKGROUND: Esophagogastric cancer (EGC) is a leading neoplasm worldwide. Perioperative chemotherapy (periCT) is currently a standard of care for most patients (pts). Prevalence of esophagogastric junction (EGJ) tumors is increasing over the last years. METHODS: The aim of this study was to retrospectively search for prognostic factors in pts. with locally advanced EGC treated with periCT. Three-year overall survival (OS) and Event-Free Survival (EFS) were main end-points. HER-2 positive tumors were defined by immunohistochemistry or FISH. RESULTS: Between June/2007 and November/2015, 128 pts. started periCT for esophagogastric junction (EGJ) or gastric adenocarcinoma (GC). Median age was 59.5 y and 64% were male. Primary site was EGJ in 27% and 65% were cN+. Diffuse subtype was seen in 42%. Ninety-seven pts. were assessed for HER-2; 14 (14.4%) were positive. After median follow-up time of 45 m, 48 deaths occurred. The 3-year OS and EFS rate was 61.3% and 51.2%, respectively. Main prognostic factors were: AJCC ypT3-T4yN1-N3 (HR 6.75 p 0.002) and EGJ primary (HR 2.64, p 0.004). Overall HER-2 was not prognostic. Still, a difference in 3-year OS was observed for GC/HER2+ compared to EGJ/HER2+ (88.9% versus 20%, p = 0.002). This difference is greater for 3-year EFS with no patient with EGJ/HER2+ free-of-event against 62.5% for GC/HER+ (p = 0.011). CONCLUSION: In our analysis, pathological staging and primary site were main prognostic factors. Moreover, a small group of EGJ/HER2+ had very poor survival.

Impact of ypT, ypN, and Adjuvant Therapy on Survival in Gastric Cancer Patients Treated with Perioperative Chemotherapy and Radical Surgery.

BACKGROUND: Perioperative chemotherapy and surgery is the standard of care in advanced gastroesophageal cancer patients, but its impact among those treated with radical surgery still needs further assessment. We present the results of this multimodality treatment approach in a gastric cancer patients cohort treated with D2 lymphadenectomy. We aimed to identify prognostic factors associated with improved survival. PATIENTS AND METHODS: This retrospective cohort study enrolled patients treated with perioperative chemotherapy and resection in a single cancer center in Brazil between 2006 and 2016. Subjects presenting tumors of the gastric stump, esophageal tumors, or treated with intraperitoneal chemotherapy were excluded. Intention-to-treat survival analysis was performed for all subjects who started neoadjuvant chemotherapy, and prognostic factors were determined among those who had R0 resection. RESULTS: This study included 239 patients, of whom 198 had R0 resection. The mean age was 59.9 years, and most had clinical stage IIB or III disease (88%). Among the 239 patients who started neoadjuvant chemotherapy, 207 (86.6%) completed all neoadjuvant treatment cycles, and surgical resection was performed in 225 subjects (94.1%). Overall 60-day morbidity and mortality rates were 35.6% and 4.4%, respectively. For the entire cohort, median survival was 78 months and the 5-year survival rate was 55.3%. Factors associated with worse survival were ypT3-4 stage, ypN + stage, extended resection, and no adjuvant chemotherapy. CONCLUSIONS: Perioperative chemotherapy resulted in very good outcomes for patients treated with radical surgery, and downstaging after chemotherapy was shown to be a major determinant of prognosis.

Survival outcomes of patients with pathological stage I gastric cancer using the competing risks survival method.

BACKGROUND: Patients with stage I gastric cancer are considered to have an exquisite prognosis. Nonetheless, the fact that some patients experience disease relapse highlights that a subgroup might benefit from multimodality treatment. We aimed to evaluate the survival of patients with stage I gastric cancer and look for harbingers of gastric cancer recurrence. METHODS: We looked for patients with stage I gastric cancer treated exclusively with surgery from 1996 to 2015. The competing risks survival method was used to allow for concurrent causes of mortality. Also, we calculated subdistribution hazards (SH) to reveal factors associated with cancer recurrence and death from unrelated causes. RESULTS: A total of 185 patients constitute the study population. Thirty-seven patients had pT2N0 tumors. Most patients (80.5%) were treated with D2 lymphadenectomy. The probability of relapse at 5 years was 3.0% and 8.6% in the study population and the pT2N0 subgroup, respectively. Among all 26 deaths, only six were related to gastric cancer. In multivariate analysis, perineural invasion (PNI) was associated with increased risk of gastric cancer recurrence. CONCLUSIONS: The prognosis of stage I gastric cancer treated with D2 lymphadenectomy is excellent. PNI may indicate higher likelihood of recurrence. Further work in this field should account for the higher risk of death from unrelated causes.

Current approaches to immunotherapy in noncolorectal gastrointestinal malignancies.

Noncolorectal gastrointestinal (GI) malignancies are among the most frequently diagnosed cancers. Despite the undeniable progress in systemic treatments in recent decades, further improvements using cytotoxic chemotherapy seem unlikely. In this setting, recent discoveries regarding the mechanism underlying immune evasion have prompted the study of molecules capable of inducing strong antitumor responses. Thus, according to early data, immunotherapy is a very promising tool for the treatment of patients with GI malignancies. Noncolorectal GI cancers are a major public health problem worldwide. Traditional treatment options, such as chemotherapy, surgery, radiation therapy, monoclonal antibodies and antiangiogenic agents, have been the backbone of treatment for various stages of GI cancers, but overall mortality remains a major problem. Thus, there is a substantial unmet need for new drugs and therapies to further improve the outcomes of treatment for noncolorectal GI malignancies. "Next-generation" immunotherapy is emerging as an effective and promising treatment option in several types of cancers. Therefore, encouraged by this recent success, many clinical trials evaluating the efficacy of immune checkpoint inhibitors and other strategies in treating noncolorectal GI malignancies are ongoing. This review will summarize the current clinical progress of modern immunotherapy in the field of noncolorectal GI tumors.

Current approaches to immunotherapy in noncolorectal gastrointestinal malignancies

Noncolorectal gastrointestinal (GI) malignancies are among the most frequently diagnosed cancers. Despite the undeniable progress in systemic treatments in recent decades, further improvements using cytotoxic chemotherapy seem unlikely. In this setting, recent discoveries regarding the mechanism underlying immune evasion have prompted the study of molecules capable of inducing strong antitumor responses. Thus, according to early data, immunotherapy is a very promising tool for the treatment of patients with GI malignancies. Noncolorectal GI cancers are a major public health problem worldwide. Traditional treatment options, such as chemotherapy, surgery, radiation therapy, monoclonal antibodies and antiangiogenic agents, have been the backbone of treatment for various stages of GI cancers, but overall mortality remains a major problem. Thus, there is a substantial unmet need for new drugs and therapies to further improve the outcomes of treatment for noncolorectal GI malignancies. "Next-generation" immunotherapy is emerging as an effective and promising treatment option in several types of cancers. Therefore, encouraged by this recent success, many clinical trials evaluating the efficacy of immune checkpoint inhibitors and other strategies in treating noncolorectal GI malignancies are ongoing. This review will summarize the current clinical progress of modern immunotherapy in the field of noncolorectal GI tumors.

REOX: Evaluation of the Efficacy of Retreatment With an Oxaliplatin-containing Regimen in Metastatic Colorectal Cancer: A Retrospective Single-center Study.

BACKGROUND: Treatment of metastatic colorectal adenocarcinoma (mCRC) has evolved, and survival is over 30 months in contemporary trials. Nevertheless, there is a paucity of effective regimes after the first or second-line treatment. Thus, reexposure to previously used drugs has become a treatment strategy for some patients. We aimed to evaluate the efficacy of retreatment with an oxaliplatin-containing regimen in mCRC and correlate this with clinicopathologic features. PATIENTS AND METHODS: We retrospectively analyzed 83 patients with mCRC who underwent reexposure to oxaliplatin (REOX). REOX was defined as a second trial of an oxaliplatin-containing regimen after a previous failure. Primary endpoint was time to treatment failure (TTF). RESULTS: The median age was 53.5 years, and the female/male ratio was 51.8%/48.2%. The site of the primary tumor was colon (67.5%) and rectal (32.5%). KRAS was mutated in 39.8%. Liver-limited metastasis was found in 19.3% of patients. The main regimen was 5-fluorouracil, levoleucovorin, and oxaliplatin (mFOLFOX6) (84.3%). Bevacizumab and cetuximab were used in 42.2% and 6% of patients, respectively. REOX was used in the third and fourth lines in 48.2% and 25.3% of patients, respectively. The median TTF after REOX was 6.04 months. Overall survival (OS) was 10.04 months. Disease control (complete response + partial response + stable disease) was observed in 56.6%, whereas 42.2% had progressive disease. Partial response + complete response to previous oxaliplatin was predictive of prolonged OS. Patients who attained disease control had better median OS compared with those with progressive disease (14.5 vs. 6.24 months; P < .0001). CONCLUSION: In the setting of heavily pretreated patients with mCRC, REOX was an effective treatment, with mTTF of 6.04 months in our cohort. Selection of patients with the longest time since previous oxaliplatin can translate in better outcome. Further studies should be conducted to confirm our data.