Association between Pre-Treatment Biological Indicators and Compliance to Neoadjuvant/Perioperative Chemotherapy in Operable Gastric Cancer.

BACKGROUND AND AIMS: Perioperative treatment is currently the gold standard approach in Europe for locally advanced gastric cancer (GC). Unfortunately, the phenomenon of patients dropping out of treatment has been frequently observed. The primary aims of this study were to verify if routine blood parameters, inflammatory response markers, sarcopenia, and the depletion of adipose tissues were associated with compliance to neoadjuvant/perioperative chemotherapy. METHODS AND STUDY DESIGN: Blood samples were considered before the first and second cycles of chemotherapy. Sarcopenia and adipose indices were calculated with a CT scan before starting chemotherapy and before surgery. Odds ratios (OR) from univariable and multivariable models were calculated with a 95% confidence interval (95% CI). RESULTS: A total of 84 patients with locally advanced GC were identified between September 2010 and January 2021. Forty-four patients (52.4%) did not complete the treatment according to the number of cycles planned/performed. Eight patients (9.5%) decided to suspend chemotherapy, seven patients (8.3%) discontinued because of clinical decisions, fourteen patients (16.7%) discontinued because of toxicity and fifteen patients (17.9%) discontinued for miscellaneous causes. Seventy-nine (94%) out of eighty-four patients underwent gastrectomy, with four patients having surgical complications, which led to a suspension of treatment. Sarcopenia was present in 38 patients (50.7%) before chemotherapy began, while it was present in 47 patients (60%) at the CT scan before the gastrectomy. At the univariable analysis, patients with basal platelet to lymphocyte ratio (PLR) ≥ 152 (p = 0.017) and a second value of PLR ≥ 131 (p = 0.007) were more frequently associated with an interruption of chemotherapy. Patients with increased PLR (p = 0.034) compared to the cut-off were associated with an interruption of chemotherapy, while patients with increased monocytes between the first and second cycles were associated with a lower risk of treatment interruption (p = 0.006); patients who underwent 5-fluorouracil plus cisplatin or oxaliplatin had a higher risk of interruption (p = 0.016) compared to patients who underwent a 5-fluorouracil plus leucovorin, oxaliplatin and docetaxel (FLOT) regimen. The multivariable analysis showed a higher risk of interruption for patients who had higher values of PLR compared to the identified cut-off both at pretreatment and second-cycle evaluation (OR: 5.03; 95% CI: 1.34-18.89; p = 0.017) as well as for patients who had a lower PLR than the identified cut-off at pretreatment evaluation and had a higher PLR value than the cut-off at the second cycle (OR: 4.64; 95% CI: 1.02-21.02; p = 0.047). Becker regression was neither affected by a decrease of sarcopenia ≥ 5% (p = 0.867) nor by incomplete compliance with chemotherapy (p = 0.281). CONCLUSIONS: Changes in PLR values which tend to increase more than the cut-off seem to be an immediate indicator of incomplete compliance with neoadjuvant/perioperative treatment. Fat loss and sarcopenia do not appear to be related to compliance. More information is needed to reduce the causes of interruption.

Clinical outcomes of patients with complicated post-operative course after gastrectomy for cancer: a GIRCG study using the GASTRODATA registry.

Gastrectomy for gastric cancer is still performed in Western countries with high morbidity and mortality. Post-operative complications are frequent, and effective diagnosis and treatment of complications is crucial to lower the mortality rates. In 2015, a project was launched by the EGCA with the aim of building an agreement on list and definitions of post-operative complications specific for gastrectomy. In 2018, the platform www.gastrodata.org was launched for collecting cases by utilizing this new complication list. In the present paper, the Italian Research Group for Gastric Cancer endorsed a collection of complicated cases in the period 2015-2019, with the aim of investigating the clinical pictures, diagnostic modalities, and treatment approaches, as well as outcome measures of patients experiencing almost one post-operative complication. Fifteen centers across Italy provided 386 cases with a total of 538 complications (mean 1.4 complication/patient). The most frequent complications were non-surgical infections (gastrointestinal, pulmonary, and urinary) and anastomotic leaks, accounting for 29.2% and 17.3% of complicated patients, with a median Clavien-Dindo score of II and IIIB, respectively. Overall mortality of this series was 12.4%, while mortality of patients with anastomotic leak was 25.4%. The clinical presentation with systemic septic signs, the timing of diagnosis, and the hospital volume were the most relevant factors influencing outcome.

Development and Multicenter Validation of a Novel Immune-Inflammation-Based Nomogram to Predict Survival in Western Resectable Gastric and Gastroesophageal Junction Adenocarcinoma (GEA): The NOMOGAST.

Background. More than 50% of operable GEA relapse after curative-intent resection. We aimed at externally validating a nomogram to enable a more accurate estimate of individualized risk in resected GEA. Methods. Medical records of a training cohort (TC) and a validation cohort (VC) of patients undergoing radical surgery for c/uT2-T4 and/or node-positive GEA were retrieved, and potentially interesting variables were collected. Cox proportional hazards in univariate and multivariate regressions were used to assess the effects of the prognostic factors on OS. A graphical nomogram was constructed using R software's package Regression Modeling Strategies (ver. 5.0-1). The performance of the prognostic model was evaluated and validated. Results. The TC and VC consisted of 185 and 151 patients. ECOG:PS > 0 (p < 0.001), angioinvasion (p < 0.001), log (Neutrophil/Lymphocyte ratio) (p < 0.001), and nodal status (p = 0.016) were independent prognostic values in the TC. They were used for the construction of a nomogram estimating 3- and 5-year OS. The discriminatory ability of the model was evaluated with the c-Harrell index. A 3-tier scoring system was developed through a linear predictor grouped by 25 and 75 percentiles, strengthening the model's good discrimination (p < 0.001). A calibration plot demonstrated a concordance between the predicted and actual survival in the TC and VC. A decision curve analysis was plotted that depicted the nomogram's clinical utility. Conclusions. We externally validated a prognostic nomogram to predict OS in a joint independent cohort of resectable GEA; the NOMOGAST could represent a valuable tool in assisting decision-making. This tool incorporates readily available and inexpensive patient and disease characteristics as well as immune-inflammatory determinants. It is accurate, generalizable, and clinically effectivex.

Conversion Surgery in Gastric Cancer Carcinomatosis.

Background: After the REGATTA trial, patients with stage IV gastric cancer could only benefit from chemotherapy (CHT). However, some of these patients may respond extraordinarily to palliative chemotherapy, converting their disease to a radically operable stage. We present a single centre experience in treating peritoneal carcinomatosis from gastric cancer. Methods: All patients with stage IV gastric cancer with peritoneal metastases as a single metastatic site operated at a single centre between 2005 and 2020 were included. Cases were grouped according to the treatment received. Results: A total of 118 patients were considered, 46 were submitted to palliative gastrectomy (11 were considered M1 because of an unsuspected positive peritoneal cytology), and 20 were submitted to Hyperthermic Intraperitoneal Chemotherapy (HIPEC) because of a <6 Peritoneal Cancer Index (PCI). The median overall survival (OS) after surgery plus HIPEC was 46.7 (95% CI 15.8-64.0). Surgery (without HIPEC) after CHT presented a median OS 14.4 (8.2-26.8) and after upfront surgery 14.7 (10.9-21.1). Patients treated with upfront surgery and considered M1 only because of a positive cytology, had a median OS of 29.2 (25.2-29.2). The OS of patients treated with surgery plus HIPEC were 60.4 months (9.2-60.4) in completely regressed cancer after chemotherapy and 31.2 (15.8-64.0) in those partially regressed (p = 0.742). Conclusions: Conversion surgery for peritoneal carcinomatosis from gastric cancer was associated with long survival and it should always be taken into consideration in this group of patients.

Resection line involvement after gastric cancer treatment: handle with care.

The optimal management of patients with resection line involvement after endoscopic or surgical treatment for gastric cancer is debated. In contrast to previous reports, we examined both the experience of endoscopists and surgeons in early-stage lesions and the wide variation in treatments proposed for advanced disease in case of infiltration of resection margins. A PubMed search for papers using the key words: gastric or stomach cancer, or Carcinoma; gastrectomy and positive margins; surgical margins or resection line or endoscopic margin involvement; and R1 resection, from January 2000 to July 2015 was undertaken. Fifty-three studies were considered pertinent to the study. Many endoscopists report that some cases of early gastric cancer with resection line involvement after endoscopic resection have good outcomes notwithstanding incomplete resection, but few surgeons share this opinion. Conversely, it is unanimously agreed that very advanced stages should not be surgically retreated because they are expression of systemic disease. Between early and very advanced cancer the usefulness of re-resection for microscopic resection lines involvement is still debated and surgery may be proposed only when radicality can be achieved. When surgery is not feasible, radiochemotherapy may represent a valid alternative.

An aggressive early gastric cancer: Kodama's PenA type.

BACKGROUND: To investigate the role of Kodama PenA subtype in influencing survival in patients with early gastric cancer (EGC). METHODS: All patients surgically treated for EGC at 7 Italian centers (Forlì, Varese, Siena, Verona, Milan, Rome and Perugia) belonging to the Italian Research Group for Gastric Cancer (GIRCG) from January 1982 and December 2009 were included. RESULTS: PenA patients were 230 (21.5%) while other types were 839 (78.5%). Nodal metastases were more common in PenA (30.7%) than non-PenA (10.4%) EGCs. Among preoperative variables, only age (OR 1.02; 95% CI 1.00-1.03, p = 0.009) and macrotype III (OR 1.95; 95% CI 1.39-2.75, p = 0.0001) were significantly associated with Pen A type. Survival analysis performed on N0 patients demonstrated that only size >2 cm (HR 1.85; 95% CI 1.12-3.05, p = 0.017) and age (HR 1.06; 95% CI 1.03-1.08, p < 0.0001) were independent poor prognostic factor. Among N+ patients age (HR 1.04; 95% CI 1.00-1.07, p = 0.048), number of positive lymph nodes (HR 1.13; 95% CI 1.05-1.20, p = 0.0002) and PenA (HR 4.23; 95% CI 1.70-10.55, p = 0.002) were significantly correlated with poor prognosis at multivariate analysis. CONCLUSIONS: Kodama PenA subtype was the most powerful independent prognostic factor in patients with nodal metastases. Its status should always be investigated in EGCs patients.

Conversion surgery for gastric cancer: A cohort study from a western center.

BACKGROUND: Advanced unresectable gastric cancer has a dismal prognosis. The aim of this study was to evaluate the short- and long-term outcomes of patients who underwent induction chemotherapy ±â€¯gastrectomy for advanced gastric cancer. MATERIAL AND METHODS: All patients referred to our center with a clinical diagnosis of unresectable locally advanced or stage IV gastric adenocarcinoma between April 2005 and August 2016 were included in the study. Cox regression was performed to find independent prognostic factor among the considered variable. RESULTS: The cohort included 73 patients: 16 had best supportive care, 35 chemotherapy alone and 22 chemotherapy plus radical surgery. Thirty-three patients underwent surgery after chemotherapy. Twenty-two patients had R0 surgery, while the remaining 11 had only an exploratory procedure. Nine patients (40.9%) underwent gastrectomy plus hyperthermic intraperitoneal chemotherapy. Three patients out of 22 developed postoperative complications with a Clavien-Dindo grade above 2. Median survival was 50 months for patients who had chemotherapy plus surgery while it was 14 and 3 for those who had chemotherapy alone and best supportive care, respectively (p < 0.0001). Cox regression analysis performed on the whole cohort identified only radical conversion surgery as an independent factor positively associated with survival (HR 0.12, 95% CI 0.05-0.29, p < 0.0001). CONCLUSION: Conversion gastrectomy, when R0 could be achieved, is associated with long survivals and it is the most important prognostic factor in patients with advanced gastric cancer. Further studies are needed to define the ideal patient who can really benefit from this treatment.

Historical assumptions of lymphadenectomy.

The role of lymphadenectomy for the treatment of gastric cancer is still very much open to debate. Consequently, Japanese, European and American surgeons perform different typologies of lymphadenectomy because of the absence of randomized clinical trials confirming the superiority of extended lymphadenectomy over less invasive surgery. In Japan, D2 lymphadenectomy has been considered as the gold standard for advanced gastric carcinoma for many years. Although numerous European studies have been conducted in an attempt to find differences between D1 and D2 lymphadenectomy, none has succeeded to date. The decision to wait for results attesting to the fact that D2 guarantees a better outcome than D1 resulted in a long delay in the implementation of D2 as the gold standard treatment in Europe. In the U.S., the study by Macdonald et al. established D1 lymphadenectomy followed by chemoradiotherapy as the treatment of choice for advanced cancer, whereas D2 is officially indicated as the gold standard in the most recent European guidelines [the Italian Research Group for Gastric Cancer (GIRGC), German, British, ESSO]. Interestingly, European guidelines for lymphadenectomy are not based on evidence-based medicine but rather on the experience of the most important centers involved in the treatment of gastric cancer.

Krukenberg Tumors of Gastric Origin: The Rationale of Surgical Resection and Perioperative Treatments in a Multicenter Western Experience.

BACKGROUND: In case of Krukenberg tumor (KT) of gastric origin it is controversial and debated whether radical surgery in case of synchronous KT or metastasectomy in case of metachronous ones is associated with additional benefits. Role of perioperative treatments is unclear. METHODS: Among 2515 female patients who were diagnosed with gastric cancer between January 1990 and December 2012 from 9 Italian centers, 63 presented simultaneously or developed KT as recurrence. RESULTS: Thirty patients presented with synchronous KT, while 33 developed metachronous ovarian metastases during follow-up. The differences between the two groups were analyzed and compared. The median age of 63 patients was 48.0 years (range 31-71). Resection was possible in 53 patients (20 synchronous and 33 metachronous). Twelve patients in the synchronous group and 15 patients of the metachronous group underwent hyperthermic intraperitoneal chemotherapy after resection of KT. All of them underwent adjuvant chemotherapy after KT resection. The median survival for all population was 23 months (95 % confidence interval, 7-39 months). The median survival time in the metachronous group was 36 months, which was significantly longer than that in the synchronous group, 17 months, p < 0.0001. CONCLUSIONS: KT remains a clinical challenge for gastric cancer therapy. The extent of disease and feasibility of removal of the metastatic lesion must be carefully evaluated prior to surgery to define the patients group who could benefit most from a resection associated with perioperative treatments.

Gastric stump carcinoma after distal subtotal gastrectomy for early gastric cancer: experience of 541 patients with long-term follow-up.

BACKGROUND: Gastric stump carcinoma (GSC) has been studied after primary gastrectomy for benign disease but few studies have evaluated its correlation with gastric cancer. PATIENTS: We assessed 541 patients submitted to subtotal gastrectomy for early gastric cancer at least 15 years ago. RESULTS: GSC was diagnosed in 16 (2.9%) patients, giving a 4% cumulative risk of GSC 20 years after surgery. Diagnosis was made within 5 years of surgery in 10 patients and after 8 years in 6 cases. GSC occurred in 13/470 (2.8%) patients submitted to Billroth 2 reconstruction, 2/30 (6.7%) patients who underwent Billroth 1, and 1/41 (2.4%) patients after Roux-en-Y reconstruction. Significant risk factors observed for GSC were histologic type and sex. Other synchronous or metachronous extragastric tumors were registered in 56 (11.2%) patients. CONCLUSIONS: The risk of GSC was low, even 20 years after subtotal gastrectomy for early gastric cancer. Lauren intestinal histotype and male sex were frequently associated with GSC. No correlation was observed between GSC and reconstruction technique or multifocality. Clinically speaking, GSC could be considered a subset of gastric cancer.

Gastric cancer and synchronous hepatic metastases: is it possible to recognize candidates to R0 resection?

PURPOSE: Management of patients with synchronous hepatic metastases as the sole metastatic site at diagnosis of gastric cancer is debated. We studied a cohort of patients admitted to surgical units, investigating prognostic factors of clinical relevance and the results of various therapeutic strategies. METHODS: Retrospective multicentre chart review. We evaluated how survival from surgery was influenced by patient-related, gastric cancer-related, metastasis-related and treatment-related candidate prognostic factors. RESULTS: Forty-four patients received palliative surgery without resection, 98 palliative gastrectomy (in 16 cases associated with R+ hepatectomy), whereas 53 patients received both curative gastrectomy and hepatic resection(s) (R0). Adjuvant chemotherapy was administered to 44 patients. Therapeutic approach was selected on the basis of extension of disease, patient's general conditions and surgeon's attitude. Surgical mortality was 4.6 % and morbidity was 17.4 %. Survival was independently influenced by the factor T of the gastric primary (p = 0.036) and by the degree of hepatic involvement (p = 0.010). T > 2 and H3 liver involvement were associated with worse prognosis with cumulative effect (p = 0.002). Therapeutic approach to the metastases (p = 0.009) and adjuvant chemotherapy (p < 0.001) displayed independent impact upon survival, with benefit for those receiving aggressive multimodal treatment. The 1-, 3-, and 5-year survival rates were 50.4, 14.0, and 9.3 %, respectively, for patients submitted to curative surgery, 16, 8.5, and 4.3 % after palliative gastrectomy, and 6.8, 2.3, and 0 % after palliative surgery without resection. CONCLUSIONS: Our data suggest some clinical criteria that may facilitate selection of candidates to curative surgery, which offers the best survival chances, especially when associated with adjuvant chemotherapy.

Gastric stump cancer after distal gastrectomy for benign disease: clinicopathological features and surgical outcomes.

PURPOSE: The purpose of the present study was to analyze clinicopathologic features and long-term prognosis of gastric stump cancer (GSC) arising in the remnant stomach 5 years or later after partial gastrectomy for benign disease. METHODS: We reviewed the results of 176 patients resected with curative intent for GSC at 8 Italian centers belonging to the Italian Research Group for Gastric Cancer (GIRCG). The median (range) follow-up time for surviving patients was 71.2 (6-207) months. RESULTS: One hundred forty-six patients were men, the mean age at the time of diagnosis was 69.2 years, and the great majority (167 cases) underwent Billroth II reconstruction. R0 resection was achieved in 158 (90 %) patients, and in 94 (53 %) lymph node dissection was ≥D2. Postoperative mortality and complication rates were 6.2 and 43.2 %, respectively. T1 tumor was diagnosed in 45 (25 %) cases. Lymph node metastases were evident in 86 patients (49 %). Thirteen patients had involvement of the jejunal mesentery nodes (pJN+); five cases were T2-T3 and eight cases were T4. Overall 5-year survival rate was 53.1 %. Five-year survival rates were 68.1, 37.8, and 33.1 % for pT1, pT2-3, and pT4 tumors, respectively (P = 0.001). Five-year survival rate was 56.5 % for node-negative tumors (pN0), 32.3 % for tumors with nodal metastases without involvement of jejunal mesentery nodes (pN+), and 17.1 % for tumors with involvement of jejunal mesentery nodes (pJN+) (P = 0.002). CONCLUSIONS: Our study suggests that an aggressive surgical approach can achieve a satisfactory outcome in GSC.

Early gastric cancer: diagnosis, staging, and clinical impact. Evaluation of 530 patients. New elements for an updated definition and classification.

BACKGROUND: The prevention and early diagnosis of gastric cancer permit clinicians to discover the tumor in the initial phase, during which time it can be completely eradicated, endoscopically or surgically. Since Murakami gave the definition of early gastric cancer (EGC) in 1971, many authors have identified various subtypes of EGC with different morphological characteristics and clinical behaviour. METHODS: We evaluated retrospectively 530 patients: the median follow-up time was 10.4 months (range 0.3-29.2). All tumors were classified according to the macroscopic and microscopic criteria proposed by the Japanese Society of Gastroenterology and Endoscopy and Lauren, respectively. The infiltrative growth pattern was evaluated according to Kodama's classification. Only tumor-related death was considered as an endpoint of interest for the survival analysis. RESULTS: The overall survival rates of our patients were 94 % (95 % CI, 92-96) and 90 % (95 % CI, 87-93) at 5 and 10 years, respectively. Only 44 patients (8.3 %) died of the disease. Kodama's type (p < 0.0001), lymph node status, both for number and pathological stage according to the 7th Edition of TNM (p < 0.0001), and depth of infiltration (p = 0.0006) were significant prognostic factors in univariate analysis. The multivariate analysis identified Kodama's PENA type (HR, 3.91; 95 % CI, 2.08-7.33; p < 0.0001) and lymph node status for more than three positive nodes versus negative nodes (HR, 12.78; 95 % CI, 5.37-30.43; p < 0.0001) as the only independent prognostic factors in our series. CONCLUSION: Lymph node status, especially when more than three lymph nodes are involved, is the most important prognostic factor in EGC. However, it is also important to evaluate the infiltrative growth pattern of the cancers in their early phase according to Kodama's classification, considering PEN A type lesions to be more aggressive than the other EGC types. Then, we propose new elements for an updated definition and classification of EGC, with an important clinical impact on the treatment of patients.

Subtotal gastrectomy as treatment for distal multifocal early gastric cancer.

INTRODUCTION: Multifocal early gastric cancer (MEGC) is frequently observed and represents a serious risk when minimally invasive treatments are performed. PATIENTS AND METHODS: We present the experience of two Italian centers situated in a relatively high incidence area for gastric cancer. Out of a total of 791 surgical resections for EGC carried out in two Italian centers from 1976 to 2006, we identified 98 patients with multifocal EGC (12.3%). Two hundred and sixteen lesions were observed. Generally sited near the principal tumors, secondary lesions were, however, sometimes detected distally from the upper primary lesion. No secondary lesions were detected in the upper third when the principal lesion was sited at the lower third. RESULTS: Survival of MEGC patients was not significantly lower than that of patients with monofocal EGC. No cases of gastric remnant relapse were observed at a mean follow-up of 9 years (range 1-28) after subtotal gastrectomy. DISCUSSION: When EGCs are detected, the possibility of MEGC must always be investigated by endoscopy and chromoendoscopy. When a MEGC is found in the lower third of the stomach and chromoendoscopy of the upper third has been performed, subtotal gastrectomy can be considered as sufficient treatment.

Does resection line involvement affect prognosis in early gastric cancer patients? An Italian multicentric study.

BACKGROUND: Resection line involvement has been indicated as an important prognostic factor for gastric cancer. Its late detection renders the choice of treatment difficult for surgeons. MATERIALS AND METHODS: We describe the multicenter experience of a group of 11 patients with early gastric carcinoma (EGC) and positive resection confirmed at histological examination who did not undergo surgical retreatment for reasons of associated disease, surgical considerations on duodenal stump, or patient refusal. RESULTS: The gastric margin was involved in 4 patients, and 7 patients had duodenal resection line involvement. No surgical complications or postoperative deaths were observed. Five and 8-year survival was 100% and 86%, respectively. The only patient who relapsed did not have lymph node involvement and died from liver metastases, without local recurrence. CONCLUSIONS: It is sometimes difficult to accurately define the resection line in gastric cancer surgery, especially in the early stages of disease, but because of the strongly negative prognostic value of an infiltrated margin, frozen sections are recommended if neoplastic invasion is suspected and a new resection is always recommended if possible. Nevertheless, the good prognosis of resected EGC patients with resection line involvement must be considered before submitting patients with associated diseases to radical surgical retreatment.

A functional Roux-en-Y gastric bypass to avoid gastric exclusion: 1-year results.

BACKGROUND: Roux-en-Y gastric bypass (RYGBP) is rarely performed in Italy because it involves gastric exclusion. RYGBP with the stomach partitioned by an adjustable gastric band has been previously described. We have developed a functional RYGBP (FRYGBP) where an adjustable band allows access from a stapled gastric bypass pouch into the distal stomach. METHODS: From October 2001 to May 2002, 16 patients underwent FRYGBP. A 30-cc vertical gastric pouch was fashioned by a 25-mm circular and 90-mm four-row stapler as in the Mason VBG. A hand-sewn retrocolic gastroenterostomy with 150-cm Roux and 30-cm afferent limbs completed the operation. The pouch outlet was encircled distal to the gastrojejunostomy by a non-inflated adjustable gastric band. The bands were inflated at 1 month during barium swallow, to demonstrate occlusion of the gastro-gastric outlet and patency of the gastrojejunostomy. RESULTS: There was no operative mortality. After 1 year, mean percent excess BMI loss (%EBMIL) was 71.2 +/- 16.2% (SD), and gastroscopy of the bypassed stomach was possible on 81% of the patients. There were three asymptomatic late complications (19%): two band erosions, converted to RYGBP, and one stenosis of the gastro-gastric outlet. CONCLUSION: FRYGBP thus far has been effective and allows the study of the excluded stomach. This ongoing study will undergo long-term evaluation.