Role of savolitinib in advanced gastric adenocarcinoma with meningeal carcinomatosis and cerebellar metastasis:A case report

BACKGROUND Brain metastases(BM)are very rare in gastric adenocarcinoma(GaC),and patients with BMs have a higher mortality rate due to stronger tumor aggressiveness.However,its pathogenesis remains unclear.Genetic testing revealed cellular-mesenchymal epithelial transition factor receptor(MET)amplification.Therefore,treatment with savolitinib,a small molecule inhibitor of c-Met,was selected.CASE SUMMARY A 66-year-old woman was diagnosed with advanced GaC 6 months prior to presentation due to back pain.Cerebellar and meningeal metastases were observed during candonilimab combined with oxaliplatin and capecitabine therapy.The patient experienced frequent generalized seizures and persistent drowsiness in the emergency department.Genetic testing of cerebrospinal fluid and peripheral blood revealed increased MET amplification.After discussing treatment options with the patient,savolitinib tablets were administered.After a month of treatment,the intracranial lesions shrank considerably.CONCLUSION BM is very rare in advanced GaC,especially in meningeal cancer,that is characterized by rapid disease deterioration.There are very few effective treatment options available;however,technological breakthroughs in genomics have provided a basis for personalized treatment.Furthermore,MET amplification may be a key driver of BM in gastric cancer;however,this conclusion requires further investigation.

Multidisciplinary therapy for treatment of patients with peritoneal carcinomatosis from gastric cancer

There is no standard treatment for peritoneal carcinomatosis (PC) from gastric cancer.A novel multidisciplinary treatment combining bidirectional chemotherapy [neoadjuvant intraperitoneal-systemic chemotherapy protocol (NIPS)],peritonectomy,hyperthermic intraperitoneal chemoperfusion (HIPEC) and early postoperative intraperitoneal chemotherapy has been developed.In this article,we assess the indications,safety and eff icacy of this treatment,review the relevant studies and introduce our experiences.The aims of NIPS are stage reduction,the eradication of peritoneal free cancer cells,and an increased incidence of complete cytoreduction (CC-0) for PC.A complete response after NIPS was ob-tained in 15 (50%) out of 30 patients with PC.Thus,a signif icantly high incidence of CC-0 can be obtained in patients with a peritoneal cancer index (PCI) ≤ 6.Using a multivariate analysis to examine the survival benef it,CC-0 and NIPS are identified as significant indicators of a good outcome.However,the high morbidity and mortality rates associated with peritonectomy and perioperative chemotherapy make stringent patient selection important.The best indications for multidisciplinary therapy are localized PC (PCI≤6) from resectable gastric cancer that can be completely removed during a peritonectomy.NIPS and complete cytoreduction are essential treatment modalities for improving the survival of patients with PC from gastric cancer.

Pathophysiology of colorectal peritoneal carcinomatosis: Role of the peritoneum

Colorectal cancer(CRC) is the third most common cancer and the fourth most common cause of cancerrelated death worldwide. Besides the lymphatic and haematogenous routes of dissemination,CRC frequently gives rise to transcoelomic spread of tumor cells in the peritoneal cavity,which ultimately leads to peritoneal carcinomatosis(PC). PC is associated with a poor prognosis and bad quality of life for these patients in their terminal stages of disease. A loco-regional treatment modality for PC combining cytoreductive surgery and hyperthermic intraperitoneal peroperative chemotherapy has resulted in promising clinical results. However,this novel approach is associated with significant morbidity and mortality. A comprehensive understanding of the molecular events involved in peritoneal disease spread is paramount in avoiding unnecessary toxicity. The emergence of PC is the result of a molecular crosstalk between cancer cells and host elements,involving several well-defined steps,together known as the peritoneal metastatic cascade. Individual or clumps of tumor cells detach from the primary tumor,gain access to the peritoneal cavity and become susceptible to the regular peritoneal transport. They attach to the distant peritoneum,subsequently invade the subperitoneal space,where angiogenesis sustains proliferation and enables further metastatic growth. These molecular events are not isolated events but rather a continuous and interdependent process. In this manuscript,we review current data regarding the molecular mechanisms underlying the development of colorectal PC,with a special focus on the peritoneum and the role of the surgeon in peritoneal disease spread.

Current treatment options for colon cancer peritoneal carcinomatosis

Peritoneal carcinomatosis(PC),the dissemination of cancer cells throughout the lining of the abdominal cavity,is the second most common presentation of colon cancer distant metastasis.Despite remarkable advances in cytotoxic chemotherapy and targeted therapy for colon cancer over the last 15 years,it has been repeatedly shown that these therapies remain ineffective for colon cancer PC.Recently,there has been a rapid accumulation of reports that cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy(CRS-HIPEC) prolongs the life of colon cancer PC patients.Here,we will review the clinical presentation,the mechanisms of disease progression,and current treatment options for colon cancer PC,with a focus on the benefits and limitations of CRSHIPEC.

Pathophysiology and biology of peritoneal carcinomatosis

Peritoneal carcinomatosis represents a devastating form of cancer progression with a very poor prognosis.Its complex pathogenesis is represented by a dynamic process comprising several steps.To the best of our knowledge pathogenesis can be partly explained by 3 major molecular pathways: (1) dissemination from the primary tumor;(2) primary tumor of peritoneum;and (3) independent origins of the primary tumor and peritoneal implants.These are not mutually exclusive and combinations of different mechanisms could occur inside a single case.There are still several aspects which need explanation by future studies.A comprehensive understanding of molecular events involved in peritoneal carcinomatosis is of paramount importance and should be systematically pursued not only to identify novel strategies for the prevention of the condition,but also to obtain therapeutic advances,through the identification of surrogate markers of prognosis and development of future molecular targeted therapies.

Recent aspects for disseminated carcinomatosis of the bone marrow associated with gastric cancer: What has been done for the past, and what will be needed in future?

Disseminated carcinomatosis of the bone marrow is characterized by widespread bone metastasis(bone marrow infiltration) from solid tumors with hematological disorders coexisted. This disease is frequently complicated with gastric cancer among solid tumors although its incidence is very rare. In recent years,technological innovations in diagnosis and treatment for cancer have remarkably improved,which made survival rates of various cancers prolonged. Prognosis of disseminated carcinomatosis of the bone marrow associated with gastric cancer,however,is still poor(less than a year),possibly because this disease has not been given attention due to low incidence. In this review,I summarize the results obtained for the past,and propose ways to improve the prognosis of this disease.

Optimizing outcomes for patients with gastric cancer peritoneal carcinomatosis

Peritoneal carcinomatosis (PC) from gastric cancer has traditionally been considered a terminal progression of the disease and is associated with poor survival out-comes. Positive peritoneal cytology similarly worsens the survival of patients with gastric cancer and treatment options for these patients have been limited. Recent ad-vances in multimodality treatment regimens have led to innovative ways to care for and treat patients with this disease burden. One of these advances has been to use neoadjuvant therapy to try and convert patients with positivecytologyorlow-volume PC to negative cytolo-gy with no evidence of active peritoneal disease.These strategies include the use of neoadjuvant systemic chemotherapy alone,using neoadjuvant laparoscopic heated intraper itoneal chemotherapy(NLHIPEC)after systemic chemotherapy,or using neoadjuvant intra-peritoneal and systemic chemother apy(NIPS)in a bi-dir ectional manner. For patients with higher volume PC,cytoreductive surgery (CRS) and hyperthermic intrape-ritoneal chemotherapy(HIPEC)have been mainstays of treatment. When used together, CRS and HIPEC can improve overall outcomes in properly selected patients,but overall survival outcomes remain unacceptably low.The extent of peritoneal disease, commonly measured by the peritoneal carcinomatosis index (PCI), and the com-pleteness of cytor eduction,has been shown to greatly impact outcomes in patients undergoing CRS and HIPEC.The uses of NLHIPEC and NLHIPEC plus NIPS have both been shown to decrease the PCI and thus increase the opportunity for complete cytoreduction. Newer therapies like pressurized intraperitoneal aerosol chemother apy and immunotherapy, such as catumaxomab, along with improved systemic chemotherapeutic regimens, are being explored with great interest.There is exciting progress being made in the management of PC from gastric can-cer and its’ treatment is no longer futile.

Current role of hyperthermic intraperitoneal chemotherapy in the treatment of peritoneal carcinomatosis from colorectal cancer

Peritoneal carcinomatosis is one of the most common routes of dissemination of colorectal cancer (CRC). It is encountered in 7% of patients at primary surgery, while it develops in about 4% to 19% of patients after curative surgery and in up to 44% of patients with recurrent CRC. Peritoneal involvement from colorectal malignancies has been considered traditionally as a manifestation of terminal disease, due to limited response to conventional surgical and chemotherapeutic treatments. In the past few years the introduction of cytoreductive surgery combined with hyperthermic intraperitoneal chemoperfusion has shown promising results in selected patients. Currently, the surgical management of peritoneal surface malignancies of colonic origin with this combined locoregional therapy has resulted in a signif icant improvement in survival of these patients. However, further controlled studies will help to standardize indications and the technique of this locoregional therapy in order to achieve an improvement of morbidity and mortality rates.

Second-look surgery plus hyperthermic intraperitoneal chemotherapy for patients with colorectal cancer at high risk of peritoneal carcinomatosis:Does it really save lives?

The treatment of peritoneal carcinomatosis (PC) of colorectal origin with cytoreductive surgery(CRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC) has a 5-year recurrence-free or cure rate of at least 16%, so it is no longer labeled as a fatal disease, and offers prolonged survival for patients with a low peritoneal carcinomatosis index. Metachronous PC of colorectal origin is so predictable that there is a model which has been used to successfully determine the individual risk of each patient. Patients at risk are clearly identified; those with the highest risk have small peritoneal nodules present in the first surgery (70% probability of developing PC), ovarian metastases(60%), perforated tumor onset or intraoperative tumor rupture(50%). Current clinical, biological and imaging techniques still lack sufficient sensitivity to diagnose PC in its initial stages, when CRS plus HIPEC has a greater impact and a higher cure rate. Second-look surgery with HIPEC or prophylactic HIPEC at the time of the first intervention have been proposed as means of preventing and/or anticipating clinical or radiological relapse in at-risk patients. Both techniques have shown a significant decrease in peritoneal relapses and should be considered essential weapons in the management of colorectal cancer.

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in treatment of gastric cancer with peritoneal carcinomatosis

Although gastric cancer with peritoneal carcinomatosis is associated with poor prognosis and is generally treated with palliative systemic therapy, recent studies have shown that cytoreductive surgery（CRS） and hyperthermic intraperitoneal chemotherapy（HIPEC） may prove to be an efficacious treatment option. In addition to reviewing the natural history of gastric cancer with peritoneal carcinomatosis, this mini-review examines literature on the efficacy of CRS and HIPEC as compared to chemotherapy and surgical options. Both randomized and nonrandomized studies were summarized with the emphasis focused on overall survival. In summary, CRS and HIPEC are indeed a promising treatment option for gastric cancer with peritoneal carcinomatosis and large randomized clinical trials are warranted.

Peritoneal carcinomatosis of colorectal origin

Peritoneal carcinomatosis is,after liver metastases,the second most frequent cause of death in colorectal cancer patients and at the present time,is commonly inserted and treated as a stage Ⅳ tumour.Because there is no published data that outlines the impact of new therapeutic regimens on survival of patients with peritoneal surface diffusion,the story of carcinomatosis can be rewritten in light of a new aggressive approach based on the combination of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy.Also if these treatment perhaps allow to obtain better results than standard therapies,we suggest,that a large prospective randomised control trial is needed to compare long-term and progression-free survival under the best available systemic therapy with or without cytoreductive surgery and hyperthermic intraperitoneal chemotherapy.

Gastric peritoneal carcinomatosis-a retrospective review

AIM To characterize patients with gastric peritoneal carcinomatosis(PC) and their typical clinical and treatment course with palliative systemic chemotherapy as the current standard of care.METHODS We performed a retrospective electronic chart review of all patients with gastric adenocarcinoma with PC diagnosed at initial metastatic presentation between January 2010 and December 2014 in a single tertiary referral centre.RESULTS We studied a total of 271 patients with a median age of 63.8 years and median follow-up duration of 5.1 mo. The majority(n = 217, 80.1%) had the peritoneum as the only site of metastasis at initial presentation. Palliative systemic chemotherapy was eventually planned for 175(64.6%) of our patients at initial presentation, of which 171 were initiated on it. Choice of first-line regime was in accordance with the National Comprehensive Cancer Network Guidelines for Gastric Cancer Treatment. Thesepatients underwent a median of one line of chemotherapy, completing a median of six cycles in total. Chemotherapy disruption due to unplanned hospitalizations occurred in 114(66.7%), while cessation of chemotherapy occurred in 157(91.8%), with 42 cessations primarily attributable to PC-related complications. Patients who had initiation of systemic chemotherapy had a significantly better median overall survival than those who did not(10.9 mo vs 1.6 mo, P < 0.001). Of patients who had initiation of systemic chemotherapy, those who experienced any disruptions to chemotherapy due to unplanned hospitalizations had a significantly worse median overall survival compared to those who did not(8.7 mo vs 14.6 mo, P < 0.001).CONCLUSION Gastric PC carries a grim prognosis with a clinical course fraught with disease-related complications which may attenuate any survival benefit which palliative systemic chemotherapy may have to offer. As such, investigational use of regional therapies is warranted and required validation in patients with isolated PC to maximize their survival outcomes in the long run.

Self-expanding metal stents for the palliation of malignant gastric outlet obstruction in patients with peritoneal carcinomatosis

AIM To evaluate the efficacy of self-expanding metal stents(SEMS) for the palliation of malignant gastric outlet obstruction in patients with and without peritoneal carcinomatosis(PC).METHODS We performed a retrospective analysis of 62 patients who underwent SEMS placement for treatment of malignant gastroduodenal obstruction at our hospital over a six-year period. Stents were deployed through the scope under combined fluoroscopic and endoscopic guidance. Technical success was defined as successful stent placement and expansion. Clinical success was defined as an improvement in the obstructive symptoms and discharge from hospital without additional parenteral nutrition. According to carcinomatosis status, patients were assigned into groups with or without evidence of peritoneal disease.RESULTS In most cases, obstruction was caused by pancreatic(47%) or gastric cancer(23%). Technical success was achieved in 96.8%(60/62), clinical success in 79%(49/62) of all patients. Signs of carcinomatosis were identified in 27 patients(43.5%). The diagnosis was confirmed by pathology or previous operation in 7 patients(11.2%) and suspected by CT, MRI or ultrasound in 20 patients(32.2%). Presence of carcinomatosis was associated with a significantly lower clinical success rate compared to patients with no evidence of peritoneal disease(66.7% vs 88.6%, P = 0.036). There was no significant difference in overall survival between patients with or without PC(median 48 d vs 70 d, P = 0.21), but patients showed significantly longer survival after clinical success of SEMS placement compared to those experiencing clinical failure(median 14.5 d vs 75 d, P = 0.0003).CONCLUSION Given the limited therapeutic options and a clinical success rate of at least 66.7%, we believe that SEMS are a reasonable treatment option in patients with malignant gastric outlet obstruction with peritoneal carcinomatosis.

Intraperitoneal Chemotherapy for Gastric Cancer with Peritoneal Carcinomatosis: Is HIPEC the Only Answer?

Gastric cancer with peritoneal carcinomatosis is notorious for its dismal prognosis. While the pathophysiology of peritoneal dissemination is still controversial, the rapid downhill course is universal. Patients usually suffer abdominal distension, intestinal obstruction and various complications before they succumb after a median of 3 - 6 months. Although not adopted in most international treatment guidelines, intraperitoneal chemotherapy has growing evidence compared with conventional systemic chemotherapy for the treatment of peritoneal carcinomatosis. Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy is well-established for clinical benefit but is technically demanding with substantial treatment-related morbidities and mortality. On the other hand, normothermic intraperitoneal chemotherapy in the form of bidirectional neoadjuvant treatment is promising with various newer chemotherapeutic agents. Regardless of the treatment technique applied, the essential element of success is meticulous patient selection and availability of expertise. Future direction is along the line of personalized treatment with the application of translational science.

Peritoneal cancer index is a prognostic indicator of survival in advanced gastric cancer with peritoneal carcinomatosis

Objective The peritoneal cancer index(PCI)has been used for the detailed evaluation of the peritoneal spread in tumors of a gynecologic origin and has been found to be a prognostic indicator of survival.The aim of this study was to identify the significance of the PCI in advanced gastric cancer(AGC)with peritoneal carcinomatosis(PC).Methods From 2010 to 2018,a retrospective analysis was carried out of 60 AGC patients with PC,including 21 patients with a PCI≤13 and 39 with a PCI>13.All patients were treated with both surgery and intraoperative peritoneal hyperthermic chemotherapy(IPHC).The performance status(Karnofsky performance status),age,sex,Borromann’s classification,differentiation,depth of invasion,lymph node metastasis,PCI,extent of gastrectomy,extent of lymph node dissection,and residual tumor volume were retrospectively evaluated and correlated to survival.Results The overall 5-year survival rate was 43%and mean survival was(54.47±4.53)months.The favorable clinical prognostic indicators of survival were Borromann’s classification,differentiation,depth of invasion,PCI,and residual tumor volume on univariate analyses(P<0.05).The Cox proportional regression hazard model showed that only the volume of residual tumor and PCI were associated with postoperative survival.The median survival time was 69.76 months for patients with a PCI≤13 and 39.96 months for patients with a PCI>13.There was a significant difference in survival rate between the two group(P=0.004).Postoperative major morbidity and mortality rates were 23.81%and 4.76%in the PCI≤13 group and 43.59%and 5.12%in the PCI>13 group,respectively.Conclusion The peritoneal spread in advanced gastric cancer with peritoneal carcinomatosis can be assessed in detail using the PCI.It is also a significant prognostic factor of survival and is useful in identifying subgroups.

Leptomeningeal carcinomatosis as the initial manifestation of gastric adenocarcinoma:A case report

Leptomeningeal involvement is usually reported as a secondary event in advanced gastric carcinoma.Leptomeningeal carcinomatosis(LMC),as the initial manifestation of asymptomatic gastric cancer,is exceedingly rare with only a few cases reported in recent years.The presenting neurologic symptoms include headache,vomiting and seizures and are usually clinically atypical.The diagnosis of LMC is made via identification of malignant cells that originate from epithelial cells in the cerebrospinal fluid by cytological examination and provides cues to track the primary tumor.Endoscopic examinations are crucial to confirm the presence of gastric cancer,and imaging studies,especially gadolinium-enhanced magnetic resonance imaging of the brain,are sometimes helpful in diagnosis.Thus far,there is no standard therapy for LMC,and despite all measures,the prognosis of the condition is extremely poor.Here,we report on the clinical features and diagnostic procedures for a patient with occult gastric cancer with Bormann typeⅠmacroscopic appearance and poor differentiation in pathology,who presented with LMC-induced neurological symptoms as the initial clinical manifestation.Additionally,we review the similar cases reported over the past years,making comparison among cases in order to provide more information for the future diagnosis.

Peritoneal carcinomatosis of gastrointestinal tumors: Where are we now?

The peritoneal stromal tissue which provides a rich source of growth factors and chemokines is a favorable environment for tumor proliferation. The pathophysiological mechanism of peritoneal carcinomatosis is an individual sequence consisting of genetic and environmental factors and remains controversial. The natural history of the disease reveals a poor median prognosis of approximately 6 mo; however aggressive surgery and multimodal treatment options can improve oncologic outcomes. Considering peritoneal carcinomatosis as though it is a locoregional disease but not a metastatic process, cytoreductive surgery and and intraperitoneal chemotherapy has been a curative option during recent years. Cytoreductive surgery implies a series of visceral resections and peritonectomy procedures. Although the aim of cytoreductive surgery is to eliminate all macroscopic disease, viable tumor cells may remain in the peritoneal cavity. At that point, intraperitoneal chemotherapy can extend the macroscopic disease elimination to microscopic disease elimination. The successful treatment of peritoneal carcinomatosis requires a comprehensive management plan including proper patient selection, complete resection of all visible disease, perioperative intraperitoneal chemotherapy and postoperative systemic chemotherapy. Surgical and oncologic outcomes are strictly associated with extent of the tumor, completeness of cytoreduction and patientrelated factors as well as multidisciplinary management and experience of the surgical team. In this review, pathophysiology and current management of peritoneal carcinomatosis originating from gastrointestinal tumors are discussed according to the latest literature.

Disseminated carcinomatosis of the bone marrow caused by granulocyte colony-stimulating factor:A case report and review of literature

BACKGROUND Disseminated carcinomatosis of the bone marrow(DCBM)is a widespread metastasis with a hematologic disorder that is mainly caused by gastric cancer.Although it commonly occurs as a manifestation of recurrence long after curative treatment,the precise mechanism of relapse from dormant status remains unclear.Granulocyte colony-stimulating factor(G-CSF)can promote cancer progression and invasion in various cancers.However,the potential of G-CSF to trigger recurrence from a cured malignancy has not been reported.CASE SUMMARY A 55-year-old Japanese woman was diagnosed with Ewing sarcoma localized on the fifth lumbar vertebrae 6 years after curative gastrectomy for T1 gastric cancer.After palliative surgery to release nerve compression,pathological diagnosis of the resected specimen was followed by curative radiation and chemotherapy.During treatment,G-CSF was administered 32 times for severe neutropenia prophylaxis.Eight months after completing definitive treatment,she complained of severe back pain and was diagnosed as multiple bone metastases with DCBM from gastric cancer.Despite palliative chemotherapy,she died of disseminated intravascular coagulation 13 d after the diagnosis.Immunohistochemical examination of the autopsied bone marrow confirmed a diffuse positive staining for the G-CSF receptor(G-CSFR)in the relapsed gastric cancer cell cytoplasm,whereas the primary lesion cancer cells showed negative staining for G-CSFR.In this case,G-CSF administration may have been the key trigger for the disseminated relapse of a dormant gastric cancer.CONCLUSIONWhen administering G-CSF to cancer survivors,recurrence of a preceding cancer should be monitored even after curative treatment.

Update on Colorectal Carcinomatosis—From Molecular Biology to Diagnosis and Management

After liver metastases, Peritoneal Carcinomatosis (PC) is the second most frequent cause of death in patients with Colorectal Cancer (CRC), although the precise incidence of Colorectal Cancer Peritoneal Carcinomatosis is not known, as the majority of the diagnostic studies cannot detect the disease in its initial stages, nowadays, the diagnosis of peritoneal carcinomatosis remains a challenge. The molecular biology of PC is only just beginning to be understood, future knowledge will permit not only identify novel strategies for PC prevention, but also contribute to therapeutic advances, through the development of molecular targeted therapies. The authors performed a literature revision about the Molecular Biology, Diagnosis and Management of Colorectal Cancer Peritoneal carcinomatosis.

Peritoneal Colorectal Carcinomatosis Treated with Cytoreductive Surgery and Perioperative Intraperitoneal Chemotherapy

Background-Aims: Peritoneal colorectal carcinomatosis is a potentially curative disease. The purpose of the study is the retrospective analysis of survival of the patients with peritoneal colorectal carcinomatosis that underwent cytoreductive surgery and perioperative intraperitoneal chemotherapy and the identification of prognostic variables of the disease. Patients-Methods: Patients with primary or recurrent colorectal cancer and peritoneal carcinomatosis were included in the study. Clinical variables were correlated to survival, recurrence, hospital mortality, and morbidity. Results: From 2000-2010, 28 patients underwent 33 cytoreductive operations. The hospital mortality and morbidity rate was 9.1% and 45.5% respectively. The overall 5-year and median survival time was 29.2% and 19 months respectively. The extent of peritoneal carcinomatosis (p = 0.0003) and the completeness of cytoreduction (p = 0.0002) were related to survival. The completeness of cytoreduction (p = 0.003) was the single prognostic variable of survival. The recurrence rate was 42.4% and the use of systemic chemotherapy was identified as the single prognostic variable of recurrence (p = 0.047). Conclusions: Patients with limited extent of peritoneal colorectal carcinomatosis who undergo complete cytoreduction may be offered long-term survival.