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Systemic para-aortic lymph node dissection PAND had been attempted in Japan as clinical studies until its survival benefit was denied in a randomized trial in which only patients without lymphadenopathy in the para-aortic region were eligible [ 5 ]. A similar result was recently reported from a Western country [ 36 ].
Thus, it is not possible to totally deny the survival benefit of PAND when lymphadenopathy restricted to the No. Patients with bulky nodal disease with or without lymphadenopathy restricted to the No. However, these retrospective studies are known to include patients who eventually underwent surgery after responding to the chemotherapy and may at least partially reflect the benefit of the multidisciplinary approach. Answer A multidisciplinary approach including surgery with curative intent could be proposed when the number of metastatic nodules is small, provided other non-curative factors are absent.
Hepatic metastases from gastric cancer are often deemed unresectable since they are liable to be found as multiple nodules distributed to both hepatic lobes and are likely to be accompanied with metastatic lesions outside of the liver. No prospective trial exploring a benefit of hepatectomy has been conducted, and only retrospective analyses of small cohorts collected over several decades mostly as single-institution studies [ 40 — 42 ] are available.
Solitary metastasis or a small number of metastatic nodules has been highlighted as a favorable prognostic factor in most of the studies [ 43 ]. Given the recent advances in imaging studies, and the fact the diagnosis of solitary metastasis could be unreliable in older cases, hepatectomy may be considered for patients with a small number of metastatic nodules, and not restricted to a solitary tumor, provided that there is no other non-curative factor.
Since there was no agreement on whether the synchronous metastases fare better than metachronous metastases, surgery could also be considered for recurrences in the liver if they fulfill the conditions mentioned above.
Most patients eventually suffer from recurrences, however, and perioperative chemotherapy could be recommended for the population that had not been treated by adjuvant chemotherapy prior to detection of the hepatic metastases. Evidence on which chemotherapeutic regimen can be recommended in this particular setting, however, is totally lacking. How should gastric cancer with positive peritoneal cytology CY1 be treated? Could there be any therapeutic proposal for patients who underwent gastrectomy and were found afterwards to have been CY1 in some institutions, results of the cytologic examination are available only after surgery in case the sample was collected at surgery?
Answer Multidisciplinary treatment including standard gastrectomy can be proposed for patients with no other non-curative factors. If the CY1 status was revealed after surgery, postoperative treatment with S-1 can be recommended as the tentative standard. In Japan, peritoneal washing samples are usually collected during surgery for cytologic examination to detect free cancer cells.
However, patients with CY1 status are often treated by standard gastrectomy in the absence of other no-curative factors.
More recently, a prospective phase II study was conducted in which technically resectable cancer with CY1 as the only non-curative factor patients with minimal and resectable peritoneal deposits included was treated by standard gastrectomy followed by S-1 monotherapy until disease progression. In addition, a single-institution retrospective study of CY1 patients who underwent surgery followed by S-1 monotherapy revealed a 5-year survival rate of These results are far better than the results obtained before S-1 became available and are equivalent to that of a series of curatively resected linitis plastica-type cancers, which often recur as peritoneal disease [ 47 ].
These facts indicate that CY1 patients could be indicated for the strategy consisting of standard gastrectomy and perioperative chemotherapy. In addition, S-1 monotherapy could be recommended for patients whose CY1 status was informed after gastrectomy.
On the other hand, if the information on CY status was available prior to surgery, a chemotherapy-first strategy could be taken whereby only patients whose cytology status turned negative could be indicated for surgery [ 48 , 49 ]. However, details of the optimal multidisciplinary treatment strategy in this setting, including the chemotherapeutic regimen to be used and the number of cycles to be delivered, remain to be elucidated in future clinical trials.
Answer Although no evidence to recommend any particular regimen exists, most physicians would avoid monotherapy with S-1 for second-line chemotherapy. However, the treatment for patients who had recurrent disease after the adjuvant treatment remains to be elucidated. This result, found in a multi-institutional retrospective analysis, suggests that cancers that recur during or early after completion of an adjuvant chemotherapy are resistant to the drug used in that chemotherapy. On the other hand, a retrospective analysis of the patients registered for the ACTS-GC study revealed that patients who received S-1 among other drugs in salvage line treatments survived longer after recurrence than those who did not receive S-1, regardless of the time interval between the adjuvant chemotherapy and recurrence.
However, results of this study will have to be interpreted with caution since the study suffers from several biases in the background of the patients such as whether oral food intake was possible patients who did not receive S-1 after recurrence might have been those with bowel obstruction who were unable to eat and suffered from poor performance status.
In treatment for colorectal cancer during the era of adjuvant chemotherapy with 5FU alone, drugs used in the salvage line treatment depended on the time interval between the completion of the adjuvant chemotherapy and recurrence.
The same rule has been applied for gastric cancer, and patients with late recurrence after adjuvant treatment have been deemed eligible for clinical trials exploring a first-line treatment, whereas those with early recurrences were registered in clinical trials for the second-line treatment.
Thus, patients with recurrences during or early after completion of the adjuvant treatment are considered as targets of second-line treatments, and S-1 monotherapy is usually avoided for this population. However, there is currently no evidence to recommend any specific regimen for this setting.
Which chemotherapeutic regimen is recommended for patients suffering from either bowel obstruction or massive ascites due to severe peritoneal metastases? Answer The indication for chemotherapy itself should be decided discreetly, taking into consideration the general status of the patient. Drugs with mild toxicity profiles such as infusional 5-fluorouracil and paclitaxel could be considered as the candidates.
Benefit for delivering chemotherapy should be weighed carefully against the risk, and best supportive care should be considered as an alternative. The JCOG study was one of the few in which only patients with peritoneal metastases detected by imaging studies such as CT and barium enema were eligible.
Thus, 5FUci will be the current first choice for patients with bowel obstruction due to peritoneal metastases, but its effect on massive ascites remains elusive. However, paclitaxel was associated with a more favorable toxicity profile [ 54 ]. These results indicate that weekly paclitaxel can be considered for patients with severe peritoneal disease in both the first- and second-line setting.
Further evidence through a randomized comparison of the combination with a single-agent treatment is awaited. S-1 monotherapy could be selected for more frail patients. Thus, a benefit of adding cisplatin is unclear for the elderly population. That said, it may still be inadequate to estimate the tolerability of elderly patients to chemotherapy based only on chronological age without taking into account the major organ functions, comorbidities and past history. Unfortunately, however, a method to comprehensively evaluate the vulnerability of each aged individual has not been established.
Further evidence through clinical trials is needed for various decision-makings when treating elderly patients with gastric cancer. Such decision will have to be based on the general condition of the patient with particular attention to the renal and cardiac function, always bearing in mind that S-1 monotherapy is quite reasonable as an alternative. Even after the treatment has started, the patient will have to be monitored with upmost care with attention paid not only to severe adverse events but also to anorexia, stomatitis and diarrhea, which could be particularly debilitating for elderly patients.
Which chemotherapeutic regimen is recommended as a second-line treatment for HER2-positive gastric cancer? Answer The taxanes or irinotecan can be recommended as in the case of HER2-negative cancer. However, in case a trastuzumab-containing regimen was not given as a first-line treatment, a combination of weekly paclitaxel and trastuzumab could be selected.
A trastuzumab-containing regimen is recommended for the first-line treatment of HER2-positive gastric cancer as a result of the ToGA trial [ 17 ]. There is no evidence to recommend any specific regimen for the specific cohort of HER2-positive patients who progressed during or after the trastuzumab-containing regimen. Either the taxanes or irinotecan could be selected as in the case of second-line treatment for HER2-negative gastric cancer. On the other hand, a promising response rate of However, results of this trial will have to be interpreted with care for the following reasons: There is currently no evidence in support of efficacy or safety for continuing with trastuzumab in case the patient was pretreated with a trastuzumab-containing regimen trastuzumab beyond progression.
English edition editors: Yasuhiro Kodera e-mail: National Center for Biotechnology Information , U. Gastric Cancer. Published online Jun Japanese Gastric Cancer Association. Author information Article notes Copyright and License information Disclaimer.
Japanese Gastric Cancer Association, Email: Received May 13; Accepted Jun 2. This article has been cited by other articles in PMC. Preface to the English edition This English edition was made based on the Japanese version published as a book in Preface Version 4 of the Japanese Gastric Cancer Treatment Guidelines was completed in May , incorporating new evidence that includes those delivered as a quick bulletin in the website of the Japan Gastric Cancer Association after publication of the previous version.
Major points of revision in the current version are listed below: The section on types and definitions of gastric surgery has been revised. Treatments Algorithm of standard treatments to be recommended in clinical practice The algorithm is shown in Fig. Open in a separate window. Investigational treatments The following treatments show promise but are as yet to be established as the standard. The following constitute investigational treatments: Laparoscopic surgery for advanced cancer and those in need of total gastrectomy.
Local tumor resection. Neoadjuvant chemotherapy. Adjuvant chemotherapy using agents other than S Neoadjuvant chemoradiotherapy. Adjuvant chemoradiotherapy. Surgery Types and definitions of gastric surgery Curative surgery Standard gastrectomy Standard gastrectomy is the principal surgical procedure performed with curative intent. Reduction surgery The role of gastrectomy is unclear in patients with metastatic gastric cancer in the absence of urgent symptoms such as bleeding or obstruction.
Extent of gastric resection Surgery for gastric cancer Surgery for gastric cancer is defined as follows in the order of the stomach volume to be resected.
Local resection. Non-resectional surgery bypass surgery, gastrostomy, jejunostomy. Determination of gastric resection Resection margin A sufficient resection margin should be ensured when determining the resection line in gastrectomy with curative intent.
Lymph node dissection Extent of lymph node dissection The extent of systematic lymphadenectomy is defined as follows according to the type of gastrectomy conducted. Total gastrectomy Fig. Distal gastrectomy Fig. Pylorus-preserving gastrectomy Fig. Proximal gastrectomy Fig. Omentectomy Removal of the greater omentum is usually integrated in the standard gastrectomy for T3 SS or deeper tumors. Bursectomy For tumors penetrating the serosa of the posterior gastric wall, bursectomy removal of the inner peritoneal surface of the bursa omentalis may be performed with the aim of removing microscopic tumor deposits in the lesser sac.
Combined resection of adjacent organ s For tumors in which the primary or metastatic lesion directly invades adjacent organs, combined resection of the involved organ may be performed in order to obtain an R0 resection. Laparoscopic surgery Laparoscopic surgery can be considered an option in general clinical practice to treat cStage I cancer that is indicated for distal gastrectomy.
Reconstruction after gastrectomy The following reconstruction methods are usually employed. Total gastrectomy Roux-en-Y esophagojejunostomy. Jejunal interposition.
Double tract method. Distal gastrectomy Billroth I gastroduodenostomy. Billroth II gastrojejunostomy. Roux-en-Y gastrojejunostomy. Pylorus-preserving gastrectomy Gastro-gastrostomy. Proximal gastrectomy Esophagogastrostomy. Endoscopic resection Methods of endoscopic resection Endoscopic mucosal resection EMR The lesion, together with the surrounding mucosa, is lifted by submucosal injection of saline normo- or hypertonic and removed using a high-frequency steel snare.
Endoscopic submucosal dissection ESD The mucosa surrounding the lesion is circumferentially incised using a high-frequency electric knife usually insulation-tipped , and the submucosal layer is dissected from the proper muscle layer.
Handling of endoscopically resected specimens Handling of resected specimens The resected specimens should be handled according to the rules described in the Japanese Classification of Gastric Carcinoma [ 1 ].
Definition of differentiated-type and undifferentiated-type carcinoma The tumor biopsy specimens and endoscopically resected tumors are histologically classified into either the differentiated or undifferentiated type. Histological predominance and intratumoral ulcerative findings UL A tumor consisting of components of both differentiated- and undifferentiated-type carcinoma is nevertheless classified into one of the two types according to the quantitative predominance.
Indication for endoscopic resection Fig. Principles of indication Endoscopic resection is considered for tumors that have a very low possibility of lymph node metastasis and are suitable for en-bloc resection.
Tumors indicated for endoscopic resection as a standard treatment absolute indication EMR or ESD is indicated as a standard treatment for the following tumor. Curability of endoscopic resection Meticulous pathologic examination of the resected specimen is mandatory. Curative resection The resection is determined as curative when all of the following conditions are fulfilled: Curative resection for tumors of expanded indication The resection is considered as curative when all of the following conditions are fulfilled: Non-curative resection Resection that does not satisfy any of the above criteria is considered non-curative.
Treatments after endoscopic resection Treatments after curative resection Follow-up with annual or biannual endoscopy is recommended.
Treatments after curative resection for tumors of expanded indications Follow-up with abdominal ultrasonography or CT scan as well as annual or biannual endoscopy is recommended. Treatment after non-curative resection Surgical treatment should be performed after non-curative resection.
Principles of indication Chemotherapy is indicated for patients with unresectable or recurrent disease, or those after non-curative R2 resection, whose general condition and major organ functions are preserved: Recommendable regimens for Japanese patients Treatment regimens were classified into the following three categories according to the degree that the regimen could be recommended.
Second-line treatment Second-line treatment is recommended for patients with sufficient performance status, following several randomized trials mentioned below. Chemotherapy as a general practice Indication Indication for chemotherapy should be decided after taking into consideration the following eligibility criteria.
Clinical and pathological diagnosis of gastric cancer has been obtained. Major organ functions are preserved. Patient does not suffer from severe comorbidities. Informed consent has been obtained from the patient. Methodology Prior to treatment, PS, body weight, clinical symptoms and laboratory data including examination for hepatitis virus should be checked, and imaging studies such as computerized tomography CT should be performed to obtain baseline measurements of the lesions.
Drugs to be used The following drugs are used in chemotherapy for gastric cancer: Postoperative adjuvant chemotherapy Postoperative adjuvant chemotherapy is delivered with an intention to reduce recurrence by controlling residual tumor cells following curative resection. Palliative care Palliative care is an approach that improves the quality of life of patients and their families facing the problems associated with life-threatening illness through the prevention and relief of suffering by means of early identification and impeccable assessment and treatment of pain and other problems, physical, psychosocial and spiritual WHO Definition of Palliative Care, Clinical pathway after surgery for gastric cancer It is extremely difficult to establish a clinical pathway for patients undergoing gastric cancer surgery that is widely applicable to various surgical procedures and institutions.
Clinical items Date on the clinical pathway Removal of nasogastric tube Before or on postoperative day 1 Initiation of oral fluid intake On or after postoperative day 1 Initiation of solid food intake Between postoperative days 2—4 Prophylactic administration of antibiotics Only on the day of operation Removal of epidural tube Before or on postoperative day 3 Removal of urinary catheter Before or on postoperative day 3 Intravenous fluid administration Until postoperative day 5—7 Removal of intra-abdominal drains Before or on postoperative day 5 Discharge from the hospital Between postoperative days 8— Follow-up surveillance after surgery for gastric cancer Follow-up at the outpatient clinic could be helpful so that the patients can readjust to their lives at home, cope with postgastrectomy symptoms and overcome the nutritional issues.
Duration after surgery Year: How should gastric cancer with hepatic metastases be treated? Compliance with ethical standards Conflict of interest Dr.
Footnotes English edition editors: References 1. Japanese Gastric Cancer Association Japanese classification of gastric carcinoma: Stomach-partitioning gastrojejunostomy for unresectable gastric carcinoma.
Arch Surg. Lancet Oncol. Randomized controlled trial to evaluate splenectomy in total gastrectomy for proximal gastric carcinoma. Ann Surg. D2 lymphadenectomy alone or with para-aortic nodal dissection for gastric cancer. N Engl J Med. Therapeutic value of lymph node dissection in advanced gastric cancer with macroscopic duodenum invasion: Ann Surg Oncol. Survival benefit of bursectomy in patients with resectable gastric cancer: Left thoracoabdominal approach versus abdominal-transhiatal approach for gastric cancer of the cardia or subcardia: Safety and feasibility of laparoscopy-assisted distal gastrectomy with suprapancreatic nodal dissection for clinical stage I gastric cancer: Morbidity and mortality of laparoscopic gastrectomy versus open gastrectomy for gastric cancer: Incidence of lymph node metastasis from early gastric cancer: Incidence of lymph node metastasis and the feasibility of endoscopic resection for undifferentiated-type early gastric cancer.
Treatment for intramucosal gastric cancer with mixed type histology differentiated and undifferentiated Stomach Intest. S-1 plus cisplatin vs S-1 in RCT in the treatment for stomach cancer. Fluorouracil versus combination of irinotecan plus cisplatin versus S-1 in metastatic gastric cancer: Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer ToGA: Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer: J Clin Oncol.
Addition of docetaxel to S-1 without platinum prolongs survival of patients with advanced gastric cancer: Phase III study of docetaxel with cisplatin and 5-fluorouracil as first-line therapy for advanced gastric cancer: Ann Oncol.
Capecitabine and oxaliplatin for advanced esophagogastric cancer. Survival advantage for irinotecan versus best supportive care as second-line chemotherapy in gastric cancer: Salvage chemotherapy for pretreated gastric cancer: Randomized, open-label, phase III study comparing irinotecan with paclitaxel in patients with advanced gastric cancer without severe peritoneal metastasis after failure of prior combination chemotherapy using fluoropyrimidine plus platinum: WJOG trial.
Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma RAINBOW: Adjuvant chemotherapy for gastric cancer with S-1, an oral fluoropyrimidine.
Feasibility study of adjuvant chemotherapy with S-1 plus cisplatin for gastric cancer. Cancer Chemother Pharmacol. Adjuvant capecitabine plus oxaliplatin after D2 gastrectomy in Japanese patients with gastric cancer: Super-extended D3 lymphadenectomy in advanced gastric cancer. Eur J Surg Oncol.
Neoadjuvant chemotherapy with S-1 and cisplatin followed by D2 gastrectomy with para-aortic lymph node dissection for gastric cancer with extensive lymph node metastasis. Br J Surg. Long-term survival and prognostic factors in patients with metastatic gastric cancers treated with chemotherapy in the Japan Clinical Oncology Group JCOG study. Jpn J Clin Oncol. Clinical characteristics and treatment outcomes of gastric cancer patients with isolated para-aortic lymph node involvement.
Favorable indications for hepatectomy in patients with liver metastasis from gastric cancer. J Surg Oncol. Long-term outcomes after surgical resection for gastric cancer liver metastasis: Langenbecks Arch Surg.
Survival benefit of combined curative resection of the stomach D2 dissection and liver in gastric cancer patients with liver metastases. Surgical resection of hepatic metastasis from gastric cancer: Intraoperative lavage for cytological examination in patients with gastric carcinoma. Am J Surg. Long-term follow up of patients who were positive for peritoneal lavage cytology: With our team of test prep specialists, we help you succeed in med school and beyond.
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