Stomach cancer medical therapy: Difference between revisions

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{{CMG}}{{AE}}{{PSD}}
{{CMG}}; {{AE}} {{PSD}} {{MAD}}
{{Stomach cancer}}
{{Stomach cancer}}
==Overview==
==Overview==
The optimal therapy for stomach cancer depends on the stage at diagnosis.
The optimal [[therapy]] for [[stomach cancer]] depends on the stage at [[diagnosis]]. Medical therapy is indicated for patients with unresectable or recurrent [[disease]], after non-curative R2 resection (macroscopic [[tumor]] removal), [[patients]] with unresectable T4b [[disease]], extensive [[Lymph nodes|nodal]] [[disease]], [[hepatic]] [[Metastasis|metastases]], [[peritoneal]] dissemination or other M1 [[disease]]. Response to the treatment should be evaluated by examinations such as [[Computed tomography|CT scan]], [[endoscopy]] and [[Contrast medium|contrast]] [[radiography]]. [[Adjuvant therapy]] includes one cycle of [[fluorouracil]] (425 mg/m2 of body surface area) plus [[Leucovorin Calcium|leucovorin calcium]] (20 mg/m2 of body surface area) for five days followed by [[radiation therapy]] for one month given with the same [[chemotherapy]] regimen on days 1 through 4 and the last three days of the month. For [[patients]] with potientially resectable [[disease]] not yet resected, [[neoadjuvant chemotherapy]] is preferred over initial [[surgery]]. Another benefit of [[neoadjuvant chemotherapy]] is that [[patients]] who are at high risk of developing distant [[metastases]] may be spared the [[morbidity]] of unnecessary [[gastrectomy]] if evidence of distant [[metastases]] emerges after [[chemotherapy]]. Preoperative combined [[chemotherapy]] and [[radiation therapy]] is more commonly used for [[esophageal]], esophagogastric junction [[cancers]], and [[cancer]] affecting the [[gastric]] [[cardia]] rather than for potentially [[Resection|resectable]] [[Adenocarcinoma|adenocarcinomas]]. For locally advanced unresectable and [[Metastatic tumor|metastatic tumors]], goals of [[chemotherapy]] include [[palliation]] of [[symptoms]], improvement in [[quality of life]], and prolongation of survival. [[Patients]] with the presence of [[Epidermal growth factor|human epidermal growth factor]] receptor 2 ([[HER2]]) overexpression are potential candidates for [[Trastuzumab|trastuzumab]]
 
==Medical therapy==
The current goal of chemotherapy is to delay the manifestation of disease-related symptoms and to prolong survival. Some patients with advanced disease survive more than 5 years by chemotherapy alone.
 
Chemotherapy is the treatmentof choice for unresectable/ recurrent gastric cancer. The median survival time achieved by chemotherapy for unresectable/ recurrent gastric cancer is 6–13 months.
 
Principles of indication
 
Chemotherapy is indicated for patients with unresectable or recurrent disease
 
After non-curative R2 resection
 
patients with unresectable T4b disease
 
extensive nodal disease
 
hepatic metastases
 
peritoneal dissemination or other M1 disease.
 
Methodology
 
Response to the treatment should be evaluated by examinations that may include CT, endoscopy and contrast radiography, followed by comparison with the baseline data.
 
Tumor shrinkage should be evaluated by response criteria of the Japanese Classification of Gastric Carcinoma or Response Evaluation Criteria in mSolid Tumors (RECIST) to decide on whether or not to continue with the treatment.
 
3. When continuation of the treatment is deemed oncologically feasible, the drug dosage and administration schedule should be reconsidered taking into account the adverse events observed in the previous cycle of treatment. Attention should also be paid to cumulative adverse events such as skin manifestations, taste disturbance and neurotoxicity.
 
4. Chemotherapy for individuals exposed or infected tonhepatitis B virus should be screened, monitored and treated
 
These drugs are to be used alone or in combination, adhering to the dose and schedule employed when being evaluated in clinical trials.
 
'''The following drugs are used in chemotherapy for gastric'''
 
cancer:
 
fluorouracil (5FU)
 
tegafur-gimestat-otastat potassium (S-1)
 
capecitabine
 
cisplatin
 
irinotecan
 
docetaxel
 
paclitaxel
 
trastuzumab
 
Ramucirumab and oxaliplatin
 
===== Postoperative adjuvant chemotherapy =====
Postoperative adjuvant chemotherapy is delivered with an intention to reduce recurrence by controlling residual tumor cells following curative resection.
 
Various regimens had been tested in numerous clinical trials in Japan without producing solid evidence in support of adjuvant chemotherapy until the efficacy of S-1 was proven in the ACTS-GC trial [29, 30], a study that secured the place of postoperative chemotherapy with S-1 as a standard of care (recommendation category 1).
 
After this, the feasibility of several combinations of anticancer drug with S-1 was explored in the postoperative setting [31, 32], and some of the combinations are currently under evaluation in phase III trials. On the other hand, other phase III evidence in support of postoperative chemotherapy was established in 2012 by the CLASSIC trial conducted mainly in Korea [33], in which significant prolongation of recurrence-free survival was shown with a combination of capecitabine and oxaliplatin.  
 
Survival benefit of postoperative adjuvant chemotherapy by combination of S-1 and another cytotoxic drug, including oxaliplatin, will have to be proven by a randomized trial with S-1 monotherapy as a control.
* AJCC staging system considers observation is more appropriate for T2N0 stage IB patients as long as they have undergone an adequate lymph node dissection (for most patients, a D2 rather than D1 lymphadenectomy
* However, adjuvant treatment would be recommended for any T stage with N1 disease.
 
==== Indications ====
The patients eligible for the ACTS-GC trial were those
 
with a tumor of pathological stage II, IIIA or IIIB,
 
excluding those classified as stage II due to pT1/pN2�pN3
 
status, as defined by the previous 13th edition of the
 
Japanese Classification of Gastric Carcinoma (2nd English
 
edition), who had undergone R0 gastrectomy with CD2
 
lymphadenectomy. The eligibility for postoperative adjuvant
 
chemotherapy will remain the same in the current
 
version of the treatment guidelines.
 
==== PATIENTS WHO HAVE ALREADY UNDERGONE POTENTIALLY CURATIVE RESECTION ====
* Adjuvant chemoradiotherapy, rather than surgery alone, is recommended for these patients. 4
* For patients with T2N0 disease, observation or adjuvant treatment is acceptable and the decision is based on the patient general condition ans risk factors.
 
===== The standard protocol: =====
* One cycle of '''fluorouracil''' (425 mg/m2) + '''leucovorin''' calcium (20 mg/m2) for five days.
 
* Followed by radiation therapy for one month given with the same chemotherapy regimen on days 1 through 4 and the last three days of the month.  
* Two more five-day cycles of chemotherapy are given at monthly intervals beginning one month after completion of radiation. [21]


==== '''Japanese S-1 trial''' ====
==Medical Therapy==
* S-1 is approved in Japan for adjuvant therapy of gastric cancer and in Europe for treatment of advanced gastric cancer.
* The goal of [[chemotherapy]] is to delay the [[disease]]-related [[symptoms]] and to prolong survival.
* S-1 is an oral fluoropyrimidine that includes three different agents:30].  
* Some [[patients]] with advanced [[disease]] survive more than 5 years by [[chemotherapy]] alone.  
* ftorafur (tegafur),
* The median survival time of [[chemotherapy]] for recurrent [[gastric cancer]] is 6–13 months.  
* gimeracil
* oteracil (responsible for treatment-related diarrhea).


* Five-year overall survival rates are significantly better with S-1 than the five-year survival rates for the INT0116 and the MAGIC trials  [3,17]
*'''Indications:'''
* The available data have not conclusively resolved the issue of which approach is best; the radiochemotherapy or the chemotherapy alone  Most of trials did not show significant importance of radiotherapy above the chemoptherapy alone.
**[[Patients]] with unresectable or recurrent [[disease]]
'''PATIENTS WITH POTENTIALLY RESECTABLE DISEASE NOT YET RESECTED''' 
**After non-curative R2 resection ([[macroscopic]] removal of [[primary tumor]] margins)
**Patients with unresectable T4b [[disease]]
**Extensive [[Lymph node|nodal]] [[disease]]
**[[Hepatic]] [[Metastasis|metastases]]
**[[Peritoneal]] dissemination or other M1 [[disease]] ([[metastatic]] [[disease]])


For most patients with potentially resectable gastric cancer
* Response to the treatment should be evaluated by examinations such as [[Computed tomography|CT scan]], [[endoscopy]] and [[Radiography|contrast radiography]], followed by comparison with the baseline data.
* [[Tumor]] shrinkage should be evaluated by response [[criteria]] of the Japanese Classification of Gastric Carcinoma or Response Evaluation Criteria to decide to continue with the treatment or not.
* When continuation of the treatment is deemed oncologically feasible, the [[drug]] [[dosage]] and administration schedule should be reconsidered taking into account the adverse events observed in the previous cycle of treatment.
* Attention should also be paid to cumulative [[adverse events]] such as [[skin]] manifestations, taste disturbance and [[Neurotoxicity|neurotoxicity.]]
* [[Chemotherapy]] for individuals exposed or [[infected]] with [[hepatitis B virus]] should be [[Screening (medicine)|screened]], monitored, and treated.
* These [[drugs]] are to be used alone or in combination, adhering to the dose and schedule employed when being evaluated in clinical trials.


we prefer neoadjuvant therapy over initial surgery.  
==== '''Drugs used in chemotherapy for gastric cancer''' ====
The following drugs may be used as [[chemotherapy]] for the treatment of [[gastric cancer]]:<ref>http://www.cancer.gov/types/stomach/patient/stomach-treatment-pdq#section/_50</ref>
* [[Fluorouracil]] (5FU)
* [[Tegafur]]-gimestat-otastat [[potassium]] (S-1)
* [[Capecitabine]]
* [[Cisplatin]]
* [[Irinotecan]]
* [[Docetaxel]]
* [[Paclitaxel]]
* [[Trastuzumab]]
* [[Ramucirumab]] and [[oxaliplatin]]


'''Neoadjuvant/perioperative chemotherapy''' 
== Postoperative Adjuvant Chemotherapy ==
* Postoperative [[adjuvant chemotherapy]] is indicated to reduce recurrence by controlling residual [[Tumor cell|tumor cells]] following curative resection.
* [[Adjuvant treatment]] would be recommended for any T stage with N1 disease. However, AJCC staging system recommends observation for T2N0 stage IB patients as long as they have undergone an adequate [[lymph node]] [[dissection]].
* S-1 efficay was proven in the ACTS-GC trial, a study that secured the place of postoperative [[chemotherapy]] with S-1 as a standard of care.<ref name="pmid17978289">{{cite journal| author=Sakuramoto S, Sasako M, Yamaguchi T, Kinoshita T, Fujii M, Nashimoto A et al.| title=Adjuvant chemotherapy for gastric cancer with S-1, an oral fluoropyrimidine. | journal=N Engl J Med | year= 2007 | volume= 357 | issue= 18 | pages= 1810-20 | pmid=17978289 | doi=10.1056/NEJMoa072252 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17978289  }}</ref>


Neoadjuvant chemotherapy may be administered as a means of "downstaging" a locally advanced tumor prior to an attempt at curative resection
* Another trial in Korea showed significant prolongation of recurrence-free survival with a combination of [[capecitabine]] and [[oxaliplatin]].<ref name="pmid25439693">{{cite journal| author=Noh SH, Park SR, Yang HK, Chung HC, Chung IJ, Kim SW et al.| title=Adjuvant capecitabine plus oxaliplatin for gastric cancer after D2 gastrectomy (CLASSIC): 5-year follow-up of an open-label, randomised phase 3 trial. | journal=Lancet Oncol | year= 2014 | volume= 15 | issue= 12 | pages= 1389-96 | pmid=25439693 | doi=10.1016/S1470-2045(14)70473-5 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25439693  }}</ref>


This approach has been applied to patients thought to have resectable disease as well as to those with apparently unresectable but nonmetastatic disease.  
* Combination of [[S-1]] and another [[cytotoxic drug]] is still under trial.<ref name="pmid20820990">{{cite journal| author=Kodera Y, Ishiyama A, Yoshikawa T, Kinoshita T, Ito S, Yokoyama H et al.| title=A feasibility study of postoperative chemotherapy with S-1 and cisplatin (CDDP) for gastric carcinoma (CCOG0703). | journal=Gastric Cancer | year= 2010 | volume= 13 | issue= 3 | pages= 197-203 | pmid=20820990 | doi=10.1007/s10120-010-0559-y | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20820990  }}</ref>


Another benefit of neoadjuvant chemotherapy is that patients who are at high risk of developing distant metastases (eg, those with bulky T3/T4 tumors, visible perigastric nodes by preoperative imaging studies, including endoscopic ultrasound [EUS], a linitis plastica appearance, or positive peritoneal cytology in the absence of visible peritoneal disease) may be spared the morbidity of unnecessary gastrectomy if evidence of distant metastases emerges after chemotherapy.
* The patients eligible for the ACTS-GC trial were those with a [[tumor]] of [[pathological]] stage II, IIIA or IIIB, excluding those classified as stage II due to T1, N2, N3 status.


'''Choice of regimen and patient selection''' 
== Patients Who Have Already Undergone Potentially Curative Resection ==
* [[Adjuvant treatment|Adjuvant chemoradiotherapy]], rather than [[surgery]] alone, is recommended for these [[patients]].<ref name="pmid11547741">{{cite journal| author=Macdonald JS, Smalley SR, Benedetti J, Hundahl SA, Estes NC, Stemmermann GN et al.| title=Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. | journal=N Engl J Med | year= 2001 | volume= 345 | issue= 10 | pages= 725-30 | pmid=11547741 | doi=10.1056/NEJMoa010187 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11547741  }}</ref>
* For [[patients]] with T2N0 [[disease]], observation or [[adjuvant treatment]] is acceptable and the decision is based on the general condition of the [[patient]] and [[risk factors]].


The best chemotherapy regimen for use in the neoadjuvant setting has not been conclusively established
===== Preferred regimen (standard protocol):  =====
* One cycle of [[fluorouracil]] (425 mg/m2 of body surface area) + [[Leucovorin Calcium|leucovorin calcium]] (20 mg/m2 of body surface area) for five days followed by [[radiation therapy]] for one month given with the same [[chemotherapy]] regimen on days 1 through 4 and the last three days of the month.<ref name="pmid8041415">{{cite journal| author=O'Connell MJ, Martenson JA, Wieand HS, Krook JE, Macdonald JS, Haller DG et al.| title=Improving adjuvant therapy for rectal cancer by combining protracted-infusion fluorouracil with radiation therapy after curative surgery. | journal=N Engl J Med | year= 1994 | volume= 331 | issue= 8 | pages= 502-7 | pmid=8041415 | doi=10.1056/NEJM199408253310803 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8041415  }}</ref>
* Two more five-day cycles of [[chemotherapy]] are given at monthly intervals beginning one month after completion of [[Radiation therapy|radiation]].


FLOT regimen (docetaxel plus oxaliplatin and LV plus short-term infusional FU) rather than an epirubicin-containing regimen (such as ECF or ECX [epirubicin plus cisplatin and capecitabine]),
==== '''Japanese S-1 trial:''' ====
* S-1 is approved in Japan for adjuvant therapy of [[gastric cancer]] and in Europe for treatment of advanced [[gastric cancer]].<ref name="pmid28850174">{{cite journal| author=Wagner AD, Syn NL, Moehler M, Grothe W, Yong WP, Tai BC et al.| title=Chemotherapy for advanced gastric cancer. | journal=Cochrane Database Syst Rev | year= 2017 | volume= 8 | issue=  | pages= CD004064 | pmid=28850174 | doi=10.1002/14651858.CD004064.pub4 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28850174  }}</ref>
* S-1 is an oral fluoropyrimidine that includes three different agents:<ref name="pmid22010012">{{cite journal| author=Sasako M, Sakuramoto S, Katai H, Kinoshita T, Furukawa H, Yamaguchi T et al.| title=Five-year outcomes of a randomized phase III trial comparing adjuvant chemotherapy with S-1 versus surgery alone in stage II or III gastric cancer. | journal=J Clin Oncol | year= 2011 | volume= 29 | issue= 33 | pages= 4387-93 | pmid=22010012 | doi=10.1200/JCO.2011.36.5908 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22010012  }}</ref>
* Ftorafur 
* Gimeracil
* Oteracil (responsible for treatment-related [[diarrhea]])


Whether the FLOT regimen is superior to FU plus cisplatin alone, oxaliplatin plus leucovorin and short-term infusional FU (FOLFOX), or oxaliplatin plus capecitabine is not established, and these are also
* Five-year overall survival rates are significantly better with S-1 than the [[Five-year survival rate|five-year survival rates]] for other trials.<ref name="pmid22585691">{{cite journal| author=Smalley SR, Benedetti JK, Haller DG, Hundahl SA, Estes NC, Ajani JA et al.| title=Updated analysis of SWOG-directed intergroup study 0116: a phase III trial of adjuvant radiochemotherapy versus observation after curative gastric cancer resection. | journal=J Clin Oncol | year= 2012 | volume= 30 | issue= 19 | pages= 2327-33 | pmid=22585691 | doi=10.1200/JCO.2011.36.7136 | pmc=4517071 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22585691  }}</ref>
* Most of trials do not show increased benefit of [[radiotherapy]] over [[Chemotherapy|chemoptherapy]] alone.<ref name="pmid28279466">{{cite journal| author=Ilson DH| title=Current Progress in the Adjuvant Treatment of Gastric Cancer. | journal=Surg Oncol Clin N Am | year= 2017 | volume= 26 | issue= 2 | pages= 225-239 | pmid=28279466 | doi=10.1016/j.soc.2016.10.008 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28279466  }}</ref>


'''ECF/ECX''' 
== Patients With Potentially Resectable Disease Not yet Resected ==
For most patients with potentially [[Resection|resectable]] gastric cancer, [[neoadjuvant therapy]] is preferred over initial [[surgery]].


One option is to administer three cycles prior to resection and then three cycles after surgery, as was actually done in the MAGIC trial; however, some clinicians attempt to administer all six courses preoperatively because several trials indicate that the chance of delivering all planned postoperative therapy is only approximately 37 to 60 percent [8,9,55].  
===== '''Neoadjuvant/perioperative chemotherapy''' =====
* [[Neoadjuvant chemotherapy]] may be administered in locally advanced [[tumors]] before [[surgery]].
* This approach has been applied to [[patients]] thought to have resectable [[disease]] as well as to those with apparently unresectable but non-[[metastatic disease]].
* Another benefit of [[neoadjuvant chemotherapy]] is that patients who are at high risk of developing distant [[metastases]] may be spared the [[morbidity]] of unnecessary [[gastrectomy]] if evidence of distant [[metastases]] emerges after [[chemotherapy]].
* Preoperative combined [[chemotherapy]] and [[radiation therapy]] is more commonly used for [[esophageal]], esophagogastric junction [[cancers]], and [[cancer]] affecting the [[gastric]] [[cardia]] rather than for potentially [[Resection|resectable]] [[Adenocarcinoma|adenocarcinomas]]
* The response rates ranging from 20 percent to 30 percent, and 70 percent to 78 percent were able to undergo an R0 resection after chemoradiotherapy.<ref name="pmid152540452">{{cite journal| author=Ajani JA, Mansfield PF, Janjan N, Morris J, Pisters PW, Lynch PM et al.| title=Multi-institutional trial of preoperative chemoradiotherapy in patients with potentially resectable gastric carcinoma. | journal=J Clin Oncol | year= 2004 | volume= 22 | issue= 14 | pages= 2774-80 | pmid=15254045 | doi=10.1200/JCO.2004.01.015 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15254045  }}</ref>


'''FLOT''' 
==== '''Choice of regimen and patient selection''' ====
* The best [[chemotherapy]] regimen for use in the [[neoadjuvant]] setting has not been conclusively established.
* FLOT regimen is indicated for [[neoadjuvant therapy]], rather than an [[epirubicin]]-containing regimen.


A regimen that includes docetaxel (50 mg/m<sup>2</sup>) plus oxaliplatin (85 mg/m<sup>2</sup>) and LV (200 mg/m<sup>2</sup>) with short-term infusional FU (2600 mg/m<sup>2</sup> as a 24-hour infusion), all on day 1 and administered every two weeks (the FLOT regimen), is also active in the neoadjuvant setting.
==== '''FLOT''' regimen ====
 
* A regimen includes [[docetaxel]] and [[leucovorin]] with short-term infusional [[fluorouracil]], administered every two weeks.
The phase II/III FLOT4-AIO trial compared the docetaxel-based triplet FLOT regimen described above (four preoperative and four postoperative two-week cycles) with epirubicin-based triplet therapy (three preoperative and three postoperative three-week cycles of epirubicin [50 mg/m<sup>2</sup>] and cisplatin [60 mg/m<sup>2</sup>], both on day 1, and either FU 200 mg/m<sup>2</sup> daily as a continuous infusion days 1 to 21 [ECF] or capecitabine 1250 mg/m<sup>2</sup>orally, daily days 1 to 21 [ECX]) [58]. In a report of the 300 patients with gastric or EGJ adenocarcinoma who were enrolled in the open-label phase II part of the trial, The FLOT regimen was associated with a higher pathologic complete response rate (16 versus 8 percent), and toxicity appeared generally more favorable. At least one serious adverse event involving a perioperative medical or surgical complication developed in 25 versus 40 percent of the patients in the FLOT and ECF/ECX groups, respectively, and there was less grade 3 or 4 nausea (9 versus 17 percent), fatigue (9 versus 14 percent), and vomiting (3 versus 10 percent). However, rates of grade 3 or 4 neutropenia were higher with FLOT (52 versus 38 percent).  
* Four preoperative and four postoperative cycles (each lasting two weeks) with [[epirubicin]]-based triplet therapy (three preoperative and three postoperative cycles of [[epirubicin]] [50 mg/m<sup>2</sup>] and [[cisplatin]] [60 mg/m<sup>2</sup>], both on day1.<ref name="pmid27776843">{{cite journal| author=Al-Batran SE, Hofheinz RD, Pauligk C, Kopp HG, Haag GM, Luley KB et al.| title=Histopathological regression after neoadjuvant docetaxel, oxaliplatin, fluorouracil, and leucovorin versus epirubicin, cisplatin, and fluorouracil or capecitabine in patients with resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4-AIO): results from the phase 2 part of a multicentre, open-label, randomised phase 2/3 trial. | journal=Lancet Oncol | year= 2016 | volume= 17 | issue= 12 | pages= 1697-1708 | pmid=27776843 | doi=10.1016/S1470-2045(16)30531-9 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27776843  }}</ref>
 
* The [[FLOT1|FLOT]] regimen is associated with a higher response rate (16 percent versus 8 percent), and has less toxicity which generally makes it more favorable.<ref name="pmid23307258">{{cite journal| author=Anter AH, Abdel-Latif RM| title=The safety and efficacy of fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) combination in the front-line treatment for patients with advanced gastric or gastroesophageal adenocarcinoma: phase II trial. | journal=Med Oncol | year= 2013 | volume= 30 | issue= 1 | pages= 451 | pmid=23307258 | doi=10.1007/s12032-012-0451-1 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23307258  }}</ref>
Preoperative combined chemotherapy and radiation therapy (RT) is more commonly used for esophageal, EGJ, and gastric cardia cancers than for potentially resectable noncardia gastric adenocarcinomas
 
There are no randomized trials addressing the benefit of preoperative chemoradiotherapy for noncardia gastric cancers. In three separate phase II studies using different chemoradiotherapy protocols, the pathologic complete response rates ranged from 20 to 30 percent, and 70 to 78 percent were able to undergo an R0 resection after chemoradiotherapy [60-62]. Whether these results are better than could be achieved with surgery alone, neoadjuvant chemotherapy, or surgery followed by adjuvant chemoradiotherapy is unclear.
 
The use of induction chemoradiotherapy for patients with initially unresectable gastric cancer is discussed below.  
 
'''LOCALLY UNRESECTABLE NONMETASTATIC DISEASE'''
* The best way to manage locally advanced, initially unresectable disease is not established. Options for anticancer therapy include chemotherapy alone or chemoradiotherapy:
* Unresectable locally advanced gastric cancer is often treated primarily with chemotherapy, using the same regimens as are used for metastatic disease.  
* Initial chemotherapy treatment may render some patients resectable.  
* use of preoperative chemotherapy for patients with locally advanced gastric cancer without distant metastases [65-68].  
* response rates are low, between 5 and 15 percent [68].
* preoperative combined modality therapy (chemoradiotherapy with or without induction chemotherapy), approximately 70 percent of patients with localized but initially unresectable gastric cancer can undergo potentially curative resection [60-62,69-71].
 
== locally advanced unresectable and metastatic ==
'''First-line chemotherapy''' 
 
Goals of chemotherapy include palliation of symptoms, improvement in quality of life, and prolongation of survival.
 
there is no consensus as to the best agent or regimen.
 
combination chemotherapy regimens provide higher response rates than do single agents
 
Patients with advanced gastric or esophageal adenocarcinoma who are potential candidates for trastuzumab should have their tumors assayed for the presence of human epidermal growth factor receptor 2 (HER2) overexpression utilizing tumor-specific criteria and/or gene amplification.
 
'''ineligibility criteria in the NSABP B-31 and NCCTG N9831 adjuvant trastuzumab trials'''
{| class="wikitable"
{| class="wikitable"
|Angina pectoris requiring antianginal medication
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Drug
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Dose
|-
|-
|Arrhythmia requiring medication
|[[Oxaliplatin]]
|85 mg/m2 [[Intravenous therapy|IV]]
|-
|-
|Severe conduction abnormality
|[[Leucovorin]]
|400 mg/m2 [[Intravenous therapy|IV]]
|-
|-
|Clinically significant valvular heart disease
|[[Fluorouracil]]
|2600 mg/m<sup>2</sup> as a 24-hour [[infusion]]
|-
|-
|Cardiomegaly on chest radiography
|[[Docetaxel]] 
|50 mg/m<sup>2</sup>
|}
 
==== '''ECF/ECX regimens''' ====
* One option is to administer three cycles prior to resection and then three cycles after surgery.
* Some clinicians attempt to administer all six courses preoperatively.<ref name="pmid22226517">{{cite journal| author=Bang YJ, Kim YW, Yang HK, Chung HC, Park YK, Lee KH et al.| title=Adjuvant capecitabine and oxaliplatin for gastric cancer after D2 gastrectomy (CLASSIC): a phase 3 open-label, randomised controlled trial. | journal=Lancet | year= 2012 | volume= 379 | issue= 9813 | pages= 315-21 | pmid=22226517 | doi=10.1016/S0140-6736(11)61873-4 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22226517  }}</ref>
 
==== Epirubicin, cisplatin, and capecitabine (ECX) regimen ====
{| class="wikitable"
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Drug
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Dose
|-
|-
|Left ventricular hypertrophy on echocardiogram (NSABP B-31  only)
|'''[[Epirubicin]]'''
|50 mg/m<sup>2</sup> [[Intravenous therapy|IV]]
|-
|-
|Poorly controlled hypertension
|'''[[Cisplatin]]'''
|60 mg/m<sup>2</sup> [[Intravenous|IV]]
|-
|-
|Clinically significant pericardial effusion (NCCTG trial  N9831 only)
|'''[[Capecitabine]]'''
|625 mg/m<sup>2</sup> per dose by mouth.
|}
 
==== Epirubicin, cisplatin, and fluorouracil (ECF) regimen ====
{| class="wikitable"
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Drug
! align="center" style="background:#4479BA; color: #FFFFFF;" + |Dose
|-
|-
|History of myocardial infarction, heart failure, or  cardiomyopathy
|[[Epirubicin]]
|50 mg/m<sup>2</sup> [[Intravenous|IV]]
|-
|-
|LVEF below the lower limit of normal
|[[Cisplatin]]
|60 mg/m<sup>2</sup> [[Intravenous|IV]]
|-
|[[Fluorouracil]] (FU)
|200  mg/m<sup>2</sup> per day [[Intravenous|IV]]
|}
|}
Acceptable option include cisplatin plus fluorouracil (FU) cisplatin plus capecitabine, oxaliplatin plus leucovorin and short-term infusional FU (FOLFOX), or oxaliplatin plus capecitabine (XELOX/CAPOX
Patients who are receiving a capecitabine-containing regimen should probably not take proton pump inhibitors concurrently. Concerns have been raised that higher gastric pH levels may inhibit dissolution and absorption of capecitabine, adversely impacting efficacy.
the choice of chemotherapy regimen is empiric.
fluoropyrimidine-containing doublet combination regimen, rather than a triplet regimen
For most patients, we prefer a fluoropyrimidine plus oxaliplatin.


Another option is the triplet combination of a fluoropyrimidine plus oxaliplatin and docetaxel
==== Patients monitoring ====
* [[Complete blood count|CBC]] and [[platelet count]] one day before every treatment cycle
* [[Creatinine]] and [[liver function tests]] once before treatment cycles
* Monitor for [[hearing loss]] prior to each dose of [[cisplatin]]
* Monitor [[epirubicin]] dose
* Reassess [[left ventricular ejection fraction]]


'''Later lines of therapy''' 
== Locally Unresectable Metastatic Disease ==
* Options for anticancer therapy include [[chemotherapy]] alone or chemoradiotherapy.
* Unresectable locally advanced [[gastric cancer]] is treated primarily with [[chemotherapy]], using the same regimens as are used for [[metastatic disease]].
* Initial [[chemotherapy]] treatment may transform a previously unresectale [[tumor]] to a resectable [[tumor]].
* Almost 70 percent of [[patients]] with localized but initially unresectable [[gastric cancer]] can undergo potentially curative resection with preoperative [[chemotherapy]] for patients with locally advanced [[gastric cancer]] without distant [[Metastasis|metastases]].<ref name="pmid10674448">{{cite journal| author=Gallardo-Rincón D, Oñate-Ocaña LF, Calderillo-Ruiz G| title=Neoadjuvant chemotherapy with P-ELF (cisplatin, etoposide, leucovorin, 5-fluorouracil) followed by radical resection in patients with initially unresectable gastric adenocarcinoma: a phase II study. | journal=Ann Surg Oncol | year= 2000 | volume= 7 | issue= 1 | pages= 45-50 | pmid=10674448 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10674448  }}</ref><ref name="pmid15254045">{{cite journal| author=Ajani JA, Mansfield PF, Janjan N, Morris J, Pisters PW, Lynch PM et al.| title=Multi-institutional trial of preoperative chemoradiotherapy in patients with potentially resectable gastric carcinoma. | journal=J Clin Oncol | year= 2004 | volume= 22 | issue= 14 | pages= 2774-80 | pmid=15254045 | doi=10.1200/JCO.2004.01.015 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15254045  }}</ref>
* Response rates are low between 5 and 15%.<ref name="pmid19644974">{{cite journal| author=Yoshikawa T, Sasako M, Yamamoto S, Sano T, Imamura H, Fujitani K et al.| title=Phase II study of neoadjuvant chemotherapy and extended surgery for locally advanced gastric cancer. | journal=Br J Surg | year= 2009 | volume= 96 | issue= 9 | pages= 1015-22 | pmid=19644974 | doi=10.1002/bjs.6665 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19644974  }}</ref>


suggest ramucirumab plus paclitaxel ('''Grade 2A''').
== Locally Advanced Unresectable And Metastatic ==


For patients with squamous cell cancer (SCC) who have disease progression on or after prior treatment with fluoropyrimidine or platinum-containing chemotherapy,  
===== '''First-line chemotherapy''' =====
* Goals of [[chemotherapy]] include [[palliation]] of [[symptoms]], improvement in [[quality of life]], and prolongation of survival. <ref name="pmid19644974">{{cite journal |vauthors=Yoshikawa T, Sasako M, Yamamoto S, Sano T, Imamura H, Fujitani K, Oshita H, Ito S, Kawashima Y, Fukushima N |title=Phase II study of neoadjuvant chemotherapy and extended surgery for locally advanced gastric cancer |journal=Br J Surg |volume=96 |issue=9 |pages=1015–22 |date=September 2009 |pmid=19644974 |doi=10.1002/bjs.6665 |url=}}</ref>


for those for whom limiting treatment-related toxicity is an important goal, we suggest monotherapy rather than combination chemotherapy ('''Grade 2C''').
* Combination [[chemotherapy]] regimens provide higher response rates than do single agents.<ref name="pmid9142380">{{cite journal |vauthors=Nakajima T, Ota K, Ishihara S, Oyama S, Nishi M, Ohashi Y, Yanagisawa A |title=Combined intensive chemotherapy and radical surgery for incurable gastric cancer |journal=Ann. Surg. Oncol. |volume=4 |issue=3 |pages=203–8 |date=1997 |pmid=9142380 |doi= |url=}}</ref>
 
*<nowiki/>[[Patients]] with the presence of [[Epidermal growth factor|human epidermal growth factor]] receptor 2 ([[HER2]]) overexpression are potential candidates for [[Trastuzumab|trastuzumab.]]
irinotecan
 
 weekly paclitaxel
 
weekly nanoparticle albumin-bound paclitaxel nabpaclitaxel
 
ramucirumab monotherapy
 
==Targeted therapy==
Targeted therapy is a type of treatment that uses drugs or other substances to identify and attack specific cancer cells without harming normal cells. [[Monoclonal antibody]] therapy is a type of targeted therapy used in the treatment of gastric cancer.
 
Monoclonal antibody therapy uses antibodies made in the laboratory from a single type of [[immune system]] cell. These antibodies can identify substances on cancer cells or normal substances that may help cancer cells grow. The antibodies attach to the substances and kill the cancer cells, block their growth, or keep them from spreading. Monoclonal antibodies are given by infusion. They may be used alone or to carry drugs, [[toxins]], or [[radioactive]] material directly to cancer cells. For stage IV gastric cancer and gastric cancer that has recurred, a monoclonal antibody such as [[trastuzumab]] may be given to block the effect of the growth factor protein [[HER2]], which sends growth signals to gastric cancer cells.<ref>http://www.cancer.gov/types/stomach/patient/stomach-treatment-pdq#section/_50</ref>


==References==
==References==
{{Reflist|2}}
{{Reflist|2}}
[[Category:Disease]]
[[Category:Types of cancer]]
[[Category:Conditions diagnosed by stool test]]
[[Category:Primary care]]
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Latest revision as of 18:09, 25 January 2019


Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Parminder Dhingra, M.D. [2] Mohammed Abdelwahed M.D[3]

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Overview

The optimal therapy for stomach cancer depends on the stage at diagnosis. Medical therapy is indicated for patients with unresectable or recurrent disease, after non-curative R2 resection (macroscopic tumor removal), patients with unresectable T4b disease, extensive nodal disease, hepatic metastases, peritoneal dissemination or other M1 disease. Response to the treatment should be evaluated by examinations such as CT scan, endoscopy and contrast radiography. Adjuvant therapy includes one cycle of fluorouracil (425 mg/m2 of body surface area) plus leucovorin calcium (20 mg/m2 of body surface area) for five days followed by radiation therapy for one month given with the same chemotherapy regimen on days 1 through 4 and the last three days of the month. For patients with potientially resectable disease not yet resected, neoadjuvant chemotherapy is preferred over initial surgery. Another benefit of neoadjuvant chemotherapy is that patients who are at high risk of developing distant metastases may be spared the morbidity of unnecessary gastrectomy if evidence of distant metastases emerges after chemotherapy. Preoperative combined chemotherapy and radiation therapy is more commonly used for esophageal, esophagogastric junction cancers, and cancer affecting the gastric cardia rather than for potentially resectable adenocarcinomas. For locally advanced unresectable and metastatic tumors, goals of chemotherapy include palliation of symptoms, improvement in quality of life, and prolongation of survival. Patients with the presence of human epidermal growth factor receptor 2 (HER2) overexpression are potential candidates for trastuzumab

Medical Therapy

  • Response to the treatment should be evaluated by examinations such as CT scan, endoscopy and contrast radiography, followed by comparison with the baseline data.
  • Tumor shrinkage should be evaluated by response criteria of the Japanese Classification of Gastric Carcinoma or Response Evaluation Criteria to decide to continue with the treatment or not.
  • When continuation of the treatment is deemed oncologically feasible, the drug dosage and administration schedule should be reconsidered taking into account the adverse events observed in the previous cycle of treatment.
  • Attention should also be paid to cumulative adverse events such as skin manifestations, taste disturbance and neurotoxicity.
  • Chemotherapy for individuals exposed or infected with hepatitis B virus should be screened, monitored, and treated.
  • These drugs are to be used alone or in combination, adhering to the dose and schedule employed when being evaluated in clinical trials.

Drugs used in chemotherapy for gastric cancer

The following drugs may be used as chemotherapy for the treatment of gastric cancer:[1]

Postoperative Adjuvant Chemotherapy

  • Postoperative adjuvant chemotherapy is indicated to reduce recurrence by controlling residual tumor cells following curative resection.
  • Adjuvant treatment would be recommended for any T stage with N1 disease. However, AJCC staging system recommends observation for T2N0 stage IB patients as long as they have undergone an adequate lymph node dissection.
  • S-1 efficay was proven in the ACTS-GC trial, a study that secured the place of postoperative chemotherapy with S-1 as a standard of care.[2]
  • Another trial in Korea showed significant prolongation of recurrence-free survival with a combination of capecitabine and oxaliplatin.[3]
  • The patients eligible for the ACTS-GC trial were those with a tumor of pathological stage II, IIIA or IIIB, excluding those classified as stage II due to T1, N2, N3 status.

Patients Who Have Already Undergone Potentially Curative Resection

Preferred regimen (standard protocol):

Japanese S-1 trial:

  • S-1 is approved in Japan for adjuvant therapy of gastric cancer and in Europe for treatment of advanced gastric cancer.[7]
  • S-1 is an oral fluoropyrimidine that includes three different agents:[8]
  • Ftorafur
  • Gimeracil
  • Oteracil (responsible for treatment-related diarrhea)

Patients With Potentially Resectable Disease Not yet Resected

For most patients with potentially resectable gastric cancer, neoadjuvant therapy is preferred over initial surgery.

Neoadjuvant/perioperative chemotherapy 

Choice of regimen and patient selection

FLOT regimen

  • A regimen includes docetaxel and leucovorin with short-term infusional fluorouracil, administered every two weeks.
  • Four preoperative and four postoperative cycles (each lasting two weeks) with epirubicin-based triplet therapy (three preoperative and three postoperative cycles of epirubicin [50 mg/m2] and cisplatin [60 mg/m2], both on day1.[12]
  • The FLOT regimen is associated with a higher response rate (16 percent versus 8 percent), and has less toxicity which generally makes it more favorable.[13]
Drug Dose
Oxaliplatin 85 mg/m2 IV
Leucovorin 400 mg/m2 IV
Fluorouracil 2600 mg/m2 as a 24-hour infusion
Docetaxel  50 mg/m2

ECF/ECX regimens

  • One option is to administer three cycles prior to resection and then three cycles after surgery.
  • Some clinicians attempt to administer all six courses preoperatively.[14]

Epirubicin, cisplatin, and capecitabine (ECX) regimen

Drug Dose
Epirubicin 50 mg/m2 IV
Cisplatin 60 mg/m2 IV
Capecitabine 625 mg/m2 per dose by mouth.

Epirubicin, cisplatin, and fluorouracil (ECF) regimen

Drug Dose
Epirubicin 50 mg/m2 IV
Cisplatin 60 mg/m2 IV
Fluorouracil (FU) 200 mg/m2 per day IV

Patients monitoring

Locally Unresectable Metastatic Disease

Locally Advanced Unresectable And Metastatic

First-line chemotherapy

References

  1. ↑ http://www.cancer.gov/types/stomach/patient/stomach-treatment-pdq#section/_50
  2. ↑ Sakuramoto S, Sasako M, Yamaguchi T, Kinoshita T, Fujii M, Nashimoto A; et al. (2007). "Adjuvant chemotherapy for gastric cancer with S-1, an oral fluoropyrimidine". N Engl J Med. 357 (18): 1810–20. doi:10.1056/NEJMoa072252. PMID 17978289.
  3. ↑ Noh SH, Park SR, Yang HK, Chung HC, Chung IJ, Kim SW; et al. (2014). "Adjuvant capecitabine plus oxaliplatin for gastric cancer after D2 gastrectomy (CLASSIC): 5-year follow-up of an open-label, randomised phase 3 trial". Lancet Oncol. 15 (12): 1389–96. doi:10.1016/S1470-2045(14)70473-5. PMID 25439693.
  4. ↑ Kodera Y, Ishiyama A, Yoshikawa T, Kinoshita T, Ito S, Yokoyama H; et al. (2010). "A feasibility study of postoperative chemotherapy with S-1 and cisplatin (CDDP) for gastric carcinoma (CCOG0703)". Gastric Cancer. 13 (3): 197–203. doi:10.1007/s10120-010-0559-y. PMID 20820990.
  5. ↑ Macdonald JS, Smalley SR, Benedetti J, Hundahl SA, Estes NC, Stemmermann GN; et al. (2001). "Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction". N Engl J Med. 345 (10): 725–30. doi:10.1056/NEJMoa010187. PMID 11547741.
  6. ↑ O'Connell MJ, Martenson JA, Wieand HS, Krook JE, Macdonald JS, Haller DG; et al. (1994). "Improving adjuvant therapy for rectal cancer by combining protracted-infusion fluorouracil with radiation therapy after curative surgery". N Engl J Med. 331 (8): 502–7. doi:10.1056/NEJM199408253310803. PMID 8041415.
  7. ↑ Wagner AD, Syn NL, Moehler M, Grothe W, Yong WP, Tai BC; et al. (2017). "Chemotherapy for advanced gastric cancer". Cochrane Database Syst Rev. 8: CD004064. doi:10.1002/14651858.CD004064.pub4. PMID 28850174.
  8. ↑ Sasako M, Sakuramoto S, Katai H, Kinoshita T, Furukawa H, Yamaguchi T; et al. (2011). "Five-year outcomes of a randomized phase III trial comparing adjuvant chemotherapy with S-1 versus surgery alone in stage II or III gastric cancer". J Clin Oncol. 29 (33): 4387–93. doi:10.1200/JCO.2011.36.5908. PMID 22010012.
  9. ↑ Smalley SR, Benedetti JK, Haller DG, Hundahl SA, Estes NC, Ajani JA; et al. (2012). "Updated analysis of SWOG-directed intergroup study 0116: a phase III trial of adjuvant radiochemotherapy versus observation after curative gastric cancer resection". J Clin Oncol. 30 (19): 2327–33. doi:10.1200/JCO.2011.36.7136. PMC 4517071. PMID 22585691.
  10. ↑ Ilson DH (2017). "Current Progress in the Adjuvant Treatment of Gastric Cancer". Surg Oncol Clin N Am. 26 (2): 225–239. doi:10.1016/j.soc.2016.10.008. PMID 28279466.
  11. ↑ Ajani JA, Mansfield PF, Janjan N, Morris J, Pisters PW, Lynch PM; et al. (2004). "Multi-institutional trial of preoperative chemoradiotherapy in patients with potentially resectable gastric carcinoma". J Clin Oncol. 22 (14): 2774–80. doi:10.1200/JCO.2004.01.015. PMID 15254045.
  12. ↑ Al-Batran SE, Hofheinz RD, Pauligk C, Kopp HG, Haag GM, Luley KB; et al. (2016). "Histopathological regression after neoadjuvant docetaxel, oxaliplatin, fluorouracil, and leucovorin versus epirubicin, cisplatin, and fluorouracil or capecitabine in patients with resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4-AIO): results from the phase 2 part of a multicentre, open-label, randomised phase 2/3 trial". Lancet Oncol. 17 (12): 1697–1708. doi:10.1016/S1470-2045(16)30531-9. PMID 27776843.
  13. ↑ Anter AH, Abdel-Latif RM (2013). "The safety and efficacy of fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) combination in the front-line treatment for patients with advanced gastric or gastroesophageal adenocarcinoma: phase II trial". Med Oncol. 30 (1): 451. doi:10.1007/s12032-012-0451-1. PMID 23307258.
  14. ↑ Bang YJ, Kim YW, Yang HK, Chung HC, Park YK, Lee KH; et al. (2012). "Adjuvant capecitabine and oxaliplatin for gastric cancer after D2 gastrectomy (CLASSIC): a phase 3 open-label, randomised controlled trial". Lancet. 379 (9813): 315–21. doi:10.1016/S0140-6736(11)61873-4. PMID 22226517.
  15. ↑ Gallardo-Rincón D, Oñate-Ocaña LF, Calderillo-Ruiz G (2000). "Neoadjuvant chemotherapy with P-ELF (cisplatin, etoposide, leucovorin, 5-fluorouracil) followed by radical resection in patients with initially unresectable gastric adenocarcinoma: a phase II study". Ann Surg Oncol. 7 (1): 45–50. PMID 10674448.
  16. ↑ Ajani JA, Mansfield PF, Janjan N, Morris J, Pisters PW, Lynch PM; et al. (2004). "Multi-institutional trial of preoperative chemoradiotherapy in patients with potentially resectable gastric carcinoma". J Clin Oncol. 22 (14): 2774–80. doi:10.1200/JCO.2004.01.015. PMID 15254045.
  17. ↑ 17.0 17.1 Yoshikawa T, Sasako M, Yamamoto S, Sano T, Imamura H, Fujitani K; et al. (2009). "Phase II study of neoadjuvant chemotherapy and extended surgery for locally advanced gastric cancer". Br J Surg. 96 (9): 1015–22. doi:10.1002/bjs.6665. PMID 19644974.
  18. ↑ Nakajima T, Ota K, Ishihara S, Oyama S, Nishi M, Ohashi Y, Yanagisawa A (1997). "Combined intensive chemotherapy and radical surgery for incurable gastric cancer". Ann. Surg. Oncol. 4 (3): 203–8. PMID 9142380.

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