Moehler M, Galle PR, Gockel I, et al. The multidisciplinary management of gastrointestinal cancer. Multimodal treatment of gastric cancer. Best Pract Res Clin Gastroenterol. 2007;21(6):965-981.

Pinto C, Di Fabio F, Siena S, et al. Phase II study of cetuximab in combination with FOLFIRI in patients with untreated advanced gastric or gastroesophageal junction adenocarcinoma (FOLCETUX study). Ann Oncol. 2007;18(3):510-517.

J.A.Chan et al, A multicenter phase II trial of single-agent cetuximab in advanced esophageal and gastric adenocarcinoma

Iqbal et al showed that Tykerb is an effective first line drug. The evidence thus far suggests that the combination of lapatinib + capecitabine shows promising efficacy and is well tolerated as 1st line treatment for advanced GC(Pishvaian et al). The same appears to be true of paclitaxel and lapatinib and studies of this combination are ongoing.

A number of issues remain to study: the type of combination therapy, the role of Taykeb in patients previousely treated with Herceptin, and efficacy in brain mets of patients with gastric cancer.

 S. Iqbal et al, Southwest Oncology Group study S0413: a phase II trial of lapatinib (GW572016) as first-line therapy in patients with advanced or metastatic gastric cancer Ann Oncol (2011) 22 (12): 2610-2615

Power, D. G., Kelsen, D. P & Shah, M. A. Advanced gastric cancer—slow but steady progress. Cancer Treat. Rev. 36, 384-392 (2010).

Ku, G. Y. & Ilson, D. H. Esophagogastric cancer: targeted agents. Cancer Treat. Rev. 36, 235-248 (2010).

Grothey, A. EGFR antibodies in colorectal cancer: where do they belong? J. Clin. Oncol. 28, 4668-4670 (2010).

M. Pishvaian, D. Sakaeva, R. K. Hsieh, S. Y. Rha, G. Caderillo-Ruiz, W. H. Miller Jr., A. M. Kemner, Y. M. Nagarwala, W. Zhang, H. Lenz; Georgetown University Medical Center, Washington, DC; Clinical Oncology Dispensary of the Republic of Bashkortostan, Ufa, Russia; Mackay Memorial Hospital, Taipei, Taiwan; Yonsei Cancer Center, Cancer Metastasis Research Center, Yonsei University College of Medicine, Seoul, South Korea; Deparment of Medical Oncology, Instituto Nacional de Cancerologia, Tlalpan, Mexico; Lady Davis Institute, Jewish General Hospital, McGill University, Montreal, QC, Canada; GlaxoSmithKline, Collegeville, PA; University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA  A global, multicenter phase II trial of lapatinib plus capecitabine in gastric cancer. J Clin Oncol 29: 2011 (suppl 4; abstr 88)

Lin NU, Diéras V, Paul D, Lossignol D, Christodoulou C, Stemmler HJ, Roché H, Liu MC, Greil R, Ciruelos E, Loibl S, Gori S, Wardley A, Yardley D, Brufsky A, Blum JL, Rubin SD, Dharan B, Steplewski K, Zembryki D, Oliva C, Roychowdhury D, Paoletti P, Winer EP. Multicenter phase II study of lapatinib in patients with brain metastases from HER2-positive breast cancer. Clin Cancer Res. 2009 Feb 15;15(4):1452-9.

For Lay versions see here

The approach of postoperative chemoirradiation with 5Fu is standard at this time. NCCN lists post chemoradiation chemotherapy as an option with ECF (epirubicin, cisplatin FU), only when ECG was administered preop as well. The Canadian Guidelines are more restrictive: “There is insufficient evidence from randomized trials to recommend neoadjuvant chemotherapy, or neoadjuvant or adjuvant radiation therapy or immunotherapy, either alone or in combination, outside of a clinical trial.”

Thus, postoperative chemoradiation is standard with 5FU but postoperative chemotherapy, unless performed exactly as in the MAGI study is not. The adjuvant chemo in other forms, irrespective of the actual agents used should be considered experimental since the strategy it is actively in trials.

To round off this discussion, it is worth it to mention that the plenary session at ASCO 2012 has reported the phase III CLASSIC study of the Xeliri regimen without radiation as adjuvant therapy. The XELOX and observation arms (ITT populations of 520 and 515 patients, respectively) were well balanced for baseline characteristics. This study showed the superior efficacy of adjuvant XELOX vs observation alone following D2 gastrectomy. Although OS data are still immature, there is a trend towards superiority of XELOX. The presenters concluded that these data support the use of adjuvant XELOX for GC but NCCN ahs not yet incorporated this result. There remains as well uncertainty as to whether they are applicable to a non-Asian population.

in Japan, standard adjuvant treatment is single-agent postoperative chemotherapy with the oral fluoropyrimidine S-1 after D2 surgery based on results of the ACTS-GC trial but this drug is not FDA approved in the USA.

Gastrointestinal Cancer Disease Site Group. Earle CC, Maroun J, Zuraw L. Neoadjuvant or adjuvant therapy for resectable gastric cancer [full report]. Toronto (ON): Cancer Care Ontario (CCO); 2003 May 21 [online update]. 21 p. (Practice guideline; no. 2-14). [79 references]

NCCN.org – GAST-4, gasric cancer

Benefit of Adjuvant Chemotherapy for Resectable Gastric Cancer A Meta-analysis JAMA. 2010;303(17):1729-1737

Fuchs CS, Tepper JE, Niedzwiecke D, et al. Postoperative adjuvant chemoradiation for gastric or gastroesophageal junction (GEJ) adenocarcinoma using epirubicin, cisplatin, and infusional (CI) 5-FU (ECF) before and after CI 5-FU and radiotherapy (CRT) compared with bolus 5-FU/LV before and after CRT: Intergroup trial CALGB 80101 (abstract 4003). J Clin Oncol 2011; 29:256s.

Takaki Yoshikawa & Mitsuru Sasako Gastrointestinal cancer: Adjuvant chemotherapy after D2 gastrectomy for gastric cancer Nature Reviews Clinical Oncology 9, 192-194 (April 2012)

Jochen K. Lennerz, Eunice L. Kwak, Allison Ackerman, Michael Michael, Stephen B. Fox, Kristin Bergethon, Gregory Y. Lauwers, James G. Christensen, Keith D. Wilner, Daniel MET Amplification Identifies a Small and Aggressive Subgroup of Esophagogastric Adenocarcinoma With Evidence of Responsiveness to Crizotinib, JCO VOLUME 29
NUMBER 36
DECEMBER 20 2011

Ajani JA: Gastroesophageal cancers: Progress and problems. J Natl Compr Canc Netw 6:813-814, 2008

nccn.org, Gastric cancer 2012

Chemotherapy is indicated for patients with unresectable tumor with good performance status. Standard regimens of chemotherapy for late stage cancer are not yet established, although combination chemotherapy with cisplatin (CDDP), and 5 fluorouracil ( 5FU) or its derivates may be the regimen of preference and recommendation. A number of controlled studies of two-drug combination chemotherapies, especially cisplatin-containing regimens, have shown a significant improvement in median survival and quality of life compared with best supportive care. Of these, 5-FU and cisplatin combination (FP) has been considered an active and safe regimen for a long time. More recently drugs such as paclitaxel, docetaxel, oxaliplatin and irinotecan have been added in various trials.
Many trials using combinations of three drugs have been conducted to improve treatment results further in advanced gastric cancer. One of the three-drug combination is adding docetaxel, to ‘5-FU + cisplatin’ (DCF). A randomized phase II comparison of ECF, DC, and DCF had been conducted. The DCF regimen consisted of a 21-day continuous-infusion FU schedule (similar to ECF) and a higher dose of docetaxel (85 mg/m2) compared with a shorter 5-day infusion of FU and a lower dose of docetaxel (75 mg/m2). Although comparisons are again limited by the phase II trial design, QOL analysis using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 indicated improvement in QOL scores for patients receiving ECF and stable QOL scores on both of the docetaxel arms. DCF resulted in detrimental QOL effects of weight loss and decline in role functioning during therapy, which were likely a consequence of the severity of toxicity. The authors declare DCF to be the superior regimen based on a higher response rate compared with DC, although both regimens had similar overall survival. Ajani et al also opted to select DCF over DC for the V325 trial, despite comparable rates of antitumor response rate, time to progression, and overall survival for DC compared with DCF and despite greater rates of GI toxicity for DCF. It appears to be the mi\ost effective, albeit a toxic regimen.
DCF is listed by NCCN.

D.-Y. Oh, T.-Y. Kim, J. H. Kwon, J.-J. Lee, Y. Joh, D.-W. Kim, T.-Y. Kim, D. S. Heo, Y.-J. Bang, and N. K. Kim Docetaxel + 5-Fluorouracil + Cisplatin 3-day Combination Chemotherapy as a First-line Treatment in Patients with Unresectable Gastric Cancer
Jpn. J. Clin. Oncol., July 1, 2005; 35(7): 380 – 385.

NCCN, Gast-12, 2

Eric D Tetzlaff et al, Review of docetaxel in the treatment of gastric cancer Ther Clin Risk Manag. 2008 October; 4(5): 999–1007.

Ajani JA, Moiseyenko VM, Tjulandin S, et al. Clinical benefit with docetaxel plus fluorouracil and cisplatin compared with cisplatin and fluorouracil in a phase III trial of advanced gastric or gastroesophageal cancer adenocarcinoma: the V-325 Study Group. J Clin Oncol. 2007b;25:3205–9.

Ajani JA, Phan A, Ho L, et al. Phase I/II trial of docetaxel plus oxaliplatin and 5-fluorouracil (D-FOX) in patients with untreated, advanced gastric or gastroesophageal cancer. J Clin Oncol (Meeting Abstracts) 2007;25(18_suppl):4612.

Ajani J, Bekaii-Saab T, D’Amico TA, Fuchs C, Gibson MK, Goldberg M, Hayman JA, Ilson DH, Javle M, Kelley S, Kurtz RC, Locker GY, Meropol NJ, Minsky BD, Orringer MB, Osarogiagbon RU, Posey JA, Roth J, Sasson AR, Swisher SG, Wood DE, Yen Gastric Cancer Clinical Practice Guidelines.J Natl Compr Canc Netw. 2006 Apr;4(4):350-66.

D.-Y. Oh, T.-Y. Kim, J. H. Kwon, J.-J. Lee, Y. Joh, D.-W. Kim, T.-Y. Kim, D. S. Heo, Y.-J. Bang, and N. K. Kim
Docetaxel + 5-Fluorouracil + Cisplatin 3-day Combination Chemotherapy as a First-line Treatment in Patients with Unresectable Gastric Cancer
Jpn. J. Clin. Oncol., July 1, 2005; 35(7): 380 – 385.

Oxaliplatin based therapy is one of the options listed by NCCN for metastatic gastric cancer. The particular regimens that is being used has been extensively studies in Phase I (2) and III(2)I; there are also studies of capecitabine and oxaliplatin.

A variety of different regimens have been studied in phase II trials (FOLFOX, EOF, XELOX [CAPOX], S1 plus oxaliplatin), all of which are associated with response rates in the range of 40 to 67 percent, with median survival durations between 8 and 15 months.

Uptodate 2015 says: ” For patients who retain an adequate performance status, there is no standard approach for second-line therapy after failure of the first-line regimen.
For other patients (not Cyramza candidates), utilization of other active cytotoxic chemotherapy agents not used in the first-line regimen is reasonable, either in combination or as serial single agents.”

NCCN recommends palliative chemohthrapy on p. GAST-7. Although it only lists Folfox in first line, using the Uptodate recommendation, I consider it to be an appropriate palliative regimen when not having been used in first line.

1.AUAl-Batran SE, Hartmann JT, Probst S, Schmalenberg H, Hollerbach S, Hofheinz R, Rethwisch V, Seipelt G, Homann N, Wilhelm G, Schuch G, Stoehlmacher J, Derigs HG, Hegewisch-Becker S, Grossmann J, Pauligk C, Atmaca A, Bokemeyer C, Knuth A, Jäger E, Arbeitsgemeinschaft Internistische OnkologiePhase III trial in metastatic gastroesophageal adenocarcinoma with fluorouracil, leucovorin plus either oxaliplatin or cisplatin: a study of the Arbeitsgemeinschaft Internistische Onkologie. SOJ Clin Oncol. 2008;26(9):1435.

2.Enzinger PC, Burtness B, Hollis D, et al. CALGB 80403/ECOG 1206: A randomized phase II stidu of three standard chemotherapy regimens (SCF, IC, FOLFOX) plus cetuximab in metastatic esophageal and GE junction cancer (Abstract 4006). J Clin Oncol 2010; 28:302s.

3.Uptodate, http://www.uptodate.com/contents/systemic-therapy-for-locally-advanced-unresectable-and-metastatic-esophageal-and-gastric-cancer, 2015

4.Provincial Gastric and Gastro-Esophageal Junction
Cancer Treatment Guidelines
As per consensus at the Provincial Upper Gastrointestinal Tract Cancers
Guideline Meeting, June 12-13, 2014

The practice of administering chemotherapy before surgery is referred to as neoadjuvant therapy. In theory, neoadjuvant chemotherapy can decrease the size of the cancer, thereby making it easier to remove with surgery. The major problems with this approach are the higher mortality rates that occur when radiation therapy and/or chemotherapy are administered before surgery and the delay of surgery for some patients who do not respond to therapy. In most but not all studies chemotherapy, radiation therapy or both given before surgery have not improved survival following surgery in patients with stage III gastric cancer. This may be related to the ineffectiveness of the drug combinations tested, which include various combination of 5-FU, doxorubicin and methotrexate. Many current clinical trials are directed at improving outcomes of patients with stage III gastric cancer by administering newer neoadjuvant treatment regimens containing taxane chemotherapy and/or radiation therapy.

There is insufficient evidence from randomized trials to recommend neoadjuvant chemotherapy, or neoadjuvant or adjuvant radiation therapy or immunotherapy, either alone or in combination, outside of a clinical trial

Gastrointestinal Cancer Disease Site Group. Earle CC, Maroun J, Zuraw L. Neoadjuvant or adjuvant therapy for resectable gastric cancer [full report]. Toronto (ON): Cancer Care Ontario (CCO); 2003 May 21 [online update]. 21 p. (Practice guideline; no. 2-14). [79 references]
nccn.org, stomach cancer.

Chemoresistance assays are a modification that tests resistance to chemo rather than sensitivity. They work on the assumption that if celss show reesistance to very high concentrations of a drug in vitro, they will also be resistant in vivo to that drug.

Going back years, the article by Schrag et al criticized the field of chemosensitivity and chemo resistance(SRA), concluding that these types of in vitro assays are not yet ready for prime time. The panel of authors attempted to present evidence that in vitro drug response assays should not be used clinically. This issue was first addressed by an exhaustive Medicare Coverage Advisory Committee (MCAC) in 1999. A panel of physicians selected by the Department of Health and Human Services reviewed hundreds of articles from the literature and heard two days of testimony by experts in the field in an open hearing. The panel voted unanimously that although chemosensitivity assays should not be covered, drug resistance assays should be paid for. This became a cause celebre with a vigorous debate in the literature and variant opinions offered by professional bodies. The American Society of Clinical Oncology vigorously objected and recommended: ”
The use of chemotherapy sensitivity and resistance assays to select chemotherapeutic agents for individual patients is not recommended outside of the clinical trial setting. Oncologists should make chemotherapy treatment recommendations on the basis of published reports of clinical trials and a patient’s health status and treatment preferences. Because the in vitro analytic strategy has potential importance, participation in clinical trials evaluating these technologies remains a priority.”  I believe that the So. California branch of ASCO dissented from this recommendation, see http://weisenthal.org/medicareletter.pdf.

The Extreme Drug Resistance Assay (EDR) Assay is a laboratory test performed on a patient’s tumor cells. This lab test is claimed to determine the probability of a tumor’s resistance to a specific chemotherapy drug. If the tumor cells grow in the presence of very high concentrations of chemotherapy drug, then the cancer cells are considered resistant to that drug.

Drug sensitivity and resistance assays have been examined for their potential utility in ovarian cancer by a number of clinical investigators. Unfortunately, analysis of these studies has suffered greatly from the absence of an appropriate control population. The majority of these trials have compared the survival of individuals whose treatment was selected by a particular assay with a historical/retrospective patient group treated at the same institution. A report in the Gynecologic Cancer session described an important attempt by investigators in Europe to directly address the value of the adenosine triphosphate (ATP)-based tumor chemosensitivity assay, by randomizing patients with platinum-resistant ovarian cancer (n = 180) to either “assay-directed therapy” or the treatment of the “physician’s choice”. The objective response rate was 40.5% for the assay-directed group vs 31.5% for the physician’s choice of treatment. Progression-free survival (intention-to-treat analysis) was 104 days in the assay-directed vs 93 days in the physician’s choice groups. In addition, there was no difference in overall survival between the strategies. This study provides support for the conclusion that the ATP-based tumor chemosensitivity assay is not superior to physician’s choice in the selection of chemotherapy in women with platinum-resistant ovarian cancer.Some experts claim that resistance assays are different from chemosensitivity assays and Medicare does cover them. However, this distinction has not been sufficiently demonstrated and most experts vigorously dispute this.

In conclusion, the technologies and the questions that they raise are quite different. It Oncotech Sensitivy testing not yet been  recommended by professional societies and gudielines pending completion of a phase III trial. With Oncotech ER the situation is more uncertain, NCCN says that “current evidence is not sufficient to supplant standard of care chemotherapy”.

More recently in ASCO 2008, researchers affiliated with Precision Therapeutics and Columbia University reported that a test of chemoresponsiveness (ChemoFX®) can predict survival of patients with advanced ovarian cancer. This remains something that must be confirmed by future studies. NCCN says that “chemosensitivity.resistance assays are being used in some NCCN centers”, which I consider something less than an endorsement. This is a level 3 recommendations, which is defined as: “The recommendation is based on any level of evidence but reflects major disagreement.”

Burstein et al (2011) updated the ASCO Technology Assessment guidelines on CSRAs published in 2004.  An Update Working Group reviewed data published between December 1, 2003, and May 31, 2010.  Medline and the Cochrane Library were searched yielding 11,313 new articles.  The limits for “human and English” were used, and then standard ASCO search strings for randomized controlled trials (RCTs), meta-analyses, guidelines, and reviews were added, yielding 1,298 articles for abstract review.  Of these, only 21 articles met pre-defined inclusion criteria and underwent full text review, and 5 reports of RCTs were included for data extraction.  Review of the literature does not identify any CSRAs for which the evidence base is sufficient to support use in oncology practice.  The authors concluded that the use of CSRAs to select chemotherapeutic agents for individual patients is not recommended outside of the clinical trial setting.  They noted that oncologists should make chemotherapy treatment recommendations based on published reports of clinical trials and a patient’s health status and treatment preferences.  Because the in vitro analytic strategy has potential importance, participation in clinical trials evaluating these technologies remains a priority.

Schrag D, Garewal HS, Burstein HJ, et al: American Society of Clinical Oncology technology assessment: Chemotherapy sensitivity and resistance assays. J Clin Oncol 22 : 3631 -3638, 2004

John P. Fruehauf In Vitro Drug Resistance Versus Chemosensitivity: Two Sides of Different Coins Journal of Clinical Oncology, Vol 23, No 15 (May 20), 2005: pp. 3641-3643

P. Hwu, A. Y. Bedikian, and E. A. Grimm
Challenges of chemosensitivity testing.
Clin. Cancer Res., September 15, 2006; 12(18): 5258 – 5259.

Cree IA. Chemosensitivity and chemoresistance testing in ovarian cancer. Curr Opin Obstet Gynecol. 2009;21(1):39-43.

C.Rass K, Hassel JC. Chemotherapeutics, chemoresistance and the management of melanoma. G Ital Dermatol Venereol. 2009;144(1):61-78.

Lyons JM 3rd, Abergel J, Thomson JL, et al. In vitro chemoresistance testing in well-differentiated carcinoid tumors. Ann Surg Oncol. 2009;16(3):649-655.

National Comprehensive Cancer Network (NCCN). Ovarian cancer including fallopian tube cancer and primary peritoneal cancer. NCCN Clinical Practice Guidelines in Oncology v.2.2011. Fort Washington, PA: NCCN; 2011.

Burstein HJ, Mangu PB, Somerfield MR, et al. American society of clinical oncology clinical practice guideline update on the use of chemotherapy sensitivity and resistance assays. J Clin Oncol. 2011;29(24):3328-3330.

Gastric (stomach) cancer is the 14th most common cancer in the United States. Approximately 90% of gastric cancers are classified as adenocarcinomas, in reference to the type of cell within the stomach that the cancer originated. The main component of treatment for patients who cannot have their cancer surgically removed due to extent of spread and/or location of the cancer is chemotherapy. There are several standard chemotherapy regimens for advanced gastric cancer, all achieving approximately a 20% anti-cancer response rate and overall survivals of 6-7 months. Researchers from Italy conducted a clinical trial in 2003 to evaluate the chemotherapy agent Alimta® in the treatment of advanced gastric cancer. This trial involved 38 patients with advanced (stage IV) gastric cancer who were treated with Alimta®. Anti-cancer responses occurred in 21% of patients, with 2 patients achieving a complete disappearance of detectable cancer and 6 patients achieving a partial disappearance of cancer. Overall survival for this group of patients was 7.8 months. Side effects included low levels of blood cells.

Another single agent ALimta study was performed in Korea and can be seen athttp://www.lillytrials.com/results_files/alimta/alimta_summary_6154.pdf

Imatinib was given accelerated approval in the US in 2008 for adjuvant treatment of completely resected GISTs ≥3 cm in size, without definitive guidance as to the optimal duration of treatment or which patients are most likely to benefit.

The Scandinavian Sarcoma Group (SSG) XVIII trial compared 36 versus 12 months of adjuvant therapy.  Data from the SSGXVIII trial provide compelling evidence that at least three years of adjuvant imatinib therapy is both safe and effective in reducing GIST recurrence and that it improves overall survival as well. Whether longer duration of therapy than three years will provide additional benefit and the optimal selection of patients for adjuvant therapy remains unclear.

In 2008, the FDA granted accelerated approved for imatinib in the adjuvant setting for completely resected primary GIST ≥3 cm without indicating the optimal length of therapy; labeling was updated in January 2012 to include the significantly prolonged survival seen with three years of therapy as compared to one year of adjuvant imatinib. However, whether all patients in this broad category have a high enough risk of recurrence to warrant adjuvant therapy is not established. The EMA (European Medicines Agency) has extended the licensed indications of imatinib to include adjuvant treatment of adult patients who are at “significant risk of relapse” after resection of a KIT-positive GIST, but does not define these subsets further.

Clinical practice guidelines from the National Comprehensive Cancer Network (NCCN) suggest adjuvant imatinib for at least 36 months for patients with high risk GIST (tumor >5 cm in size with high mitotic rate [>5 mitoses/50 HPF] or a risk of recurrence that is >50 percent). The European Society of Medical Oncology (ESMO) does not give a strong recommendation for the use of adjuvant imatinib, stating that its use can be “proposed as an option for those patients with a substantial risk of relapse for shared decision-making”; however, these recommendations were written prior to the publication of results from the SSGXVIII trial, which established a survival benefit from the use of three as compared to one year of adjuvant imatinib.

Uptodate, 2012
Adjuvant and neoadjuvant imtinib for GIST

Maki RG, Pisters PW, Demetri GD, Blackstein ME, Blanke CD, von Mehren M, Brennan MF, Patel S, McCarter MD, Polikoff JA, Tan BR, Owzar K, American College of Surgeons Oncology Group (ACOSOG) Intergroup Adjuvant GIST Study TeamSO, Adjuvant imatinib mesylate after resection of localised, primary gastrointestinal stromal tumour: a randomised, double-blind, placebo-controlled trial.AUDematteo RP, Ballman KV, Antonescu CR,  Lancet. 2009;373(9669):1097.

AUJoensuu H, Eriksson M, Sundby Hall K, Hartmann JT, Pink D, Schütte J, Ramadori G, Hohenberger P, Duyster J, Al-Batran SE, Schlemmer M, Bauer S, Wardelmann E, Sarlomo-Rikala M, Nilsson B, Sihto H, Monge OR, Bono P, Kallio R, Vehtari A, Leinonen M, Alvegård T, Reichardt One vs three years of adjuvant imatinib for operable gastrointestinal stromal tumor: a randomized trial.PSOJAMA. 2012 Mar;307(12):1265-72.

AUCasali PG, Blay JY, Gastrointestinal stromal tumours: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up., ESMO/CONTICANET/EUROBONET Consensus Panel of ExpertsSOAnn Oncol. 2010 May;21 Suppl 5:v98-102.

For Lay version see here

nccn, GIST(Sarcoma) 2012