Cancer Treatment Today » Gastric (Stomach) Cancer

Erbitux for stomach cancer

M Levin, MD — Fri, 31 May 2013 22:44:23 +0000

Epidermal growth factor receptor (EGFR) is over-expressed in amany esophageal and gastric carcinomas. Pteintiall it can be targer for Erbitux*cetiximab) and there has been significant interest in targeting it. Unfortunately, it has not yet shown much progress. A phase II study showed minimal clinical activity of cetuximab. A recent phase III trial, EXPAND (Erbitux in Combination With Xeloda and Cisplatin in Advanced Esophagogastric Cancer), involved 904 patients in 24 countries in Asia Pacific, Europe, and Latin America, and in Japan. Patients had advanced cancer of the stomach or gastroesophageal junctio. Results weres similar between treatment groups and the primary and secondary endpoints were not met; progression-free survival was 4.4 versus 5.6 months and overall survival was 9.4 versus 10.7 months with cetuximab combination and control treatment, respectively. Overall response rates were 29% with cetuximab and 30% with control. More research remains to be done.

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Tykerb for stomach cancer

M Levin, MD — Fri, 02 Nov 2012 12:24:51 +0000

Stomach cancer is known to have amplification of the ErbB2 (HER2) gene and responds to the drug Herceptin, which used this pathwayto attach cacner cells . Recently, there has been an interest in using Tyker(lapatinib) which is a drug that utalizes the same mechanism of action as Herceptin. One such trial is: LOGiC – Lapatinib Optimization Study in ErbB2 (HER2) Positive Gastric Cancer: A Phase III Global, Blinded Study Designed to Evaluate Clinical Endpoints and Safety of Chemotherapy Plus Lapatinib. This is an international multi-center trial for patients stomach, esophagus, or gastro-esophageal junction cancer with amplification of the ErbB2 (HER2) gene. The triallooks at whether lapatinib, when added to the chemotherapy regimen, capecitabine extends the time to progression and overall life. Chemothrapy is administered to all patients, who then randomly get either lapatinib or placebo. There is evidence of effectiveness for braa metastaes, at least in breast cancer(Lin et al).

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. The same appears to be true of Taxol and lapatinib and studies of this combination are ongoing.

A number of issues remain to study: how to combine Tykerb with toehr drugs, the role of Taykeb in patients previousely treated with Herceptin, and efficacyfor brain metastases.

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Adjuvant Gleevec for GIST

M Levin, MD — Fri, 31 Aug 2012 18:22:48 +0000

Results from several randomized, placebo-controlled clinical trials for patients with primary gastrointestinal stromal tumor (GIST), a type of tumor usually found in the stomach or small intestine, showed that patients who received imatinib mesylate (Gleevec ®) after complete removal of their tumor were significantly less likely to have a recurrence of their cancer compared to those who did not receive imatinib. For example, ACOSOG Z9001 trial was stopped early when planned interim analysis disclosed that significantly fewer patients in the treated group recurred. At Strangely, however, on farther followup, no overall survival differences have emerged in favor of imatinib in the ACOSOG Z9001 trial. It is not clear why this is so. Among the possible reasons are the short duration of follow-up, the limited number of relapses, and the high degree of efficacy of imatinib in relapsed disease. Furthermore, after the study was stopped, all patientswere allowed to crossover to active treatment, thus obscuring any potential differences in overall survival between the groups. 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 and supports giving Gleeven for three eyars.

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.

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FAP and AFAP testing: Genetic colon cancer

M Levin, MD — Fri, 24 Aug 2012 13:48:34 +0000

A small proportion of colon and rectal cancers arise in individuals who have genetic mutations. Familial Adenomatous Polyposis(FAP) and AFAP are autosomal dominant disorders with 50% risk of inheritance and about 75–80% of individuals with these conditions have an affected parent. Autosomal dominant inheritance means that an offspring of an affected individual has a 50% risk of inheriting the altered APC gene.
Adenomas develop in approximately half of all patients with FAP by age 15, and in 95% by age 35. Without intervention, most individuals with FAP will develop colon or rectal cancer by the fourth decade of life. Thus, screening and intervention for at-risk persons is critical and typically begins at puberty (National Comprehensive Cancer Network® [NCCN®], 2012). AFAP is an attenuated variety of FAP. Evidence in the published, peer-reviewed scientific literature indicates that genetic testing for mutations in the APC gene is appropriate for a specific subset of individuals who have been identified as at high-risk for FAP or AFAP. Among the specialty organizations that have recognized the role of FAP and AFAP genetic testing are the American Gastroenterological Association (AGA), American College of Medical Genetics (ACMG), NCCN and National Cancer Institute (NCI). It is generally accepted that genetic testing for FAP and AFAP is appropriate for the following purposes:
• to confirm the diagnosis of FAP and AFAP in an affected patient
• to provide predictive testing for at-risk relatives of AFAP and FAP-affected patients with known APC gene mutation.
MYH-Associated Polyposis (MAP), also known as MUTYH-associated polyposis, is a recently described syndrome that is related to FAP and that is also characterized by adenomatous polyps. It is, however, an autosomal-recessive syndrome, in which half of the affected individuals are carriers of the disease but are not affected, unless they receive one gene from each parent.

American College of Medical Genetics (ACMG) and the American Society of Human Genetics (ASHG) and American Gastroenterological Association (AGA) also offer guidelines. For genetic counseling and testing for adenomatous polyposis syndromes, including FAP, and AFAP, the guidelines include the following (NCCN, 2012):
• FAP Inclusion criteria include:
Presence of over 100 polyps, or fewer polyps at younger ages, especially in family known to have FAP
Autosomal dominant inheritance
Possible associated additional findings, including:
o Congenital hypertrophy of retinal pigment epithelium (CHRPE)
o Osteomas, supernumerary teeth, odontomas
o Desmoids, epidermoid cysts
o Duodenal and other small bowel adenomas
o Gastric fundic(body) gland polyps
increased risk of medulobastoma, papillary carcinoma of the thyroid (<2%) or hepatobalstoma (usually ?age 5 years)
Pancreatic cancers (<1%)
Gastric cancers (<1%)
• AFAP inclusion criteria include:
Fewer than 100 adenomas (range 0 – >1000) (average of 30 polyps)
Frequent right-sided distribution of polyps
Adenomas and cancers at age older than classic FAP (i.e., mean cancer age greater than 50)
Upper GI findings and thyroid cancer risk is similar to classic FAP
?Other extraintestinal manifestations, including CHRPE and desmoids are rare
• If personal history is positive, then refer to genetic screening
• If family mutation is known, then refer at-risk family members to genetic screening
For genetic counseling and testing for MAP, the guidelines include the following (NCCN, 2012):
• MAP inclusion criteria include:

Polyposis or colon cancers consistent with autosomal recessive (i.e., parents unaffected, siblings affected)
Fewer than 100 adenomas (range 0–100s and uncommonly >1000)
Adenomas and colorectal cancer at age older than classical FAP (median age >50)
Duodenal adenomas are uncommon
Attenuated polyposis with negative APC gene mutation

• If personal history is positive, then refer to genetic screening
• Testing for APC gene mutations usually precedes testing for MYH mutations, except in families in which only siblings are affected
• Recommend genetic counseling and testing for germ line MYH mutations for siblings of affected patients
• If family mutation is known, then refer at-risk family members to genetic screening

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Research in GE Junction Gastric Cancer

M Levin, MD — Mon, 13 Aug 2012 13:58:09 +0000

Gatrointestinal junction(GE) cancer (where esophagus and stomach meet) is a type of cancer that has similarities to both gastric and esophageal cancer. Since GE Junctions cancers that express HER turned out to respond well to Herceptin, there is great interest in targeting other molecules, such as the epidermal growth factor receptor, vascular endothelial growth factor receptor, and P13k/Akt/mTor pathway, as well as the insulin-like growth factor receptor, c-Met pathways, fibroblast growth factor receptor, and other pathways in this type of cancer. Much remains to be done before clinical therapies based on this concept become available and proven but there is much research activity. One study looking at a C-MET inhibitor is: MET111643 ,A Phase 2 Study of GSK1363089 (XL880) Administered Orally to Subjects with Metastatic Gastric Cancer.

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Tykerb (Lapatinib) for Gastric Cancer

M Levin, MD — Thu, 09 Aug 2012 19:06:06 +0000

22% of patients with advanced gastric cancer overexpress human epidermal growth-factor receptor 2 (HER2), and these patients had significantly improved overall survival when trastuzumab (Herceptin), a drug against this receptor, is added to chemotherapy when compared with chemotherapy alone. In a study presented in 2009 ASCO, the improvement in overall survival was 2.7 months, from 11.1 months in the chemotherapy group to 13.8 months in the trastuzumab group (hazard ratio, 0.74, P = .0046). Similar results were shown by ToGA, a large international Phase III trial investigating the benefit of Herceptin as the first therapy for patients with advanced and inoperable stomach cancer (first line).
This greatly increased and interest in Tykerb for gastric cancer which works in a similar way. Preclinical studies in gastric cancer have shown that the drug slows down the growth of HER2-positive gastric cancer cell lines, showing synergy with trastuzumab. This agent is under study alone and combinations. A recent study by Iqbal concluded that Lapatinib is well tolerated, with modest single-agent activity in advanced/metastatic gastric cancer patients.

There are several ongoing studies of Tykerb and gastric cancer, for example: LOGiC – Lapatinib Optimization Study in ErbB2 (HER2) Positive Gastric Cancer: A Phase III Global, Blinded Study Designed to Evaluate Clinical Endpoints and Safety of Chemotherapy Plus Lapatinib, NCT00680901. There is also the TYTAN trial investigating weekly paclitaxel plus or minus Tykerb in second-line therapy.

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