Is there a role for second-line chemotherapy in advanced gastric cancer?

Gastric cancer remains one of the most common forms of cancer worldwide. Unfortunately, most patients will present with advanced-stage disease, and will therefore need palliative chemotherapy. Some chemotherapy regimens have been well established as first-line therapy, and have been shown to increase survival; however, almost all patients with metastatic gastric cancer will develop progressive disease after first-line therapy. With the availability of several active chemotherapy drugs, many patients who retain a good performance status after the initial treatment remain good candidates for additional therapy; however, no standard approach for second-line therapy exists. Many small, phase 2 trials have been done and the findings are variable. No data from randomised-controlled trials suggest a benefit of second-line chemotherapy compared with supportive care alone. We review the published data concerning the use of chemotherapy in the second-line setting for the treatment of advanced gastric cancer.     

“Crawling-type” adenocarcinoma of the stomach: a distinct entity preceding poorly differentiated adenocarcinoma

Background

Gastric “crawling-type” adenocarcinoma (CTAC) is a neoplasm histologically comprising irregularly fused glands with low-grade cellular atypia that tends to spread laterally in the mucosa. It is necessary to elucidate the clinicopathological characteristics of CTAC.

Methods

We evaluated 25 CTACs–16 intramucosal (M-) and 9 submucosal invasive (SM-) cancers–clinicopathologically and immunohistochemically.

Results

CTAC was most frequently located in the lesser curvature of the middle-third of the stomach. Macroscopically, 21 lesions were superficial-depressed and 4 were superficial-flat type. Histologically, all CTACs had cystic dilated glands and 16 lesions had focal signet-ring cells. All invasive areas of the SM-CTACs were occupied by poorly differentiated adenocarcinoma with an infiltrative growth pattern and abundant stroma. Fifteen CTACs were surrounded by mucosa with partial or no intestinal metaplasia. In the intramucosal area, 24 lesions were mixed phenotype with mucin and brush border immunoexpression. SM-CTAC was frequent in lesions with an intramucosal poorly differentiated component (PDC) greater than 10 mm in size (P = 0.041), and lymph node metastasis (LNM) was frequent in lesions with a PDC greater than 20 mm (P = 0.039). The frequency of an expanded pattern (Ki-67-positive cells occupying > 50 % of the mucosa) was higher in SM-CTAC than in M-CTAC (P = 0.027). p53 overexpression was not detected in the intramucosal areas of any of the lesions.

Conclusion

CTAC is a distinct subgroup of gastric adenocarcinoma in the early phase. A larger PDC and a Ki-67 expanded pattern were predictive of submucosal invasion or LNM.     

Is signet-ring cell carcinoma a specific entity among gastric cancers?

Background

The prognosis and chemoresistance of signet-ring cell (SRC) gastric adenocarcinoma have been reported and debated, and the utility of perioperative chemotherapy for such a tumor has been questioned. This study was performed to assess the impact of the SRC type on survival following resection of gastric adenocarcinoma, and to assess whether the prognostic factors (including perioperative chemotherapy) for non-SRC adenocarcinoma differed from those for SRC adenocarcinoma.

Methods

1799 cases of adenocarcinoma that were consecutively treated from 1997 to 2010 in 19 French centers by subtotal or total gastrectomy were included in a retrospective study. A D2 lymphadenectomy was performed for antropyloric tumors, and a modified D2 for upper tumors. SRC adenocarcinoma was diagnosed based on the presence of isolated carcinoma cells containing mucin.

Results

A total gastrectomy was performed in 979 (54.4 %) patients. SRC adenocarcinoma was diagnosed in 899 (50 %) patients. Patients with an SRC tumor were more frequently female, younger, and malnourished, had lower ASA scores, and had larger tumors than non-SRC patients. Median survival in patients with non-SRC carcinoma was 51 months, as compared to 26 months in patients with SRC carcinoma (p < 0.001). At multivariate analysis, SRC type remained an independent adverse prognostic factor (HR = 1.182). Factors that were prognostic in the SRC subgroup but not in the non-SRC subgroup were age >60 years, linitis, and involvement of adjacent organs. In contrast to non-SRC tumors, pre- and postoperative chemotherapy did not significantly impact on survival following resection of SRC adenocarcinoma.

Conclusion

In comparison to non-SRC adenocarcinoma, the SRC type has a worse prognosis, different prognostic factors, and is only poorly sensitive to perioperative chemotherapy. Non-SRC and SRC adenocarcinomas should be considered different entities in future therapeutic trials.

     

Colorectal cancer in young patients: is it a distinct clinical entity?

Background

The incidence of colorectal cancer in young patients is increasing. It remains unclear if the disease has unique features in this age group.

Methods

This was a single-center, retrospective cohort study which included patients diagnosed with colorectal cancer at age ≤40 years in 1997–2013 matched 1:2 by year of diagnosis with consecutive colorectal cancer patients diagnosed at age >50 years during the same period. Patients aged 41–50 years were not included in the study, to accentuate potential age-related differences. Clinicopathological characteristics, treatment, and outcome were compared between groups.

Results

The cohort included 330 patients, followed for a median time of 65.9 months (range 4.7–211). Several significant differences were noted. The younger group had a different ethnic composition. They had higher rates of family history of colorectal cancer (p = 0.003), hereditary colorectal cancer syndromes (p < 0.0001), and inflammatory bowel disease (p = 0.007), and a lower rate of polyps (p < 0.0001). They were more likely to present with stage III or IV disease (p = 0.001), angiolymphatic invasion, signet cell ring adenocarcinoma, and rectal tumors (p = 0.02). Younger patients more frequently received treatment. Young patients had a worse estimated 5-year disease-free survival rate (57.6  vs. 70 %, p = 0.039), but this did not retain significance when analyzed by stage (p = 0.092). Estimated 5-year overall survival rates were 59.1 and 62.1 % in the younger and the control group, respectively (p = 0.565).

Conclusions

Colorectal cancer among young patients may constitute a distinct clinical entity. Further research is needed to validate our findings and define the optimal approach in this population.

     

Is the hypoxia-inducible factor pathway important in gastric cancer?

Tumour hypoxia is well recognised in oncology to be a key factor resulting in treatment resistance and poor prognosis. Hypoxia leads to the expression of a number of gene products that are involved in tumour progression, invasion and metastasis formation. The most important of these proteins is thought to be hypoxia-inducible factor-1α (HIF-1α), which appears to be a master regulator of the cellular response to hypoxia. HIF-1α expression is associated with a poor prognosis and treatment response in a number of tumour sites. There is some evidence that the HIF-1α pathway might be involved in gastric carcinogenesis. Studies have shown reactive oxygen species from Helicobacter pylori, associated with the development of gastric cancer, stabilise HIF-1α. Non-steroidal anti-inflammatory drugs, shown to reduce the risk of gastric cancer, can decrease HIF-1α expression. Although a large study correlating HIF-1α expression with prognosis is lacking in gastric cancer, the immunohistochemical expression of HIF-1α target genes (Glut-1, VEGF, CA9, iNOS) is associated with a poor prognosis. In addition, the targeted inhibition of HIF-1α has been shown to inhibit the growth of gastric tumours in animals. Increased understanding of the importance of hypoxia and the HIF-1α pathways may therefore hold the key to prevention strategies, improved selection of patients for adjuvant therapy and new treatments for the disease.     

Is there a role for advanced radiation therapy technologies in the treatment of pancreatic adenocarcinoma?

Pancreatic cancer remains a highly challenging problem in oncology. Oncologists continue to search for therapies that are more effective than those currently available to improve on the existing poor treatment results. Persistence of both systemic and local disease causes high rates of morbidity and mortality for patients. Radiation continues to play a role in the treatment of pancreatic cancer, in both the adjuvant and locally advanced settings. Efforts to improve on the results of radiotherapy have led to the use of new and improved technologies. This review discusses a variety of these technological improvements and their current and potential future roles in the clinic.     

Is intraductal tubulopapillary neoplasia a new entity in the spectrum of familial pancreatic cancer syndrome?

We report on a 78-year old male with a positive family history for pancreatic cancer, who underwent total pancreatectomy for a suspected intraductal papillary mucinous neoplasm with extensive involvement of the main pancreatic duct and multiple branch ducts. The post operative course was uneventful. Macroscopic examination of the specimen revealed multiple solid non-mucinous tumour nodules throughout the main pancreatic duct and within multiple branch ducts. The microscopic appearance of the tumour, in particular its tubulopapillary growth pattern and immunohistochemical mucin profile (MUC1, MUC6 positive; MUC2, MUC5AC negative) were consistent with intraductal tubulopapillary neoplasia (ITPN) showing high-grade dysplasia. No evidence of stromal invasion was identified. To the best of our knowledge, this is the first report on ITPN in a high-risk patient based on a history of familial pancreatic cancer (FPC). The potential association between this entity and the spectrum of neoplastic lesions in FPC should be investigated with particular consideration of the lower biological aggressiveness of ITPN.     

Is tumor size a predictor of preoperative N staging in T2–T4a stage advanced gastric cancer?

BackgroundThe aim of this study was to assess the relationship between tumor size and preoperative N staging in patients with T2–T4a stage advanced gastric cancer.MethodsA total of 697 patients with gastric cancer were analyzed. The correlations between the number of metastatic lymph nodes (LNs) and other clinicopathologic factors were investigated. The Kappa consistency test was used to test the agreement between predicted and pathologic N staging.ResultsMultivariate analysis showed that tumor size was independently (r = 0.987, P < 0.05) and linearly (R² = 0.940, P < 0.05) correlated with the number of metastatic LNs. The numbers of predicted metastatic LNs in patients with primary tumors <2.02 cm, 2.02–4.07 cm, 4.07–6.80 cm, and ≥6.80 cm in size were 0 (Stage N0), 1–2 (Stage N1), 3–6 (Stage N2), and ≥7 (Stage N3), respectively. There was good agreement between N staging predicted by tumor size and pathologic N staging (Kappa value = 0.531, P < 0.05). The overall accuracy of tumor size for preoperative N staging was 82.13%. The 5-year survival rates of patients with predicted Stages N0, N1, N2, and N3 were 80.0%, 71.1%, 56.8%, and 39.8%, respectively (P < 0.05). There were no significant differences in the survival rates of patients with predicted N staging and the corresponding pathologic N staging.ConclusionsTumor size is correlated with the number of LN metastases in patients with stage T2–T4a advanced gastric cancer. The measurements of tumor size can predict preoperative N staging.