ARTICLES

ONCOINFOSCAN

Compiled by
Dr. P. J. Halder
Sr. Surgeon,
Jagjivanram Hospital,
Bombay Central,Western Railway,
Mumbai

IMMUNOTHERAPY-A RAY OF HOPE IN PANCREATIC CANCER

Inspite of poor results in pancreatic cancer, the search for more accurate methods of diagnosis and better methods of treatment should be actively pursued, a recent review on pancreatic, cancer states. In the light of this observation, further study of immunotherapy may be appropriate.

Immunotherapy is currently at the fore, as we can now, actively or passively, stimulate the immune system of patients with pancreatic cancer, creating an immunotherapeutic regimen which may be partially or completely effective in curing the disease. Why this optimism ? Recently, developments in genetic engineering techniques have led to breakthroughs in identifying tumour antigens, the description of numerous cytokines (approximately 25, including 1 L 1-18, tumour necrosis factor-(TNF) 0/0, interferons (INF) a., y and others) and more recently, chemokines, of which there are more than 30, including their receptors. Possible peptides targets in immunotherapy for pancreatic cancer are as shown in the table.

MUC I is found in virtually all pancreatic cancers. The current plethora of agents will take many years to sort out, but better response will be generated by Granulocyte macrophage colony stimulating factor (GM-GSF) before blood harvest, IL-4 and GM-GSF for dendritic cells possibly with IL-7, and followed by IL-12.

A BREATHALYSER FOR LUNG CANCER

Many volatile organic compounds (VOC), principally alkanes and benzene derivatives, have been identified in breath from patients with lung cancer. Breath samples from 108 patients with abnormal chest radiograph who were scheduled for bronchoscopy were collected with a portable apparatus, then assayed by gas chromatography and mass spectroscopy. Lung cancer was confirmed histologically in 60 patients. A combination of 22 VOCs, predominantly alkanes, alkane derivatives, and benzene derivatives, discriminated between patients with and without lung cancer, regardless of stage (all p<0.0003). For stage 1 lung cancer a combination of 22 VOCs had 100% sensitivity and 81.3% specificity. Cross validation of the combination correctly predicted the diagnosis in 71.7% patients with lung cancer and 66.7% of those without lung disease.

Testing for breath VOC profiles might complement other innovative methods currently being investigated. either as markers of early cancer or, perhaps more importantly, as markers of pre neoplastic bronchial epithelial changes. There is hope that in future a breathalyser will be used for more than screening for ethanol intoxication.

BIOMARKERS IN LUNG CANCER

The expression of several putative surrogate biomarkers in sputum cytology has been studied. Preliminary results suggest that the most accurate marker for prediction of an antigen detected by monoclonal antibody 703 04. The accuracy (True positive + True negative/ Total) of this biomarker was 88% in 62 archived dysplastic (but not diagnostic) specimens collected 2 years in advance of clinical lung cancer. The antigen target was subsequently identified as heterogenous nuclear ribonucleoprotein (hn ANP) A2/B1. hnRNP is an RNA binding protein that is required for maturation of mRNA precursors. The predictive value of hnANPA2/B1 overexpression has been prospectively assessed in two high risk populations: 595 patients with stage 1 resected lung cancer, for whom the annual risk of second primary lung cancer is 1-5%: and 6285 Chinese tin miners with extensive exposure to tobacco smoke, ra- don, and arsenic, among whom the annual incidence of lung cancer is 1 %. In these two populations, hnRNP A2/B1 over expression predicted lung cancer in 67% and 69%. a 35-fold and 76-fold improvement in positive predictive value over background cancer risks of 2.2% and 0.9% respectively.

MOLECULAR BIOLOGY IN GALL BLADDER CANCER

Recently, genetic, immunohisto chemical and molecular biology techniques have been applied to explore the pathogenesis of cancer of gallbladder. The p53 tumour suppressor gene, located on the short arm of chromosome 171 has roles in cell division and apoptosis. The data suggests that corelation exists between p53 abnormalities and the development of gall bladder cancer. In one study 8 out of 11 gallbladder cancers expressed p53 immunopositivity. p53 Protein expression was related to higher grades of malignancy. K-ras mutations have also been investigated and more recent evidence suggests that K-ras mutation may also be an important factor in the early stage of carcinogenesis when associated with an anomalous junction of the pancreatico biliary tract. Malats et al found that K-ras 12 mutations were an independent prognostic indicator in patients with extra hepatic biliary system cancer, including gallbladder cancers and also postulated that mutations at codons 13 and 61 might have oncogenic potential. Biliary phospholipase A2 is also associated with such cancers.

TAMOXIFEN ---THE WONDER DRUG ?

Is there anything that Tamoxifen cannot do ? An overview published in Lancet, 1998, suggests that the scope and effectiveness of the drug as an adjuvant have been underestimated. Now Bernard Fisher and colleagues in 1999, report that Tomoxinfen reduces, by about 40%, the risk of cancer recurrence in women treated for ductal carcinoma in situ (D CIS). In this randomised trial, NSABP-24, about, 1800 women with D CIS were treated with lumpectomy, radiotherapy, and either tamoxifen or placebo. Primary end points were same (ipsilateral) or opposite breast (contralateral) invasive or in situ tumours. After a median follow-up of 5 years, the incidence of breast tumours was 13.4% among the controls and 8.2% in treatment group (p=0.0009), a relative reduction of nearly 40%. Recurrence of D CIS was also reduced (a relative reduction of 30%). Although most recurrences were ipsilateral, contralateral tumour recurrences, both invasive and in situ, also developed and were reduced by about 40%.

A reasonable view of the data presented should be that the benefits of tamoxifen far outweigh the risks. The question arises -Should all women with mammographically detected DCIS have tamoxifen ? Probably -no. Should most ? Probably -Yes.

FAMILY HISTORY AND CANCER MORTALITY

What is the association between family history of cancer and cancer mortality in women ? A case controlled study nested within a large cohort, the American Cancer Society Cancer Prevention Study-1 was conducted to test associations between a family history and cancer mortality in women. By using logistic regression, the authors analysed family history, as reported by 429483 women enrolled in 1959, relative to subsequent mortality through 1972 from cancer within and across multiple sites. The association between family history and cancer mortality were generally stronger within cancer sites than across cancer sites. Within site associations were found for breast cancer (odds ration OR=1.91 ), colorectal cancer (OR=1.6), stomach cancer (OR=1.9), and lung cancer (OR=1.7).

Across site associations were observed for a family history of (1) Breast cancer as a risk factor for ovarian cancer mortality (OR=1.6), (2) Stomach cancer as a risk factor for ovarian cancer mortality (OR=1.5), and (3) Uterine cancer as a risk factor for pancreatic cancer mortality (OR= 1.6). A general pattern of positive association was observed between a family history of cancer at several sites and subsequent death from pancreatic cancer. These findings suggest that inherited cancer -susceptibility genes increase the risk of cancer at many sites and are not specific to cancer risk within a single site.

SEROLOGICAL TESTS FOR PANCREATIC CANCER

The role of serological tests for screening of pancreatic cancer has not been established. However Yiannakon et al (1997) have prospectively assessed a new type of combined lectin/antibody enzyme -linked mucin assay, (CAM 17.1), in 250 patients whose differential diagnosis included pancreatic cancer. The control group comprised of 75 patients who did not have symptoms of pancreatic cancer and had alternative diagnosis. The patients were followed up for at least 8 months.

Of the 250 patients, 36 had pancreatic cancer, as defined by histological and imaging criteria, and 8 of these patients had a resectable tumour. Sensitivity and specificity of the CAM 17.1 assay were 86% and 91% respectively, in all patients, 85% and 81% in those who presented with jaundice, and 89% and 94 % in patients who did not have jaundice. The sensitivity of the assay compared well with that of ultrasound scanning (59%) and CT (83%) in these patients. Use of the CAM 17.1 assay in combination with ultrasonography identified 94% of patients with pancreatic tumours and all of those with resectable tumours.

RADIATION ENTERITIS

More and more patients are now receiving radiotherapy and chemotherapy for various intra-abdominal malignancies. The hazards of these are troublesome post-radiation enteritis. Columnar epithelial cells of the intestine, are extremely susceptible to radiation as they are rapidly proliferating cells. It is postulated that the damage can be minimised by reversibly preventing cell cycle progression before radiotherapy. Transforming growth factor (TGF) is such an agent. TGF, in experimental animals can effectively protect enterocytes against agents like vinblastin, vincristine, taxol, methotrexate, SFU, etc. However, TGF is not effective against cisplatin and adriamycin which act throughout the cell cycle. Keratinocyte growth factor (KGF), akin to the fibroblast growth factor has also been shown to prevent radiation injury if given before radiotherapy. Following radiation enhanced production of prostaglandin E2 has been shown to promote crypt cell survival. Vitamin A is also a potential protector against radiation injury to the bowel. Enteral glutamine, a non essential amino acid, has mucosal barrier action and hence acts as a radioprotector.

CANCER STOMACH

Stomach partioning gastrojejunostomy has been shown to give better results than a standard gastrojejunostomy. Ability to tolerate food and survival (13.4 v/s 5.8 months) are better in the former case. In unresectable disease, hyperthermic chemoperfusion has shown good results (median survival 4 years). Using bone marrow immunohistochemistry and tumour immunohistochemistry, Heiss et al have shown that low levels of plasmino gen activator-inhibitor (PAI-1) urokinase type plasminogen activator (UPA) and cathepsin (UPA activator) are associated with better disease-free survival. Aggressive tumours, on the other hand, E-cadherin-catenin, CD44, cathepsin B, plasma matrix metalloproteinasc, platelet-derived growth factor, epidernal growth factor, cyclin Dl and cyclin E. Tumours with these markers have a higher pathological stage with higher nodal status.

REFERENCE

1. GUT 1999;44:767-69.

2. Lancet 1999; 353:1930-33.

3. Journal of Gastroenterology and Hapatology 1999;14:215-19

4. Lancet 1999;353:1986.

5. American Journal of Epidemiology 1999;149:454-62.

6. Lancet 1999;349:389-92.

7. Curr Opin Gastroenterol 1998; 14:458-66.

8. Br J Cancer 1997;75: 1454-59.