Escalated radiation dose alone vs. concurrent chemoradiation for locally advanced and unresectable rectal cancers: results from phase II randomized study.

PURPOSE: This trial was undertaken to compare the rates of resectability between patients treated with neoadjuvant concurrent chemoradiation vs. boosted radiotherapy alone. MATERIALS AND METHODS: Patients with clinically unresectable rectal cancer were randomized to receive external beam radiation therapy (EBRT) to pelvis (45 Gy) with concurrent oral Capecitabine (CRT group; Arm 1) or EBRT to pelvis (45 Gy) alone followed by 20 Gy dose of localized radiotherapy boost to the primary tumor site (RT with boost group, Arm 2). All patients were assessed for resectability after 6 weeks by clinical examination and by CT scan and those deemed resectable underwent surgery. RESULTS: A total of 90 patients were randomized, 46 to Arm 1 and 44 to Arm 2. Eighty seven patients (44 in Arm 1 and 41 in Arm 2) completed the prescribed treatment protocol. Overall resectability rate was low in both the groups; R0 resection was achieved in 20 (43 %) patients in Arm 1 vs. 15 (34 %) in Arm 2. Adverse factors that significantly affected the resectability rate in both the groups were extension of tumor to pelvic bones and signet ring cell pathology. Complete pathological response was seen in 7 and 11 %, respectively. There was greater morbidity such as wound infection and delayed wound healing in Arm 2 (16 vs. 40 %; p = 0.03). CONCLUSION: Escalated radiation dose without chemotherapy does not achieve higher complete (R0) tumor resectability in locally advanced inoperable rectal cancers, compared to concurrent chemoradiation.

Gastrointestinal stromal tumors: case series of 29 patients defining the role of imatinib prior to surgery.

BACKGROUND: The aim of this study was to assess the role of neoadjuvant imatinib in redefining treatment for gastrointestinal stromal tumors (GISTs). METHODS: A total of 76 patients were reviewed. Among them, 29 patients who were administered neoadjuvant imatinib for borderline resectable and locally advanced GISTs followed by surgery were analyzed. Adjuvant imatinib was administered based on risk stratification. RESULTS: The median age of the neoadjuvant imatinib group was 51 years. The median duration of neoadjuvant imatinib administration was 8.5 months. The response rate with neoadjuvant imatinib was 79.3%. Five patients, initially considered to have locally unresectable lesions, ultimately underwent resection (three R0, two R2). Another three patients, who had M1 disease, underwent R2 resection (due to the presence of metastasis) with complete resection of the primary lesion. In 19 patients, who would have originally required extensive surgery, underwent conservative surgery (R0). In two patients, neoadjuvant imatinib did not influence the final procedure. The postoperative complication rate was 13.8%, and there were no postoperative deaths. There was one locoregional recurrence and two cases of distant metastasis. The 1-, 2-, and 3-year overall survivals were each 100%. CONCLUSIONS: Neoadjuvant imatinib for locally advanced GISTs is a safe concept for downsizing, improving resectability, and aiding organ-preserving surgery. It also improves the chance of long-term survival. Surgery, however, remains the cornerstone of curative treatment of GISTs even after neoadjuvant imatinib.

Production of immunogenic human papillomavirus-16 major capsid protein derived virus like particles.

BACKGROUND & OBJECTIVE: Recombinant DNA technology allows expression of the human papillomavirus (HPV) major capsid protein (L1) in heterologous expression systems and the recombinant protein self assembles to virus-like particles (VLP). We took up this study to produce recombinant HPV-16 L1 in yeast, establish the process of recombinant L1 derived VLP preparation and develop an ELISA using VLP as the antigen for serological evaluation of anti HPV-16 L1 antibody status. METHODS: Complete HPV-16 L1 was amplified from genomic DNA of an esophageal cancer biopsy, cloned and the protein was expressed in a galactose-inducible Saccharomyces cerevisiae expression system. Self assembled VLP was purified by a two-step density gradient centrifugation process and the VLP preparation used to test its suitability in developing an ELISA. RESULTS: The recombinant protein was predominantly a ~55 KD species with distinct immunoreactivity and formed VLP as confirmed by electron microscopy. An ELISA using the VLP showed its efficacy in appropriate immunoreactivity to serum/plasma IgG. INTERPRETATION & CONCLUSION: Recombinant HPV-16 capsid protein derived VLP was produced and the VLP antigen based ELISA can be used to probe serological association of HPV with different clinical conditions. The VLP technology can be improved further and harnessed for future vaccine development efforts in the country.

A new scoring system for gallbladder cancer (aiding treatment algorithm): an analysis of 335 patients.

BACKGROUND: There is currently no preoperative staging/scoring system available for gallbladder cancer. Unfortunately, in gallbladder cancer, patients manifest advanced stages of the disease. There is need for a methodology that can aid accurate preoperative staging and the subsequent treatment algorithm. We thus sought to validate a new scoring system, the Tata Memorial Hospital Staging System (TMHSS), for gallbladder cancer. METHODS: TMHSS is based on the cumulative impact of specific features of computed tomographic scan, presence or absence of jaundice, and serum cancer antigen 19-9 levels. This scoring system was first proposed in 2004. Patients with gallbladder cancer were enrolled onto the testing sample for TMHSS to ascertain its validity. A total of 335 consecutive patients with gallbladder cancer who sought care at the Tata Memorial Hospital between May 1, 2005, and December 31, 2006, were studied. Treatment was suggested on the basis of current existing protocols. Each patient was assigned a TMHSS score, and the treatment decision taken was compared with the algorithm generated for each individual score. Concurrence of the decision taken with the score generated algorithm was tested by the Kendall tau-b test. RESULTS: Ordinal-by-ordinal analysis of the value of the test was .75, which showed excellent concurrence and a statistically significant P value (P < .0001). CONCLUSION: TMHSS provides an excellent correlative treatment plan for patients with gallbladder cancer. It has the potential to reduce unnecessary surgical explorations and to direct patients to the ideal treatment strategy, thereby offering a degree of prognostication.

Can we do better than 'incidental' gallbladder cancer?

The term 'incidental' gallbladder cancer is used to describe the histopathologic surprise of a malignancy following simple cholecystectomy for presumed benign gallstone disease. However, there remains a persistent doubt, especially so in large volume centers - whether some of these cases should have been detected on preoperative imaging. Under the broad definition of 'incidental' gallbladder cancer are we condoning the fact that some of the 'missed' gallbladder cancers may actually have been 'potential' gallbladder cancers, or 'suspicious' gallbladder cancers? In this report we try to answer this question. There exists a group of patients in whom preoperative imaging raises the suspicion of gallbladder cancer but are yet subjected to a laparoscopic simple cholecystectomy, possibly because adequate heed was not paid to the preoperative imaging. In this situation, the correct strategy would be to subject the excised gallbladder to an intraoperative frozen section and conversion to open radical cholecystectomy if the disease is more than T1. On the basis of experience gained with this problem at the Tata Memorial Center, we attempt to introduce two new terms: 'Potential' gallbladder cancer and 'suspicious gallbladder cancer', to highlight these clinical situations so that the correct procedure is performed where indicated.

Cholecystectomy for asymptomatic gallstones can reduce gall bladder cancer mortality in northern Indian women.

Gall bladder cancer (GBC) is a leading cause of cancer-related mortality in the northern parts of the Indian subcontinent. A majority of patients with GBC are middle-aged women, who normally would have substantial family responsibilities. Most patients are diagnosed with advanced cancer and are suitable for palliative care only. There is a strong association between long-standing gallstone disease and the development of GBC. Although randomized trials are lacking, prospective population-based data from low-risk and high-risk regions reveal that cholecystectomy reduces the mortality from GBC. Prophylactic cholecystectomy is recommended in populations with high incidence of GBC. The morbidity and mortality of laparoscopic cholecystectomy in uncomplicated gallstone disease is very low in India. Because of these reasons we argue that prophylactic cholecystectomy should be offered to young healthy women from high-risk regions of India whenever they are diagnosed to have asymptomatic gallstones. Simultaneously, population-based observational studies could be undertaken to generate more evidence.

Subjective global assessment: a simple and reliable screening tool for malnutrition among Indians.

BACKGROUND AND AIMS: Subjective global assessment (SGA) is a simple and reliable malnutrition-screening tool. The SGA has not been evaluated in India or in populations where chronic energy deficiency (CED) is rampant. We evaluated the value of preoperative nutrition, determined using the SGA, in predicting postoperative adverse outcomes in cancer patients. METHODS: Two hundred and ninety-four cancer patients undergoing elective surgery were screened for malnutrition using a modified version of the SGA, and 266 patients (aged 14-73 years [median 50]; 165 male) were eligible. All patients were followed up till discharge, and number of days on antibiotics, length of postoperative stay, occurrence of major adverse events, and death within 30 days were recorded. The association of preoperative SGA scores (A, B, or C) and BMI groups (< 18.5, 18.5-20 or> 20 Kg/m2) and four outcome variables were tested for statistical significance. RESULTS: The cancer sites included head and neck region in 112, gastrointestinal tract in 53, thoracic organs in 28, and other sites in 73 patients. The SGA scores were A in 152, B in 98, and C in 16 patients. The BMI was < 18.5 in 110 (41.8%) patients. The length of postoperative stay and the number of antibiotic days revealed a significant trend from SGA-A to SGA-C (p=0.000). Pre-defined adverse events occurred in 7.9%, 17.3% and 25% of SGA groups A, B, and C, respectively (p=0.025). The risk for adverse events was significantly higher in SGA-C group (OR 5.27, 95% CI 1.35-20.51, p< 0.016) compared to SGA-A group. Three patients in SGA-B group and one in SGA-C group died within 30 days (p=0.04). No significant association was detected between the three BMI groups and duration of antibiotic use, length of postoperative stay, adverse events or mortality. CONCLUSION: SGA is a simple and inexpensive way to identify clinically relevant malnutrition in Indian patients undergoing cancer surgery. Low BMI was not associated with postoperative adverse outcomes, and its use for nutritional screening is likely to overestimate severe malnutrition in Indian patients.

Impact of intra-operative ultrasonography in liver surgery.

BACKGROUND/OBJECTIVE: Intra-operative ultra-sonography (IOUS) during surgery for primary and metastatic hepatic tumors identifies additional lesions and helps in determining the most optimal surgical strategy. We assessed the impact of IOUS in liver surgery at our hospital, a tertiary-care cancer center. METHODS: Patients with potentially resectable hepatic tumors underwent surgical exploration. The relationship of the tumor with regard to the intrahepatic vasculature was determined by IOUS. A search was also made for additional lesions not detected by pre-operative imaging modalities. In appropriate cases, IOUS was also used to assist resection and radiofrequency ablation/ethanol injection. RESULTS: Between January 2003 and January 2005, 52 patients underwent surgery for primary or secondary hepatic tumors. IOUS was performed in 48 of these patients. It detected additional hepatic lesions in 14 patients (29.2%). IOUS contributed to changing the operative plan in 21 patients (43.8%). It was directly responsible for avoiding resection or ablation in 7 patients (14.6%), 5 of whom had multiple bilobar lesions, 1 had IOUS-guided biopsy that revealed caseating granuloma on frozen section, and 1 patient had no lesion on IOUS. Three patients had extent of resection changed based on IOUS findings. IOUS also guided radiofrequency ablation in 8 patients and ethanol injection in one patient. CONCLUSION: IOUS is an essential tool in surgery for hepatic tumors. In addition to accurate staging, it also aids in safe resection and radiofrequency ablation in appropriate cases.

Combination chemotherapy and radiation for palliation of hepatocellular carcinoma.

Twenty seven patients with hepatocellular carcinoma were treated by sequential methotrexate (75 mg/m2) and 5-fluorouracil (5-FU) (750 mg/m2) on day 1 followed on days 8-36 by external beam radiotherapy (total dose 30 cGy). The response was assessed by liver size on clinical examination. One patient had complete response, and six patients had partial response. The overall response to the treatment was 25.9%. More than a 50% reduction in serum alfa-fetoprotein level was noted in 66.6% patients. Seventy-one percent of patients had palliation of pain following therapy. The median survival of responders was 11 months and of nonresponders, 2 months. Radiation was discontinued in two patients who developed radiation hepatitis. Additional trials with different dosages and schedules are needed to fully evaluate this form of therapy.

Duodenal diversion of percutaneous biliary drain through a percutaneous endoscopic gastrostomy: report of a case.

Occasionally, percutaneous biliary drainage is the only possible form of treatment in a patient with a malignant obstruction at the porta hepatis. We report on a case of gallbladder carcinoma with a complete block at the porta hepatis, which was palliated with a percutaneous biliary drain. Enteral reinfusion of bile was accomplished through a duodenal tube placed through a percutaneous endoscopic gastrostomy.

Total parenteral nutrition.

Parenteral nutrition is a form of therapy in which elemental nutrients (sugars, lipids, amino acids, vitamins and minerals) are given as an intravenous infusion. It is complementary and not competitive to enteral nutrition. While a vast majority of patients can be managed by enteral nutrition, a few patients need parenteral nutrition for survival. Very few patients may need both enteral and parenteral nutrition for short periods. The indications, delivery methods and formulations of parenteral nutrition have been refined in the past 30 years. It is now possible to give parenteral nutrition for prolonged periods at home. Three-in-one parenteral nutrition mixture bags are presently available in India. This article discusses the practical aspects of using parenteral nutrition in everyday practice.

Enteral nutrition by tube feeding in adults.

Patients who cannot eat enough require alternatives to oral feeding. Tube feeding is one such method for patients with a functioning gut. The techniques for the placement of feeding tubes and diets for tube feeding have improved during the past 20 years. Comfortable thin-bore polyurethane tubes are replacing the thicker vinyl tubes. Long term access routes such as gastrostomy and jejunostomy are being done by endoscopic or radiological techniques. Pre-defined formula feeds have reduced the effort and labour involved in the preparation, storage and administration of blenderized tube feeds. However, the use of soft feeding tubes and commercial formulae will increase the cost of nutrition therapy in India. The ultimate cost-effectiveness of tube feeding will depend on whether it is used appropriately during an illness with adequate delivery of feeds, and whether attention is given to small details by a dedicated nutritional support team. A strong commitment to the scientific use of nutritional support is necessary for getting the best results from tube feeding in everyday practice.

Percutaneous endoscopic gastrostomy for long term enteral nutrition.

BACKGROUND: Percutaneous endoscopic gastrostomy for long term enteral nutrition is often indicated in patients with head, neck and oesophageal cancer but despite its growing popularity elsewhere, it is not widely used in India. METHODS: Between March 1990 and July 1991, we performed percutaneous endoscopic gastrostomy in 54 patients. The primary sites of tumour were the hypopharynx (11), oral cavity (7), tongue (7), cricopharynx (7), oesophagus (16) and other sites (6). The indications were difficulty in swallowing following treatment (22), preoperative nutritional support (7) and terminal care (21). In 49 patients, it was performed by the 'pull' technique in the endoscopy room under local anaesthesia and mild sedation. Indigenously prepared tubes and blenderised foods were used. Fifteen patients underwent dilatation of the tumour prior to the gastrostomy. RESULTS: The procedure was successful in 50 (93%) patients. Three failures were caused by obstructing tumours and one by a previous gastric resection. Feeding was started 18 to 24 hours after the procedure in 48 patients. No major complications occurred but minor complications were seen in 11 (22%) patients. Fourteen patients had their gastrostomy tube removed after 2 to 6 months of use while 15 patients undergoing therapy or with persistent dysphagia were on gastrostomy feeds for 1 to 6 months. Of the 21 terminally ill patients, 8 died, 6 were lost to follow up and 7 were on feeds for 1 to 6 months. CONCLUSIONS: Percutaneous endoscopic gastrostomy is a simple, safe and effective method for long term enteral feeding. Indigenous tubes and home made blenderised foods are adequate substitutes for the more expensive commercial kits and enteral formulations.

Mucocutaneous exposure to body fluids during digestive endoscopy: the need for universal precautions.

BACKGROUND: Endoscopy personnel are at high risk of exposure to infectious body fluids during endoscopy. There are no studies documenting the frequency of such exposure. AIM: To determine the frequency of exposure to body fluids, and factors that may modify the risk of exposure during digestive endoscopy. METHODS: During a 10-month period, 948 endoscopy procedures done by two endoscopists were assessed for the occurrence of splashes to uncovered parts of the body. Odds ratio was used to determine any change in the exposure risk with different risk factors. RESULTS: The overall frequency of splash to any part of the body was 13.2% (95% CI 10.8-15.9). Common sites of exposure were the eyes, face, forearms and feet. Splash to the skin of the face, forearms and feet occurred in 9.5% (95% CI 7.5-11.8). The risk remained unchanged during therapeutic endoscopy, assisted endoscopy, or endoscopy with biopsy or cytology. Using video endoscopy led to significant reduction in splashes on the skin. Overall splash rate to the eyes was 4.1% (95% CI 2.9-5.6). This remained unchanged during therapeutic endoscopy, assisted endoscopy, and endoscopic biopsy or cytology sampling. The risk was not reduced during video endoscopy. CONCLUSIONS: Endoscopy results in muco-cutaneous exposure to potentially infectious body fluids in 13% or more procedures. The risk of exposure is not reduced by video endoscopy, or by avoiding instrumentation of the biopsy channel. We recommend that all endoscopists and endoscopy assistants must follow universal precautions.

Epidemiology of digestive tract cancers in India. V. Large and small bowel.

The large bowel is a leading site for cancers in developed countries whereas small bowel cancers are rare worldwide. The incidence rates of both large and small bowel cancer are low in India, and rectal cancer is more common than colon cancer. The incidence rates of colon cancer in eight population registries vary from 3.7 to 0.7/100,000 among men and 3 to 0.4/100,000 among women. For rectal cancer the incidence rates range from 5.5 to 1.6/100,000 among men and 2.8 to 0/100,000 among women. One intriguing observation is the occurrence of rectal cancer in young Indians. Rural incidence rates for large bowel cancers in India are approximately half of urban rates. Based on data from eight registries, we estimate that, in the year 2001, the incidence of large bowel cancer in India will be 18,427 in men and 13,092 in women. Immigrant studies reveal an increase in incidence as compared to the rates in native counterparts. Reliable time trends for India are available only from the Bombay registry. Significant increase in the incidence of colon cancer has been reported for both men and women over two decades, but the rates of rectal cancer are steady. The low incidence of large bowel cancers in Indians can be attributed to high intake of starch and the presence of natural antioxidants such as curcumin in Indian cooking. The role of hereditary factors has been evaluated in a few studies. Some studies have reported the occurrence of both FAP and HNPCC in India. There are no Indian studies on large bowel cancer prevention. The prevalence of adenomas is rare in elderly Indians undergoing colonoscopy, even in those with large bowel cancers. Small bowel cancers are extremely rare in India and no analytical studies have been published. Hospital-based data suggest that lymphomas of small bowel are more common than carcinomas. In conclusion, the incidence of large and small bowel adenomas and cancers is low in Indians. Increase in the incidence of large bowel cancers in immigrants and urban Indians compared to rural populations supports a role for environmental risk factors including diet. High rates of rectal cancers in young Indians could suggest a different etiopathogenesis, which is neither inherited nor traditional diet-related.

Epidemiology of digestive tract cancers in India. VI. Projected burden in the new millennium and the need for primary prevention.

The incidence rates of most digestive cancers in India are moderate or low. The highest rates are recorded in the urban population of Mumbai and the lowest in the rural population of Barshi in Maharashtra state. The rates will rise as the life expectancy of Indians increases along with urbanization and, within the next few decades, may reach those recorded in Indians living abroad. Based on available population data, we estimate that in the year 2001 there will be approximately 145,000 new cases of digestive cancers in India. In men, the esophagus would be the commonest site (n = 24,925), followed by the stomach (23,100), rectum (10,462), liver (8812), colon (8004), pancreas (5757) and gall bladder (3967). In women, the esophagus would be the commonest site (n = 18,608), followed by the stomach (11,890), gall bladder (7360), rectum (6983), colon (6115), liver (4227) and pancreas (3435). The incidence of cancers of the esophagus and stomach is declining spontaneously in India. It may be possible to accelerate this by reducing the use of tobacco and improving the diet. At the same time the incidence of cancers of the colon, pancreas, liver and gall bladder is rising, largely due to urbanization that leads to major changes in the diet and personal habits. A preventive approach is needed by public health education. Indians should be encouraged to retain their traditional protective diets, eat more fruits and vegetables, do more physical activity, and abstain from tobacco. Gastroenterologists can also help in secondary prevention by screening high-risk individuals, e.g., patients with chronic liver disease for liver cancer and relatives of patients with familial bowel cancer.

Epidemiology of digestive tract cancers in India. III. Liver.

Liver cancer or hepatocellular carcinoma (HCC) is the fourth commonest cause of cancer deaths in the world. The condition is extremely common in Southeast Asia and Africa. In this report the available data on the epidemiology of HCC from India are summarized. We estimate that 12,750 new patients will be diagnosed to have HCC in India in the year 2001; this will comprise 1.6% of all incident cancers. Published studies from India and those involving Indian immigrants to other countries suggest that the prevalence of HCC is relatively lower in Indians than in most parts of the world. This contrasts with the widespread contamination of foods with aflatoxin and the moderately high prevalence of hepatitis B (HBV) and hepatitis C (HCV) virus-related chronic liver disease in India. There are no studies available to explain this observation. There are several articles on HBV and HCC in India but there is a paucity of analytical epidemiological data on HCV and HCC from India. Published studies indicate HBV to be the single most important etiologic association, with HCV playing a lesser but important role. About 80% of Indian patients with HCC have hepatitis virus-associated liver disease. Multicenter epidemiological studies are needed to solve some of the enigmas and observations peculiar to India.

Epidemiology of digestive tract cancers in India. II. Stomach, and gastrointestinal lymphomas.

The incidence of stomach cancer and GI lymphomas is low in most parts of India. There is paucity of analytical epidemiologic data on these from India. While the time trends for the incidence of gastric cancer are encouraging, most cancers are diagnosed in an advanced stage when long-term cure is only a remote possibility. Multi-center epidemiologic studies should be undertaken to solve some of the enigmas and observations peculiar to India.