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GastroIntestinal Cancers Guidelines

EVIDENCE-BASED MANAGEMENT FOR GASTRO-INTESTINAL CANCER

  1. COLON CANCER
  2. RECTAL CANCER
  3. STOMACH CANCER
  4. PERIAMPULLARY & PANCREATIC CANCER
  5. GALL BLADDER CANCER
  6. PRIMARY LIVER CANCER (HCC)

Diagnostic work up and staging

  • CBC, Biochemistry
  • Chest X-ray
  • CT scan Abdomen & Pelvis
  • Colonoscopy and biopsy,CEA
  • Significant family history Familial Adenomatous Polyposis (FAP)
  • Hereditary Non Polyposis Colon Cancer(HNPCC)
  • For obstructive lesions-post operative colonoscopy advised/EUS to assess sphincter involvement

Modified Dukes' Staging for Colorectal Cancer (Astler Coller)
A: Tumor involves only the submucosa
B1: Tumor infiltrates muscularis propria & lymph nodes negative
B2: Tumor infiltrates full thickness of colonic wall & lymph nodes negative 
C1: Tumor infiltrates upto muscularis propria & lymph nodes positive
C2: Tumor infiltrates full thickness of colon & lymph nodes positive
D: Distant metastasis

Model histopathology report for Colo-Rectal Cancers

  • Tumor size and type
  • Tumor grade
  • Depth of invasion
  • Cut margins including the circumferential cut margin
  • No. of positive / total no. of lymph nodes dissected
  • Any e/o perforation

Optional details

  • Lymphovascular emboli
  • Perineural spread
  • Serosal deposit >3 mm in size

TREATMENT OF CARCINOMA COLON

Operable disease

  • The principle is to remove the affected part of the colon with the draining lymph node stations.
  • Surgical resection is the best option for curative treatment of colonic cancer.
  • Extent of surgical resection depends on the site of the tumor.

  • 1Caecum, ascending colon: Right radical hemicolectomy.
  • 2Hepatic flexure: Right extended hemicolectomy.
  • 3Transverse colon: Transverse colectomy.
  • 4Descending colon: Left radical hemicolectomy.
  • 5Sigmoid colon: Sigmoid colectomy.
  • 6FAP/HNPCC: Total colectomy.


Indication for Post-operative adjuvant chemotherapy 1

  • 1Tumor infiltrates through full thickness of the colonic wall [Modified Dukes' B2] or
  • 2Positive lymph nodes [Modified Dukes' C]

Chemotherapy Schedule:
5-FU (375-450 mg/m2) + leucovorin (20 mg/m2) x 5 days.
6 cycles for 6 months1.

Inoperable disease

  • Palliative ileotransverse bypass for inoperable ascending colon tumor
  • Loop Ileostomy for advanced disease with intestinal obstruction
  • Good Performance status: Palliative Chemotherapy
  • Poor Performance status: Best supportive care or Palliative Chemotherapy
  • Palliative stenting may be tried for obstructive lesions

Metastatic Colon Cancer

Liver metastases

  • Good performance status and resectable liver metastasis: Surgery after resection of primary [2].
  • Good performance status and inoperable liver metastasis: Palliative resection of the primary followed by palliative Chemotherapy or best supportive care/ intraarterial chemotherapy through hepatic artery
  • Poor performance status and inoperable metastasis: Palliative Chemotherapy or best supportive care

Other Visceral Metastasis or Ascites: Palliative Chemotherapy or best supportive care

Follow-up

  • 3 monthly for 2 years & then 6 monthly
  • CBC, Biochemistry, CEA
    Optional

  • Chest X-ray and CT scan as indicated
  • Colonoscopy at 3 - 5 year intervals

Diagnostic work up and staging: 
Same as for colon cancer

Treatment

A. Operable disease

Surgery as per the site of the tumor (All patients undergo Total Mesorectal Excision)[3,4]

  • High lesions - above 7 cms - high Anterior Resection (AR) with or without covering colostomy
  • Low lesions - between 4 and 7 cms - low AR
  • Very low lesions - if feasible, intersphincteric resections for tumors just above the anorectal ring[5]. A covering ileostomy is always performed in intersphincteric resections.
  • Abdomino Perineal Resection (APR) with permanent colostomy in patients with lesions below the anorectal ring or in patients whose sphincter is involved.

Post-operative adjuvant protocol

  • Modified Dukes' A & B1 - observe
  • Modified Dukes' B2 , C - RT and CT as per the following GI Intergroup study Protocol [6]. The addition of Levamisole or Leucovorin to 5-FU did not improve the results in this GI intergroup study.

5-FU (500 mg/m2) x 5 days repeated at 4 weeks interval

5-FU (500 mg/m2) x 3 days repeated at 4 weeks interval on day 1- 3 
and day 29 - 31 of Pelvic Radiotherapy (50Gy / 28fr / 5.5 weeks)

4 weeks after completion of RT, one more cycle of 5-FU (400 mg / m2
x 5days)

 

Last cycle of 5 FU ( 500 mg/m2 )


Radiation Therapy For Rectal Cancer
The Swedish rectal cancer trial[7] reported reduced local recurrence rates and increased overall survival following preoperative radiotherapy that was followed by surgery. However, there are a number of studies that have not reported the benefits of radiation alone. Also, there are no randomized studies of preoperative combined modality treatment in rectal cancer. In contrast, a number of studies have reported the benefits of postoperative combined modality8 therapy. This protocol is followed at the TMH. The intent of treatment is to include the tumor bed with margins plus internal iliac and pre sacral lymph node groups. The external iliac nodes are included if indicated or involved by direct extension. Radiation therapy is usually delivered to the pelvis using 3-field technique: Posterior and bilateral portals and parallel opposed AP portals when indicated (R1/ R2 resection with disease adherent to prostate / bladder / uterus). Dose: 50Gy / 28 fractions / 6 weeks

B. Loco regionally advanced disease
Palliative resections are performed if feasible. For obstructive lesions diverting colostomy is required9.

  • Good Performance status: Radiotherapy plus Chemotherapy and if tumour becomes operable then attempt surgery
  • Poor Performance status: Best supportive care or palliative radiotherapy or chemotherapy

C. Metastatic disease
Liver metastases

  • Good performance status and resectable liver metastasis: surgical excision
  • Good performance status and inoperable liver metastasis: Palliative systemic chemotherapy or regional infusion[10]
  • Poor performance status and inoperable metastasis: Palliative Chemotherapy or best supportive care

Other Visceral Metastasis or Ascites: Palliative Chemotherapy or best supportive care

Follow-up

  • 3 monthly for 2 years & then 6 monthly
  • CBC, Biochemistry, CEA
  • Chest X-ray and CT scan as indicated
  • Colonoscopy at 3 - 5 year intervals (optional).

Diagnostic work up and staging

  • CBC, Biochemistry.
  • Upper GI endoscopy & biopsy
  • CT scan Abdomen & Pelvis
  • Laparoscopic assessment where indicated[11]

Model Histopathology Report

  • Tumor size
  • Tumour type
  • Tumor location
  • Tumor grade
  • Depth of infiltration
  • Cut margins including circumferential cut margins
  • Lymph nodes positive / total no. of lymph nodes dissected
  • Levels of lymph nodes

    Optional details
  • Perineural invasion
  • Lymphovascular embolization

A. Operable disease

The type and extent of surgery is as per the site of the tumor.

  • Tumors of the CO junction and the cardia: Proximal Gastrectomy with partial oesophagectomy
  • Tumors of the body and fundus: Total Gastrectomy
  • Tumors of the antrum and pylorus: Distal Gastrectomy

Extent of lymphadenectomy

  • Standard: Excision of perigastric lymph nodes (D1)
  • Extended: Excision of lymph nodes along the common hepatic artery, left gastric artery and splenic artery (D2)

D2 resection in its present form without distal Pancreatico- splenectomy is a validated procedure12,13. However all 4 randomized controlled trials done for D1 Vs D2 resections have not shown any improvement in overall as well as disease free survival14. The question as yet remains open to discussion.

Distal and proximal cut margins are confirmed to be microscopically negative by frozen section.

Post-operative adjuvant treatment

Indications: For lymph node positive tumors we recommend Macdonald's regimen of adjuvant CT / RT in patients with a good performance status[15]. The other indication is full thickness involvement with serosal disease. Patients with a poor performance score are not offered any adjuvant therapy as they may not tolerate or complete the treatment.

Macdonald's Regime [15]

5-FU (425 mg/m2)+ leucovorin (20 mg/m2) for 5 days

Radiotherapy is given to the tumor bed and the draining lymph nodal region using mega voltage beams to a dose of 45Gy / 25 cycles / 5 weeks along with 5-FU (dose reduced to 400 mg/m2) on day 1-4 and on last 3 days of RT.

After completion of RT, 2 more cycles of 5FU plus leucovorin are given with the original dosage.

B. Loco-regionally Advanced or metastatic disease

  • Poor performance status: Palliative care
  • Good performance status: Palliative surgery (Resection or bypass) or palliative chemotherapy as appropriate

Follow-up

  • 3 monthly for 2 years & then 6 monthly

Diagnostic work up and staging

  • CBC and Biochemistry
  • CT scan abdomen
  • Endoscopy & biopsy for periampullary tumors
  • Endoscopic ultrasound for accurate staging
  • ERCP & stenting is used judiciously for cholangitis / severe pruritis etc.

A. Operable disease

Appropriate surgery: Pylorus Preserving Pancreatico-Duodenectomy is the surgery of choice16. Classical Whipple resection is indicated for tumors of the first or second part of the duodenum17.

Post operative Adjuvant therapy
Of the two randomized trials[18,19] evaluating the benefit of post operative adjuvant treatment in resected pancreatic cancer, survival benefit with adjuvant chemotherapy was seen in one study. However this advantage was seen primarily in patients with R0 resections than in R1 resections.

B. Unresectable disease

  • Endoscopic biliary stenting.
  • Surgical bypass where indicated [20]. This is for patients with both biliary and digestive obstruction. It is also performed when patient is explored with intent to resect but has unresectable disease on exploration.
  • Palliative chemoradiation with Gemcitabine has shown objective responses but the final results are awaited and hence no recommendation can be made [21].

Follow-up

  • 3 monthly for 2 years & then 6 monthly

Diagnostic work up and staging

  • CBC, Biochemistry
  • Chest X Ray
  • CT scan abdomen
  • MRI & MRCP if jaundiced

Model Histopathology Report (Histology review essential for cases presenting after a cholecystectomy outside)

  • Tumor size
  • Depth of infiltration
  • Tumor grade
  • Cut margins (liver cut margin & cystic duct cut margin)
  • Positive lymph nodes / total no. of lymph nodes cleared

    Optional details
  • Perineural spread
  • Lymphovascular emboli

Treatment: Primary presentation

A. Operable disease

  • Tumors limited to the mucosa / submucosa: simple cholecystectomy.
  • Tumors involving muscularis propria and beyond: Radical cholecystectomy. This entails removal of the gall bladder, wedge resection of the liver (segment 4 & 5), and removal of the portal, hepatic, retropancreatic and retroduodenal lymph nodes22

B. Inoperable disease

  • Good performance status - Palliative CT may be offered
  • Poor performance status - Palliative care
  • Symptomatic jaundice: ERCP & stenting may be provide palliation.

 

 

Treatment: Presentation following cholecystectomy

Radical second resection may offer survival benefit for patients with gallbladder cancer detected on cholecystectomy. If the cancer infiltrates the muscle layer or beyond - radical re-surgery (wedge resection of the liver with lymph node clearance) is offered [23].

Post-operative adjuvant therapy
If the histology for lymph nodes / liver fossa is positive, adjuvant RT and / or chemotherapy may be considered [24].

Follow-up
3 monthly for 2 years and then 6 monthly. CT scan annually.

PRIMARY LIVER CANCER (HCC)

  • CBC, AFP, LFT's
  • Hepatitis B & C screening
  • CT scan abdomen

A. Operable cases

  • Appropriate liver resection (preferably anatomical)25is performed in non-cirrhotics and Child A cirrhotics.
  • Right hepatectomy for lesions in right lobe, right extended hepatectomy for right lobe lesions encroaching on segment 4, left hepatectomy for left lobe lesions.
  • For Child B & C cirrhotics - Chemoembolization [26,27] with interventional radiologists help (Injection of gel foam impregnated with cisplatinum into the feeding vessel) or radiofrequency ablation28 or systemic chemotherapy may be offered if the performance status of the patient and the liver tumor characteristics permit.

Follow-up

  • 3 monthly for 2 years & then 6 monthly
  • AFP and LFT's 6 monthly

GastroIntestinal Cancers Abstracts

COLON CANCER1
EBM

1. The benefit of leucovorin-modulated fluorouracil as postoperative adjuvant therapy for primary colon cancer: results from NSABP protocol C-03. 
Wolmark N, Rockette H, Fisher B et al. J Clin Oncol 1993;11:1879-87.

PURPOSE: This study was designed to evaluate the efficacy of leucovorin-modulated fluorouracil (5-FU) as adjuvant therapy for patients with Dukes' stage B and C colon cancer. PATIENTS AND METHODS: Data are presented from 1,081 patients with Dukes' stage B and C carcinoma of the colon entered into National Surgical Adjuvant Breast and Bowel Project (NSABP) protocol C-03 between August 1987 and April 1989. Patients were randomly assigned to receive lomustine (MeCCNU), vincristine, and 5-FU (MOF), or leucovorin-modulated 5-FU (LV + 5-FU). The mean time on study was 47.6 months. RESULTS: Comparison between the two groups indicates a disease-free survival advantage for patients treated with LV + 5-FU (P = .0004). The 3-year disease-free survival rate for patients in this group was 73% (95% confidence interval, 69% to 77%), compared with 64% (95% confidence interval, 60% to 68%) for patients receiving MOF. The corresponding percentage of patients surviving was 84% for those randomized to receive LV + 5-FU and 77% for the MOF-treated cohort (P = .003). At 3 years of follow-up, patients treated with postoperative LV + 5-FU had a 30% reduction in the risk of developing a treatment failure and a 32% reduction in mortality risk compared with similar patients treated with MOF. CONCLUSION: Treatment with LV + 5-FU significantly prolongs disease-free survival and results in a significant benefit relative to overall survival. These findings, when considered together with results from a recent meta-analysis demonstrating a benefit from LV + 5-FU in advanced disease, provide evidence to support the concept of metabolic modulation of 5-FU.

 

2. Clinical score for predicting recurrence after hepatic resection for metastatic colorectal cancer: analysis of 1001 consecutive cases. 
Fong Y, Fortner J, Sun RL, et al. Ann Surg 1999; 230:309-18.

OBJECTIVE: There is a need for clearly defined and widely applicable clinical criteria for the selection of patients who may benefit from hepatic resection for metastatic colorectal cancer. Such criteria would also be useful for stratification of patients in clinical trials for this disease. METHODS: Clinical, pathologic, and outcome data for 1001 consecutive patients undergoing liver resection for metastatic colorectal cancer between July 1985 and October 1998 was examined. These resections included 237 trisegmentectomies, 394 lobectomies, and 370 resections encompassing less than a lobe. The surgical mortality rate was 2.8%. RESULTS: The 5-year survival rate was 37%, and the 10-year survival rate was 22%. Seven factors were found to be significant and independent predictors of poor long-term outcome by multivariate analysis: positive margin (p = 0.004), extrahepatic disease (p = 0.003), node-positive primary (p = 0.02), disease-free interval from primary to metastases <12 months (p = 0.03), number of hepatic tumors >1 (p = 0.0004), largest hepatic tumor >5 cm (p = 0.01), and carcinoembryonic antigen level >200 ng/ml (p = 0.01). When the last five of these criteria were used in a preoperative scoring system, assigning one point for each criterion, the total score was highly predictive of outcome (p < 0.0001). No patient with a score of 5 was a long-term survivor. CONCLUSION: Resection of hepatic colorectal metastases may produce long-term survival and cure. Long-term outcome can be predicted from five criteria that are readily available for all patients considered for resection. Patients with up to two criteria can have a favorable outcome. Patients with three, four, or five criteria should be considered for experimental adjuvant trials. Studies of preoperative staging techniques or of adjuvant therapies should consider using such a score for stratification of patients.

RECTAL CANCER2
EBM

3. Mesorectal excision for rectal cancer.
MacFarlane JK, Ryall RD, Heald RJ. Lancet 1993 20; 457-60.

Concern about world wide local recurrence rates for rectal cancer of 20-45%, together with anxiety at the recent proliferation of adjuvant therapies, led us to review the efficacy of total mesorectal excision (TME) with which no adjuvant therapy had been combined. Precise, sharp dissection is undertaken around the integral mesentery of the hindgut, which envelops the entire mid rectum. This procedure adds to operative time and complications but has been claimed to eliminate virtually all locally recurrent disease after "curative" surgery. Independent analysis (J. K. M.) of prospective follow-up data extended over a 13-year interval (1978-91; mean 7.5 years). The actuarial local recurrence rate after curative anterior resection at 5 years is 4% (95% Cl 0-7.5%) and the overall recurrence rate is 18% (10-25%). 10-year figures are 4% (0-11%) and 19% (7-32%). In view of the high-risk classification used for the North Central Cancer Treatment Group (NCCTG), which has led to a trend to chemoradiotherapy, a similar group of high-risk Basingstoke cases was constructed for comparison purposes. This group included 135 consecutive Dukes' B (B2) and Dukes' C cancer operations, both anterior resection and abdominal-perineal excision, for tumours below 12 cm from the anal verge. Results from TME alone are substantially superior to the best reported (NCCTG) from conventional surgery plus radiotherapy or combination chemoradiotherapy: 5% local recurrence at 5 years compared with 25% and 13.5%, respectively; and 22% overall recurrence compared with 62.7% and 41.5%, respectively (Dukes' B cases [B2], 15%; Dukes' C cases, 32%). Meticulous TME, which encompasses the whole field of tumour spread, can improve cure rates and reduce the variability of outcomes between surgeons. Far more genuine "cures" of rectal cancer are possible by surgery alone than have generally been believed or are currently accepted. Better surgical results are an essential background for the more selective use of adjuvant therapy in the future.


4. Improved survival and local control after total mesorectal excision or D3 lymphadenectomy in the treatment of primary rectal cancer: an international analysis of 1411 patients.
Havenga K, Enker WE, Norstein J, et al. Eur J Surg Oncol 1999; 25 4: 368-74.

AIMS: Improved local control and survival in the treatment of rectal cancer have been reported after total mesorectal excision and after extended lymphadenectomy. Comparison of published results is difficult because of differences in patient populations and definitions. We compared three series of patients who underwent standardized surgery [i.e. total mesorectal excision (TME) or D3 lymphadenectomy] with patients who underwent conventional surgery, using actual patient data and uniform definitions. METHODS: TME was performed at Memorial Sloan-Kettering Cancer Center, New York, USA (n=254) and the North Hampshire Hospital, Basingstoke, UK (n=204). D3 lymphadenectomy was performed at the National Cancer Center, Tokyo (n=233). Conventional surgery was used in hospitals in Norway (n=366) and in hospitals of the Comprehensive Cancer Center West, The Netherlands (n=354). Only patients with a curatively resected primary TNM Stage II or Stage III rectal cancer within 12 cm from the anal verge were included. RESULTS: Five-year overall survival and cancer-specific survival were 62-75% and 75-80%, respectively, in the standardized surgery groups and 42-44% and 52%, respectively, in the conventional surgery groups. Local recurrence rates ranged from 4 to 9% in the standardized surgery groups and 32-35% in the conventional surgery groups. CONCLUSIONS: A 30% survival difference and 25% local recurrence difference is not likely to be caused by the shortcomings which are inherent in a non-randomized study: selection bias, assessment variability or stage migration. This study suggests that standardized surgery give superior survival and local control when compared to conventional surgery.

5. Intersphincteric resection with excision of internal anal sphincter for conservative treatment of very low rectal cancer.
Rullier E, Zerbib F, Laurent C, et al. Dis Colon Rectum 1999; 42: 1168-75

PURPOSE: Standard surgical treatment for low rectal cancer situated below 5 cm from the anal verge or at less than 1 cm from the anal ring is abdominoperineal resection. This is because of the necessity both to achieve a sufficient distal margin and to preserve the whole of the anal sphincter. The aim of this study was to evaluate morbidity, oncologic, and functional results of intersphincteric resection with excision of the internal anal sphincter and low coloanal anastomosis for carcinomas of the anorectal junction. METHODS: From January 1990 to December 1996, 16 patients were studied prospectively. All patients had an infiltrating adenocarcinoma (5 T2 and 11 T3), located between 2.5 and 4.5 (mean, 3.6) cm from the anal verge. Rectal resection with a minimum distal margin of 2 (mean, 2.4) cm was performed in all cases; six patients underwent partial resection of the internal sphincter, and ten patients had a subtotal resection. A colonic J-pouch was associated with coloanal anastomoses in eight cases. Twelve patients had preoperative radiotherapy, 3 with concomitant chemotherapy; 5 patients had postoperative chemotherapy. RESULTS: There was no postoperative mortality. Morbidity occurred in four patients, of whom two underwent permanent colostomy after pelvic hemorrhage or anovaginal fistula. After a median follow-up of 44 (range, 11-92) months, no local recurrence was observed, and two patients died of distal metastases. The five-year actuarial survival rate was 75 percent. Continence was normal in one-half of patients and was altered in the other patients who suffered from occasional minor leaks. The median resting pressure was lower after subtotal than after partial resection of the internal sphincter (40 vs. 70 cm H2O; P = 0.02), but functional results were similar in the two groups. CONCLUSION: These preliminary results suggest that intersphincteric resection can be an alternative to abdominoperineal resection for selected rectal tumors situated at the anorectal junction, without compromising chance of cure. Functional results and continence were not altered by subtotal resection of the internal anal sphincter.


6. Adjuvant therapy in rectal cancer: analysis of stage, sex, and local control--final report of intergroup 0114.
Tepper JE, O'Connell M, Niedzwiecki D, et al. J Clin Oncol 2002; 20: 1744-50.

PURPOSE: The gastrointestinal Intergroup studied postoperative adjuvant chemotherapy and radiation therapy in patients with T3/4 and N+ rectal cancer after potentially curative surgery to try to improve chemotherapy and to determine the risk of systemic and local failure. PATIENTS AND METHODS: All patients had a potentially curative surgical resection and were treated with two cycles of chemotherapy followed by chemoradiation therapy and two additional cycles of chemotherapy. Chemotherapy regimens were bolus fluorouracil (5-FU), 5-FU and leucovorin, 5-FU and levamisole, and 5-FU, leucovorin, and levamisole. Pelvic irradiation was given to a dose of 45 Gy to the whole pelvis and a boost to 50.4 to 54 Gy. RESULTS: One thousand six hundred ninety-five patients were entered and fully assessable, with a median follow-up of 7.4 years. There was no difference in overall survival (OS) or disease-free survival (DFS) by drug regimen. DFS and OS decreased between years 5 and 7 (from 54% to 50% and 64% to 56%, respectively), although recurrence-free rates had only a small decrease. The local recurrence rate was 14% (9% in low-risk [T1 to N2+] and 18% in high-risk patients [T3N+, T4N]). Overall, 7-year survival rates were 70% and 45% for the low-risk and high-risk groups, respectively. Males had a poorer overall survival rate than females. CONCLUSION: There is no advantage to leucovorin- or levamisole-containing regimens over bolus 5-FU alone in the adjuvant treatment of rectal cancer when combined with irradiation. Local and distant recurrence rates are still high, especially in T3N+ and T4 patients, even with full adjuvant chemoradiation therapy.

7. Improved survival with preoperative radiotherapy in resectable rectal cancer. Swedish Rectal Cancer Trial. 
N Engl J Med 1997; 336: 980-7.

BACKGROUND: Adjuvant radiotherapy for rectal cancer has been extensively studied, but no trial has unequivocally demonstrated improved overall survival with radiotherapy, despite a reduction in the rate of local recurrence. METHODS: Between March 1987 and February 1990, we randomly assigned 1168 patients younger than 80 years of age who had resectable rectal cancer to undergo preoperative irradiation (25 Gy delivered in five fractions in one week) followed by surgery within one week or to have surgery alone. RESULTS: The irradiation did not increase postoperative mortality. After five years of follow-up, the rate of local recurrence was 11 percent (63 of 553 patients) in the group that received radiotherapy before surgery and 27 percent (150 of 557) in the group treated with surgery alone (P<0.001). This difference was found in all subgroups defined according to Dukes' stage. The overall five-year survival rate was 58 percent in the radiotherapy-plus-surgery group and 48 percent in the surgery-alone group (P=0.004). The cancer-specific survival rates at nine years among patients treated with curative resection were 74 percent and 65 percent, respectively (P=0.002). CONCLUSIONS: A short-term regimen of high-dose preoperative radiotherapy reduces rates of local recurrence and improves survival among patients with resectable rectal cancer.

8. Randomized controlled trial of postoperative radiotherapy and short-term time-scheduled 5-fluorouracil against surgery alone in the treatment of Dukes' B and C rectal cancer. Norwegian Adjuvant Rectal Cancer Project Group.
Tveit KM, Guldvog I, Hagen S, et al. Br J Surg 1997; 84:1130-5

BACKGROUND: The purpose of the present study was to investigate whether a 1-month regimen of postoperative radiotherapy combined with 5-fluorouracil could reduce the local recurrence rate and improve survival in patients with Dukes B and C rectal cancer. METHODS: One hundred and forty-four patients were randomized to surgery alone or surgery combined with postoperative radiotherapy (46 Gy) and bolus 5-fluorouracil 30 min before six of the radiotherapy fractions. One hundred and thirty-six patients were eligible. RESULTS: The adjuvant treatment was well tolerated. After an observation time of 4-8 years, patients in the adjuvant treatment group had a cumulative local recurrence rate of 12 per cent compared with 30 per cent in the group that had surgery only (P = 0.01). The 5-year recurrence-free and overall survival rate was 64 per cent in the adjuvant group compared with 46 per cent (P = 0.01) and 50 per cent (P = 0.05) respectively in the surgery group. The adjusted relative risk of recurrence and death for the adjuvant group was 0.48 (95 per cent confidence interval 0.28-0.82) and 0.56 (0.33-0.94) respectively. CONCLUSION: The 1-month postoperative combination regimen improved treatment results in patients with Dukes B and C rectal cancer, in terms of local recurrence rate, recurrence-free survival and overall survival, without serious side-effects.

9. Advanced rectal cancer. What is the best palliation?
Longo WE, Ballantyne GH, Bilchik A, et al. Dis Colon Rectum 1988; 31: 842-7
The best treatment of advanced rectal cancer remains uncertain. The aim of this study was to determine the outcome after palliative procedures in-patients with advanced rectal cancer. One hundred and three patients treated over a seven-year period were identified, including 30 with local invasion, 18 with local metastases, and 55 with distant metastases. Patients were grouped into two groups: those who underwent palliative resection (68) and those who were treated without rectal resection (55). The nonresected group included patients who underwent diverting colostomies (28) and those who received multimodality therapy without surgery (7). The average age of all patients was 63.1 years. Patients in the nonresected group had more distant disease (68 percent) than the resected group (46 percent). Significant pelvic pain was a more common problem in the nonresected group (15 percent) than in the resected group (4 percent). Similarly, pelvic sepsis was more common in the nonresected group (14 percent) than in the resected group (9 percent). Postoperative mortality was 4.3 percent after palliative resection and 3.8 percent after diverting colostomy. Survival of the resected group at one year was 65 percent and at two years 20 percent. Survival of the nonresected group at one year was 20 percent and at two years 0 percent. Survival in the resected group was significantly (P less than .01) better than the nonresected group but probably can be attributed to the more extensive disease generally present in the patients who did not undergo resection. These results suggest that patients with advanced rectal cancers should undergo palliative resection whenever possible because resection decreases pelvic complications and may improve quality of life.

10: Current Treat Options : Liver Metastases.
 
Kemeny NE, Ron IG. Gastroenterol 1999; 2: 49-57.

Liver metastases, especially from colorectal primary cancers, are treatable and potentially curable. Imaging techniques such as CT, MRI,and sonography have advanced in recent years and led to increased sensitivity and specificity in the diagnosis of liver metastases. Liver surgery also has been revolutionized in the past two decades. Dissections along nonanatomic lines have permitted the resection of multiple lesions that previously might have been considered unresectable. We regard resection of a solitary hepatic metastasis or up to four metastases from colorectal carcinoma as the best treatment for this condition. In-patients over 70 years of age and those with medical conditions preventing surgery, we endorse expectant follow-up as long as the tumor remains stable. But if the tumor begins growing rapidly and local techniques cannot be used, we consider systemic chemotherapy. In-patients with progressive metastatic liver disease, we initiate systemic therapy or hepatic arterial infusion. In young patients with metastatic disease, even when the disease is indolent or symptomatic, it may be difficult not to treat. We use either local regional therapy (resection or regional infusion) or systemic chemotherapy followed by regional therapy. In patients with neuroendocrine tumors metastatic to the liver, the first approach we use is not to treat because there may be a long period of stable disease. We use Sandostatin to treat symptoms. If the tumor progresses and symptoms cannot be controlled, these vascular tumors can be treated by embolization or chemoembolization, with high expectations of response. Newer approaches to liver metastases such as cryosurgery, chemoembolization, and interstitial radiation are also available. Cryosurgery is an ablative procedure that has not been proven yet to be as effective as surgical removal of metastases. However, in a situation where surgery cannot be performed, cryosurgery is an alternative. Chemoembolism has not been proven to be more effective than systemic therapy for liver metastases, but it allows another regional approach. External localized radiation can be used for patients who fail first-line treatment or in new protocols to delineate its value, perhaps in concert with chemotherapy. We also consider offering external localized radiation in patients who fail first-line treatment, perhaps in concert with chemotherapy. The usefulness of these techniques compared with surgery or regional therapy is being investigated.

Colorectal cancers

CT scan is useful in the preoperative staging of colorectal cancer. In case of rectal cancers, a combination of digital rectal examination and a high resolution CT scan usually ensures an accurate pretreatment disease staging and assessment of operability. A transrectal ultrasound (TRUS) is now being used when intersphincteric and other sphincter saving procedures are contemplated in low rectal cancers. Benefits of pre-op RT have been shown in a number of European studies. However, clear evidence is lacking as regards the chances of increasing a sphincter saving procedure by pre-op RT. Instead chemoradiotherapy may down size or down stage a locally advanced tumor that is primarily considered unresectable. This is the protocol adopted by us in case of locally advanced rectal cancer. If the lesion is stenotic or if obstruction is imminent, a sigmoid colostomy is performed prior to initiation of chemoradiotherapy. In resectable lesions, we adopt the well established protocol of surgery followed by adjuvant chemoradiotherapy.

GASTRIC CANCER3
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11. Impact of diagnostic laparoscopy on the management of gastric cancer: prospective study of 120 consecutive patients with primary gastric adenocarcinoma.
Lehnert T, Rudek B, Kienle P, et al. Br J Surg 2002; 89:471-5

BACKGROUND: Peritoneal seeding or liver metastases found at laparotomy usually preclude curative treatment in-patients with gastric adenocarcinoma. Such exploratory laparotomies may be avoided by diagnostic laparoscopy. However, routine diagnostic laparoscopy does not benefit those patients who proceed to laparotomy after negative laparoscopy. The aim of this study was to evaluate prospectively the selective use of laparoscopy in uncertain situations. METHODS: One hundred and twenty consecutive patients with primary gastric adenocarcinoma were studied prospectively. Diagnostic laparoscopy was performed in patients with clinical T4 tumours or suspected metastases, unless laparotomy was required for symptomatic disease. RESULTS: Ninety-six of 120 patients were selected for immediate laparotomy with curative intent (n = 81) or for palliation (n = 15). In two of the 81 patients gastrectomy was abandoned because of unexpected peritoneal carcinomatosis. Fifteen patients underwent diagnostic laparoscopy, which identified intra-abdominal metastases in six; the other nine patients proceeded to laparotomy, which revealed peritoneal metastases not detected at laparoscopy in four patients. The remaining nine patients had overt metastases and were referred for systemic chemotherapy without abdominal exploration. CONCLUSION: Diagnostic laparoscopy in selected patients effectively limits the number of unnecessary invasive staging procedures. Routine use of diagnostic laparoscopy in all patients with gastric adenocarcinoma is not warranted.

12. An evaluation of the effectiveness of extended lymph node dissection in-patients with gastric cancer: a retrospective study of 1403 cases at a single institution.
Kasakura Y, Mochizuki F, Wakabayashi K, et al. J Surg Res 2002; 103:252-9.


BACKGROUND: Many investigators have reported that extended lymph node dissection (D2 dissection) is probably an effective procedure. However, the theory that D2 dissection leads to an improvement in survival has not been confirmed in randomized trials. We attempted to confirm the effectiveness of D2 dissection with gastrectomy for gastric cancer. MATERIALS AND METHODS: Gastric cancer patients (1403) underwent curative resection by D1 (991 patients) or D2 (412 patients) dissection with gastrectomy. Survival rates calculated for all patients and subdivided for stage, depth of invasion, and lymph node metastasis were compared between the two groups. The diagnosis of lymph node metastasis was compared between macroscopic and histological findings. RESULTS: There was no significant difference in the survival of patients overall. However, in the patients with stage II, T1 or T2, or N1 disease, the survival of the D2 group was significantly better than that of the D1 group. The false positive rates of lymph node metastasis were 53.3% in the N1 group, 26.2% in the N2 group, and 9.2% in the N3 group. In a considerable proportion of the N1 and N2 patients, histological findings proved more or fewer metastases than macroscopic diagnosis. CONCLUSIONS: Metastatic lymph nodes should be resected as far as possible. D2 dissection with gastrectomy is recommended for T1, N1 or T2, N1 disease, particularly in younger patients.


13. Survival benefit of extended D2 lymphadenectomy in gastric cancer with involvement of second level lymph nodes: a longitudinal multicenter study.
Roviello F, Marrelli D, Morgagni P,et al. Ann Surg Oncol 2002; 9:894-900

BACKGROUND: The survival benefit of extended lymphadenectomy in the surgical treatment of gastric cancer is still being debated. The aim of this longitudinal multicenter study was to evaluate long-term survival in a group of patients with involvement of second level lymph nodes, which would not have been removed in the case of a limited lymphadenectomy. Results were compared with those in patients with involvement of first level lymph nodes. METHODS: Between 1991 and 1997, 451 patients with primary gastric cancer underwent curative resection with extended lymphadenectomy at three surgical departments in Italy according to the rules of the Japanese Research Society for Gastric Cancer. RESULTS: In 451 cases treated by extended lymphadenectomy, morbidity and mortality rates were 17.1% and 2%, respectively. In 126 patients (27.9%) (group A), metastases were found in lymph node stations 7 to 12; 109 patients (24.2%) had metastases confined to the first level (group B). Lymph node stations 7 and 8 showed the highest incidence of metastases in the second level (17.1% and 12.4%, respectively). A significant difference in 5-year survival was observed between group A and group B (32% vs. 54%; P =.0005). This difference disappeared when cases were stratified according to the number of positive lymph nodes. By multivariate analysis, only the number of positive lymph nodes (relative risk, 1.8; P <.0001) and the depth of invasion (relative risk, 2.1; P <.0001), but not the level of involved nodes, showed to be independent predictors of poor prognosis. CONCLUSIONS: Japanese-type extended lymphadenectomy yields low morbidity and mortality rates if performed in specialized centers. This procedure could provide a good probability of long-term survival, even for patients with involvement of regional lymph nodes.

14. Postoperative morbidity and mortality after D1 and D2 resections for gastric cancer: preliminary results of the MRC randomised controlled surgical trial. The Surgical Cooperative Group.
Cuschieri A, Fayers P, Fielding J et al ; Lancet 1996;347:995-9

BACKGROUND: In Japan the surgical approach to treatment of potentially curable gastric cancer, including extended lymphadenectomy, seems in retrospective surveys to give better results than the less radical procedures favoured in Western countries. There has, however, been no evidence from randomised trials that extended lymphadenectomy (D2 gastric resection) confers a survival advantage. This question was addressed in a trial involving thirty-two surgeons in Europe. METHODS: In a prospective randomised controlled trial, D1 resection (level 1 lymphadenectomy) was compared with D2 resection (levels 1 and 2 lymphadenectomy). Central randomisation (200 patients in each arm) followed a staging laparotomy. FINDINGS: The D2 group had greater postoperative hospital mortality (13% vs 6.5%; p=0.04 [95% Cl 9-18% for D2, 4-11% for D1] and higher overall postoperative morbidity (46% vs 28%; p<0.001); their postoperative stay was also longer. The excess postoperative morbidity and mortality in the D2 group was accounted for by distal pancreaticosplenectomy and splenectomy. In the whole group (400 patients), survival beyond three years was 30% in patients whose gastrectomy included en-bloc pancreatico-splenic resection versus 50% in the remainder. INTERPRETATION: D2 gastric resections are followed by higher morbidity and mortality than D1 resections. These disadvantages are consequent upon additional pancreatectomies and distal splenectomies, and in long-term follow-up the higher mortality when the pancreas and spleen are resected may prove to nullify any survival benefit from D2 procedures.


15. Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction.
Macdonald JS, Smalley SR, et al ;N Engl J Med 2001; 345: 725-30

BACKGROUND: Surgical resection of adenocarcinoma of the stomach is curative in less than 40 percent of cases. We investigated the effect of surgery plus postoperative (adjuvant) chemoradiotherapy on the survival of patients with resectable adenocarcinoma of the stomach or gastroesophageal junction. METHODS: A total of 556 patients with resected adenocarcinoma of the stomach or gastroesophageal junction were randomly assigned to surgery plus postoperative chemoradiotherapy or surgery alone. The adjuvant treatment consisted of 425 mg of fluorouracil per square meter of body-surface area per day, plus 20 mg of leucovorin per square meter per day, for five days, followed by 4500 cGy of radiation at 180 cGy per day, given five days per week for five weeks, with modified doses of fluorouracil and leucovorin on the first four and the last three days of radiotherapy. One month after the completion of radiotherapy, two five-day cycles of fluorouracil (425 mg per square meter per day) plus leucovorin (20 mg per square meter per day) were given one month apart. RESULTS: The median overall survival in the surgery-only group was 27 months, as compared with 36 months in the chemoradiotherapy group; the hazard ratio for death was 1.35 (95 percent confidence interval, 1.09 to 1.66; P=0.005). The hazard ratio for relapse was 1.52 (95 percent confidence interval, 1.23 to 1.86; P<0.001). Three patients (1 percent) died from toxic effects of the chemoradiotherapy; grade 3 toxic effects occurred in 41 percent of the patients in the chemoradiotherapy group, and grade 4 toxic effects occurred in 32 percent. CONCLUSIONS: Postoperative chemoradiotherapy should be considered for all patients at high risk for recurrence of adenocarcinoma of the stomach or gastroesophageal junction who have undergone curative resection.

Stomach Cancer

Staging laparoscopy is now being increasingly used in gastric cancer and may avoid unnecessary laparotomy. We have adopted a policy of undertaking a staging laparoscopy only in those cases where resectability is in doubt. A high resolution CT scan of the abdomen and pelvis usually provides a good assessment of resectability as regards the relationship of the tumor with pancreas, the left lobe of liver & the coeliac axis. It has been suggested that D2 dissections should be reserved only for those tumors where the chances of lymph node involvement are high. However, pre and intraoperative evaluation of lymph nodes can often be misleading. D2 lymphadenectomy is feasible and as safe as the D1 dissection in high volume centers. Adjuvant chemotherapy and radiotherapy after gastric cancer resection improves survival. We currently employ the Macdonalds' regimeS only in good performance subjects with nodal metastases.

PANCREATIC CANCER4
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16. Randomized prospective trial of pylorus-preserving vs. Classic duodenopancreatectomy (Whipple procedure): initial clinical results.
Seiler CA, Wagner M, Sadowski C, et al. J Gastrointest Surg 2000;4:443-52.
During the past decades, the classic Whipple resection (cWhipple) and the pylorus-preserving Whipple (ppWhipple) operation have been advanced for the resection of cancer of the pancreatic head. However, no definitive answer exists as to whether the more conservative ppWhipple operation indeed equalizes the short- and long-term results of the cWhipple procedure. Therefore we conducted a randomized prospective trial in a nonselected series of consecutive patients. Demographics, diagnostic, intraoperative, and histologic findings (tumor type and tumor stage of these patients) as well as postoperative mortality, morbidity, and follow-up after discharge were analyzed. For statistical evaluation Kruskal-Wallis and chi-square tests were used where appropriate. Survival was analyzed according to Kaplan-Meier curves, and differences were examined using the log-rank test. From June 1996 to April 1999, a total of 114 patients with suspected pancreatic or periampullary tumors were prospectively randomized to undergo either a cWhipple or a ppWhipple (intention to treat) operation. Based on the inclusion and exclusion criteria, 77 of these patients were included in the final analysis. Forty had a cWhipple and 37 had a ppWhipple resection. There were no differences with regard to age, sex distribution, ASA classification, histologic classification, UICC stage, length of stay in the intensive care unit, and length of hospital stay. The ppWhipple group had a significantly shorter operative time, reduced blood loss, and fewer blood transfusions. There was no difference in mortality, but the cWhipple group showed a significantly higher total morbidity. The incidence of delayed gastric emptying was identical in both groups. For long-term follow-up, a total of 61 patients with histologically proven pancreatic or periampullary carcinoma were analyzed. There were no differences in tumor recurrence or in long-term survival at a median follow-up of 1.1 years (range 0.1 to 2.9 years). Our initial results demonstrate that the cWhipple and ppWhipple operation are equally radical. However, ppWhipple may be the procedure of choice for the treatment of pancreatic and periampullary cancer.

17.Pylorus-preserving pancreaticoduodenectomy versus conventional whipple operation.
Di Carlo V, Zerbi A, Balzano G et al World J Surg 1999 ;23:920-5

During 1990 to 1997 a series of 39 patients underwent a classic pancreaticoduodenectomy and 74 a pylorus-preserving pancreaticoduodenectomy for pancreatic adenocarcinoma. The two groups had similar tumor characteristics and received comparable adjuvant treatments. No significant differences were found between the two groups in terms of mortality, morbidity, gastric emptying, food intake resumption, and hospital stay. Postoperative survival was not affected by the preservation of the pylorus, determined by both univariate and multivariate analyses. Postoperative nutritional outcome was similar in the two groups, although patients receiving adjuvant chemotherapy had a better nutritional recovery if the whole stomach was preserved. In our opinion pylorus-preserving pancreatoduodenectomy is the treatment of choice of pancreatic head cancer.

18. Adjuvant radiotherapy and 5-fluorouracil after curative resection of cancer of the pancreas and periampullary region: phase III trial of the EORTC gastrointestinal tract cancer cooperative group.
Klinkenbijl JH, Jeekel J, et al. Ann Surg 1999;230:776-82 
OBJECTIVE: The survival benefit of adjuvant radiotherapy and 5-fluorouracil versus observation alone after surgery was investigated in patients with pancreatic head and periampullary cancers. SUMMARY BACKGROUND DATA: A previous study of adjuvant radiotherapy and chemotherapy in these cancers by the Gastrointestinal Tract Cancer Cooperative Group of EORTC has been followed by other studies with conflicting results. METHODS: Eligible patients with T1-2N0-1aM0 pancreatic head or T1-3N0-1aM0 periampullary cancer and histologically proven adenocarcinoma were randomized after resection. RESULTS: Between 1987 and 1995, 218 patients were randomized (108 patients in the observation group, 110 patients in the treatment group). Eleven patients were ineligible (five in the observation group and six in the treatment group). Baseline characteristics were comparable between the two groups. One hundred fourteen patients (55%) had pancreatic cancer (54 in the observation group and 60 in the treatment group). In the treatment arm, 21 patients (20%) received no treatment because of postoperative complications or patient refusal. In the treatment group, only minor toxicity was observed. The median duration of survival was 19.0 months for the observation group and 24.5 months in the treatment group (log-rank, p = 0.208). The 2-year survival estimates were 41% and 51 %, respectively. The results when stratifying for tumor location showed a 2-year survival rate of 26% in the observation group and 34% in the treatment group (log-rank, p = 0.099) in pancreatic head cancer; in periampullary cancer, the 2-year survival rate was 63% in the observation group and 67% in the treatment group (log-rank, p = 0.737). No reduction of locoregional recurrence rates was apparent in the groups. CONCLUSIONS: Adjuvant radiotherapy in combination with 5-fluorouracil is safe and well tolerated. However, the benefit in this study was small; routine use of adjuvant chemoradiotherapy is not warranted as standard treatment in cancer of the head of the pancreas or periampullary region.

19. Adjuvant chemoradiotherapy and chemotherapy in resectable pancreatic cancer: a randomised controlled trial. 
Neoptolemos JP, Dunn JA, Stocken DD, et al. Lancet 2001;358:1576-85.
BACKGROUND: The role of adjuvant treatment in pancreatic cancer remains uncertain. The European Study Group for Pancreatic Cancer (ESPAC) assessed the roles of chemoradiotherapy and chemotherapy in a randomised study. METHODS: After resection, patients were randomly assigned to adjuvant chemoradiotherapy (20 Gy in ten daily fractions over 2 weeks with 500 mg/m(2) fluorouracil intravenously on days 1-3, repeated after 2 weeks) or chemotherapy (intravenous fluorouracil 425 mg/m(2) and folinic acid 20 mg/m(2) daily for 5 days, monthly for 6 months). Clinicians could randomise patients into a two-by-two factorial design (observation, chemoradiotherapy alone, chemotherapy alone, or both) or into one of the main treatment comparisons (chemoradiotherapy versus no chemoradiotherapy or chemotherapy versus no chemotherapy). The primary endpoint was death, and all analyses were by intention to treat.Findings 541 eligible patients with pancreatic ductal adenocarcinoma were randomised: 285 in the two-by-two factorial design (70 chemoradiotherapy, 74 chemotherapy, 72 both, 69 observation); a further 68 patients were randomly assigned chemoradiotherapy or no chemoradiotherapy and 188 chemotherapy or no chemotherapy. Median follow-up of the 227 (42%) patients still alive was 10 months (range 0-62). Overall results showed no benefit for adjuvant chemoradiotherapy (median survival 15.5 months in 175 patients with chemoradiotherapy vs 16.1 months in 178 patients without; hazard ratio 1.18 [95% CI 0.90-1.55], p=0.24). There was evidence of a survival benefit for adjuvant chemotherapy (median survival 19.7 months in 238 patients with chemotherapy vs 14.0 months in 235 patients without; hazard ratio 0.66 [0.52-0.83], p=0.0005). Interpretation This study showed no survival benefit for adjuvant chemoradiotherapy but revealed a potential benefit for adjuvant chemotherapy, justifying further randomised controlled trials of adjuvant chemotherapy in pancreatic cancer.

20. Biliary stenting versus bypass surgery for the palliation of malignant distal bile duct obstruction: a meta-analysis.
Taylor MC, McLeod RS, Langer B. Liver Transpl 2000;6:302-8.

The objective of this analysis is to compare endoscopic stenting with surgical bypass in patients with unresectable, malignant, distal common bile duct obstruction using the technique of meta-analysis. The inclusion criteria for the studies were randomized patient assignment, publication in the English language, 20 or more patients per group, all patients followed up until death, and follow-up and complications reported in an equivalent way for both treatment arms. Data extraction was performed independently by 2 of the authors. The number of treatment failures, serious complications, requirement for additional treatment sessions, and 30-day mortality were extracted. Three existing trials met the inclusion criteria, all of which compared surgery with the use of plastic stents. There were no studies identified that used metallic expandable stents. For the rate of treatment failure and serious complications, the odds ratios (ORs) of the 3 trials were heterogeneous, and no summary ORs were calculated. More treatment sessions were required after stent placement than after surgery, and a common OR was estimated to be 7.23 (95% confidence interval [CI], 3.73 to 13.98). Thirty-day mortality was not significantly different (OR = 0.522; 95% CI, 0.263 to 1.036). Although surgical bypass required fewer additional treatment sessions, existing data do not allow a definitive conclusion on which treatment is preferable. A larger randomized controlled trial using newer metallic stents and proper quality-of-life instruments is required.

20.Combining capecitabine and gemcitabine in patients with advanced pancreatic carcinoma: a phase I/II trial.
Hess V, Salzberg M, Borner M et al :J Clin Oncol 2003 1;21:66-8

PURPOSE: Preclinical studies indicate positive interactions between capecitabine, an oral fluorouracil precursor, and gemcitabine, the current standard treatment for advanced pancreatic carcinoma (APC). In this study, we investigated the addition of capecitabine to gemcitabine treatment for patients with APC. PATIENTS AND METHODS: This multicenter study included patients naive to chemotherapy who had histologically or cytologically confirmed, nonresectable or metastatic pancreatic carcinoma. Gemcitabine was given at a fixed dose of 1,000 mg/m(2) on days 1 and 8 of a 21-day cycle. Capecitabine was given in increasing doses orally bid for 14 days followed by a 1-week rest. The maximum-tolerated dose (MTD) was defined as one dose level below the dose causing dose-limiting toxicity (DLT) in >or= one third of a cohort of six patients. We included an additional 15 patients at the MTD. RESULTS: Thirty-six patients were included. DLT occurred at a dose of 800 mg/m(2) bid of capecitabine and consisted of myelotoxicity and mucositis. Hand-foot syndrome was not observed, and other toxic effects were mild. Thus, in this regimen, the recommended dose of capecitabine is 650 mg/m(2) bid. In 27 patients with measurable disease, we observed one complete and four partial remissions. In addition, significant drops (> 50% from baseline value) of the tumor marker CA 19-9 occurred in 14 of 24 assessable patients. CONCLUSION: The combination of capecitabine and gemcitabine is well tolerated, with apparent efficacy in patients with APC. Therefore, it is currently being compared with gemcitabine monotherapy in a phase III study. 

Pancreatic Cancer

Surgery remains the gold standard for the treatment of periampullary malignancies. Pylorus preserving pancreaticoduodenectomy is now being accepted as an oncologically equivalent procedure to the classical Whipple procedure. Both these procedures have a similar perioperative morbidity and mortality. Pylorus preserving procedure is preferred by many as it is believed to be more physiological.Adjuvant chemotherapy in resectable pancreatic cancer has shown benefits in recent trials. However this advantage is seen more in patients with R0 resections and negative cut margins. More studies are awaited before adjuvant treatment modalities can be advocated in resectable periampullary and pancreatic cancer.For unresectable disease, the options include endoscopic stent placement and surgical bypass.

GALL BLADDER CANCER5
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22. S4 S5 subsegmentectomy of the liver for gallbladder carcinoma
Unno M, Suzuki M, Katayose Y, et al. Nippon Geka Gakkai Zasshi 2002;103:543-8.

Although innovations have occurred in imaging technology and surgical techniques, carcinoma of the gall-bladder still has a poor prognosis. Since the 1960s, we have performed extended cholecystectomy in patients with gallbladder cancer. Extended cholecystectomy is a safe and common treatment for advanced cancer, but the extent of necessary hepatic resection has not been established. In 2000, we reported that the gallbladder veins infused into the intrahepatic portal venous branch, mostly at P4 and P5(96.7%). Based on those results, we now perform resection of the lower part of segment 4(S4a) and segment 5 for advanced cancer with subserosal invasion and/or negligible direct invasion to the parenchyma of the liver. S4aS5 subsegmentectomy is thought to have a clear advantage over extended surgical margins. This procedure can remove almost all the area perfused by the gallbladder veins and as a results, it may also remove latent and occult metastatic foci. The steps in the procedure are as follows: 1) lymph nodes cleaning of the posterior of the pancreas head; 2) skeletonization of the hepatoduodenal ligament; 3) identification and ligation of the lower branch of P4; 4) identification of the boundary between the anterior and posterior segment; and 5) hepatic resection with the plate of the gallbladder. Since 1991, we have performed S4aS5 subsegmentectomy in 12 patients with gallbladder cancer. Although the follow-up period is short, it is thought that the outcome of this procedure is better than that of extended cholecystectomy because of the low mortality and morbidity rates.

23. Radical second resection provides survival benefit for patients with T2 gallbladder carcinoma first discovered after laparoscopic cholecystectomy.
Wakai T, Shirai Y, Hatakeyama K. World J Surg 2002;26:867-71

Port site recurrence or peritoneal seeding is a fatal complication following laparoscopic cholecystectomy for gallbladder carcinoma. The aims of this retrospective analysis were to determine the association of gallbladder perforation during laparoscopic cholecystectomy with port site/peritoneal recurrence and to determine the role of radical second resection in the management of gallbladder carcinoma first diagnosed after laparoscopic cholecystectomy. A total of 28 patients undergoing laparoscopic cholecystectomy for gallbladder carcinoma were analyzed, of whom 10 had a radical second resection. Five patients had recurrences; port site/peritoneum recurrence in 3 and distant metastasis in 2. The incidence of port site/peritoneal recurrence was higher in patients with gallbladder perforation (3/7, 43%) than in those without (0/21, 0%) (p = 0.011). The outcome after laparoscopic cholecystectomy was worse in 7 patients with gallbladder perforation (cumulative 5-year survival of 43%) than in those without (cumulative 5-year survival of 100%) (p <0.001). Among 13 patients with a pT2 tumor, the outcome after radical second resection (cumulative 5-year survival of 100%) was better than that after laparoscopic cholecystectomy alone (cumulative 5-year survival of 50%) (p = 0.039), although there was no survival benefit of radical second resection in the 15 patients with a pT1 tumor (p = 0.65). In conclusion, gallbladder perforation during laparoscopic cholecystectomy is associated with port site/peritoneal recurrence and worse patient survival. Radical second resection may be beneficial for patients with pT2 gallbladder carcinoma first discovered after laparoscopic cholecystectomy.

24. Gallbladder cancer: role of radiation therapy.
Houry S, Haccart V, Huguier M, et al. Hepatogastroenterology 1999;46:1578-84.

BACKGROUND/AIMS: Gallbladder carcinoma is characterized by late diagnosis, ineffective treatment and poor prognosis. These tumors were usually considered to be radioresistant. So far, the role of radiotherapy has not been adequately evaluated. The aim of this report is to assess the value of radiotherapy in carcinoma of the gallbladder. METHODOLOGY: We reviewed all publications concerning the role of radiation therapy in gallbladder carcinoma. External radiation therapy, intra-operative radiation therapy, and brachytherapy were evaluated in two groups in which the prognosis is quite different; a group operated on, with apparent complete resection of the tumor, and a palliative surgery group. RESULTS: It appears that gallbladder carcinomas are not as radioresistant as was formerly thought. Local control of the tumor and reduction of tumor size was reported in several publications. Collected data showed a slight improvement of survival after adjuvant or palliative radiotherapy, especially in the advanced stage of gallbladder carcinomas. It appears preferable to give a "boost" (15 Gy) to the gross lesion or residual lesion at operation (intra-operative irradiation or brachytherapy), and deliver an additional 45-50 Gy post-operatively. CONCLUSIONS: The results published encourage further trials in well defined populations. Radiotherapy seems to be a safe procedure, morbidity is minimal, and a slight effect on survival is observed after curative or palliative surgical procedures.

Gall Bladder Carcinoma

Gall bladder carcinoma continues to have a dismal prognosis. Radiological imaging with a CT is useful in the preoperative evaluation. MRCP is performed if the patient has obstructive jaundice.Surgery is the treatment of choice. Extended cholecystectomy (wedge resection of the liver and portal lymphadenectomy) is the preferred treatment for deeply invasive tumors. For less invasive tumors and in situ (stage 1), a less extensive resection (simple cholecystectomy) is sufficientThere is a role of a radical reoperation after an incidental discovery of gall bladder carcinoma. Available evidence appears to suggest that this procedure does offer some benefit. Certain questions as to the optimal timing of resurgery and the extent of resurgery remain unanswered.Role of adjuvant chemotherapy and radiotherapy is being currently evaluated in ongoing trials. The preliminary results from these trials show the efficacy of Gemcitabine based chemotherapy. Further evaluation is required before routine implementation of adjuvant therapy.

HEPATOCELLULAR CARCINOMA6
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25. Anatomical and atypical liver resections
Scheele J. Chirurg 2001;72:113-24.

Liver resection has evolved to an established treatment for various malignant primary and secondary hepatic tumours, some benign tumours, and other conditions. The anatomical approach, the preferred concept of the author, rests on knowledge of the intrahepatic segmentation according to the portal structure branching and the course of major hepatic veins. As most of the malignant tumours respect the corresponding intrahepatic boundaries this resectional approach offers superior tumour clearance and, probably, better long-term outcome. Besides the four standard resections along the main fissure and left intersectorial plane, respectively, there are less common sector-orientated procedures including central hepatectomies and operations along the right intersectorial plane. Segment-orientated resections are defined by additional use of the transverse boundary according to the cranially and caudally directed third-order ramification of the portal trunks. Despite the advantage of anatomical resections there are rational indications for non-anatomical procedures such as removal of small benign tumours, excision of HCC in liver cirrhosis, re-resection following major hepatectomies, an excision biopsy in a non-resectable situation, and liver trauma care. Irrespective of the resectional approach, routine use of intraoperative ultrasound, maintenance of a low central venous pressure during parenchyma transsection, intermittent hilar clamping, and ischemic preconditioning all contribute to a safe and oncologically effective operation. In the future, augmentation of the liver remnant by preoperative portal vein embolisation, and multicentre trials on multidisciplinary strategies, may help to enhance resectability and to improve both safety and long-term outcome.

26. Systematic review of randomized trials for unresectable hepatocellular carcinoma: Chemoembolization improves survival. Llovet JM, Bruix J. Hepatology 2003;37:429-42.
There is no standard treatment for patients with unresectable hepatocellular carcinoma (HCC). Survival benefits derived from medical interventions are controversial. The aim of this systematic review was to assess the evidence of the impact of medical treatments on survival. Randomized controlled trials (RCTs) that were published as full papers assessing survival for primary treatments of HCC were included. MEDLINE, the Cochrane Library, CANCERLIT, and a manual search from 1978 to May 2002 were used. The primary end point was survival, and the secondary end point was response to treatment. Estimates of effect were calculated according to the random effects model. Sensitivity analysis included methodological quality. We identified 61 randomized trials, but only 14 met the criteria to perform a meta-analysis assessing arterial embolization (7 trials, 545 patients) or tamoxifen (7 trials, 898 patients). Arterial embolization improved 2-year survival compared with control (odds ratio [OR], 0.53; 95% confidence interval [CI], 0.32-0.89; P =.017). Sensitivity analysis showed a significant benefit of chemoembolization with cisplatin or doxorubicin (OR, 0.42; 95% CI, 0.20-0.88) but none with embolization alone (OR, 0.59; 95% CI, 0.29-1.20). Overall, treatment induced objective responses in 35% of patients (range, 16%-61%). Tamoxifen showed no antitumoral effect and no survival benefits (OR, 0.64; 95% CI, 0.36-1.13; P =.13), and only low-quality scale trials suggested 1-year improvement in survival. In conclusion, chemoembolization improves survival of patients with unresectable HCC and may become the standard treatment. Treatment with tamoxifen does not modify the survival of patients with advanced disease.

27 Chemoembolization of hepatocellular carcinoma-what to tell the skeptics: Review and meta-analysis.
Ramsey DE, Geschwind JF. Vasc Interv Radiol 2002;5:122-6
Transcatheter arterial chemoembolization (TACE) has become the standard treatment for patients with unresectable hepatocellular carcinoma (HCC). When untreated, patients with inoperable HCC have a median survival of three months. Given the widespread use of chemoembolization, accurate evidence of the impact of TACE on patient survival is critical. Several review articles have examined randomized controlled trials (RCTs) of TACE; however, these analyses are inherently flawed by including trials in which control groups were treated. There have been only four RCTs comparing TACE to untreated controls to date. None has demonstrated a significant impact of TACE on patient survival. However, in addition to severe methodological flaws, these RCTs were limited by low patient enrollment, precluding any meaningful conclusions. In contrast, several non-randomized trials have clearly demonstrated a significant benefit of TACE on patient survival. New RCTs examining the impact of chemoembolization on survival are urgently needed to provide definitive evidence for the increasing number of patients treated with TACE. A new, well-designed RCT would provide significant insight on the impact of chemoembolization on patient survival.

28. Percutaneous radiofrequency ablation combined with transcatheter arterial chemoembolization for hepatocellular carcinoma.

Zhang Z, Wu M, Chen H, et al. Zhonghua Wai Ke Za Zhi 2002;40:826-9.
OBJECTIVE: To assess the significance of the method of percutaneous radiofrequency ablation (PRFA) combined with transcatheter arterial chemoembolization for hepatocellular carcinoma. METHODS: Thirty patients with hepatocellular carcinoma were divided into PRFA group and TACE + PRFA group between January 2000 and July 2001. All patients were followed up to examine the value of AFP, MRI or CT. Kaplan-Meier estimation was used for the analysis of disease-free survival and the cumulative survival rate. RESULTS: The complete necrosis rates were 86.7% (13/15) and 26.7% (4/15) in the TACE + PRFA group and group PRFA group respectively. The rates of AFP positive down to negative were 66.7% (6/9) for the former and 20% (2/10) for of the latter, and the six-month disease-free survival rates were 100% (13/13) and 75% (3/4) in the two groups. The 1-, 1.5- and 2-year survival rates of the group TACE + PRFA were 100%, 100% and 66.7% respectively. The survival rates of 1 and 1.5 years of the group PRFA only were 80% and 40%. CONCLUSIONS: For those hepatocellular carcinomas over 3 cm in size, located in the porta hepatis, or with indistinct boundary or the presence of foci, TACE can be performed first and then followed by PRFA in suitable time. This method can enlarge the necrosis range and increase the rate of complete necrosis of tumors, thereby decrease the recurrence and improve the disease-free survival and total survival of patients.

 

Hepatocellular carcinoma

Advanced hepatocellular carcinoma carries a poor prognosis. There has been a vast improvement in the surgical technique for liver resection over the past few years. Specialized high volume centers perform liver resections with very low morbidity rates. Careful evaluation of the liver function and reserve is mandatory before embarking on a liver resection. Proper radiologic evaluation with a triphasic CT Scan / MRI is invaluable. Newer techniques like chemoembolization, radiofrequency ablation and regional chemotherapy through a hepatic arterial port show promise, especially in patients with unresectable disease and in those unfit for surgery. However these procedures should be individualized and evaluated further before their routine implementation can be advocated.

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