CHEMOTHERAPY FOR ADVANCED COLORECTAL CANCER 335 there is currently no standard treatment regime. Irinotecan is a novel topoisomerase I inhi bitor. Several non-randomized studies have demonstrated activity in colo- rectal cancer. A recent randomized controlled trial, comparing irino- tecan with best supportive care in patients w ith 5-FU-refactory disease, has shown a signi \201cant increase in one-year survival (36% vs. 14%) and a signi \201cantly improved quality of life favoring irinotecan. A further st udy, comparing irinotecan with infusional 5-FU, has demon- strated a 40% improvement in one -year survival in the irinotecan- treated group. Novel cytotoxic agents Oxaliplatin This platinum derivative is not effective as a single ag ent against colorectal cancer. However, oxaliplatin combined with 5- FU/leucovorin can incr ease response rate and progression-free sur- vival (but not overall survival) when compared with 5-FU/leucovorin alone. Oral 5-FU analogs Because of marked variability in bioavaila- bility, 5-FU cannot be given orally. Capecitabine is an oral agent, which is activated by a series of enzymes, resulting in 5-FU release preferentially at the site of tumor. Preliminary data suggest activity aga inst colorectal cancer, with fewer side-effects than intravenous 5-FU. Future directions Results of clinical trials using several new agents, including novel thym idylate synthase inhibitors (e.g. uracil/tegafur, UFT) and novel biochemical modulators (e. g. trimetrexate, 5-ethyny- luracil) are awaited. OHO-18(323-338) 11/16/02 12:32 PM Page 336 COLORECTAL CANCER 336 Radiotherapy in colorectal cancer Radiotherapy in colonic cancer is limited to the palliative situation in most circumstances . It is used for painful bone metastases, skin secon- daries, and occasionally for tumors w ith local in \201ltration into sur- rounding organs. The mobile nature of the colon makes it impossible to deliver multiple fractions of treatment to anatomically de \201ned region s of the colon. Conversely, the rectum is immobile and \201xed within the pelvis and therefore a suitable target for radiotherapy. Radiotherapy has been used in both the pre-operative and post-ope rative setting in this disease. In the pre-operative situation there are a group of patients (10 \200\22315%) who present w ith large \201xed or tethered tumors that are non-resectable. Only half of this group wil l have distant metastases at presentation. The conversion rate to resectability is 35 \200 \22375%, with a dose of 50 \200\22360 Gy given over a \201ve-week period. This group is a lso often offered combined chemo-irradiation, though the precise bene \201ts (or otherwise ) of this approach are not yet known. The suc- cessful use of radiotherapy in this situatio n has helped promote it, even in those with initially resectable cancers. (cid:2) Local rec urrence of rectal cancer in up to half of patients (cid:2) 13 trials \200\224comparing surg ery alone with surgery plus radiotherapy (cid:2) Data con \202icting \200\224local recurre nce less (cid:2) Survival unchanged (cid:2) Post-operative radiotherapy for 4 weeks \200 \224less recurrence \200\224no difference in survival OHO-18(323-338) 11/16/02 12:32 PM Page 337 RADIOTHERAPY IN COLORECTAL CANCER 337 OHO-18(323-338) 11/16/02 12:32 PM Page 338 COLORECTAL CANCER 338 Further reading Cancer Guidance Sub-Group of the Clinical Outcomes Group. (1997) Improving outcomes in colon cancer: the research evidence. NHS Executive, Department of Hea lth, London. Bleiburg, H. et al. (1997) Management of colorectal cancer. Martin Dunitz, London. MRC Rectal Cancer Working Party. (1996) Randomized trial of surgery alone versus surgery fo llowed by radiotherapy for mobile cancer of the rectum. Lancet 348, 1610 \200\22314. O \200\231Connell, M., Martenson, J.A., Wieand, H.S., et al. (1994) Improving adjuvant ther apy for rectal cancer by combining protracted infusion \202uorouracil with radiation ther apy after curative surgery. NEJM 331, 502 \200\2237. Punt, C.J. (1998) New drugs in the treatment of colorectal carcinoma. Cancer 83(4); 679 \200\22389. Swedish Rectal Cancer Trial. (1997) Improved survival with pre-operative radiotherapy in resectable rectal cancer. NEJM 336, 980 \200\2237. OHO-19(339-348) 11/18/02 8:26 AM Page 339 Chapter 19 Anal cancer Introduction 340 Anal squamous cell carcinoma 342 Rarer tumors 346 Practical points 348 OHO-19(339-348) 11/18/02 8:26 AM Page 340 ANAL CANCER 340 Introduction Anal cancer accounts for only 3 \200\2235% of all large bowel malignancies. Most anal tumor s arise from the epidermal elements of the anal canal lining (squamous cell \200\22485% of anal tumors), though some arise from the glandular mucosa of the uppermost part of the anal canal or from the anal ducts and glands (adenocarcinomas \200\22410% of anal tumors). Mali gnant melanoma of the anus is very rare (<5% of anal tumors) and carries a poor prognosis. Traditionally, the anal region is divided into the anal canal and the anal margin or verge. The boundaries of these areas differ from one group of authors to another, making interpre tation of studies dif \201cult. OHO-19(339-348) 11/18/02 8:26 AM Page 341 INTRODUCTION 341 OHO-19(339-348) 11/18/02 8:26 AM Page 342 ANAL CANCER 342 Anal squamous cell carcinoma There is wide geographical variation in the incidence of anal cancers around the world. Are as of high incidence include Recife in Brazil and the Philippines. Interestingly, those are as with a high incidence of anal cancer also tend to have a high incidence of cervical, vul val, and penile tumors. Epidemiological evidence has suggested that anal cancer may be associated with anal sexual activity. Male homosexual activity and HIV infection are strongly associated with the incid ence of anal squa- mous carcinoma. Most speci \201cally, human papillomavirus has been sho wn to be an important aetiological factor in anal, cervical, vulval, and penile squamous tu mors. (cid:2) Ano-genital papillomavirus lesion \200\224condylomata \200\224intra-epithelial neoplasia \200\224invasive carcinoma (cid:2) Colposcopy useful (cid:2) High-grade and intra-epithelial lesions (AIN 111) \200\224pigmented or white \200\224 \202at or raised \200\224if ulcerated, may be invas ive (cid:2) Biopsy is essential Pathology Included within the category of epidermoid tumors are: (cid:2) Squamous cell (cid :2) Basaloid (or cloacogenic) carcinomas (cid:2) Mucoepidermoid cancers Anal canal cancer s preads locally. The anal sphincters and the recto- vaginal septum, perineal body, and the v agina (in more advanced cases) are common sites of spread. Lymph node spread occurs initial ly to the perirectal group of nodes and thereafter to inguinal, haemor- rhoidal, and latera l pelvic lymph nodes. Approximately 10% of patients will present with inguinal lymph node i nvolvement, but this rises to approximately 30% when the primary tumor is greater than 5 cm in diameter. Synchronously involved nodes carry a poorer prog- nosis than metachronous nod al involvement. Blood-borne spread tends to occur late and is usually associated with advanced local diseas e. The most common sites of metastases are the liver, lung, and bones. OHO-19(339-348) 11/18/02 8:26 AM Page 343 ANAL SQUAMOUS CELL CARCINOMA 343 Clinical presentation and staging (cid:2) Symptoms of epidermoid anal cancer \200\224pain \200\224bleeding \200\224itch \200\224discharge \200\224mass (cid:2) Later \200\224fecal incontinence \200\224ano-vaginal \201stula Cancer of the anal margin often has the appearance of a malignant ulcer, with a raised, eve rted, indurated edge. Lesions within the canal may not be visible, although they may spread to the anal verge. Digital examination of the anal canal is usually painful and the canal often feels indurated and distorted. It is often dif \201cult to distinguish an anal cance r from a low rectal tumor. Approximately one-third of patients with anal carcinoma have enlarged inguinal lymph nodes on presentation, but less than half this number have metastatic nodes. Often the nodes are secondarily infected or reactive. Biopsy or \201ne-needle aspiration is therefore necessa ry to con \201rm involvement of the groin nodes if radical block dissection is contemplate d. The most widely used staging system is that of the UICC (Union International Contr Cancer). Investigations Examination under anesthesia is the mainstay in the diagnosis and investigat ion of this tumor. Ultrasound scanning, CT, and magnetic resonance scanning may provide add itional information. Treatment Until 10 years ago the standard treatment for anal canal tumors was abdominoperin eal resection, while anal margin growths were viewed as equivalent to skin tumors elsewhere and treated by local excision. Over the past few years, radiotherapy and/or chemotherapy h ave become increasingly popular and in many cases are the treatment of choice. Compared to anal margin cancer, anal canal cancer is more likely to be locally advanced and to be associated with subsequent metastases, perhaps explaining the general preference for radical surgery. Around 20% are incurable surgically at presentation. Most recurrence occu rs loco-regionally. Non-surgical treatment (chemo-irradiation) for anal cancer has become increasingly popular after pioneering work in the US by Norman Nigro. The drugs used are usually 5FU and mitomyc in C. OHO-19(339-348) 11/18/02 8:26 AM Page 344 ANAL CANCER 344 This particular combination of chemotherapy was developed empiri- cally as a pre-operative regimen aimed at improving the results of radical surgery1. The radiotherapy consists of 30 Gy of external-beam irradiation over a period of three weeks. Chemo-irradiation was shown to be superior to radiotherapy alone in a recent British trial2. Small lesions at the anal margin may still best be treated by local excision alone, obviati ng the need for protracted courses of non- surgical therapy. An important role for the surgeon is in treatment after failure of primary non-surgical the rapy, either early or late. The appearance of the primary site can be misleading after radi otherapy. A proportion of patients develop complications such as radio-necrosis, \201stul a, or incontinence, following radical radiation or combined therapy. OHO-19(339-348) 11/18/02 8:26 AM Page 345 ANAL SQUAMOUS CELL CARCINOMA 345 OHO-19(339-348) 11/18/02 8:26 AM Page 346 ANAL CANCER 346 Rarer tumors Adenocarcinoma Adenocarcinoma in the anal canal is usually a very low rectal cancer that ha s spread downwards to involve the canal, but true adenocarcin- oma of the anal canal does o ccur, probably arising from the anal glands that arise around the dentate line and pass rad ially outwards into the sphincter muscles. This is a very rare tumor; although it is radio- sensitive, it is still usually treated by radical surgery. Malignant melanoma This tumor is excessively rare, accounting for just 1% of anal canal mal ignant tumors. The lesion may mimic a thrombosed external pile due to its color, though ame lanotic tumors also occur. It has an even worse prognosis than at other sites. As the chanc es of cure are minimal, radical surgery as primary treatment has been all but abandoned. OHO-19(339-348) 11/18/02 8:26 AM Page 347 RARER tumors 347 OHO-19(339-348) 11/18/02 8:26 AM Page 348 ANAL CANCER 348 Practical points (cid:2) Rectal bleeding and anal pain are common \200\224a high degree of suspi- cion is required to diagnose anal cancer correctly. (cid:2) Multifocal anal and genital disease may co-exist \200\224be sure to exam- ine the anal and genital areas. (cid:2) Examination under anesthetic is essential for adequate staging and also permits a generous biopsy. (cid:2) Biopsy or needle aspiration of enlarged inguinal lymph nodes is essential prior to treatment. (cid:2) Local excision may be appropriate for small anal margin cancers. (cid:2) Chemo-irra diation is the treatment of choice for most anal squa- mous carcinomas. 1. Nigro, N.D., Vaitkevicius, V.K., Considine, B. (1974) Combined therapy for cancer of the anal canal. Diseases of the colon and rectum 27, 763 \200\2236. 2. Arnott, S.J., Cunningham, D., Gamacher, J., et al. (1996) Epidermoid anal cancer: Result s from the UKCCCR randomized trial of radiotherapy alone versus radiotherapy, 5-fluorouraci l and mitomycin. Lancet 348, 1049 \200\22354. OHO-20(349-374) 11/18/02 8:27 AM Page 349 Chapter 20 Upper gastrointestinal cancer Oesophageal cancer 350 Gastric cancer 354 Small intestine and carcinoid tumors 358 Cancer o f the liver 362 Cancer of the biliary tract 366 Pancreatic cancer 370 Controversies in mana gement 374 OHO-20(349-374) 11/18/02 8:27 AM Page 350 UPPER GASTROINTESTINAL CANCER 350 Oesophageal cancer Incidence and etiology In the UK, approximately 4000 people die each year from oesophageal cancer (0.7% of cancer deaths). It is at least twice as common in males than females, excep t for tumors arising in the post-cricoid area, for which there is a female preponderance. T he incidence increases with age eight-fold between 45 \200\22354 and 65 \200\22374 years. In most published series, squamous cell carcinoma is the most com- mon histological type, b ut adenocarcinoma is increasing in incidence, especially in younger, white men. This trend is evident in the US where 50% of cases are now adenocarcinoma. Historically, alcohol and smoking have been major risk factors in the West \200\224heavy sm okers and drinkers have a 100-fold increased risk. Other associated conditions include: (ci d:2) Barrett \200\231s esophagus (up to 1 in 2 risk if high-grade dysplasia is present) (cid:2) Tylosis palmaris (90% probability of developing oesophageal cancer) (cid:2) Chronic iron-de \201ciency states (cid:2) Chemical or radiation exposure (cid:2) Achalasia Obesit y may increase oesphageal re \202ux and incidence of Barrett \200\231s esophagus and offer s one possible explanation for the increase in incidence of adenocarcinoma. Diagnosis and staging The onset of dyspepsia or dysphagia in a person over 50 years of age requires investigation with upper GI endoscopy and biopsy. When the diagnosis is made, adeq uate staging is essential to decide on the appro- priate treatment. A combination of the TN M and AJCC systems is commonly used: T1 Tumor involves mucosa or submucosa T2 Tumor invades the muscularis propria T3 Tumor inva des the adventitia T4 Tumor invades adjacent organs Stage 1 Stage II Stage III T3 N1, T4 N0 \200\2231 Stage IV M1 disease T1 N0 T2 \200\2233 N0, T1 \200\2232 N1 A barium swallow/meal will delineate the length of the tumor. CT scan indicates the apposit ion of the tumor to major structures (aorta OHO-20(349-374) 11/18/02 8:27 AM Page 351 OESOPHAGEAL CANCER 351 and carina) in addition to giving information about nodal involve- ment and distant metasta tic disease. Endoscopic ultrasound (EUS) allows evaluation of the depth of oesophageal wall penetration in up to 85% of cases, provided that stenosis does not prevent full assess- me nt. Regional nodes are more accurately evaluated with EUS than with CT scan. Bronchoscopy m ay be necessary to inspect the carina and the bronchial tree. Laparoscopy may also be valua ble, especially in low oesophageal tumors, to exclude peritoneal metastases. Treatment Following adequate staging, case selection is important in the treat- ment of oes ophageal cancer. A multidisciplinary approach involving surgeon, gastroenterologist, radiol ogist, oncologist, and dietitian is strongly advised for optimum patient management. Resectable tumors Surgical resection is the treatment of choice for Stage I and II disease; for more advanced localized tumors there is no de \201nite evidence that surgery is super ior to radiotherapy or chemo-irradiation. Most surgeons believe that there is no role for p alliative oesophagectomy. Various techniques are used to resect the esophagus and, most com - monly, the stomach is used to re-establish continuity of the GI tract. Operative mortalit y is around 10%. Fit patients with Stage I and II tumors treated with resection alone have expected \201ve -year survival rates of 68 \200\22385%. Even with T1 tumors, 30% of patients have nodal met astases and the evidence from patterns of relapse and autopsy studies is that oesophageal c ancer is often a systemic, not localized disease. Stage III disease patients treated by res ection have a \201ve-year survival rate of only 15 \200\22328% and it is for these patien ts that other treatment strategies such as pre-operative chemo-irradiation are being invest igated. Despite the chemosensitivity of advanced disease, adjuvant chemotherapy has not been shown to confer a survival advantage and is dif \201cult to deliver after major oesophageal surg ery. Post-resection irradiation improves the loco-regional control in patients with posi- t ive resection margins, but not if there is nodal involvement. The dose is limited to 50 Gy in 25 daily fractions (usually delivered with an anterior and two posterior oblique \201e lds) in patients who have under- gone a gastric pull-up or intestinal interposition procedu re. The principles underlying pre-operative (neo-adjuvant) chemo- therapy are that in addition to downstaging the primary tumor, micro-metastases are treated before the post-operative, s timulatory surge of growth factors. Drugs effective in oesophageal cancer include: (cid:2) 5- \202uorouracil (5FU) (cid:2) Cisplatin (cid:2) Mitomycin OHO-20(349-374) 11/18/02 8:27 AM Page 352 UPPER GASTROINTESTINAL CANCER 352 (cid:2) Paclitaxel (cid:2) Methotrexate Bleomycin was used in early studies but pulmonary t oxicity has led to its replacement. The most commonly used combination is continuous infusi on of 5FU and cisplatin. Despite reported response rates with chemotherapy of up to 60%, no randomized trial has sho wn a survival advantage for pre-operative chemotherapy for oesophageal cancer. However, mos t studies have randomized fewer than 200 patients. Pre-operative radiotherapy has been studied but no reliable data are available to suggest i ncrease in resectability improvement in local control or survival. A recent overview sugges ts that combined pre- operative chemoradiotherapy holds some promise in this disease.1 Pre-operative chemo-irradiation may be delivered with the com- bined modalities applied con currently or sequentially. Inevitably, combination therapy causes increased normal tissue d amage, in par- ticular oesophagitis and pneumonitis, and as a result both chemo- therapy an d radiotherapy doses may be compromised. Some studies have included only squamous tumors an d in these there has been no signi \201cant improvement in survival. An Irish study includ ed 113 patients with adenocarcinoma and at three years the survival rates were 32% for comb ined therapy compared with 6% for surgery alone. It is not certain whether treatment should be determined according to histological type, and strati \201cation for histology within large ran- domized trials is essential for resolution of this issue. Pathological complete response rates of up to 70% have been reported in phase II studies of chemo-irradiation and the necessity for oesophageal resec- tion after combined therapy questioned. Many patients with oesophageal cancer will have serious co-morbid conditions due to age or lifestyle. In elderly or un \201t patients (e.g. poor respiratory reserve) with apparently resectable tumors, oesophago- gastrectomy may be poorly tolerated and insertion of an oeso phageal stent \200\224usually metal \200\224is often the most appropriate palliative mea- s ure. With proper technique, the risk of perforation is less than 5%. The stent should exten d 3 cm beyond each end of the tumor. At least one randomized trial has demonstrated superio rity of palliation with stenting rather than laser therapy. Unresectable tumors The majority of oesophageal tumors are diagnosed at an advanced stage w hen resection is not possible. Combined chemo-irradiation is more effective than radiothera py alone in locally advanced oesopha- geal cancer and cure is not impossible, although rare . In one of the larger randomized trials, Herskovic reported an increase in 5-year survival from 0 to 27% (median survival 9.3 months v. 14.1 months) in 123 patients randomized to re ceive either cisplatin and 5FU with OHO-20(349-374) 11/18/02 8:27 AM Page 353 OESOPHAGEAL CANCER 353 50 Gy RT or 64 Gy RT alone. These encouraging results in advanced tumors indicate that rand omized trials of combined modern chemo-irradiation (where optimal doses of each modality ar e deliv- ered) versus surgery alone are warranted in earlier stage disease. In patients with metastatic disease, those of ECOG performance status <2 should be consider ed for chemotherapy. The median sur- vival for Stage IV disease remains around eight months . Palliation of dysphagia, usually through stenting, is often necessary before chemo- thera py starts, although effective chemotherapy may return swal- lowing to normal after one cour se of treatment. Intraluminal radiotherapy (brachytherapy), laser treatment, and intratumou ral alcohol injection are alternative palliative measures for control of local symptoms onl y. References 1. Gen, J.I., Crellin, A.M., Glynne-Jones, R. (2001) Preoperative (neoadjavant) chemoradiotherapy in oesophageal cancer. British Journal of Surgery 88, 338 \200\22356. OHO-20(349-374) 11/18/02 8:27 AM Page 354 UPPER GASTROINTESTINAL CANCER 354 Gastric cancer Etiology (cid:2) Helicobacter pylori \200\2243 \200\2236-fold increase in risk \200\224causes atrophic gastritis, decrease in acid secretion, bacteria overgrowth, increase in nitrites (cid:2) Barrett \200\231s esophagus \200\224associated with increase in gastro-oesophageal cancer (cid:2) Blood group A (cid:2) Pernicious anemia (3-fold increase) (cid:2) Lower social clas s Epidemiology Globaly, stomach cancer is the second commonest cancer with an estimated 775 0 00 new cases per annum. In the UK, there were 11 851 new cases in 1990, being the sixth com monest cancer in men and the seventh in women (male:female ratio 3:2). The diagnosis is rare prior to the sixth decade with the incidence ris- ing steeply thereaf ter. Wide variations in incidence are observed, from rates of >90 per 100 000 in Japan to < 10 per 100 000 for Caucasians in the US, Africa, and India. China and Eastern Europe have r elatively high rates \200\22428 \200\22350 per 100 000, whilst Western European rates are 1 5 \200\22320 per 100 000. In most countries the incidence of stomach cancer is declining. However, despite this decli ne, several countries, including the UK, have detected an increase in cancers of the oesoph ageal gastric junc- tion (OGJ). In Japan, screening for gastric cancer is routinely performed with a double-contrast barium meal and gastroscopy. This increases the pro- portion of resectable early gastric cancers by 30 \200\22340%. In Western Europe and the US, screening of asymptomatic patients is not practic- able because of the lower incidence of the disease. A British study in which patie nts over 40 years presenting with dyspepsia underwent gastroscopy detected tumors in 2%. Pathology 90% of stomach tumors are adenocarcinomas, that are further divided into \200 \230intestinal \200\231 and \200\230diffuse \200\231 types. The remainder are mainly lymph omas (up to 8%) and leiomyosaromas (1 \200\2233%). Intestinal type gastric cancers are ulce rative and occur more often in the distal stom- ach than diffuse types, including linitis p lastica, which occur through- OHO-20(349-374) 11/18/02 8:27 AM Page 355 GASTRIC CANCER 355 out the stomach. Gastric cancers are evaluated according to the TNM staging system. This sy stem stages tumors according to: (cid:2) Depth of invasion of the primary tumor (cid:2) Deg ree of lymph node involvement (cid:2) The absence (M0) or presence (M1) of distant metastas es Endoscopy with biopsy is the optimal means of diagnosis of gastric cancer. CT scanning d etects spread to regional lymph nodes and distant metastases. Endoluminal ultrasound is sup erior to CT in deter- mining the depth of invasion of the primary tumor and presence of loc al adenopathy. Laparoscopy should be used in patients being con- sidered for curative surge ry to con \201rm operability and exclude peri- toneal metastases. Surgery The best results are achieved in patients with T1N0 or T1N1 tumors; 70% of such pat ients are alive at \201ve years. However, under 5% present with T1 tumors. Penetration of the serosa by the tumor predicts a risk of recurrence of 80 \200\22385%. The type of operation will depend on the site of the tumor; oesophagogastrectomy may be req uired for cancers of the OGJ and proximal stomach, total gastrectomy for mid-stomach tumors , and partial gastrectomy may be adequate treatment for tumors in the distal stomach. A further consideration is the extent of lymphadenectomy under- taken. In Japan, patients r outinely undergo extensive lymphaden- ectomy, whereas in Western countries most patients ha ve more limited lymph node resection. MRC and Dutch studies have com- pared R1 dissection ( lymph nodes within 3 cm of the tumor) to R2 dissection (more extensive lymphadenectomy). In both studies post- operative mortality was signi \201cantly higher with R2 resection and no survival advantage has been observed. Consequently, R2 resection should not be used as s tandard treatment at present; long-term sur- vival data are awaited from these studies. Chemotherapy and radiotherapy Adjuvant (cid:2) Post-operative adjuvant radiotherapy \200\224no survival effect (cid:2) Meta-analys is of 11 trials, 2096 patients \200\224no bene \201t from adjuvant chemotherapy (cid:2) More recent trials encouraging \200\224patient should go into trial if eligible (cid:2) Mitomycin C (MMC), tegafur-encouraging results (cid:2) Current MRC trial of peri-op erative chemotherapy (ECF) OHO-20(349-374) 11/18/02 8:27 AM Page 356 UPPER GASTROINTESTINAL CANCER 356 Palliative Many patients will be suitable for palliative chemotherapy, with radio- therapy being reserved for the control of pain from bone metastases. Four randomized studies compar ing chemotherapy with best sup- portive care have been reported, three of which demonstrate bene \201t with palliative chemotherapy. Many cytotoxic agents demonstrate single-agent activity in gastric cancer. Few randomized s tudies compare single agents with combina- tion chemotherapy. One study comparing single-ag ent 5- \202uorouracil (5-FU) to 5-FU combined with cisplatin and to FAM (5-FU, adria- myci n, MMC) demonstrated signi \201cantly improved response rates and progression-free surviva l with cisplatin/5-FU. However, overall survival was similar in the three groups. This stud y suggests that response and survival bene \201ts may be achieved with the use of effec- t ive combinations compared to single-agent treatment. While FAM, with response rates of 22 \200\22340% in patients with gastric cancer, was once the most used regimen in gastric cancer, this has now been surpassed by other combinations. In a randomized trial, FAMTX (5-FU, adriamyicn, and methotrexate) demonstrated superior re sponse rates and survival when compared to FAM. The ECF regimen (epirubicin, cisplatin, pro tracted venous infusion 5-FU) was developed at the Royal Marsden Hospital. The rationale fo r the three drugs was based on single-agent activity and the synergy between 5-FU and cispl atin in experimental models. An anthracycline was included because of the enhanced cytotoxi city afforded in combina- tion with the other two drugs. 5-FU was given as a protracted inf usion because of its improved therapeutic index compared to bolus 5-FU. A multi-center rand omized comparison to FAMTX demonstrated superior response rates, failure-free survival, and overall survival with ECF. In addition, global quality of life was improved with ECF at 24 weeks. New drugs being evaluated in gastric cancer include irinotecan (a topoisomerase I inhibitio r) and docetaxol, both of which have response rates of 20%. In addition, orally bioavailabl e \202uoropyri- midines such as UFT and capecitabine are being evaluated in combi- nation therapy in place of intravenous 5-FU. High-dose chemotherapy In a Phase II study of 235 patients treated with ECF, 10% survival a t four years was observed. One way to attempt to increase the propor- tion of long-term sur vivors is to use high-dose chemotherapy as con- solidation in patients achieving a partial or complete remission. A previous study observed an 89% partial remission rate with high-do se etoposide and cisplatin. The lack of complete response was probably due to the fact that patients were not cyto-reduced with conventional chemotherapy prior to high-dose therapy. A randomized study is OHO-20(349-374) 11/18/02 8:27 AM Page 357 GASTRIC CANCER 357 underway in patients who achieve complete or partial remission at 12 weeks, with randomizat ion to high-dose carboplatin/etoposide with peripheral stem cell transplant or to continuat ion of initial treat- ment. Palliative therapies Patients with dysphagia from inoperable tumors of the OGJ and cardia m ay bene \201t from the insertion of rigid or expandable metal stents. Bleeding from intral uminal tumors can be reduced by abla- tion of the tumor with endoscopic laser treatment. Th ere remains a role for palliative surgery to bypass gastric outlet obstruction. OHO-20(349-374) 11/18/02 8:27 AM Page 358 UPPER GASTROINTESTINAL CANCER 358 Small intestine and carcinoid tumors Introduction Small bowel tumors, both benign and malignant, are exceedingly unusual, and co nstitute less than 10% of all gastrointestinal tumors; and approximately 65% of all small b owel tumors are malignant. More than 35 pathological variants have been described. Most com - mon are adenocarcinomas that constitute 40% of all malignant small bowel tumors. Carcinoi d tumors represent 30% of all small bowel malignancies. Other forms of tumors are lymphomas , sarcomas, as well as benign tumors such as leiomyomas, angiomas and lipomas. The incidence of small bowel tumors is 0.4 \200\2231.0/100 000 popula- tion with a slight m ale predominance. The prevalence increases with age and is rare below 30 years of age, peak ing between 50 \200\22360 years. Occasionally, small bowel tumors are related to the Peutz \200\223Jegher \200\231 syndrome or von Recklinghausen \200\231s neuro \201bromatosis. Met astases from melanoma may be found in the small bowel. Etiology Despite the fact that the small bowel constitutes about 75% of the length of the g astrointestinal tract, small bowel tumors account for only 1 \200\2233% of all gastrointest inal malignancies. Rapid transit of its liquid contents might be one explanation. Increased incidence is noticed in immunocompromised patients e.g. AIDS, chronic immuno- suppressant therapy. Frequent consumption of red meat or smoked foods has been asso- ciated with a two- to three fold increased risk of small bowel tumors. There is also a correlation between dietary fat intake and risk of small bowel carcinoma. Crohn \200\231s disease is associated with an in creased risk of small bowel malignancies. Pathology Tumors can derive from all cell types of origin in the small intestine. The same staging system as for colorectal tumors is usually used. In general, initial symptoms of small bowel tumors are rather vague and a diagnostic delay of 8 \200\22312 months is common. Tumor markers are useful for carcinoids, particularly chr omogranin A and 5- HIAA. Markers such as CEA, CA-19-9, CA-50 are too non-speci \201c for d iagnosing small bowel tumors. Any patient who has a primary small bowel malignancy should b e monitored for the development of a second malignant tumor, frequently in the colon. OHO-20(349-374) 11/18/02 8:27 AM Page 359 SMALL INTESTINE AND CARCINOID tumors 359 Adenocarcinoma (cid:2) Commonest in proximal small bowel (80%) (cid:2) presents with abdominal pain and ja undice (obstruction) (cid:2) Anemia \200\224occult bleeding (cid:2) Diagnosis \200\224bariu m studies Endoscopy Carcinoid tumors 90% arise in the ileum and appendix and although they are often silent, ab dominal pain is a common symptom. Small bowel obstruct- ion can result from intense desmopl astic reaction around the primary tumor. The syndrome of chronic mesenteric ischaemia has b een described, related to elastic vascular sclerosis. Less than 20% present with the carcin oid syndrome which includes: (cid:2) Flushing (cid:2) Diarrhea (cid:2) Bronchial constricti on (cid:2) Right-sided valvular heart disease A majority of these patients are found to hav e liver metastases and have elevated urinary 5-HIAA levels and plasma chromogranin A and ta chykinins (neurokinin A and substance-P). Approximately 30% of small bowel carcinoids are m ultiple. Pre-operative diagnostic tests are both biochemical and radiological. Urinary 5-HI AA and chromogranin A are assayed, the latter is particularly useful in earlier stage disea se. The primary tumors and metastases can be seen by somatostatin receptor scintigraphy (Octreo scan); 80% of these tumors express somatostatin receptor subtype 2 that binds this somatost atin ana- logue. This investigation should be supplemented with CT or MRI scan for detectio n of lymph node and liver metastases. Sometimes a small bowel contrast enema can be informa tive in patients with inter- mittent obstructive symptoms. Lymphoma Primary small bowel lymphoma constitutes about 1% of all gastro- intestinal malign ancies. There are \201ve clinical distinct subtypes of primary small intestinal lymphoma: (cid:2) Adult Western type (cid:2) Pediatric type Immunoproliferative small intestinal disease (cid:2) (cid:2) Mediterranean type, enteropathy-associated T-cell lymphoma (cid:2) Hodgkin \200\231 s lymphoma Most small bowel lymphomas show intermediate or high histological grade. The dia gnosis of small intestinal lymphoma is often made only OHO-20(349-374) 11/18/02 8:27 AM Page 360 UPPER GASTROINTESTINAL CANCER 360 at laparotomy. Radiological \201ndings that might suggest this diagnosis include diffuse segment-thickened distal small bowel on a follow- through barium examination. CT can someti mes better demonstrate this \201nding. However, the radiological appearances are easily c onfused with other segmental diseases of the distal small intestine such as Crohn \200\231s disease. Sarcoma These tumors are exceedingly rare and most are of smooth muscle origin (leiomyoma/s arcoma). Recently, tumors derived from the autonomic nervous system have also been describe d. The clinical pre- sentation is either bleeding or obstruction. Treatment Surgery Surgical resection is the most important therapy for all small bowel tumors. All be nign tumors, such as leiomyomas, small bowel ade- nomas, angiomas, and lipomas, can be cure d by adequate segmental resections with clear serosal margins. The same holds true for the malignant tumors, although surgery should include lymph node resection. Pancreaticoduodenectomy may be required in patients with tumors arising in the proximal and second portion of the duoden- um. Carcinoid tumors con \201ned to the distal ileum requir e resection that sometimes includes part of the caecum. In patients with Peutz \200\223Jegh ers \200\231 syndrome and multiple polyps only limited resection should be performed and mo st of the tumors can be removed by endoscopic polypectomy. Resection of involved bowel is recommended for lymphomas, except the Mediterranean type, th at often involves the entire small bowel and responds to systemic therapy. Chemotherapy Chemotherapy for most malignant small bowel tumors is based around 5- \202uor ouracil (5FU). 5FU can be applied either alone or in combination with leucovorin and/or (ci d:2)-interferon. Sarcomas are treated, as at other sites, with doxorubicin-based regimens. Similarly, lymphomas are commonly treated with regimens such as CHOP. Carcinoid tumors, although malignant, should not be treated with cytotoxics in most cases. Streptozotocin and 5-FU or doxorubicin give modest (10 \200\22320%) response rates of short duration. Most patients with low-grade carcinoid tumors can be treated with (cid:2)-interf eron alone or in combination with somatostatin analogs. Five-year survival in patients with malignant adenocarcinoma of the small intestine is only 20 \200\22330%. For carcinoid tumors with local disease, \201ve-year survival is 75 \200 \22395%; with regional lymph node OHO-20(349-374) 11/18/02 8:27 AM Page 361 SMALL INTESTINE AND CARCINOID tumors 361 involvement, 40 \200\22360%; and with liver metastases and the carcinoid syndrome, 20 \200 \22330%. \200\230Aggressive \200\231 surgery combined with biotherapy ((cid:2)-interferon plus somatostatin analog) has recently afforded a \201ve-year survival rate of 60% in pat ients with liver metastases and the carcinoid syndrome. For lymphomas of the small bowel th e majority of deaths occur within two years of diagnosis, with \201ve-year survival of 20 \200\22330%. Combination therapy with resection and chemotherapy has been reported to give \201ve-year survival of 60%. The survival rate for patients with small bowel sarcoma is about 20%. Radiotherapy Radiotherapy is of limited value in most small bowel malignant tumors, not lea st because of the dif \201culty of localizing disease in a mobile organ and because of the low tolerance of the small bowel for ionizing radiation. However, tumor-targeted radiother apy can be applied to carcinoid tumors, using either Indium111-DTPA- octreotide or MIBG. Re sponse rates of 30 \200\22350% have been reported, but these are still considered investiga tional treatments. Cytokine therapy (cid:2)-interferon can be used both for adenocarcinomas and carcinoids of the small bowel, either alone or in combination with 5-FU. Bio- chemical response rates of 40 \200\22350% are reported in malignant carci- noids, although only 10 \200\22315% show me asurable reduction in tumor bulk, (cid:2)-interferon can be combined with somatostatin anal ogs in carcinoid tumor patients. Somatostatin analog treatment Somatostatin analogs are particularly useful for ameliorating clini- cal symptoms such as diarrhea and \202ushing related to carcinoid tumors. They al so demonstrate some anti-tumor effects with about 10% of patients showing signi \201cant t umor reduction and 30 \200\22340%, stabilization of the disease. High-dose therapy (>3 mg/d ay) has been shown to induce apoptosis in carcinoid tumors. Their parenteral administration is simpli \201ed with the recently mar- keted long-acting formulations (10 \200\22330 mg intramuscular injection monthly). Future treatment Novel approaches will be based on tumor biology, taking into con- siderati on the proliferation capacity, expression of adhesion mole- cules, and angiogenic factors. The carcinoid tumor determination of somatostatin receptor subtypes will be of importance a s subtype- speci \201c analogs are developed. New tumor-targeted radioactive treatments ar e also in development. OHO-20(349-374) 11/18/02 8:27 AM Page 362 UPPER GASTROINTESTINAL CANCER 362 Cancer of the liver