OHO-17(295-322) 11/18/02 8:24 AM Page 310 BREAST CANCER 310 Breast cancer \200\224presentation and staging The diagnosis of breast cancer is made by \200\230triple assessment \200\231: (cid:2) Clin ical examination (cid:2) Bilateral mammography (cid:2) FNA cytology or core biopsy This com bined approach to assessment has >90% sensitivity and speci \201city. The axilla is staged surgically. In the absence of locally advanced breast cancer or symptoms of metastatic dis ease or bio- chemical abnormality, routine radiological staging with CXR, CT scan, and isot ope bone scan has not been found useful. The TNM staging system is commonly used. OHO-17(295-322) 11/18/02 8:24 AM Page 311 BREAST CANCER \200\224PRESENTATION AND STAGING 311 Table 17.4 TNM staging system Tis Carcinoma in situ, non-in \201ltrating intraductal carcinoma, or Paget \200\231s disease o f the nipple with no demonstrable tumor T0 No evidence of primary tumor T1 Tumor <2 cm T2 Tumor >2 cm but <5 cm T3 Tumor >5 cm T4 Any size with extension to chest wall or skin T4a Fixation to chest wall only T4b Oedema, in \201ltration, or ulceration of skin Ipsilateral satellite nodules T4c Both aand bpresent NX Regional nodes cannot be assessed N0 No regional node metastases N1 Mobile ipsilateral axillary node metastases N2 Fixed ipsilateral axillary node metastases N3 Ipsilateral internal mammary node metastases OHO-17(295-322) 11/18/02 8:24 AM Page 312 BREAST CANCER 312 Management of non-invasive breast cancer DCIS and LCIS are rarely symptomatic although extensive pre- invasive disease may present w ith a mass or thickening of breast tissue. Treatment options (cid:2) Simple mastectomy 95% cure rate Rarely relapse, due to micro-invasive cancer No need for axillary dissection (cid:2) Wide excision alone \200\22430% recurrence at 5 years (cid:2) Wide excision + radio therapy \200\22415% recurrence at 5 years The management of LCIS is controversial; Bilatera l breast excision of LCIS should be followed by close surveillance. Few surgeons would inst ead advocate bilateral subcutaneous mastectomies and immediate reconstruction. OHO-17(295-322) 11/18/02 8:24 AM Page 313 MANAGEMENT OF NON-INVASIVE BREAST CANCER 313 OHO-17(295-322) 11/18/02 8:24 AM Page 314 BREAST CANCER 314 Management of early breast cancer Early breast cancer is de \201ned as disease that can be completely extir- pated by surger y, that is T1 \200\2233, N0 \200\2231 tumors. The management of this disease comprises: (ci d:2) Treatment of the breast and axilla (cid:2) Pathological staging to direct adjuvant the rapy (cid:2) Adjuvant therapy \200\224endocrine, chemotherapy, radiotherapy (cid:2) Follow- up Breast surgery All patients require removal of the primary tumor with either wide local exc ision or mastectomy. Halsted mastectomy was the operation most extensively applied to breas t cancer patients during the \201rst half of the twentieth century, but it has gradually been replaced by a variety of less radical operations. Total mastectomy and axillary dissection is a less mutilating opera- tion preserving the pe ctoralis major muscle and its neurovascular bundle. Quadrantectomy, introduced at the begin ning of the 1970s, is a breast-conserving operation that removes the primary cancer with a margin of 2.0 cm of normal breast tissue. Lumpectomy is an opera- tion that provides for th e removal of the tumor mass with a limited portion of normal tissue (1 cm). Randomized trials comparing breast-conserving surgery followed by radiotherapy with mastect omy alone have demonstrated similar local control rates and survival. Breast conservation i s not always suit- able for women with multifocal disease and large tumors in small breasts . Some patients simply prefer mastectomy, not least because of the possible avoidance of ra diotherapy. Either treatment should afford a local recurrence rate of <10% after 10 years. Breast reconstruction can be done either at the time of primary surgery or at a later date \200\224streetcar \202ap, latissimus dorsi \202ap, and implants all have a role. Treatment of the axilla (cid:2) Clinical assessment is inaccurate (cid:2) 30% of involved nodes are impalpable (cid :2) Surgery \200\224axillary node sampling (>4 nodes) (diagnostic) \200\224axillary clearance levels, I, II, and III (therapeutic); lymphodema and arm pain are complications OHO-17(295-322) 11/18/02 8:24 AM Page 315 MANAGEMENT OF EARLY BREAST CANCER 315 \200\224sentinel node biopsy: \200\224removal of \201rst node which contains secondary deposit \200\224ongoing UK trial \200\224use either blue dye or 99MTc colloid \200\224negative s entinel node avoids clearance Loco-regional radiotherapy Breast irradiation has been shown to reduce the risk of local re cur- rence after breast-conserving surgery from about 30% to <10% at 10 years. Typically, t he whole breast is treated with tangential \201elds to a dose of 50 Gy in 25 fractions (o r an equivalent dose-fractionation regimen), with care taken to minimize the volume of lung and heart irradiated. Although a boost of 10 \200\22315 Gy is commonly delivered to the tu mor bed, using electrons or 192Ir implant, its bene \201ts are unproven. (cid:2) Older tec hniques \200\224cardiac side-effects (cid:2) Modern techniques \200\224safe \200\224may improve survival Irradiation of axilla \200\224not required if clearance performed (cid:2) (cid:2) Radiation to axilla may cause lymphodema and brachial neuro- pathy Adjuvant systemic therapy Breast cancer patients who remain disease-free after local and re gional treatment may eventually relapse and die of overt metastases. The cur- rent hypothes is ascribes the failure to obtain a cure to occult micro- metastases in distant organs, alr eady present at the time of \201rst surgery. The risk of harboring occult metastases is l ow in cases with a small carcinoma and negative nodes and increases with the size of the pr imary carcinoma and number of axillary metastatic nodes. There have been many trials among women with operable breast cancer, examining the effects of systemic treatment, either endocrine maneuvers or chemotherapy or both, on the survival of these patients. The basis of all these therapies is the reduction or eradication of micr oscopic systemic metastatic disease in women in whom all macroscopic local tumor has been e ffectively removed. In 1992 the Early Breast Cancer Trialists \200\231 Collaborative Group published an overview of 133 randomized trials involving 75 000 women with early breast can cer1 \200\2233. This has had major impact, setting standards of care for adjuvant therapy f or this disease. Adjuvant endocrine therapy (cid:2) 60% of breast cancers are estrogen receptor positive (cid:2) Ovarian ablation \200 \224improves survival in women under 50 years \200\224morbidity of vascular disease and osteoporosis OHO-17(295-322) 11/18/02 8:24 AM Page 316 BREAST CANCER 316 (cid:2) Tamoxifen \200\224improves disease-free and overall survival \200\224all women, especially post-menopausal \200\224little bene \201t if ER negative \200\2245 years is suf \201cient: better than 2 years; no need for longer \200\22410% increase in survival for node-positive disease \200\2245% increase in surviva l for node-negative disease (cid:2) Side-effects of tamoxifen \200\224menopausal symptoms \200\224endometrial cancer, 4-fold increase in risk \200\224decreases contralateral breast cancer risk Adjuvant chemotherapy (cid:2) Combination chemotherapy reduces recurrence and mortality \200\224absolute 10-year survival bene \201t: 7 \200\22311% women <50 years; 2 \200\2233% women >50 years (cid:2) CMF (cyclophosphamide, methotrexate, 5FU) used in most trials (cid:2) Anthracycline regimes may be better (cid:2) Used most often in node-positive, large, Grade 3, ER-negativ e, pre- menopausal tumor patients (cid:2) Used in some ER-negative, node-positive, post-menopausal patients Neo-adjuvant therapy Primary chemotherapy or hormone therapy for operable breast cancer pro vides early systemic treatment and allows assessment of the response to treatment; by de \201nition this is impossible with adjuvant therapy. Its disadvantages are the delay in de \201nitive local surgery and the risk of over-treatment with chemotherapy in the absence o f pathological staging (e.g. post-menopausal, ER-positive, node-nega- tive tumor). A large randomized trial (NSABP-B18) has shown no difference in survival when pre- and post -operative chemotherapy (doxorubicin and cyclophosphamide) was compared. Pre-operative trea tment does downstage the primary tumor and, in some women, facilitates breast-conserving su rgery where mastectomy would otherwise be required. OHO-17(295-322) 11/18/02 8:24 AM Page 317 MANAGEMENT OF EARLY BREAST CANCER 317 OHO-17(295-322) 11/18/02 8:24 AM Page 318 BREAST CANCER 318 Management of locally advanced breast cancer Locally advanced disease is de \201ned by the presence of in \201ltration of the skin or the chest wall or \201xed axillary nodes. The probability of metastatic disease is high ( >70%) but long-term survival is possible and the median survival of these patients exceeds two years. Local control of the tumor and the prevention of fungation are of major importance to the q uality of life of these women. A combina- tion of primary systemic treatment and radiothera py is commonly used. Many of these patients are elderly and have indolent ER-positive disea se that responds to endocrine therapy with tamoxifen, aromatase inhibitors, or progestins. In younger women, particularly with aggres- sive \200\230in \202ammatory \200\231 breast cancer, primary chemotherapy is preferred. In patients with a good response to systemic tre atment surgery may be feasible. OHO-17(295-322) 11/18/02 8:24 AM Page 319 MANAGEMENT OF LOCALLY ADVANCED BREAST CANCER 319 OHO-17(295-322) 11/18/02 8:24 AM Page 320 BREAST CANCER 320 Management of metastatic breast cancer (cid:2) Aim is palliation If hormone-sensitive, bony disease \200\224may survive years (cid:2) (cid:2) 20% survive 5 years (cid:2) visceral ER-negative disease has bad prognosis (cid:2) Usual sites \200\224lung, liver, bone, brain (cid:2) Rare sites \200\224choroid, pituitary Endocrine therapy Treatment with tamoxifen, ovarian ablation, progestins, or aromatase inhi bitors will provide an objective response in 30% of women with advanced disease, and in 50 \200\22360% of those with ER-positive tumors. Disease that responds to endocrine therapy an d then progresses has a 25% response rate with second-line treatment; the response to a thi rd agent is 10 \200\22315%. Chemotherapy Advanced breast cancer is moderately chemosensitive. Active agents include: (c id:2) Anthracyclines (cid:2) Alkylating agents (cid:2) Antimetabolities Combinations such a s FAC (5- \202uorouracil, doxorubicin, cyclophos- phamide) produce response rates of 40 \200\22360%, with a median time to progression of around 8 months. Despite the toxicity of such combi- nations (alopecia, nausea, mucositis, lethargy, myelosuppression) it has been s hown that the quality of life of women improves as they respond to treatment. 25 \200\22350% of women respond to second-line chemotherapy with a taxane and studies are c urrently evaluating the promising combina- tion of anthracycline plus taxane as \201rst-l ine chemotherapy. Although Phase II studies have suggested that high-dose chemotherapy may produce durable remissions from metastatic breast cancer, no survival bene \201t has yet b een proven for such treatment. OHO-17(295-322) 11/18/02 8:24 AM Page 321 MANAGEMENT OF METASTATIC BREAST CANCER 321 Radiotherapy Low-dose radiotherapy provides effective palliation for painful bone metastase s, soft tissue disease, and spread to sites such as the brain and choroid. Bisphosphonates These agents are the mainstays of treatment for malignant hyper- calcaemia. In addition, they can produce healing of some osteolytic metastases and prolonged treatmen t with bisphosphonates for bone metastases from breast cancer reduces osteolysis, improves bone pain, and prevents hypercalcaemia and fractures. Recent data suggest that prophylactic treatment with these agents may prevent the future development of bone metastases in women with high-risk early breast cancer. OHO-17(295-322) 11/18/02 8:24 AM Page 322 BREAST CANCER 322 Prevention of breast cancer The initial results of three tamoxifen studies in the prevention of breast cancer in \200 \230high-risk \200\231 well women are controversial. An American study has shown a signi \201cant reduction in breast cancer with tamoxifen, but a UK and an Italian study have not con \201rmed this. The groups of women in each study were different, and it may be that th e US study was positive because of the preponderance of older women (in whom tamoxifen may be more effective). Fenretinide, a derivative of retinoic acid, appears a good candidate for chemoprevention as it has been shown to reduce the risk of con- tralateral and ipsilateral breast carcinomas in menopausal women. Other agents such as raloxifene have also shown promise. 1. Early Breast Cancer Trialists \200\231 Collaborative Group. (1992) Systemic treatment of early breast cancer by hormonal, cytotoxic or immune therapy \200\224Parts I and II. Lance t 339, 1 \200\22315, 71 \200\22385. 2. Early Breast Cancer Trialists \200\231 Collaborative Group. (1998) Tamoxifen for early b reast cancer: an overview of the randomized trials. Lancet 351, 1451 \200\22367. 3. Early Breast Cancer Trialists \200\231 Collaborative Group. (1998) Polychemotherapy for early breast cancer: an overview of the randomized trials. Lancet 352, 930 \200\22342. OHO-18(323-338) 11/16/02 12:32 PM Page 323 Chapter 18 Colorectal cancer Introduction 324 Colorectal cancer \200\224surgery 326 Adjuvant chemotherapy of colorectal cancer 328 Chemotherapy for advanced colorectal cancer 332 Radiotherapy in colorectal cance r 336 Further reading 338 OHO-18(323-338) 11/16/02 12:32 PM Page 324 COLORECTAL CANCER 324 Introduction Colorectal cancer is the fourth commonest cancer worldwide. Around two-thirds of a million people will present with the disease each year. It affects men and women almost equally and tends to be more com- mon in \200\230developed \200\231 countries and is particularly com mon in the US, Europe, and Australia. Ethnic and racial differences, as well as migrant studies, suggest that environmental facto rs (probably diet) play a major role in the aeti- ology of the disease. Several distinct, i nherited, predisposition syn- dromes have been described such as familial adenomatous polyp osis (FAP) and hereditary non-polyposis colon cancer (HNPCC), but these account for a minor ity of cases (<8%). The left side of the colon was more commonly affected, but over the last two decades there has been a steady increase in the incidence of cancer in the proximal colon. Colorectal cancers are almost always adenocarcinomas. The tumor often starts as a polypoida l mass and then tends to in \201ltrate into and through the bowel wall. The loco-regional lymph nodes tend to be involved before the development of disseminated disease. This behavi or is the basis for all the staging systems for colorectal cancer. In rectal cancer speci \201cally there is also a propensity for the tumor to in \201ltrate laterally into the per irectal fat and lymph nodes. OHO-18(323-338) 11/16/02 12:32 PM Page 325 INTRODUCTION 325 OHO-18(323-338) 11/16/02 12:32 PM Page 326 COLORECTAL CANCER 326 Colorectal cancer \200\224surgery Introduction Surgery is the mainstay of curative therapy for colorectal cancer. There is co nsiderable controversy about who should perform this surgery \200\224 general or colorectal surgeons. Currently there is no clear answer, but surgeons working regularly in the pelvis may get better results in rectal cancer. Curative resection requires the excision of the primary tumor and its lymphatic drainage wi th an enveloping margin of normal tissue. Pre-operative preparation The precise site and local extent of the tumor should be known be fore laparotomy; knowledge of distant spread is helpful. Full colonoscopy or proctosigmoido scopy and air-contrast barium enema (in the absence of obstruction or perforation) is requi red. The liver is imaged with CT and/or ultrasound examination; CT and endo-anal ultrasound imaging of the pelvis may offer additional information of the depth of invasion of rectal cancers. Additional decisions are required before surgery for rectal cancer: (cid:2) Should transanal local excision be considered? If radical surgery is contemplated, should/can the sphincters be spared? If a stoma is plan ned the stoma care team must meet with the patient and plan the site of the stoma with atte ntion to belt lines and skin creases. In choosing the operative approach, especially in rec tal cancer, functional consequences are of prime importance \200\224will the patient be abl e to cope with a colostomy or the different bowel habit associ- ated with altered anatomy c onsequent on avoiding a colostomy? Peri-operative antibiotics and thrombo-embolic prophylax is are mandatory. (cid:2) (cid:2) (cid:2) Principles in primary resection The local anatomy of the disease and signs of distant sprea d are sought, perhaps using intra-operative ultrasound liver scan. The extent of resection is de \201ned and the appropriate segment mobilized, including the arteries and veins asso ciated with its lymphatic drainage, dividing these at their origins. The bowel segment and its lymphatic \201eld are excised intact. If an anastomosis is planned, it is fashioned w ithout OHO-18(323-338) 11/16/02 12:32 PM Page 327 COLORECTAL CANCER \200\224SURGERY 327 tension, ensuring a good lumen and secure apposition. Minimally invasive colon cancer surge ry is still unproven. Rectal cancer The rectum is mobilized circumferentially by sharp dissection in the plane ou tside the mesorectal fascial envelope, either to 3 cm below the tumor if part of the rectum is being preserved, or to the pelvic \202oor if a coloanal anastomosis or abdomino-perin eal resection (APER) are planned. If performing an anastomosis with anal observation, the meso- rectum is divided and after c ross-stapling the bowel, the specimen is removed and an anastomosis made, either hand-sutur ed or by transanal circular stapling. If an APER is planned, an oval incision is made aroun d the anus; the ischiorectal fat and pelvic \202oor muscles are incised to allow the spec imen to be delivered intact through the peri- neum. Total excision of the mesorectum is con sidered essential. Local excision Around 5% of rectal cancers may be removed by non-radical transanal surgery. This is particularly appropriate in small, low, well- differentiated cancers on the poster ior wall, especially if the patient is not an ideal candidate for major abdominal surgery. Via a Parks \200\231 anal retractor, a disc of rectal wall is marked with a 1 cm margin aro und the tumor. Diathermy is used to cut through the full thickness of the rectal wall, taki ng a sliver of extra-rectal fat. The spec- imen should be pinned on cork to orientate it fo r the pathologist. The rectal defect may be closed if possible. If the pathologist reports incomplete excision, spread through the rectal wall, or poorly differ- entiated carcinoma, radical surgery may be required to obtain local extirpation of tumor, if the patient is \201t. Some lesions not reachable by the Parks \200\231 approach may be locally removable by trans anal endoscopic microsurgery (TEM), using a spe- cial 4 cm rigid endoscope with binocular v ision. Surgery of recurrent cancer Local recurrence occurs most commonly in rectal cancer, usually out- side the bowel lumen. If investigations suggest that a recurrence is isolated and pot entially resectable, further surgery should be consid- ered. Clearance may involve removal of residual rectum and other pelvic organs, including the bladder and/or uterus. Metastasis con \201ned to one lobe of the liver or less than four in both lobes may warrant resection, as there is up to a 30% chance of cure. OHO-18(323-338) 11/16/02 12:32 PM Page 328 COLORECTAL CANCER 328 Adjuvant chemotherapy of colorectal cancer Rationale Nearly half the patients undergoing apparently curative resection of bowel cancer are destined to relapse and eventually die with either locally recurrent or distant metast atic disease. This is due to the pres- ence of residual micro-metastases invisible at the t ime of surgery. The aim of adjuvant chemotherapy is to eradicate these micro-metastases and thereby prevent future relapse. Current available chemotherapy does not completely eradicate bulky, advanced metastatic bow el cancer. It does however eradicate micro-metastases in a proportion of patients. In view of the high incidence of colorectal cancer, even a small percentage bene \201t with adjuva nt chemotherapy may have a signi \201cant impact in terms of pre- vention of death and mor bidity. Indications Adjuvant chemotherapy is an exercise in risk reduction. Questions to be conside red after a potentially curative operation: (cid:2) What is the probability of micro-metast ases? (cid:2) Will adjuvant therapy prevent/delay relapse? (cid:2) What are the side-effect s? (cid:2) Multidisciplinary team is essential. The risk that the patient has micro-metasta ses is estimated, after surgery, by examining the pathological features of the primary canc er; best-established is the histological stage (Dukes \200\231 or Astler \200\224Coller). D ukes \200\231 A cancers, ie those which have not breached the muscle layers of the bowel wa ll, carry only a 10% chance of relapse, and adjuvant therapy is not considered worthwhile. Dukes \200\231 C cancers, which have spread to the nearby lymph nodes, carry a much higher risk (around 50%). There is good evidence that this risk is reduced by adjuvant chemotherap y, which is now offered routinely in most centers unless there is a strong contraindication . Dukes \200\231 B cancers, which have breached the muscle layers but not spread to lymph nod es, carry an intermediate risk of around 30%. The evidence for adjuvant chemotherapy is les s clear-cut in these patients, and other factors including other pathological features, the patient \200\231s age, \201tness, and attitudes come into the equation. Further trials t o assess bene \201ts in these groups are under way. OHO-18(323-338) 11/16/02 12:32 PM Page 329 ADJUVANT CHEMOTHERAPY OF COLORECTAL CANCER 329 Molecular markers in the primary tumor may potentially predict invasiveness or determine se nsitivity to chemotherapy; sensitive PCR- based tests are being developed to detect micro-m etastases in blood, bone marrow, or other tissues. Rectal cancer, which accounts for nearly 40% of bowel cancers, pre- sents some special cons iderations. A relative lack of a barrier to lateral spread and increased technical dif \201culty of surgery in the pelvis combine to make local recurrence a particular problem. R adiotherapy, targeted to the pelvis either before or after surgery, reduces local recur- re nce rates. Adjuvant therapy for rectal cancer may therefore include both radiotherapy and c hemotherapy aimed, respectively, at local and systemic micro-metastases. The evidence for t he contribution of chemotherapy in these combined programs is less clear than for chemother apy alone in colon cancer. Treatment The current \200\230international standard \200\231 adjuvant chemotherapy regime n for colon carcinoma is 5- \202uorouracil (5FU) given in combination with folinic acid, b y bolus intravenous injection. Two commonly used schedules involve treatment for \201ve c onsecutive days, repeated every four weeks, or treatment on one day each week, in both case s contin- ued for six months. 5FU interferes with nucleotide synthesis, and hence the synth esis of DNA in dividing cells. It also has effects on RNA. The addition of folinic acid enh ances the DNA-directed effects of 5FU and prolongs its duration of action. 5FU given by these standard schedules appear to reduce the relative risk of death by around a fourth. For a patient with Dukes \200\231 C colon cancer the absolute gain may be more t han 10%, but for a patient with an earlier-stage cancer, who is already at low risk followi ng surgery, the absolute gain from adjuvant therapy may be much smaller. 5FU is also a radi osensitiser. For patients with rectal cancer, pre- or postoperative pelvic radiotherapy is sometimes given concurrently with chemotherapy to harness this effect. This may be followed by a more prolonged course of standard adjuvant chemotherapy aimed at distant micrometasta ses. Side-effects Both the wanted and the unwanted effects of 5FU are critically depen- dent upo n the dose and schedules used, and vary considerably from patient to patient. The side-effe ct pro \201le should, for most patients, be quite easily tolerable and consistent with con tinuing normal activity, including work. Treatment is feasible even in the elderly. Side-effects: (cid:2) Hair loss and vomiting (cid:2) Oral mucositis OHO-18(323-338) 11/16/02 12:32 PM Page 330 COLORECTAL CANCER 330 (cid:2) Diarrhea (cid:2) Tiredness Rare side-effects of 5FU include: (cid:2) Red, painful p alms and soles (cid:2) Photosensitivity of face Irritation to eyes and nose (cid:2) (cid:2) Myleosuppression (cid:2) Cardiotoxicity (angina, infarction, or arrhythmias) (cid:2 ) Cerebellar syndrome (ataxia, slurred speech, and nystagmus) Some patients may also experi ence unwanted psychological or social effects of adjuvant chemotherapy: (cid:2) Prolongatio n of the \200\230patient \200\231 status (cid:2) Feelings of anxiety or depression (cid:2) Loss of earnings (cid:2) Strains on family relationships Newer treatments It is known from research in patients with advanced colorectal cancer that there are more effective methods of giving 5FU, involving higher doses delivered by contin uous or intermittent intravenous infusions. Ongoing randomized trials are evaluating whethe r these are worth- while as adjuvant therapy. 5FU itself is not reliably absorbed if given by mouth, but a number of new oral preparation s involving pro-drugs of 5FU and/or inhibitors of 5FU catabolism are being evaluated. Other research approaches involve regional delivery of 5FU to the tissues most at risk of contai ning micro- metastases, via the peritoneal cavity or the hepatic portal vein. New cytotoxic agents are continually under investigation, the most promising of which are: Irinotecan (a drug which works by interfering with the nuclear enzyme topoisomerase-I) (cid:2) (cid:2) Oxaliplatin (which forms covalently bonded adducts with DNA) OHO-18(323-338) 11/16/02 12:32 PM Page 331 ADJUVANT CHEMOTHERAPY OF COLORECTAL CANCER 331 OHO-18(323-338) 11/16/02 12:32 PM Page 332 COLORECTAL CANCER 332 Chemotherapy for advanced colorectal cancer Advanced colorectal cancer is that which is metastatic or locally advanced such that surgic al resection is not likely to be curative. This may be at initial presentation (25% of new cases) or develop during follow-up of previously treated patients (50% of \200\230curative ly \200\231 resected). It has a poor prognosis with \201ve-year survival <5%. Indications for chemotherapy Any patient with good performance status. Patients who are eli gible for surgery for isolated metastasis (e.g. liver, lung) should be excluded. Resection of such metastasis may be curative in a small subset of patients. Timing of chemotherapy A single randomized study has demonstrated that chemotherapy given e arly imparts a small but signi \201cant survival advantage when compared to delaying treat ment until symptoms arise. First-line chemotherapy 5-Fluorouracil (5-FU) First introduced in 1957, 5-FU is still the most widely used single a gent. It acts, following conversion to active metabolites, as a false sub- strate for thymi dylate synthase, preventing DNA synthesis. Several trials suggest a response rate of 10 \200\22320%. No increase in overall survival is seen when analyzing all patients treated. A number of small randomized trials, comparing chemotherapy to best supportive care, suggest that there may be an average survival bene \201t of around six months in favor of chemoth erapy. Modulation Understanding the complex pathways by which 5-FU acts has allowed the developmen t of biochemical modulation techniques. Leucovorin enhances 5-FU toxicity by stabilizing th e interaction of thymidylate synthase and active 5-FU metabolites. Several studies, when me ta- analyzed, have shown a doubling of response rate with the addition of leucovorin to 5-F U compared to 5-FU alone (23% vs. 11%). No differ- ence in response rate has been seen when comparing high-dose to low-dose leucovorin. O H O 1 8 ( 3 2 3 3 3 8 ) 1 1 / 1 6 Table 18.1 Commonly used regimens in \201rst-line treatment of advanced colorectal cancer / 0 2 Regimen 5-FU Leucovorin Interval Mode Duration 425 mg/m2 20 mg/m2 Daily for 5 days Mayo Bolus 4 \200\2235 weeks 1 2 : 400 mg/m2 Bolus, 8 g/m2, 46 hrs DeGramont 2 weeks 200 mg/m2 Bolus/infusion 2 days 3 2 300 mg/m2 per day Lokich \200\223 8 \200\22312 weeks Continuous infusion \200\223 P 3 mg/m2 \200\223 Tomudex 15 mins 3 weeks Bolus M P a g e 3 3 3 3 3 3 OHO-18(323-338) 11/16/02 12:32 PM Page 334 COLORECTAL CANCER 334 Table 18.2 Toxicities of commonly used regimens in \201rst-line treatment of advanced col orectal cancer Mayo DeGramont Lokich Tomudex Nausea/vomiting + + + + Diarrhea +++ + + Mucositis +++ + + + Myelosuppression ++ + + + Alopecia \200\223 \200\223 \200\223 Hand/food syndrome \200\223 \200\223 ++ \200\223 Modes of administration The optimum schedule of 5-FU leucovorin administration has yet t o be elucidated. Intravenous bolus 5-FU, usually given with leucovorin, is currently most commonly used (e.g . Mayo). Such regimes have the advantage of being outpatient-based. Bolus/infusion regimes (e.g. DeGramont) have been shown to increase response rates and improve treatment tolerabil ity. Continuous infusion 5-FU regimes, delivered by portable pumps, have the theoretical ad vantage of increasing the likelihood of cancer cells being exposed to 5-FU during cell cycl e and show improved response rates and good tolerability compared to bolus 5- FU. They suff er from the disadvantage of venous thrombosis and intravenous line occlusion. Raltitrexed ( \200\230Tomudex \200\231) Raltitrexed is a potent inhibitor of thymidylate sy nthase. It can be used as an alternative to 5-FU-based regimes for \201rst-line treatment . It does not require co-administration of a biochemical modulator. Response rates appear t o be similar to those seen with 5-FU/ leucovorin. It has the advantage of being administere d as an intra- venous bolus every three weeks and causes less neutropenia and mucositis. Regional chemotherapy Intra-hepatic 5-FU, following surgical placement of a hepatic artery catheter, may be considered for patients with unresectable liver metas- tases. Response rat es of 40 \200\22360% have been reported, although survival bene \201ts are marginal. Second-line chemotherapy Irinotecan, CPT-1 Further chemotherapy depends on patient wishes and performance status. Fo r patients previously treated with 5-FU-based chemotherapy, OHO-18(323-338) 11/16/02 12:32 PM Page 335 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.