KEY ISSUES RELATED = TO RADIOTHERAPY AND CHEMOTHERAPY ASPECTS FOR TUMORS OF INTESTINE = AND

From: Subject: KEY ISSUES RELATED TO RADIOTHERAPY AND CHEMOTHERAPY ASPECTS FOR TUMORS OF INTESTINE AND Date: Thu, 28 Sep 2006 17:02:13 +0530 MIME-Version: 1.0 Content-Type: text/html; charset="iso-8859-1" Content-Transfer-Encoding: quoted-printable Content-Location: file://C:\WINNT\Profiles\Administrator\Desktop\IIfolderonlearningmaterials22.9.2006\surgery\TUMORS_INTESTINE.htm X-MimeOLE: Produced By Microsoft MimeOLE V5.00.2314.1300 KEY ISSUES RELATED = TO RADIOTHERAPY AND CHEMOTHERAPY ASPECTS FOR TUMORS OF INTESTINE = AND

Name of = speciality =20 : =20 General=20 Surgery

Name of case =20 : =20 Tumors of=20 Intestine

Name of expert =20 : =20 Dr. Ajay = Kumar

Name of Hospital =20 : =20 Lady Hardinge Medical = College,=20 New Delhi - 110001

Clinical Features

a) Small Intestine = Tumors

The = average=20 age of presentation is in the 7th decade with malignant lesions = presenting=20 earlier than benign. The symptoms can be divided into four categories=20 namely-obstructions, hemorrhage, mass or perforation. Obstruction is the = most=20 common presentation and is partial with patient presenting with crampy = abdominal=20 pain, distension and bilious vomiting. Obstruction is generally caused = by=20 luminal narrowing or intussusceptions with tumor as lead = point.

The = signs are=20 generally unrevealing 25% of patients presents with palpable mass & = further=20 25% with intestinal obstruction. The patient may present with metastatic = disease=20 like hepatomegaly and ascites. Periampullary tumors may present with = surgical=20 obstructive jaundice or pancreatitis. Patient with carcinioid present = with=20 carcinoid syndorome after metastasis to liver which includes diarrhea, = flushing,=20 hypotension, tachycardia, and fibrosis of endocardium and valves of = right heart.=20 The patients with gastrointestinal stromal tumors generally present with = hemorrhage.

b) Large Intestine = Tumors

The = tumors of=20 right sid colon(caecum & ascending colon) most commonly presents = with ANAEMIA which is severe and = unyielding=20 to treatment. The patient can also present with mass in right iliac = fossa or=20 acute appendicitis if tumor blocks the lumen of appendix. Lastly the = patient can=20 also present with intusussception with tumor as lead = point.

The = tumors of=20 left side colon most commonly presents with increasing INTESTINAL OBSTRUCTION. The = patient=20 presents with suprapubic pain or alteration of bowel habits. There may = be=20 assosciated palpable lump which is generally impacted feces rather than = tumor=20 mass

The = tumors of=20 rectum most commonly present with BLEEDING PER RECTUM which is = slight in=20 amount, bright red in colour & occurs at the end of defaecation. The = patient=20 may complain of TENESMUS which is defined as painful straining at = defaecation=20 with passage of only mucus and blood. The patient may go may times to empty his bowel(SPURIOUS DIARRHOEA) or = present with EARLY MORNING BLOODY = DIARRHOEA where=20 patient has to get up before accustomed hour & passes blodd & = mucus in=20 addition to feces.

The = patients=20 with large bowel tumors can also present directly with signs & = symptoms of=20 metastatic diseas like jaundice, ascites, hepatomegaly & lung or = brain=20 metastasis.

Investiagations (Excluding=20 Radiological)

SMALL BOWEL = TUMORS

&nbs= p; =20

The = diagnosis=20 is rarely made preoperatively. He investigatins are non specific. There = can be=20 increased 5-Hydroxy Indole Acetic Acid in case of carcinoid or increased = Carcinoembryoni antigen only in presence of liver metastasis.=20 Oesophagogastroduodenoscopy can be done for upper small bowel tumors = &=20 colonoscopy can detect lesions in terminal ileum. Nuclear Medicine = studies like=20 Technetium labeled RBC = can be done=20 for detecting occult source of chronic gastrointestinal blood=20 loss.

LARGE BOWEL = TUMORS

COLON

i. = FECAL=20 OCCULT BLOOD TESTING

It = is used=20 as a screening test for colonic neoplasms in asymptomatic average risk = patints.=20 It is done by using GUAIAC impregnated paper slides & it tests = ability of=20 heme to catalyze oxidation of guaiac in peroxide to produce blue strain. = The=20 false negative rates are 20-30% as not all colonic malignanies bleed = & those=20 that do they do it intermittently. The false positive results are = obtained in=20 people consuming red meat, salicylates or Vitamin C. For best results it = is=20 necessary to test two samples for three consecutive stool samples with = patients=20 adhering to restricted diet.

ii. =20 SIGMOIDOSCOPY

Rigid=20 sigmoidoscopy can detect lesions up to 18 cm & flexible till 60 cm. = It is an=20 OPD procedure & can detect lesions in sigmoid/distal colon &=20 simultaneous biopsy can provide tissue diagnosis.

iii. = COLONOSCOPY

It = can=20 detect lesions upto 160 cm & also provide with tissue diagnosis. It = is very=20 useful for detecting synchronous lesions which are present in up to 5% = of=20 patients.

RECTUM

i. = DIGITAL=20 RECTAL EXAMINATION

With patient=20 placed in left lateral position(Sim=92s position) one ca detect lesion = up to 10 m.=20 90% of rectal lesions can be detected digitally. The lesions can either = be=20 palpated as nodule with indurated base or depression with everted edges. = With=20 bimanual examination lower extremity of rectosigmoid tumors can also be = felt.=20 Lymph nodes can also be felt posteriorly/posterolaterally. In female = patints=20 simultaneous vaginal & rectal examinations can be done & in = patients=20 with growth blood or mucopurulent material with blood can be seen = smeared on=20 gloved finger after digital examination.

ii. =20 PROCTOSIGMOIDOSCOPY

This can also=20 detect rectal and lower sigmoid lesions.

ROLE OF TUMOR=20 MARKERS

=20 Carcinoembryonic Antigen(CEA) can be elevated in 60-90% of = colorectat=20 patients. It has no diagnostic value & is a prognostic indicator = & also=20 useful as follow-up investigation for detection of = relapse.

RECENT ADVANCES

SMALL BOWEL = TUMORS

=20 =20 Total small bowel ENTEROSCOPY=20 have been tried with = more=20 sophisticated instrumentation. It can detect both focal and diffuse = lesions=20 & source of occult bleeding.

=20 LARGE BOWEL TUMORS

=20 IMMUNOCHEMICAL fecal=20 occult blood testing with the use of Monoclonal/Polyclonal antibodies = provides=20 increased sensitivity.

Reference:

Bowden=20 TA, Endoscopy of the small intestine: Surg. Clin North Am 1989;69;237=20
Charles=20 B, Dana K, Timothy R, David L, John G, Raphal E, : Schwartz=92s, = Principles of=20 surgery, Eight Edition; 2005, p 1038-1040, 1064
Russell=20 R.C.G., Norman S.W., Christopher J.K.: Bailey & Love=92s, Short = practice of=20 surgery, Twenty Forth Edition, 2004, p1178-1179-1233.
Vincent=20 T. Devita, Samuel H, Steven A: Cancer, Principles & practice of = oncology,=20 Sixth edition, p1205-1207

Key = Issues=20 Related To Radiotherapy And Chemotherapy Aspects For Tumors Of Intestine = And=20

Related Recent=20 Advances

Dr. = S.V. Rantam,=20 Department of radiation Oncology, Nizams Institute of Medical Sciences,=20 Hyderabad

Tumors=20 of small intestine presents significant diagnostic and therapeutic = challenges to=20 the cancer clinician because (1) it is not a single pathologic entity = but rather=20 a diverse group of histologically benign and malignant tumors; (2) it is = relatively rare, making collection, collation, and analysis of = epidemiologic=20 data, as well as treatment outcomes, difficult; and (3) it usually = presents with=20 vague or nonspecific symptoms, making early diagnosis difficult. The four most common subtypes, = adenocarcinoma, carcinoid, lymphoma, and sarcoma/gastrointestinal = stromal tumor=20 (GIST), which account for greater than 98% of malignancies arising in = the small=20 intestine are reviewed individually.

Incidence

Cancer=20 arising in the small intestine is extremely rare. In 2004, there are = expected to=20 be 5200 new cases, accounting for just 0.3% of all new expected cancer = cases in=20 the United States. It accounts for approximately 2% of all = gastrointestinal (GI)=20 cancers. The incidence of malignant tumors arising in the small = intestine has=20 been estimated to be between 5.9 and 9.9 per million people in the = United States=20 and 5.1 per million people in the United Kingdom.

The=20 incidence of benign small bowel tumors is difficult to ascertain from = the large=20 retrospective reviews, as they are inherently biased toward the = reporting of=20 symptomatic tumors. In one large study of 9721 consecutive autopsies, = 112=20 neoplasms of the small bowel were discovered, 72 of which were benign=20 lesions. 95% of the time = that=20 malignancy is discovered it is either adenocarcinoma, carcinoid, leiomyoma / leiomyosarcoma = (GIST), or=20 lymphomas. Most of the information that we have regarding the incidence = of=20 individual histologic subtypes of cancers arising in the small intestine = is=20 derived from a handful of reviews of large cancer databases or large=20 single-institutional retrospective case series^1-7. Adenocarcinoma = (24% to=20 44%), carcinoid (20% to 42%), sarcoma/GIST (7% to 9%), and lymphoma (12% = to=20 27%).

Adenomas=20 and Adenocarcinomas Arising in the Setting of Familial Adenomatous = Polyposis=20

Approximately=20 90% of patients with FAP develop duodenal involvement with polyps. These = polyps=20 are of malignant potential, and 2% to 5% of all patients with FAP = develop=20 adenocarcinoma of the duodenum at some time during their=20 lifetime^5,8.

Treatment=20 of Localized Disease

Surgery is=20 the mainstay of treatment of adenocarcinoma arising in the small bowel. = Complete=20 surgical resection with negative margins remains the single best = curative=20 regimen. For those tumors arising in the duodenum, there are a variety = of=20 surgical options, including segmental duodenal resection. For duodenal tumors, it = appears that=20 segmental resection leads to overall less survival.⁹⁼⁹⁶¹¹=20 Sohn et al.¹⁰ reported improved overall survival in patients=20 undergoing pancreaticoduodenectomy versus segmental resection (only a = 14%=20 disease-free survival rate was reported in patients undergoing segmental = resection). Similarly, Rose et al.¹²=20 from Memorial Sloan-Kettering reported a 60% 5-year survival rate with a = combination of a pancreas-preserving and pancreas-resecting technique.=20

The rare nature of = adenocarcinomas=20 arising in the small bowel has led to a paucity of information in the = literature=20 as to the benefits of adjuvant chemotherapy and radiation therapy. In = the=20 National Cancer Database series reviewed by Howe et al ¹², = only=20 approximately 8.2% of the patients with localized disease received = radiotherapy=20 and 15.6% of those with regional involvement received radiation therapy. = Similarly, chemotherapy was given to 14.2% of those with local disease, = 35% with=20 regional disease, and 36% with distant metastasis. In this retrospective = review=20 with very little clinical information and large selection bodies, there = appeared=20 to be overall better survival for those patients treated with = combination=20 treatment. Most chemotherapy regimens that have been examined consists = of=20 5-fluorouracil (5-FU) alone in combination with a variety of other = agents,=20 including doxorubicin, cisplatin, mitomycin C, and cyclophosphamide. = One study by the Royal = Marsden=20 Hospital showed that protracted venous infusion of 5-FU has activity in = primary=20 adenocarcinoma of the small bowel.¹³=20 Several other isolated studies have reported response rates with 5-FU = and=20 methotrexate.

Carcinoid = Tumors Arising=20 in the Small Intestine

The=20 traditional classification of carcinoid tumors is according to the = embryonal=20 site of origin, which includes foregut (lung, thymus, stomach, pancreas, = and=20 proximal duodenum), midgut (distal duodenal to proximal colon), and = hindgut=20 carcinoids (distal colon and rectum). Midgut carcinoids are usually = referred to=20 as classic carcinoids. They are thought to arise from the = neuroendocrine=20 cells of Kulchitsky in the intestinal tract.

Demographics=20 of Carcinoids Arising in the Small Intestine

National=20 Cancer Institute programs. In this large database the most frequent site = for=20 occurrence of carcinoid tumors was the GI tract (67.5%). =

Treatment=20 of Localized Disease

Segmental=20 resection of the tumor with accompanying draining lymph nodes is the = treatment=20 of choice for primary carcinoids arising in the small bowel. As noted = above even=20 very small carcinoids (less than 0.5 cm) arising in the small intestine = are=20 associated with a substantial risk of nodal metastases. Therefore, even=20 incidentally discovered, small tumors should be resected with their = nodal=20 basins. Five-year survival after resection of localized disease has been = reported to range between 50% and 85% = ^14-19.

Carcinoid=20 Syndrome

The most=20 effective tool for relieving symptoms of carcinoid syndrome is the use = of the=20 long-acting somatostatin analog octreotide. This has been found in = multiple=20 series to improve, and even prevent, flushes as well as=20 diarrhea^20-22.

Surgery/Local=20 Ablative Therapy

The most=20 common site of metastasis from the carcinoid syndromes after the = original lymph=20 nodes is the liver. A majority of these patients present with bilobar=20 disseminated liver metastasis; however, in several anecdotal and small = case=20 series, those patients with a small number of metastases who underwent = surgical=20 excision of these enjoyed prolonged disease-free = survival^23-25. A=20 retrospective review of all patients at the Mayo Clinic undergoing = hepatic=20 metastasectomy for neuroendocrine tumors between 1977 and 1998 was = published by=20 Sarmiento and Que²⁵. This included 120 patients with hepatic=20 metastasis from carcinoid tumors that had arisen in the ileum. Major = hepatectomy=20 was performed in 54% of the patients, and the postoperative complication = rate=20 was 14%, with a mortality of 1.2%. Surgical debulking of the tumor = controlled=20 symptoms of carcinoid syndrome in 104 of 108 patients. The recurrence = rate was=20 59% at 5 years for carcinoid syndrome and 84% at 5 years for tumor. = Overall=20 survival was 61% and 35% at 5 and 10 years compared to historic 5-year = survival=20 of 36%.

Orthotopic=20 liver transplantation has been reported in a series of patients with = metastatic=20 carcinoid^26-28. In a=20 series of 31 patients undergoing orthotopic liver transplantation for = metastatic=20 neuroendocrine tumors (15 carcinoid patients), Le Treut et = al²⁶=20 reported an overall 5-year survival of 73% and a disease-free survival = of 47%.=20 Lehnert et al.^28a=20 reported 47% and 24% overall survival and recurrence-free survival from = 103=20 patients. Other cytoreductive techniques for treatment of carcinoid = tumors have=20 been reported as well. These include local ablative techniques such as=20 radiofrequency ablation. = Other=20 cytoreductive techniques for treatment of carcinoid tumors have been = reported as=20 well. These include local ablative techniques such as radiofrequency = ablation.=20 Preliminary reports on radiofrequency ablation by Berber et = al²⁹.=20 demonstrate that it is safe, and in a small series of seven patients, no = postoperative complications were reported and several patients were able = to=20 reduce their dose of octreotide, corresponding to a decrease in overall=20 symptoms.

Chemoembolization=20 Therapy

In a=20 retrospective review of all patients treated with hepatic arterial=20 chemoembolization at the M. D. Anderson Institute from the year 1992 to = December=20 2000, 81 patients with carcinoid tumor underwent hepatic=20 chemoembolization²⁹. Fifty patients underwent strictly=20 straightforward embolization, and 31 underwent a combination of = intraarterial=20 chemotherapy and embolization. Sixty-nine patients could be evaluated = for=20 response. In these, 67% were found to have a partial response, greater = than a=20 50%.

Chemotherapy

The two=20 most successful regimens have included streptozotocin combined with=20 cyclophosphamide or 5-FU, showing response rates for the 5-FU = combination of 44%=20 and 37% for cyclophosphamide regimens to biochemical response=20 rates³⁰.

Subtypes=20 of Lymphom Arising in the Small Intestine. =20

1. Diffuse Large B-Cell Lymphoma=20

Diffuse=20 large B-cell lymphoma is the most common non-Hodgkin's lymphoma = occurring in the=20 GI tract, developing most often in the ileocecal region. Other names for = the=20 large diffuse B-cell lymphoma include the large cell immunoblastic,=20 large-cleaved follicular center cell, centroblastic D immunoblastic = cell, and=20 diffuse mixed lymphocytic and histiocytic cells. Morphologically, these = tumors=20 are composed of diffuse large B cells with large nuclei that are twice = the size=20 of a normal lymphocyte. These tumor cells are CD19, positive CD20, = positive=20 CD22, positive CD79a. They tend to have a high percentage of BCL2 gene = that is=20 rearranged in approximately 30% of them. Immunodeficiency virus, as well = as=20 general immunodepressed states, have been found to be risk factors for = the=20 development of this lymphoma.

Treatment=20 of localized disease consists primarily of surgical resection followed = by=20 adjuvant radiation or chemotherapy^31-33. Overall 5-year survival has = been=20 reported to be between 50% and 70% for tumors treated with multimodality = therapy.

2. Mucosal-Associated Lymphoid = Tissue=20 Lymphoma

In the=20 REAL classification, MALT is known as the marginal zone B-cell lymphoma. = These=20 tumor cells express immunoglobulin M greater than immunoglobulin G or=20 immunoglobulin A. They express B-cell=96associated antigens, including = CD19, CD20,=20 CD22, and CD79a. They are usually CD5 negative, CD10 negative, CD23 = negative,=20 and CD43 variable. Treatment is multimodality, including surgical = resection and=20 adjuvant chemoradiation therapy. Survival from small MALT arising in the = small=20 intestine has been reported to be better than MALT arising in the = stomach³⁴.=20

3. Burkitt's Lymphoma=20

5% of all=20 small intestinal lymphomas. Burkitt's lymphoma cells are monomorphic=20 medium-sized cells with round nuclei and abundant basophilic cytoplasm. = The=20 tumor has an extremely high rate of proliferation, giving it a = starry-eyed=20 pattern that is usually present. Treatment consists primarily of = chemotherapy,=20 usually vincristine, cyclophosphamide, doxorubicin, and methotrexate.=20

4. T-Cell Lymphomas of the Small = Intestine=20

This tumor=20 was originally termed malignant=20 histiocytosis of the intestine but has since been shown to be=20 conclusively T-cell lymphoma arising in the small intestine. It accounts = for=20 approximately 15% of all lymphomas arising in the small intestine. The = tumor=20 cells are CD3 positive, CD7 positive, CD8 positive, CD4 negative, and = CD103=20 positive. Treatment consisted of surgery and chemotherapy. The 5-year = survivor=20 rate was quite poor, approximately 11%³⁵. =

Mesenchymal = Tumors=20 Arising in the Small Intestine

It is now=20 recognized that a vast majority of the tumors that had been previously=20 identified as leiomyoma and leiomyosarcoma are actually CD117-positive = GIST. In=20 fact, GISTs are now thought to be the most common mesenchymal tumors = arising=20 from the small intestine. True leiomyomas and leiomyosarcomas are rare = in the GI=20 tract, with the exception of the esophagus.

STI 571,=20 which is now known by its trade name Gleevec, is a compound that was=20 specifically designed to inhibit the Abl protein tyrosine kinase, which = is=20 present in 95% of patients with chronic myelogenous leukemia. This = compound can=20 inhibit several families of tyrosine kinases, including c-kit. Clinical = trials=20 have found that this compound is very effective in treating GISTs = without many=20 of the side effects associated with traditional chemotherapies.=20

Treatment=20 of Localized Disease

The=20 principal treatment for primary GISTs arising in the small intestine is = complete=20 surgical excision. Great care has to be taken during the operative = procedure, as=20 these tumors are somewhat soft, fleshy, and prone to rupture, which has = been=20 reported to lead to early and diffuse intraabdominal recurrence. The = goal for=20 the surgical margins should be gross margins. In a retrospective review = of 200=20 patients with GISTs who underwent primary surgery with complete excision = of=20 their tumors at Memorial Sloan-Kettering, disease-specific survival rate = was 88%=20 at 1 year, 65% at 3 years, and 54% at 5 years^36,37. The = median=20 survival of those patients who undergo a complete excision was 66 = months, as=20 opposed to those who had incomplete resection at 22 months. In this = series 86%=20 of 93 patients with primary disease were able to undergo complete = resection.=20

Distant or=20 local recurrence develops at some point in their disease course. In = fact, only=20 13 of 132 patients in a series from M. D. Anderson Cancer Center, who = underwent=20 complete resection of the primary tumor, were disease free after median=20 follow-up of 68 months³⁸. Currently, there are no data to = support=20 adjuvant chemotherapy or radiation therapy for the management of = completely=20 resected GISTs. Because of the risk of local recurrence after primary = resection=20 of GISTs, the efficacy of conventional chemotherapy and radiotherapy in=20 preventing this, and the demonstration of considerable activity of STI = 571 and=20 metastatic disease, there has been an increased interest in examining = the use of=20 this drug in the adjuvant setting. The American College of Surgeons = Oncology=20 Group is leading a phase II intergroup trial, which is supported by the = Cancer=20 Therapy Evaluation Program, that is examining the use of STI 571, 400 = mg/d for 1=20 year, after complete resection of high-risk GISTs. For the purpose of = this=20 trial, high risk is to find a tumor size growing within 10 cm, tumor = rupture or=20 tumor hemorrhage at the time, or markedly focal tumors. The American = College of=20 Surgeons Group is also opening up a randomized trial looking at patients = with=20 tumors greater than 3 cm and a randomized double-blind placebo trial of = 400 mg=20 STI 571 versus placebo. The primary end point in this trial is survival, = and it=20 is a crossover design, so that patients who experience recurrence can = then be=20 crossed over to STI 571.

Other=20 Mesenchymal Lesion Tumors Arising in the Small Intestine =

The=20 majority of the mesenchymal tumors that arise in the small intestine are = GISTs.=20 The other tumors that need to be differentiated from GISTs include = inflammatory=20 fibroid polyps, fibromatoses, inflammatory and myofibroblastic tumors, = solitary=20 fibrous tumors, schwannomas, simple leiomyomas, and true leiomyomas.=20

Leiomyomas=20 and Leiomyosarcomas

They are=20 positive for desmin and actin and are negative for CD117 (c-kit and = CD34).=20

Malignant Tumors of the Small Intestine =96 New = Insights into=20 a Rare Disease.

Tumors=20 of the small bowel are very rare. =20 They constitute only 2.4% of all gut tumors which is a very small = percentage compared to the 90% mucosal surface area of the small=20 bowel.

Resistance of small bowel mucosa to=20 tumorigenesis.

The=20 recurrence of colorectal tumors after ileocolonic anastomosis is = significantly=20 higher at the colonic site (14%) = than in the small bowel (0.7%). =20 A variety of protective antitumor mechanisms unique to the small = bowel=20 have been suggested (4.12) but none were investigated in humans.

Tumor=20 markers

Approximately 75% of the symptomatic small bowel = tumors are=20 malignant, while about half of the benign lesions remain = asymptomatic.

Treatment

Benign=20 lesions in the duodenum can be resected endoscopically or by local = ampullary=20 resection and intraperative frozen section. The ultimate treatment = modality for=20 neoplastic lesions is surgery although in high risk or elderly patients=20 endoscopic resection with negative margins ma be sufficient. The surgical resection rate of = malignant=20 tumors is almost 100% and curative resection is achieved in = approximately 50% of=20 cases. Aggressive = resections are=20 recommended even in large tumors with positive nodes if it can be = performed with=20 negative resection margins in one study. =20 The 5 year survival was 81% when resection was complete versus = 40% in=20 patients with incomplete resection. =20 Adjuvant therapy with 5 fluorouracil, adramycin, miomycin-C or = other=20 agents was tried in unresected tumors and as adjuvant therapy in 26% of=20 patients. Many physicians = offer=20 their patients a standard adjuvant therapy protocol as in colorectal=20 cancer. Radiotherapy was = not found=20 to be effective. = Prolonged survival=20 periods are reported with combinations of chemo-radiotherapy. Close follow-up is necessary = as many=20 patients harbor a second malignancy elsewhere in the gastrointestinal=20 tract. =

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