impacto da terapia antica na nutricao

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The Impact of Antitumor Therapy on NutritionWILLIAM A. KOKAL, MD

The treatment of the cancer patient by surgery, chemotherapy or radiation therapy can impose signifi-cant nutritional disabilities o n the host . Th e nutritional disabilities seen in the tumor-bearing hos t fromantitumor therapy are produced by factors which either limit oral intake or cause malabsorption ofnutrients. The h ost malnutrition caused as a consequenc e of surgery, chemot herapy or radiation therapyassum es even more importance when one realizes that many cancer patients are already debilitated fromtheir disease.Cancer 55273-278,1985.

T H A S BEEN well documented that cancer can produceI malnutrition in the tumor-bearing host. The varioustherapeutic modalities used to treat cancer, such as sur-gery, chemotherapy, and radiation therapy, may alsohave a dramatic impact on the nutritional status of thehost. Antitumor therapies may produce only transientmild nutritional disturbances in the cancer patient, suchas mucositis from chem otherapy, or may lead to severepermanent nutritional problems, as in the case of mas-sive small bowel resection. This report provides an over-view of the nutritional consequences of surgery, chemo-therapy and radiation therapy seen in the treatment ofthe cancer patient.Surgery

Surgery is the primary m ode oftreatm ent o falmost allcancers arising in the alimentary tract. Thus, it is notunexpected that surgical resection of alimentary tracttumors can have a m ajor nutritional impact on the host.The nutritional disability imposed on the host dependson many factors, including the site of the tumor, theextent of resection of the alimentary canal, and wh ethervagotomy was performed. The nu tritional consequencesof radical cancer surgery are listed in Table 1 .Radical resection of cancers arising in the oropharynxmay lead to prolonged nutritiona l sequela. Resection ofsegments of the mandible, tongue, or pharynx can leadto significant difficulties in ma stication as well as deglu-tition. T he difficulties in mastication a nd deglutition inthe postsurgical patient are greatly compo unded w henradiation therapy has been given either preoperatively or

From the Department of Surgery, City of Hope National MedicalAddress for reprints: William A. Kok al, MD , City ofHope NationalCenter, Du ane, California.Medical Center. I500 East Duarte Road, D uane , CA 9 1010.

postoperatively. The xerostomia a nd fibrosis secondaryto radiation therapy adds to the difficulty in swallowingin this group of patients. Although the ma lnutrition pro-duced by rad ical resection of head an d neck canc ers canbe alleviated by tu be feedings, enteral alime ntation maybe needed for extended periods of time. Pittman andassociates noted that 43% of the patients undergoingradical head and neck surgery needed nutritional sup-port via tube feeding for more than 15 days.'Resection of thoracic esophagus has been associatedwith steatorrhea an d diarrh ea.2 Various authors havenoted that the fat malabsorption and diarrhea demon-strated in the esophagectom ized patient is similar to thatnoted in patients who have truncal vagotomy and gastricdrainage procedure^.^-^ This suggests that th e vagotomydon e as part of the en bloc resection of the esophagealcancer, plays the majo r role in causing steatorrhea anddiarrhea in esophagectomized patient^.^ The nutritionaldisability imposed by esophagectomy with the asso-ciated vagotomy is relatively minor and can be easilycorrected with increased caloric intake or subsitution ofmedium -chain triglycerides in the diet.5The surgical resection of gastric cancer can cause hostmalnu trition due to m alabsorption, as well as other fac-tors which may lim it the host's caloric intake. M alnutri-tion, as defined by patients who were less than 85% oftheir ideal body w eight, occurred in 30%of the patientswho had total gastrectomies in th e series by Schrock andWay.6 Lawrence and co-workers have demonstratedmalabsorption of fat and protein in th e total gastrectomy~ a t i e n t . ~he me an values for fat absorption in the totalgastrectomy patient were approximately 80%of that ofcontrol^.^ The fat malabsorption seen, however, does notcorrelate with weight loss experienced by the ~ a t i e n t . ~Furtherm ore, the nutritio nal disability from steatorrheais mino r. A similar observation is made on protein mal-absorption in the gastrectomized patient. Although mal-

273


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214 CANCER anuary 1 Supplement 1985 VOl. 5 5TABLE. Nutritional Consequences o f Radical Resection*Organs resected Nutrition al sequelae

Oral cavity and pharynxThoracic esophagus

Stomach

Small intestineDuodenumJejunumIleumMassive (>75%)

Colon (total or subtotal)

Dependency on tube feedingsGastric stasis (secondary to vagotomy)Fat malabsorptionGastrostomy feedings in patientsDumping syndromeFat absorptionAnemiaPancr eatobiliary deficiency with fatDecrease in efficiency of absorptionVitamin BIZ and bile salt absorptionFat malabsorption and diarrhea;vitamin B I2 malabsorption; gastrichypersecretion

without reconstruction

malabsorption(general)

Water and electrolyte loss* Reprinted with permission from Lawrence W Jr . Nutritional con-sequences of surgical resection of the gastrointestinal tract for cancer.Cancer Res 1977; 3712379-2386.

absorption of protein does occur after total gastrectomy,it is of little clinical impact and can be easily overcomeby a minor increase in protein intake.The major nutritional disability after total gastrec-tomy appears to be a lim itation of caloric intake by thepatient. This limited caloric intake is due to several fac-tors as loss of food reservoir, esophagitis and the dum p-ing syndrome. The dumping syndrome consists of amyriad of gastrointestinal symptoms such as diarrhea,nausea, abdominal cramps, as well as sympa thetic auto-nomic discharge. Lawrence has noted that significantdumping sym ptoms occur in 10% o 25% of those pa-tients who underw ent subtotal gastrectomy, and noted ahigher percentage in patients who had total gastric resec-t i o n ~ . ~he gastrointestinal symptoms and sympatheticdischarge can be so unpleasant for the patient that anaversion to eating develops. The correction of the nutri-tional disabilities in t he gastrectomy patient is primarilythrough prevention of the dumpin g syndrome. This pre-vention h as classically been do ne by freque nt sm all feed-ings of a low carbohydrate, high protein and fat diet.Occasionally, the dum ping sym ptoms are not alleviatedby dietary measures. Various surgical procedures havebeen devised in this small group of patients refractory todietary control. The operations proposed to correctdump ing symp toms include such procedures as a reverseperistaltic loop of small bowel or creation of an intestinalreservoir.a Other nutritional deficiencies which mayoccur in the patient following gastrectomy are decreasedabsorption of calcium, iron, and vitamin B12.Massive small bowel resection is infrequently per-formed in surgery for abdom inal cancers. How ever, sig-nificant metabolic disturb ances can arise when such ex-

tensive intestinal resection isnecessary. The extent o fth enutritional deficiencies seen after intestinal resection aredependent on several factors such as the amou nt of thesmall bowel resected, the extent t o which ileum or je -ju nu m is resected, and whether the ileocecal valve andright colon are removed in conjunction with the smallbowel. Significant malabsorp tion usually does not occuruntil over 75Yo of the en tire sm all bowel is resected. Th emalabsorp tion seen in these patients after extensive sur-gical resection can be compounded by postoperativeg a s t r i c h y p e rs e c re t i~ n .~ ~ ~his gastric hypersecretioncan further intensify the diarrhea seen in the patientswith short-gut syndrome. The increase in intraluminalintestinal acid concentration after massive small bowelresection can also inhibit enzyme digestion of nu-trients. Nu trition al deficits caused by the extensive in-testinal resection consist of fluid and electrolyte losses,steatorrhea, as well as deficiences in iron, calcium andvitamin D. When more than 100cm of the ileum isremoved, marked increases in steatorrhea occur. Thediarrhea noted in the patients with extensive ileal resec-tions can further be intensified by m alabsorption of bilesalts5Vitamin B 12 deficiencies can occur in th is setting.Although extensive small bowel resection may have atremend ous initial metabolic imp act on the patient, thesmall bowel has a great capacity for adaptation. Theremaining small bowel has been shown t o significantlyincrease its absorptive capacity following extensiveresections.I2-I4The phenomena ofadaption by the smallbowel may lessen the long term nutritional impact ofmassive intestinal resection.Colectomy performed for colon carcinoma has a lim-ited effect on th e nutritional status ofthe host. In p atientswho have had a total colectomy or ileoanal anastomosis,profuse diarrhea may occur, producing large fluid andelectrolyte losses. Th e rem aining bowel rapidly ad aptsafter colon resection, so that these fluid losses quicklydiminish. T herefore, the long-term nutritional disabili-ties in patients who have had a total colectomy orileoanal anastomosis are of m inor clinical importan ce.Cancer of the pancreas is on e of the leading causes ofdeath from cancer in the United States. Although onlyabout 10%of the patients with carcinoma of the pan-creas will be resectable for cure, pancreatectomy mayhave a significant impact on th e nutritional status of thehost.Is Pancreatic exocrine insufficiency has been re-ported in 22% to 28% of the patients undergoing a pan-creaticoduodene ctomy for carcinoma of the head of thepancreas o r periampullary region.I6-I8 Pancreatic exo-crine deficiency can lead to malabsorption of fat, fatsoluble vitamins (vitam insA,D, E, an d K), amin o acids,and various minerals such as calcium and m ag ne ~ iu m . ~The pancreatic exocrine insufficiency which occurs fol-lowing surgical resection can be reasonably managed by


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No . I A N T I T U M O RH E R A P Y Kokal 27 5use of a commercial pancreatic enzyme preparation.Various authors have proposed that total pancreatec-tomy is the preferred treatment for all operable carci-n o m a s o f t h e p a n ~ r e a s . ~ , ~ ~otal pancreatectomy canimpose an even greater metabolic disturbance on thehost beyond that of pancreatic exocrine insufficiency.Al l such patients have diabetes.A severely labile diabetescan occur in 20% of the patients.2 Furtherm ore, t heusual diabetic type diet with its increased percentage ofprotein and fat can further exacerbate the pre-existingsteatorrhea. 9

ChemotherapyChemotherapy may have important nutritional con-sequences in the tum or bearing host. Chemotherap euticagents may contribute to host malnutrition through avariety of direct and indirect mechanisms, includingnausea and vomiting, mucositis, organ injury, andlearned food aversions. The adverse nutritional effects ofchemotherapy can be compounded in the host who isalready cachectic from his tumor, or who has receivedprior or concurrent radiation therapy.Nausea and vomiting frequently accompany admin-istration of most antitu mo r drugs. The nausea and vom-iting induced by chemotherapy is mediated through th evomiting center in the medullary reticular formation.The severity and duration of the nausea and vomitingseen from chem otherapeutic agents is dependent on theagent used, its dose and route of administration, and

whether the patient has developed anticipatory vomit-ing or a conditioned aversion to the chemotherapy.Chemotherapeutic agents most commonly associatedwith severe nausea an d vomiting are nitrogen m ustard,chloroethyl nitrosoureas, streptozotocin, cisplatin, an dimidazole carboxam ide (DTIC)22Table 2). Virtually allof the patients who receive these agents will experiencesignificant nausea and vomiting. Other com mo n an titu-mor agents can show a high incidence of vomiting duringtheir administration. Adriamycin (doxorubicin) hasbeen reported to induce vomiting in about 60%of thepatients.23Vomiting seen in 5-fluorou racil(5-FU) ther-apy has been reported from only occasional, to a n inci-dence of 50Yo to 65% depending on the dose and fre-quency of drug admini~tration.~*-~he nausea andvomiting that occurs during chemotherapy can have amarked nutritional impact on the host who may alreadybe debilitated from can cer or complications of treatmen tof the tum or by either surgery or radiation therapy.22Chemotherapeutic agents are most active on rapidlyproliferating cells. Since the mucosa of alimentary tracthas cells with a very rapid growth fraction, it is not sur-prising that many chemotherapeutic drugs could havesignificant gastrointestinal toxicity. Mucositis is the

TABLE. Chemotherapeutic Agents Commonly Associatedwith Severe Nausea and VomitingDrug Severity and duration

Nitrogen mustard

Chloroethyl nitrosoureasStreptozotwin

Cisplatinum

lmidazole carboxamide(DTIC)

Occurs in virtually all patientsMay be severe but usually subsides withinVariable but may be severeOccurs in nearly all patientsTolerance improves with each succeedingdose on a 5d ay scheduleMa y be very severeTolerance improved with intravenous

24 hours

hydration and continues 5da yinfusions.Nausea may persist for several days.Occurs in virtually all patientsTolerance improves with each succeedingdose on a 5d ay schedule

* Reprinted with permission from Mitchell EP , Schein PS.Gastroin-testinal toxicity of chemotherapeutic agents. Semin Oncol 1982; 9 5 2 -64.

major gastrointestinal toxicity of chemotherapeuticagents. Significant mucositis can be produced by variousagents including methotrexate, 5-W, actinomycin D,Adriamycin, bleomycin, and vinblastine22 (Table 3) .The mucositis produced by these agents may be greatlyenhanced when concurrent radiation therapy isgiven.23-28,29ucositis from methotrexate infusion canpresent as severe painful ulcerations in t he oral cavity.30Mucositis from such agents as 5-FU can present asbloody diarrhea. As mentione d, th e renewal rate of thealimentary tract mucosa is rapid, so that the mucositisfollowing chemotherapy is usually short lived.The vinca alkaloid, vincristine, can cause abdom inal

TAB LE . Chemotherapeutic Agents CommonlyAssociated with Mucositis*Drug Related factors

~~

Methotrexate May be quite severe with prolonged infusions orcompromised renal function.Severity is enhanced by irradiation.May be prevented with adequate citrovorumMore severe with higher doses, frequent schedule,Very common and may prevent oralSeverity enhanced by irradiation.May be severe and ulcerative.Increased with liver disease.Severity enhanced by irradiation.May be severe and ulcerative.

rescue factor.and arterial infusions.alimentation.

5-FluorouracilActinomycin D

Adriamycin

BleomycinVinblastine Frequently ulcerative.* Reprinted with permission from Mitchell EP, chein PS.Gastroin-testinal toxicity of chemotherapeutic agents. Semin Oncol 1982; 952-64.


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27 6 CANCER anuary I Supplement 1985 Vol. 55TABLE. Effects of Radiotherapy Creating Nutritional Sequelae.

Region Early LateHead and Neck OdynophagiaXerostomiaMucositis

AnorexiaDysosmiaHypogeusiaThorax Dysphagia

Abdomen and Anorexiapelvis NauseaVomitingDiarrheaAcute enteritisAcute colitis

UlcerXerostomiaDental cariesOsteoradionecrosisTrismusHypogeusiaFibrosisStenosisFistulaUlcerMalabsorptionDiarrheaChronic enteritisChronic colitis

Adapted with permission from Donaldso n SS, n o n RA.Alterationsof nutritional status: Impact o f chemotherapy a nd radiation therapy.Cancer 1979; 43:2036-2052.

p ain , c on stip atio n a nd ad yn amic i l e ~ s . ~ l - ~ ~his auto-nomic nervous system dysfunction appears to be m oresevere in the elderly patient, a s well as in the dose -depen -dent patient.33The ileus produced by vincristine maylast up to two weeks. Thus, vincristine administrationmay lead to major m etabolic disturbances in the h ost.Indirect effects of chemotherapy in the tumor-bearinghost may also play a role in host malnutrition. Candi-diasis or moniliasis of the gastrointestinal tract is a notuncommon occurrence during chemotherapy, espe-cially in patients with leukemias and ly m p h o r n a ~ . ~ ~as-trointestinal candidiasis can occur in oral cavity, phar-ynx, or esophagus. Candidiasis in these areas canproduce symptoms of a painful mouth, odynophagia,and dysphagia. All of these symptom s can lead to a dra-matic reduction of oral intake in the cancer patient.Learned food aversions, the intense dislikes that de-velop as a result of the association of vario us foods withunpleasant gastrointestinal symptom s,35 re ano ther in-direct mechanism through which chemotherapy can ad-versely affect the nutritional status of the host. Symp-toms such as nausea and vo miting are frequently fromantitumor therapy. Although any antitumor therapymay cause learned food aversions, chemotherapy is themost common clinical cause. The severe nausea andvomiting that occurs during chemotherapy can causeaversions to food consumed prior to chemotherapy ad-ministration. The aversion developed to food is mostlikely to be against foods which are new or novel to thepatient.36 Repeated association of gastrointestinal dis-comfort with a specific food can produce learned foodaversions even to familiar items.37Berstein has show nthat 48% of the patients who received gastrointestinaltoxic chemotherapy developed learned food aversion^.'^Learned food aversions occurring during chemo therapy

can persist long after all gastrointestinal symptom s havesubsided.Radiation Therapy

Radiation therapy can cause a variety of effects on thehost which may have a significant metabolic impact.Early radiation effects such as muco sitis, diarrhea , xero-stomia, alterations in taste and learned food aversionscan contribute to host malnu trition. P roblems seen longafter the completion of radiotherapy, such as mucosalulceration, alimentary tract strictures or obstruction, os-teoradionecrosis of the mandible, trismus, intestinal fis-tulas, malabsorption an d enteritis, may also contributeto prolonged nutritional impairment of the host38s39(Table 4). Radiation effects in th e alimentary tract aredependent on n ume rous factors such as the site, the totaldose, fractionation and field size of the radiation ad-ministered. Furthermore, the radiation complicationsmay be significantly affected by associated antitumortherapy such as surgery or ~ h em o th er ap y .~ ~Radiotherapy is an impor tant therape utic modality inthe treatment of head and neck cancers. Such therapycan dramatically decrease food intake on the tumor-bearing host through several mechanisms. One of themost important mechanisms that occur in the patientduring head and neck irradiation is mouth blindnessor alterations in taste.40As early as 2 weeks following theinitiation of therapy, changes in taste acuity may occur,consisting of a decreased ability to recognize certaintastes, especially bitter a nd salty.41 n the study by Chen-charick and M ossman over 85% of the patients undergo-ing head and neck irradiaton developed subjectivechanges in their taste perception. T hese changes in tasteperception were manifested as either a loss of taste or anunpleasant taste during eating.42Of note, over 50%of thepatients in the latter study complained tha t high proteinfoods, i.e., meat, eggs, etc., were associated with an ab-norm al It is easily appreciated that as food losesits taste or actually becomes unpleasant tasting, oralintake will quickly dim inish.Xerostomia is a common problem during radiother-apy in the head and neck cancer patient. When the m ajorsalivary glands are in the field of ionizing radiation , theam oun t of salivary production decreases in conjunc tionwith an increase in the viscosity of the saliva. Thechanges in salivary secretion can lead to a thick tena-cious saliva, which in itself can greatly impair swallow-ing.43Furtherm ore, xerostomia can also lead to acceler-ated dental caries.* The combined factors of dysphagiaand accelerated dental caries can both co ntribute to re-duction in oral intake of the patient.The m ucosa of the alimentary tract is sensitive o radi-ation exposure. Th e degree to which mucositis occurs is


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No . I ANTITUMOR H E R A P Y Kokal 277dependent on such factors as dose fractionation and sizeof the treatment field. Stomatitis during the course ofhead and neck radiation may prod uce such problems aspainful m ucosal ulcerations and intraoral bleeding, con-tributing to host hypophagia.

Other acute radiation effects that could impair hostnutrition have been described in the head and neck pa-tient, including loss of smell and learned food aver-s i o n ~ . ~ - ~ ~ith all the oral intake-suppressive mecha-nisms operative in the irradiated head and neck cancerpatient, it is not surprising that malnu trition can occurduring the cancer therapy. Donaldson has shown that93 %of the patients lost weight while undergoing curativeradiation therapy to the oropharynx and hy p o p h a r y n ~ .~ ~When o ne appreciates that a large num ber of head andneck cancer patients are already malnourished prior toantitumor therapy, the nutritional deficits imposed onthese patients during radiotherapy could be devastat-i r ~ g . ~ ~ggressive nutritional support in the head andneck cancer patient undergoing radiation therapy is fre-quently needed in the form of tube feeding.Late effects of head and neck radiotherapy can pro-duce such problems as mucosal ulceration and osteora-dionecrosis of the m andible or trismus. Larson and asso-ciates have examined patients with oropharyngealcarcinomas who were treated solely by radiation ther-apy. He noted that 56% of those patients developed mu -cosal ulcerations, osteoradionecrosis of the mandible, orboth complications following therapy.47 Of those pa-tients who developed the latter, 41% required a partialmandi bulectom y.Radiation therapy, a comm on modality of treatmentof patients with thoracic malignancies, may produceesophagitis during the course of treatment. Esophagealstricture, ulceration, or even perforation may be lateradiation therapy manifestation^.^^ Esophageal injuryfrom irradiation may therefore contribute to nutritionalimpairment of the host.Radiation therapy to the ab dom en o r pelvis has beenassociated with dramatic metabolic effects on thetumor-bearing host. Acute radiation enteritis appears tobe related to the dose fractionation an d volum e of intes-tine in th e radiation portals. Other factors, such as priorabdominal surgery, hypertension, and d iabetes, may fur-ther exacerbate the effects of abdominal pelvicr a d i a t i ~ n . ~ ~ - lhe a cute effects of irradiation to th e ab-domen or pelvis consist of nausea and vomiting, diar-rhea and enteritis.48Donaldson and Lenon have notedthat 88% of patients with Hodgkins disease undergoingabdominopelvic irradiation lost weight during ther-with 13% of those patients losing over 10%oftheirpretreatment weight.Abdominal or pelvic irradiation can produce m alab-sorption of fat, carbohydra te, and p rotein, a s well as fluid

and electrolyte A m ajor cause of stea-torrhea and diarrhea in the patients undergoing suchtherapy is choleretic e n t e r ~ p a t h y . ~ ~ ~ ~ ~holeretic en-teropathy represents malabsorption of bile salts by theirradiated sm all bowel, which will cause fat m alabsorp-tion in the host. In addition , bile salts entering the colonin sufficient quantity will inhibit water absorption an dstimulate colonic peristalsis, causing further fluid andelectrolyte deficiencies. Deficiencies in both disacch ari-dase and peptidase enzymes have also been noted in theirradiate small bowel.57The late radiation effects of abdominopelvic irradia-tion occur in 0.5% to 15% of the pa tients s8 These effectscan be noticed m onths to y ears after completion of ra-diotherapy, and can be m anifested as intestinal obstruc-tion, enteritis, or colitis or fistula formation. All theselate complications of radiation therapy can have an ad-verse effect on the hosts nutritional status.

SummaryIt has been well docum ented that surgery, chemother-apy, and radiation therapy used in the treatment ofcancer may produce significant nutritional disabilities nthe host. Th e nutritional disabilities imposed by antitu-mor therapy have even greater importance when onerealizes that th e cancer patient may already be m alnour-ished from his disease prior to treatm ent. The clinicianresponsible for the care of the cancer patient must beaware of nutritional deficits imposed by the various mo-dalities of antitum or therapy. In th is manner, th e detri-mental effects of host m alnutrition may be prevented.

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impacto da terapia antica na nutricao

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