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Gastrointestinal Bleeding In Advanced Cancer Patients

      To the Editor:
      There is a lack of information about the frequency of symptomatic gastrointestinal bleeding in patients with advanced cancer. Clinical manifestations of gastrointestinal bleeding, such as melena or hematemesis, have never been reported in advanced cancer patients. A longitudinal study was planned to assess clinically evident hemorrhagic complications, possible causal factors, and the outcome in a sample of 800 consecutive advanced cancer patients followed at home until death.

      Survey Results

      Eight-hundred consecutive patients who were referred to a home palliative care program were surveyed in a two-year period. They were followed until death by a multidisciplinary palliative care team. Episodes of melena or hematemesis were recorded. Age, sex, primary cancer and known metastases, possible associated pathologies, history of peptic disease, use of nonsteroidal anti-inflammatory drugs (NSAIDs) and steroids, drugs used to prevent gastric complications, use of alcohol, drugs used for controlling bleeding, eventual blood transfusion, Karnofsky status, and hemoglobin values, when available, were recorded.
      Eighteen patients presented clinically evident gastrointestinal bleeding, which manifested as melena, hematemesis or both (2.5%). The mean age was 68 ± 12 (range 47–87). Eleven patients were males. The mean Karnofsky status was 40 (Range = 20–70). Data collected are presented in Table 1. The hemorragic events presented as melena in twelve patients, as hematemesis in three patients, as both melena and hematemesis in three patients. Liver disease was predominantly associated with hemorragic intestinal complications, five and eight patients having hepatic cancer or liver metastases, respectively. Eighty-five of the 800 patients surveyed had primary liver or biliary cancer, or liver metastases (10.6%). Therefore, thirteen of eighteen patients (72%) who had bleeding were found to have a neoplastic involvement of the liver, and 15.2% (13/85) of patients with liver involvement had gastrointestinal bleeding. The risk of gastrointestinal bleeding for patients with liver cancer or metastases was more than two-hundred-fold in comparison with the remaining population (15.2% versus 0.69%). Bleeding was fatal in four and three patients of these patients, respectively.
      Table 1Characteristics and Parameters Recorded in Patients Presenting with Clinical Gastrointestinal Bleeding
      AgeSexPCEventa-NSAIDp-NSAIDSteroidsProphylAlcTransfKarnofskyOutcome
      183MCoMelNNNYNY50R
      276MUnMelYNNYNN30D
      360FLiMelNNYYNY70R
      460MLiMelNNYYNN70R
      565FLiMelNNNNNN30D
      665FPaMelYNYNNN30D
      775MPrMel-HemNNYYNN50R
      847MLuMel-HemNNNNNN20D
      970MUnHemNYNYNN30D
      1062FUtMelNYNYNN30D
      1157MLiHemNNNNNY40D
      1265MLuMelYNYYNY50R
      1387FLiHemNNNNNN40D
      1467FMeMelYNYNNN60R
      1572MPrMelYYNYNN30R
      1676FUtMelYYYYYN40D
      1755MLaMel-HemYYYYYN30D
      1886MCoMelNNYYNN50R
      PC = Primary Cancer; Co = colon; Li = liver; Pa = pancreas; Pr = prostate; Lu = lung; Un = unknown; Ut = uterum; Me = meningioma; La = larynx; Mel = melena; Hem = hematemesis; N = no; Y = yes; a-NSAID = actual use of NSAIDs; p-NSAID = previous use of NSAIDs; Prophyl = prophylactic drugs (prostaglandins, ranitidine, omeprazole); Alc = alcohol; Transf = Blood transfusion; R = recovered; D = died.
      Two patients had a history of peptic disease. Seven and five patients were taking NSAIDS, or had previously received NSAIDS for more than two weeks, respectively. Four patients who were taking NSAIDs died. Nine patients were receiving steroids, and three of them were given a combination of NSAIDs and steroids. Twelve patients were taking prophylactic drugs, including prostaglandins (three patients), ranitidine (eight patients), or omeprazole (two patients). Previous alcohol consumption was reported in two patients, who died.
      Eight patients recovered, and ten patients died within 48 hours after the hemorragic event took place. Four patients were transfused and three of them recovered. Eight patients received anti-hemorrhagic drugs. Hemoglobin levels were available in eight patients (mean 6.2 g/l, range 4.6–7.4). The performance status was the only parameter significantly associated with a negative outcome (P<0.019).

      Comment

      The incidence of gastrointestinal bleeding was 2.25% of the total population admitted to a home palliative care program. In a demographically defined population, hospitalization for acute gastrointestinal bleeding was 1 per 1000.
      • Longstreth G.F.
      Epidemiology of hospitalization for acute upper gastrointestinal hemorrage a population-based study.
      Patients with liver cancer or hepatic metastases represented a group at higher risk of developing gastrointestinal bleeding during the course of the advanced illness. The concomitant use of NSAIDs may have had a facilitating role, as about 38% of patients on NSAID treatment developed gastrointestinal tract bleeding.
      Risk factors for ulcer in patients receiving NSAIDs are advanced age, male sex, peptic ulcer history, smoking, and dyspepsia.
      • Hansen J.M.
      • Hallas J.
      • Lauritsen J.M.
      • Bytzer P.
      Non-steroidal anti-inflammatory drugs and ulcer complications a risk factor analysis for clinical decision-making.
      In cancer pain management, NSAIDs often are chronically administered for prolonged periods, without significant complications.
      • Zech D.F.J.
      • Grond S.
      • Lynch J.
      • Hertel D.
      • Lehmann K.A.
      Validation of World Health Organization guidelines for cancer pain relief a 10-year prospective study.
      • Mercadante S.
      Pain treatment and outcomes for patients with advanced cancer who receive follow-up care at home.
      In a survey on 785 consecutive patients admitted with upper gastrointestinal bleeding, NSAID users appeared to have a better prognosis as compared with non-users.
      • Wilcox C.M.
      • Alexander L.N.
      • Cotsonis G.A.
      • Clark W.S.
      Nonsteroidal antiinflammatory drugs are associated with both upper and lower gastrointestinal bleeding.
      In a survey on the magnitude of risk factors for severe upper gastrointestinal bleeding, NSAID utilization was not identified as a relevant factor, except in patients with a history of peptic ulcer.
      • Hallas J.
      • Lauritsen J.
      • Villadsen H.D.
      • Gram L.F.
      Nonsteroidal anti-inflammatory drugs and upper gastrointestinal ble eding, identyfing high-risk groups by excess risk estimats.
      In another experience, the increased risk of gastrointestinal bleeding and perforation with NSAIDs was only apparent for subjects without a history of gastrointestinal events.
      • McMahon A.D.
      • Evans J.M.
      • White G.
      • Murray F.E.
      • McGilchrist M.M.
      • McDevitt D.G.
      • MacDonald T.M.
      A cohort study (with re-sampled comparator groups) to measure the association between new NSAID prescribing and upper gastrointestinal hemorrhage and perforation.
      It is well known that hemorragic events may also occur in absence of previous dyspeptic symptoms, regardless of NSAID use. Asymptomatic patients taking antacids or H2 receptor antagonists may paradoxically have more risks for gastrointestinal complications compared with those who do not take such medications.
      • Singh G.
      • Ramey D.R.
      • Morfeld D.
      • Shi H.
      • Hatoum H.T.
      • Fries J.F.
      Gastrointestinal tract complications of nonsteroidal anti-inflammatory drug treatment in rheumatoid arthritis. A prospective observational cohort study.
      The use of steroids cannot be excluded as a further risk factor. This class of drugs is widely prescribed in palliative care for different indications. The role of corticosteroid use in inducing major gastrointestinal complications is controversial, as reported in a recent review.
      • Ellershaw J.E.
      Corticosteroids and peptic ulceration.
      The other important finding of this survey is that gastrointestinal bleeding has a poor prognosis in patients with a low performance status. Due to the advanced status of the patients studied, it often was not possible to make a precise diagnosis concerning the causes of bleeding. Further studies with a larger sample of patients and an appropriate design should better address if these complications are ineluctable events, which only require terminal care, or if it is possible to prevent this complication and improve outcomes with an aggressive use of blood components, antihemorrhagic substances, or prophylactic drugs.

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