Supportive care for patients with small cell lung cancer

Supportive care for patients with small cell lung cancer

Lung Cancer, 5 (1989) 319-324 Elsevier 319 LUNG ONI Supportive care for patients with small cell lung cancer W.K. Evans Ottaw Regional Cancer Cente...

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Lung Cancer, 5 (1989) 319-324 Elsevier

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LUNG ONI

Supportive care for patients with small cell lung cancer W.K. Evans Ottaw Regional Cancer Center, Ontario Cancer Foundation, Ottoma (Canah) (Accepted 18 June 1989)

Weight loss is frequently seen in patients with small cell carcinoma of the lung even when the tumour is small and there is no mechanical interference with the gastrointestinal tract [ 11. The use of increasingly aggressive chemotherapy drug regimens and combined modality programs increase the probability of weight loss and debility. These intensive programs can also produce severe and sometimes protracted myelosuppression with risk of intercurrent infections. This review will focus on these two aspects of supportive care: nutritional support and prophylaxis against infection. The etiology of cancer-related weight loss is likely multifactorial. Increased energy requirements, anorexia secondary to tumour-induced changes in taste, insulin resistance and other metabolic abnormalities and anorexia induced by psychological reactions to the disease likely all play a role in patients with small cell lung cancer. The frequency of weight loss in lung cancer (approximately 40-501 of patients) and its known negative impact on survival, led to several studies of intravenous nutritional support These studies, which administered the intravenous nutrients at the beginning of antineoplastic therapy, were given in the hope that they might increase response to therapy, improve survival and ameliorate toxicity [2,3]. As a result of encouraging preliminary observations, the Division of Cancer Treatment, National Cancer Institute organized a number of randomized controlled clinical trials in tumour types known to be responsive to chemotherapy, including small cell lung cancer. In the study of patients with SCLC mported by Clamon [4], 119 evaluable patients were randomized to receive either 28 days of intravenous hyperalimentation (IVH) or an ad lib oral diet. The IVH consisted of an amino acid mixture, hypertonic glucose and a lipid emulsion and the amount of calories and protein delivered was calculated to maximize nutritional repletion. The median survival time for patients with limited disease treated on the study was 18 months and for those with extensive disease, it was 11 months. However, there were no differences in the response rate or survival between the nutritionally supported group and the control group. In particular, IVH did not sigCorrespm&nce: W.K. Evans, Gttawa Regional C!sncm center. Ontario Cancer Foundation, 190 Melrose Ave.. Ottawa KlY 4K7. Canada. 0169-5002 / 89/$03.50 8 1989 Elsevier Science F’ublisheraB.V. (Biomedical Divisia~)

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nificandy alter the survival of patients who had a pretreatment weight loss of >5%, low caloric intake, decreased serum albumin or reduced total iron binding capacity. Intensive nutritional support was associated with important toxicities including an increased frequency of febrile episodes compared with the control group (p>o.OOl). In addition, other complications were seen in the IVH treated group: mechanical difficulties with catheters leading to temporary or permanent discontinuation of the IVH, subclavian vein thrombosis, fluid overload, hyponatremia and hyperglycemia requiring insulin [5]. The impact of 4 weeks IVH on nutritional status and body composition was limited. Although there was a significant increase in both the mean caloric intake and weight of IVH-treated patients, it appeared that the weight gain was largely attributable to fluid retention and a modest increase in body fat as measured by triceps skinfold thickness [a]. There was no increase in lean body mass as determined by anthropometric measurements and by body composition studies including total body nitrogen [7]. Those changes that were observed were brief in duration and by the time of the third chemotherapy cycle, there were no significant differences in weight or in anthropometric values between the two groups of patients. Whether IVH improved strength, enhanced performance or quality of life cannot be answered, as this study did not specifically address these questions. It might be argued that short duration nutritional support is unlikely to be of benefit and that longer term interventions might yield better results. This question has not been addressed in a study in small cell lung cancer but it has been investigated in patients with non-small cell lung cancer [8]. In another NM-sponsored trial, patients were randomixed either to ad lib nutritional intake or a 1Zweek period of nutritional intervention in which they were counselled to take oral nutrients with a caloric intake equal to 1.7-l .95 times their basal energy expenditure. Those that did not achieve this goal were to receive nasogastric feedings or IVH to reach this targetted caloric intake. There was no difference in the response rate to chemotherapy or survival of the nutrition intervention group compared with the control group. One point of practical importance learned during this study was the fact that nutritional counselling was effective in increasing caloric intake in patients with lung cancer and that there was a positive association between caloric intake and weight change. In particular, lung cancer patients on the nutrition intervention arms of the study showed less weight loss in the first 4 weeks of the study than the control group did. In the setting of small cell lung cancer, it may be possible, by nutritional counselling, to increase caloric intake and to reduce weight loss. Recently, megestrol acetate has been observed to stimulate appetite and produce weight gain in patients at conventional doses of the drug (160 mg/day) and in a greater proportion of patients when high doses have been used [9]. These observations have been made primarily in patients with breast cancer but a recent report also included 15 patients with lung cancer (type unspecified). Among these lung cancer cases, 8 (53%) had a subjective improvement in their sense of well-being and 5 (33%) gained more than 2.3 kg. Further studies in a larger lung cancer population and specitlcally in small cell lung cancer will be needed to determine whether this is a useful strategy for the anorexic or cache& small cell lung cancer patient. Nutritional interventions in small cell lung cancer patients, would be placed on a firmer base if there was greater understanding of the metabolic abnormalities that underlie the wasting syndrome. Some light has been shed on this matter by the University of Toronto group who examined metabolic and nutritional perturbations in a cohort of 31 patients treated in the NIH nutritional support study. Resting energy expenditure (REE), measured by indirect calorimetry, was found to be significantly higher than the mean predicted REE [lo]. Overall, there was a 3 1% increase in resting energy expenditure above predicted and REE was noted to be greater in those

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patients with metastatic disease (40%) compared with those with limited disease (25%) (fkO.08). prior to any therapeutic intervention, the mean caloric intake, as determined by diet history was 2OOOHO7kcal/day which exceeded the mean resting requirements by only about 150 kc&lay. This small excess of caloric intake over resting energy expenditure is clearly insufficient to meet the energy demands of day-today activity. It would appear that weight loss in small cell lung cancer patients represents a combination of hypermetabolism and a relative anorexia. Substrate-hormone profiles were assessed in these patients and it was noted that the dominant fuel used for energy was fat [lo]. Fasting plasma free fatty acid levels and l3-hydroxybutyrate levels were elevated as seen with fat mobilization. The respiratory quotient was low (0.74) indicating that fat was oxidized in preference to carbohydrate. There was a significant increase in fasting blood lactate compared with normal and the elevated levels fell in responding patients but persisted high in non-responders. These findings suggest that fatty acid mobilization is an indirect effect of tumour and that lactate production is the result of tumour glycolytic activity and the action of tumour-specific lactic acid dehydrogenase. Insulin resistance appears to be responsible, at least in part, for the elevation of the free fatty acids as the marked increase in insulin levels during TPN failed to reduce the level of circulating free fatty acids. Catecholamine levels (epinephrine, norepinephrine and dopamine), were all found to be elevated whereas glucagon and cortisone levels were normal. The mechanism responsible for catecholamine elevation is unclear but might be tumour-related. Altered protein metabolism was also evident. whole body protein turnover and protein synthesis rates were elevated and an abnormal amino acid profile was seen with a significant increase in certain amino acids (arginine. aspartic acid, asparagine. glutamine and glutamic acid) with a significant decrease in other amino acids (citrulline, omithine and methionine). The branched chain amino acids were normal. The amino acid profile is not typical of that seen in semistarvation. One possible explanation is that the amino acid profile is the result of increased nitrogen entry into the urea cycle with a reduced concentration of omitbine and metbionine due to biotransformation of these amino acids for polyamine synthesis. Further understanding of the fundamental mechanisms responsible for these metabolic perturbations may lead to more effective strategies to prevent weight loss in the small cell lung cancer patient. Treatment also contributes substantially to impaired nutritional intake. Intensive chemotherapy regimens commonly induce nausea and vomiting and may be associated with protracted anorexia. Recently, investigators have directed increasing attention to this issue and there is a large and expanding literature on the subject. Several general points emerge from a review of this literature [ll]. (1) The antiemetic program must be tailored to suit the chemotherapy regimen. Not all cytotoxic agents are emetogenic but the majority used in the treatment of small cell lung cancer are. Certainly most combination chemotherapy programs are moderate to severely emetogenic. The type of drug(s) used and the mode of delivery (bolus versus infusion) are factors to be considered. (2) Combination antiemetics are generally more effective than the use of single (standard) antiemetics [121. Various combinations which include drugs such as prochlorperaxine, dexamethasone, metoclopramide, and the benxodiaxepines (loraxepam) have been evaluated. The single most effective agent is the benzamide, metoclopramide, but only when given in high dosages by the intravenous route [ 111. (3) New antiemetics show promise to more effectively control emesis induced by potent emetogenic agents such as cisplatin. Evidence has accumulated that the action of high dose metoclopramide is, at least in part, related to antagonism of 5-m receptors at peripheral and possibly central sites. In animal models, the

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322 importance of the S-H’l3receptor antagonists in cisplatinum-induced emesis has been clearly demonstrated [13]. A number of these antagonists have been developed by the pharmaceutical industry and have entered clinical trials. There is limited published data at present but anecdotal experience suggests that these agents will quickly fmd a place in the management of patients receiving potent combination chemotherapy regimens. The use of aggressive therapy is also associated with myelosuppression, and granulocytopenia is of particular concern because of the incmased incidence of infection. Some of these infections are life-threatening. Most infectious episodes are associated with organisms that colonize the patient’s own gastrointestinal tract and manifest as oral infections, perianal cell&is, esophagitis and pneumonias. In an effort to reduce the frequency of infection during periods of granulocytopenia, prophylactic antibiotics have been administered to suppress endogenous pathogens. The use of oral non-absorbable antibiotics or absorbable, anaerobic-sparing agents has been investigated extensively, but primarily in patients with acute leukemia and prolonged marrow suppression [14]. In the setting of solid tumour chemotherapy where drugs are given intermittently and neutropenia is generally brief in duration, considerable controversy still exists concerning the use of prophylactic antimicrobials.Based on the reduction in the incidence of infection in patients with acute leukemia, trimethoprim/sulfamethoxaxole(TMP/SMZ) has been investigated in two trials in small cell lung cancer. In the study reported by Figueredo et al., patients received two different dose levels of cyclophosphamide, adriamycin and vincristine [151. Those receiving the high dose were given TMP/SMZ prophylaxis. The standard arm did not receive prophylaxis. Patients on the high dose arm had a higher incidence of neutropenia but a lower incidence of infection for similar degrees of neuuopenia than the control arm. The authors argued that the TMP/!WZ allowed for the administrationof higher doses of chemotherapy to outpatients by affording them protection from infection. The report by de Jongh et al. evaluated the efficacy of TMP/SMZ in a randomized trial in which patients with SCLC received cyclophosphamide, doxorubicin and etoposide [16]. They were randomly assigned to receive TMP/SMZ (320/1600 mgklay) or placebo. Sixty-one patients were evahutted (32 on TMP/SMZ and 29 on placebo). The incidence of infection when the granulocyte count was ~1OO/jtlwas significantly reduced in the TMFVSMZgroup (two infections per 100 days), compared to placebo (11 infections per 100 days, P=O.OOS). The number of bacteremias and the proportion of study time on broad spectrum antibiotics was also significantly reduced in the group receiving the prophylactic antibiotics (kO.01). This study also clearly showed that the incidence of infection is directly related to the degree of suppression of the granulocyte count. Seventy-four percent of the infections that occurred were identified when the granulocyte count was <500&l. The infection rate was highest when the granulocyte count was clOO/pl. As the treatments for small cell lung cancer become more intensive and more analogous to the therapy for acute leukemia, a stronger argument can be made for routine prophylaxis with agents such as TMP/SMZ which reduce the number of febrile and infectious episodes in leukemic patients with prolonged neutropenia On the other hand, the type of intensive regimen that would produce severe and protracted myelosuppression, has not become standard treatment for SCLC, as such treatments have not been clearly shown to be more effective than moderately aggressive regimens. Currently, there is not a strong argument for the routine prophylaxis of all patients receiving cytotoxic therapy for SCLC. In addition, there are arguments against such routine use including concerns about emerging aerobic bacterial resistance. For this latter reason, the new quinolone antibiotics (Norfloxacinand Ciprofloxacin)are being evaluated in patients who would be anticipated to have protracted and severe neutropenia [ 141.They have

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demonstrated efficacy in suppressing Gram-negative bacterial infections and reducing septic events but provide poor coverage for the Gram-positive organisms which are increasingly of concern in those individuals with venous access devices. Current clinical trials are evaluating the efficacy of quinolone antibiotics in combination with agents against Gram-positive organisms (penicillin, vancomycin, rifampin) in patients with protracted neutropenia. If these studies prove to be of benefit in the leukemic population and bone marrow transplantation situation, it would be appropriate to evaluate the use of these agents in studies of small cell lung cancer when intensive chemotherapy regimens are employed. Recombinant human colony-stimulating factors (GCSF, GM-CSF) may prove useful in the treatment of lung cancer by reducing the severity and duration of myelosuppression induced by chemotherapy. This in turn might allow chemotherapy to be given more safely and/or at higher doses. Bronchud et al. have demonstrated that G-CSF, given with alternate cycles of chemotherapy for SCLC, reduced the duration of neutropenia and allowed neutrophil counts to recover more quickly [17]. These observations suggest exciting opportunities for future theral~utic research. At the same time, caution is advisable as some tumour cell lines, including lung cancer lines, have responded to GMCSF with proliferation in in vitro experiments [18,19]. In the future, combinations of growth factors may be used. Studies in monkeys have shown that GM-CSF in combination with IL-3 is very effective in accelerating neutxophil and platelet recovery [u)]. IL-3 appears to expand an immature population of progenitor cells that in turn become responsive to GM-CSF. Other biologicals that will soon enter clinical trials include interleukins-1,4, -5 and -6. These interleukins may be used to support bone marrow recovery, fight infections and overcome residual malignant disease. References

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Dcwys, W.D., Begg. C.. L&n, P.T. et aL (1980) Prognostic effect of weight loss prior to chemotherapy in cancer patients: Eastern Cooperative Oncology Group study. Am. J. Med. 69: 491-497. Issell. B.F., Valdivieso, M.. &en. H.A. et al. (1978) Pmtectiou against chemc&empy toxicity by i.v. hyperalimentat&. Cancer Treat Rep. 62: 113%1143. Copeland. E.N., Daly, J.N. and Dudrick, S.J. (1977) Nutrition as an adjunct to cancer treatment in the adult. Cancer Res. 37: 2451-2456. Clamon. G.H., Feld. R. Evans, WK. et aL (1985) Effect of adjuvant central iv. hyperalimentation on the survival and msponse to treatment of patiems with small osB lung cancer: a mndomixed triaL Cancer Treat. Rep. 69: 167177. Weiner, RS., Kramer, B.S.. Clamat. G.H. et aL (1985) Effects of intravenous hyperahmentation during treatment in patients with small cell lung cancer. J. Clin. GncoL 3: 949-957. Evans, WK.. Makuch. R., CLamon. G.H. et aL (1985) Limited impact of total pamnteral nutrition on nutritional status during treatment of small cell lung cancer. Cancer Res. 45: 3347-3353. Shike. M.. RusseJl, D.M.. Detsky, A.S. et aL (1984) Changes in body composition in patients with small-cell lung cancer: the effect of t&al pamnteral nutrition as an adjunct to chemotherapy. Ann. Intern. Med. 101: 303-309. Evans, W.K.. Nixon, D.W., Daly. J.M. et aL (1987) A randomized study of oral nutritional support versus ad lib nutritional intake during chemotherapy for advanced colorectal and non-small-cell lung cancer. J. Clin. GncoL 5: 113-124. Tchekmedyian. N.S.. Tait, N., Moody, M. et al. (1986) Appetite stimulation with Megestrol Acetate in cache&c cancer patients. Sem. Gncol. 13 (Suppl. 4): 3743. Evans, W.K.. Russell, D.M., Shepherd. EA. et aL (1983) A profile of the metabolic and nutritional pemnbatiuts of patients that accompany small cell lung cancer. KHItb Intemational Congress of Chemctherapy. Vi-a 1983 Separamm. Edwards, CM. (1988) Chemotherapy-induced emesis -mechanisms and treatment: review. J. Roy. Sot. Med. 81: 658-662. Rawlins. M.D., Taylor, W.B. and Bateman, D.N. (1984) Rational approaches to theraw for nausea and vomiting: two common solutia~s. In Nausea and Vomiting: Me&amsms and Treatmat (Davis, C.J. ed.) Springer-Vcrlag, Heidelberg,pp. 167-171. Miner, W.D. and Sanger, G.J. (1986) Inhibition of Cisplatin-induced vomiting by selective 5-Hydroxytqptamine

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