Clinical Nutrition (1995) 14 (Suppl. 1): 3640 © Pearson Professional Lid 1995
Home total parenteral nutrition in cancer patients F. BOZZETTI Instituto Nazionale Tumori, Divisione Oncologia Chirurgica "A" Via Venezian 1, 20133- Milano (MI), Italy
The mean survival time is usually around 6 months but about 10% of patients survive for 2 years in the USA 1 mad Italy) This obviously reflects the heterogeneity of cancer patients receiving HTPN and stresses the need to define criteria to identify those patients who may benefit from TPN, whilst not completely excluding cancer patients. Although different criteria have been reported for HTPN for cancer patients, they can be subdivided into three groups. 4 Group A includes patients who do not have active disease but suffer from iatrogenic malnutrition and/or intestinal failure as a result of treatment. The conditions which most commonly precede the need for HTPN are severe chronic radiation enteropathy which manifests as irreversible intestinal obstruction, or short bowel syndrome due to surgery for post-irradiation complications. We have frequently used primary HTPN in subacute obstructive non-localised radiation enteritis in order to maintain bowel rest until symptoms subside. Patients are eventually able to resume oral alimentation. This approach has proven to be successful in over 50% of patients. According to the Italian Register of HTPN, 3 those with radiation enteropathy account for 10% of all registered patients. Another condition for which patients receive HTPN is almost total enterectomy for huge abdominal desmoids or aggressive fibromatosis which are incompatible with spontaneous oral nutrition and survival. We have treated many patients because this condition is genetically linked to familiar adenomatous poliposis (FAP), and the head office of the Italian Register of FAP is based at our Institute. Group B includes cancer patients with active disease in whom treatment is difficult because of their compromised nutritional status and insufficient intestinal function. Usually such patients have huge intraabdominal tumours (such as lymphomas, germinal tumours, some paediatric turnouts and some kinds of sarcomas) which are rather responsive to radiation therapy and anti-proliferative drugs. Obviously, the more aggressive the treatment, the stronger is the indication for nutritional support. Group C includes cancer patients with advanced
Issues surrounding the nutritional management of cancer patients have always been controversial. Does nutritional support improve survival of patients with cancer or does the patient feel better and have an improved quality of life? These problems are obviously magnified when we deal with a demanding and expensive procedure such as home total parenteral nutrition (HTPN). Controversy is mainly reflected in the 'sociopolitical' attitude of some countries (or authors) which evaluate medical procedures in terms of cost-benefit and consequently exclude all patients with incurable diseases. Differences in the availability of HTPN are also related to the different 'cultural' approaches of the physicians involved in the care of advanced patients. Some oncologists regard their main goal as prolonging the life of their patients and consequently they consider HTPN according to its ultimate effect on survival. Others consider their primary responsibility is to provide an effective palliation of symptoms and to improve or maintain an acceptable quality of life. There is also controversy because of the great variability between cancer patients who are candidates for HTPN with respect to their life expectancy, quality of life and suitability for aggressive or palliative treatment.
Magnitude of the problem Excluding the dogmatic position of some countries, in most, cancer malnutrition and/or intestinal failure represent two of the most common conditions of patients on HTPN. Cancer patients account for 33.43% of the patients registered in North America, 1 about 50% of those in the Italian Register of HTPN (Italian Society of Parenteral and Enteral Nutrition) and 17% in a multicentre survey of European adults. 2 Preliminary results from Japan and Australia also indicate that a substantial number of HTPN patients have cancer. 36
CLINICAL NUTRITION 37
and refractory disease together with intestinal failure. It is generally agreed that these so-called terminal cancer patients are those in which the indication for HTPN is most problematic and controversial.
Rationale for recommending TPN in terminal cancer patients Most of the literature refers to Group C patients as 'terminal' cancer patients. Terminally-ill patients according to common jargon are those admitted to intensive care units because their vital functions (gas exchange, circulation and so on) need to be mechanically supported. However, it is important to stress that the oncological definition of 'terminal' simply means patients who have exhausted all available oncologic therapy. This definition does not cover either the quantity and quality of life or the nutritional status of the patients. TPN is a tool for artificially restoring deteriorated nutritional status or keeping a patient alive whilst their gut is not functioning. Therefore the m~dn reason for recommending TPN is in patients in whom the primary cause of death is likely to be starvation, rather than the neoplastic spread of the disease itself. It would be nonsense to intravenously feed a cancer patient who is going to die because of multiple metastatic involvement of vital organs, rather than food deprivation. Nutritional status and support has to be considered within the overall context of physical and psychological symptoms which characterise advanced neoplastic disease. We have referred to this as the quality of life of the patient.
Assessment of the cause of death and life expectancy Between 5-23% of cancer patients with advanced disease die of cachexia. 5-8 However, these figures Table
give no information about the cause of death of individual patients. The data only provide evidence of the potential to either prevent or delay death by controlling cancer cachexia by nutritional support. There is much evidence in the literature 9,1° that although TPN often cannot completely restore a depleted nutritional state, it can prevent, at least temporarily, further deterioration in nutritional status which often occurs in the advanced stage of disease. With respect to predicting probable cause of death in a given cancer patient, only a detailed knowledge of the natural history of their disease, including routes of spread and proliferative kinetics, proper staging and biological characterisation of the tumours enable the oncologist to form an accurate prognosis. A crucial point is assessing the life expectancy of such patients. The usefulness of a nun:tber of indices, clinical, nutritional, or related to quality of life, in predicting survival have been studied. Almost all proved to be unsuccessful for clinical purposes (Table). Nutritional indices are probably the most reliable, but they are confounded by the fact that variables may be favourably modified by active nutritional intervention. If it is accepted that semi-starvation (2.5 MJ or 500 kcal, 18 g amino-acids per day) in cancer patients is usually associated with a negative nitrogen balance of between 5-10 g per day, this will result in a loss in lean body mass of 140-280 g per day. A 30% loss of body energy reserves which is incompatible with survival is likely to occur after 2-3 months of unbalanced loss TM (an arm muscle area of about 9-12 cm 2 is almost incompatible with survivalt9). However, depending on the nutritional status of the patient at the beginning of the period of clinical observation, survival time may be substantially shorter. It may be of more value to identify patients who are not appropriate for HTPN, such as those with low Karnofsky Index, or who have many symptoms, some of which may be intolerable, rather than to try and identify those who would certainly benefit. Further investigation in this area is wmTanted.
Studies which have investigated the accuracy of the estimation of survival in advanced cancer patients
Conclusion Insufficiently accurate Inaccurate Predicts one month survival with 74% accuracy
Yates et all 4
Clinical Spitzer quality of life Weight loss of 10 kg in addition to cognitive failure and dysphagia Kamofsky Index
Mor et a115 Evans et a116 Rueban et a117
Karnofsky Index Karnofsky Index Karnofsky Index
Parkes et al n Addington-Hall et all2 Bruera et a113
Low score (50) predicts short-term survival High score inaccurate Insufficiently accurate Wide confidence limits Valuable when associated with symptom profile
HOME TOTAL PARENTERAL NUTRITION IN CANCER PATIENTS
The quality of life Information pertaining to the quality of life of cancer patients on HTPN is scanty. It has been reported that 13-18% of patients on American and European Registries were completely rehabilitated and an additional 27% had a partial social rehabilitation with a hospital re-admission rate of 3.5% per year. 1,2 Encouraging results on the effects of HTPN on the quality of life of those with gynaecological malignancies have also been reported. 24 Recent data from the Italian Register of HTPN has shown that 45% of patients maintained some working activity during the first year of TPN and about 20% were able to spend holidays away from home. Quality of life is difficult to evaluate. The patient who theoretically represents the best candidate for HTPN is one with no symptoms, except aphagia or intestinal failure, or with symptoms which are amenable to palliative therapy. A major concern would be prolonging the life of a patient without being able to control the other symptoms that make life unacceptable.
Case report The case reported here is an example of our policy with terminal cancer patients. The patient was a 42year-old woman, actively working as a physician, unaware of her diagnosis, with refractory peritoneal carcinosis from ovarian cancer which had been treated with multiple drugs and repeated surgery. She had a chronic intestinal obstruction that caused vomiting, stomach dilation and prevented oral food intake. The performance status was good and there was no apparent involvement of vital organs. We had the opportunity to maintain this patient on HTPN but this would have been inconceivable without palliation of the intestinal obstruction. We also felt that a nasogastric tube in addition to a venting gastrostomy would have definitely reduced her quality of life. The patient was operated on with the purpose of performing a gastroenterostomy or some type of intestinal by-pass. At laporotomy we found a completely frozen abdomen due to widespread carcinosis from the pelvis to the diaphragm that precluded any conventional by-pass procedure. We then performed what we have termed an 'intra-abdominal tube by-pass' by constructing two Witzel gastrostomy and jejunostomy over a T-tube placed in the abdomen with one arm extending outwards (Fig.). The patient is currently on nocturnal HTPN. The internal tubes prevent gastric stasis and enable her to receive some liquids by mouth. The external arm is
closed and can be periodically irrigated or even work as a venting tube in the case of progressive obstruction. More than four months have elapsed since the operation, the patient is fully ambulatory and she has partially resumed work. The procedure was therefore successful, neither HTPN alone nor tube by-pass alone would have accomplished the goal of keeping the patient alive with an acceptable quality of life.
Non-nutritional determinants in the choice of HTPN When TPN is integrated into the multi-dimensional treatment approach of an advanced cancer patient, it is natural that it incurs some changes for the patient. A typical example is that the patient has a central venous line which is necessary for drug administration and blood sampling. Should the patient become hypophagic, they would gradually receive some nutritional support through the central line, without the need for more demanding procedures such as gastrostomy or jejunostomy. For the patient, receiving HTPN in such cases is more acceptable because they perceive it more as further intensive intravenous therapy rather than the loss of normal bodily functions (i.e. oral feeding) which requires specialised intravenous or enteral nutrition. A further point that needs consideration is when to cease HTPN. A typical example is that of patients undergoing pre-operative TPN due to malnutrition and intrabdominal obstruction, who are found unresectable at laporotomy. Interrupting TPN in such cases clearly means to the patients and their families that there is no chance for longer survival or further therapeutic treatment.
Conclusions Approximately 148 000 patients per year die from cancer in Italy. 25 If we consider that at least 5% of these deaths are primarily due to cachexia, 5 this means that theoretically only 7400 patients would be candidates for HTPN. Between 30-50% of 115 terminal cancer patients in a cross-sectional study at the Instituto Nazionale Tumori in Italy26 were symptomatic or unresponsive to palliative care. If these figures are extrapolated nationally, the potential number of suitable patients for HTPN in Italy is reduced to 2300-3700. Obviously, due to the high cost of HTPN (approximately 55 ECU per day in Italy) and the limited
CLINICAL NUTRITION 39
Fig. An internal-external drainage system constructedby connectingintrabdominally a gastrostomyand a~tenterostomyover a T-tube, as shown here, may delay or even avoid intestinal obstruction. succe, ss over a period of time, patients have to be carefully selected. However, it must be pointed out that it is not the cost per day of HTPN that is excessive, (at least compared to the cost of some antibiotics, anti-emetics and anti-hemicrania) but that the costs are sustained for weeks or even months. However, it could[ be argued that since the major objection to HTPN in cancer patients is that those being fed will die prematurely from their turnout, this group of patients represents less of a financial burden compared to those surviving for several months in whom HTPN may be considered more appropriate. Like many others, we do not accept that the efficacy of HTPN in cancer patients is scientifically proven, especially when scientific validation means demonstration through randomised clinical trials. Randomised clinical trials are appropriate if a 'gold standard' treatment (which is used in the control group) is compared to a new, possibly 'more promising' treatment. In the current context, the 'gold
standard' is death from starvation and it is deemed ethically unacceptable to randomise these patients to TPN or no TPN. The fact that starving subjects are condenmed to die does not require any further demonstration. 27 This point of view agrees perfectly with a statement from the American Society of Parenteral and Enteral Nutrition in its official guidelines for the use of parenteral and enteral nutrition. 28 These state that when differences in drag therapy or nutrition regimens are tested for in a randomised clinical trial that 'withholding of a drug or other intervention will not produce disease in otherwise healthy humans, whereas essential nutrients must be provided to healthy and diseased humans alike at some point'. The attempt to resolve every medical problem with randomised clinical trials has yielded scientific anomalies whenever clinicians deal with life-saving procedures. In the history of TPN in oncology, the attempt to validate the efficacy of TPN in patients receiving chemotherapy has compelled researchers to
40 HOME TOTAL PARENTERAL NUTRITION IN CANCER PATIENTS
consider only those patients with mild depletion to be suitable for randomisation and to exclude those who are severely malnourished or hypophagic, but who would probably have benefited more from nutritional support. Of course, on the other hand, as discussed above, it would have not been ethical to randomise for no TPN. Studies have yielded the wrong conclusion, namely that TPN was useless for cancer patients, only because researchers felt necessary to draw conclusions from randomised clinical trials. Our preliminary investigation in this area29 has shown that performance status by the Karnofsky Index (KI) relates to survival (KI _ 40, median survival time of 2 months; KI > 70, median survival 6 months). Moreover, approximately 50% of patients survived more than 3 months on HTPN, and in this group an improvement in performance status and an overall positive judgement of the attending clinician were reported in 41% and 68% of patients respectively. Whatever the choice of the clinician, who may have to recommend HTPN, we feel that it is imperative that the end-points of HTPN for the individual patient (that is, to prolong survival whilst maintaining an acceptable quality of life) are clear. This is necessary in order to validate whether or not these goals are accomplished and thus decide whether to continue or interrupt HTPN. The most important challenge for the physician involved in the care of terminal cancer patients is not whether to recommend HTPN, but to decide which group(s) of patients HTPN may be suitable. This was also the conclusion from an international multidisclipinary consensus meeting of the European Association of Palliative Care, on TPN vs hydration in terminal cancer patients, held in Palermo, Italy in 1992.
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