total parenteral nutrition and cancer clinical trials

Total Parenteral Nutrition and Cancer Clinical Trials

SAMUEL KLEIN, MD, SM,*,t JOHN SIMES, MBBS, SM,* AND GEORGE L. BLACKBURN, MD, PHD*

Twenty-eight prospective randomized controlled clinical trials evaluating the use of total parenteral nutrition (TPN) in cancer patients were identified through a search of major indexing sources. The data were pooled across studies to increase the ability to detect therapeutic effects. The impact of publication bias and the quality of reporting each trial were used to critically assess the conclusions drawn from the pooled analysis. The authors conclude that TPN may be useful when used preoperatively in patients with gastrointestinal tract cancer. It appears to be beneficial in reducing major surgical complications (pooled P = 0.01) and operative mortality (pooled P = 0.02). No statistically significant benefit from TPN could be demonstrated in survival, treatment tolerance, treatment toxicity, or tumor response in patients receiving chemotherapy or radiotherapy. An increase in the risk of developing an infection in chemotherapy patients given TPN (pooled P < 0.0001) underscores the importance of demonstrating significant benefits in randomized trials before TPN is used routinely in these patients.

Cancer 58:1378-1386, 1986.

HE ABILITY TO USE the superior vena cava for com- T plete nutritional support was demonstrated by Dudrick and co-workers in 1968.1.2 Today the use of total parenteral nutrition (TPN) has become commonplace, and its use in the treatment of cancer patients is widespread. It has been estimated that cancer patients consti- tute one third of the 200,000 patients receiving TPN each ear.^,^ Since the clinical course of these patients often results in weight ~ o s s , ~ , ~ and since weight loss itself is an important prognosticator of it seems reasonable that attempts to improve nutritional status with TPN could have a favorable impact on outcome. If malnutrition is simply an associated finding in terminally ill cancer patients, however, nutritional intervention may have little appreciable benefit. Furthermore, since the use of TPN is associated with a certain risk of complication^,^ costs approximately $200 per and has been shown to stimulate tumor growth in animals,''-'4 its ability to reduce morbidity and mortality should be demonstrated before its widespread use is adopted in the clinical setting.

Several retrospective studies, evaluating TPN in cancer, have reported improvements in treatment tolerance, tumor response, and survival in patients given intravenous

From the *Nutrition and Metabolism Laboratory, New England Dea- coness Hospital, Harvard Medical School, and *Division of Biostatistics, Dana Farber Cancer Institute, Boston, Massachusetts.

Supported in part by NIH Grants CA 09459 and CA 38202. t Fellow of the National Institutes of Health (post-doctoral research)

at Harvard Medical School. Address for reprints: Samuel Klein, MD, Division of Gastroenterology,

Room 4.1 18, OJS E7 I , The University of Texas Medical Branch at Gal- veston, Galveston, TX 77550.

Accepted for publication February 28, 1986.

nutritional support. 15-20 Observed differences in retrospective trials, however, may be due to inherent differences in the treatment groups, biases in patient selection, and changing patterns of care rather than the treatment itself. In fact, many of these studies did not include a control group at all. Prospective randomized controlled clinical trials remain the most reliable means of evaluating the efficacy of

This article reviews the prospective randomized controlled clinical trials identified through a literature search that evaluates the use of TPN in cancer. The results of these studies are pooled on major endpoints of clinical importance including survival, surgical complications, chemotherapy toxicity, tolerance to radiotherapy, tumor response, and infection rates. The quality of reporting each trial as judged by a proposed set of guidelines is used to help the reader evaluate the validity of the published reports. In addition, the impact of publication bias and the quality of reporting each trial are used to critically assess the conclusions drawn from the pooled analysis.

Materials and Methods Literature Search

The English language periodical literature was exam- ined from 1968 through 1985. A computer search of the indexed literature was combined with a manual bibliographic search of all references referred to in pertinent articles. All prospective randomized controlled trials evaluating the use of TPN in cancer patients were in- ~ l u d e d . ~ ~ - ~ ' For the purposes of this study, the use of TPN is defined as providing complete caloric and protein re- quirements through an intravenous line placed in the su-

1378

No. 6 TOTAL PARENTERAL NUTRITION A N D CANCER - Klein et a/. 1379

perior vena cava or subclavian vein. Trials involving surgical therapy in which no patient received TPN for more than 24 hours before operation were excluded. Of over 100 articles identified on the initial search, a total of 27

and 1 1 abstractss0-60 met these criteria. Within these 38 publications, there were 28 separate trials reported. When the results of an individual trial were reported in more than one publication, the more recent and complete report was used for evaluation. Two paper^^^,^^ and five a b s t r a ~ t s ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ were preliminary reports of subsequently published trials. If different aspects of one trial were published in separate articles, the results were combined and evaluated as a single trial. One of the papers43 reviewed the results of two trials reported elsewhere35.36,38,39 and another4' reported the results of two separate trials. Six papers3',42,35.36,38,39 reported different aspects of three separate trials. Although two trial^^^,^^ included some of the same patients, these were evaluated as separate studies.

Quality of Reporting

Only the trials reported in full paper form were con- sidered for evaluation in the category of study quality. The criteria used to evaluate the quality of each trial were adapted from Zelen's guidelines for publishing cancer clinical trials.61 The criteria are as follows:

(1) Population Under Study: a clear description of eligibility criteria, population source and patient characteristics;

( 2 ) Therapy: a detailed description of the treatment plan and treatment actually received;

(3) Study Design: includes a description of study objectives and method of randomization;

(4) Patient Accounting: information of withdrawals and whether any additional analysis was done with such patients included;

(5) Data Quality: information regarding a second party review;

(6) Censored Data: information on the kinds of censoring, follow-up information, and whether the analysis takes account of censored data; and

(7) Statistical Analysis: information on reporting statistical methods, statistical power and whether the analysis is adjusted for prognostic factors. A detailed explanation of these criteria is available from the authors upon request.

Two of the authors (S.K. and J.S.) reviewed the criteria together and then surveyed each paper individually to determine whether each of the criteria were reported. If a disagreement was found regarding a specific item, the study was reevaluated and the item discussed. A final de- cision was then made, and the item was scored accord- ingly. A disagreement usually meant that one reviewer

had missed something in the study, or that the information in the study was ambiguous, resulting in a different interpretation among the two reviewers. Overall there was good agreement regarding each of the items (90%) and most disagreements were easily resolved with further discussion and reevaluation of the paper.

Each trial was assigned a quality-of-reporting index defined as the percent of items reported of all applicable items. This index was used in assigning weights to the studies in the pooled analysis.

Evaluation of Endpoints In evaluating the results of these trials, both the full

papers and abstracts were included. Since TPN does not act as a specific anticancer agent but supports nutritional status, its effect may be similar among various tumor types undergoing a comparable treatment stress. Therefore, the trials were divided into three groups according to the type of primary cancer therapy: surgery, chemotherapy, or radiation therapy. Based on the information available within the trials, a set of major endpoints were devised for each group of studies, as follows:

( 1) Surgery: Operative mortality (in-hospital mortality within 30 days of surgery); Surgical complications (wound infection, or other major complications including anastomotic leak, peritonitis, abdominal abscess, prolonged ileus, intestinal obstruction and multiple wound complications).

(2) Chemotherapy: Survival; Tumor response; Treat- ment toxicity (myelosuppression); Infection rate (sepsis, pneumonia, cellulitis, urinary tract infection, or other an- tibiotic requiring infections).

( 3 ) Radiation Therapy: Survival; Treatment tolerance (as judged by dose or duration of treatment, or toxic effects). The criteria for measuring survival, tumor response and infection rates varied across studies and are reported as defined by the authors of each study.

Statistical Methods Data in the form of proportions (e.g., complications)

were combined by assuming that each study was estimating a common odds ratio. The odds ratio for a particular event is defined as:

where PI and P2 refer to the probability of the event for the TPN and control groups, respectively. Before combining information across the studies, an exact test for heterogeneity6* was used to test the assumption of a uniform odds ratio across studies. This was not significant for any of the endpoints tested with P values ranging from 0.36 to 0.77.

1380 CANCER September 15 1986 Vol. 58

TABLE 1. Oualitv of ReDortine. TPN and Cancer Clinical Trials

Criteria No. of studies

reporting each criteria

1. Population under study a. Eligibility criteria b. Source of patients c. Patient characteristics

2. Therapy a. Treatment plan b. Treatment received

3. Study design a. Study objectives b. Randomization method

4. Patient accounting* a. Number of withdrawals b. Reason for withdrawals c. Additional analysis

16/22 (73%) 9/22 (41%)

17/22 (77%)

19/22 (86%) 8/22 (36%)

17/22 (77%) 3/22 (14%)

11/13 (85%) 10113 (77%) 2/13 (15%)

5. Data quality 0122 (0%)

6 . Censored data? a. Kinds of censoring 4/ 10 (40%) b. Follow-up period 5/10 (50%) c. Lost to follow-up 3/10 (30%) d. Lost to follow-up/length of stay 217 (29%)

7. Statistical analysis a. Basic methods b. Methods in depth c. Prognostic factors d. Statistical power

14/22 (64%) 6/22 (27%) 8/22 (36%) 1/22 (5%)

All criteria 1551340 (46%)

* In 418 surgical, 219 chemotherapy and 214 radiotherapy trials this

t In 118 surgical, 119 chemotherapy and 314 radiotherapy trials this

TPN: total parenteral nutrition.

category was not applicable for evaluation.

category was not applicable for evaluation.

For each major endpoint, an exact test for several 2 X 2 tables was then used to test if the uniform odds ratio was significantly different from one.62 For example, an odds ratio significantly less than (greater than) one indi- cates a significantly lower (higher) probability of the event for the TPN group compared with controls. Results for each endpoint were also expressed as an exact 95% confidence interval and point estimate of the common odds ratio based on a conditional reference set.63,64

In addition to the exact tests, an approximate P value (testing the odds ratio different from one) using a weighted sum of log odds ratios65 was calculated. By using weights in the approximate test, proportional to the quality-of- reporting index, we were able to assess the impact of the quality of reporting each study on our conclusions. (This is explained in more detail in the Appendix.)

Whenever a significant result was obtained at the 5% level, the potential impact of publication bias was evaluated. This was done by calculating the number of similar sized unpublished studies averaging null results which would be necessary to render the conclusion insignificant

at the 5% level. The method of assessing the impact of unpublished clinical trials has been adapted from Rosen- thal’s approach to unweighted P values.66

Survival outcomes in medical studies, which could not be summarized as proportions, were summarized as P values and then combined by using the weighted Stouffer method.67 This is done by taking a weighted average of standard normal deviates associated with the one-sided P values with weights given by sample size. If the P value for a particular trial was not known exactly (e.g., 0.025 < P < O S ) , then the average of the known range was used. All final P values reported in this article are two-sided.

Results

From 1968 through 1985, 28 prospective controlled clinical trials were identified in the English Language periodical literature evaluating the use of TPN in cancer patients. Eleven trials were conducted in patients treated with s ~ r g e r y , ~ ~ - ~ ~ , ~ ~ - ~ ~ 12 trials in patients treated with ~hemotherapy,~ 1-43s6-59 4 trials in patients with radiation therapy44-49,60 and 1 trial in terminal patients given no primary form of the rap^.^',^^ Twenty-two of these studies were reported in full paper form and 6 as abstracts only.

Quality of Reporting

In general, the quality of reporting (Table 1) was poor, with only 46% of applicable items being reported from the proposed set of criteria. There were no significant differences in the frequency of items reported between the surgery, chemotherapy, or radiotherapy trials.

Most of the studies gave a reasonable description of the study population, particularly regarding eligibility criteria (73%) and patient characteristics (77%). The protocol was often clearly defined (86%), but few gave details of the therapy actually received (36%). Although the study objectives were described adequately in 77% of the studies, only 14% clearly described the method of randomization. The number of and reason for withdrawals were reported frequently (8 1 %), but an additional analysis, attempting to assess the impact of these exclusions on the study’s conclusions, was often not done (1 5%). No study described the use of a second party review or even an internal review of the data. Information on censored data was not reported frequently (38%). Basic statistical methods were usually reported (64%), but an in-depth description was often not given (27%). Prognostic factors were used in analyzing the study results in 36%, but this usually involved a subgroup analysis only. Only 1 of the 22 trials (5%) discussed statistical power.

Major Endpoints

Surgical Trials (Table 2)23-30,50-55: Operative Mortality: Six of the 10 surgical trials that reported operative mor-

No. 6 TOTAL PARENTERAL NUTRITION AND CANCER * Klein et al. 1381

tality showed a decrease in the TPN group, but this decrease was statistically significant in only one study,28 which had the largest sample size of approximately 60 patients per treatment arm. One study, involving head and neck cancer patients, showed an increase in mortality for the TPN group.

The pooled odds ratio for operative mortality (see Table 4) was 0.44 (exact 95% confidence limits 0.21-0.90), in- dicating that the estimated odds of early in-hospital mortality for the TPN group is approximately one-half that of the control group ( P = 0.02). One trial5' excluded 32% of the randomized patients. If this trial were to be deleted from the pooled analysis, the pooled odds ratio would be 0.50 ( P = 0.06).

Surgical Complications: In 8 of 10 trials that reported surgical complications, there was either a trend toward or a statistically significant decrease in complications (anastomotic leak, peritonitis, abdominal abscess, prolonged ileus, intestinal obstruction, and multiple wound complications). One which reported a trend toward increased complications in the TPN group, was reported in abstract form and details were not given. (This study is not included in the pooled results.) Four trials reported on wound infections separately from other complications, all finding fewer wound infections in the TPN group.

The pooled analysis (see Table 4) indicated a significant decrease in major surgical complications ( P = 0.01) in the TPN group. The estimated odds of developing a major complication was about one-half that of the control group with estimated odds ratio of 0.50. The estimated odds of developing a wound infection in the TPN group was also about one-half that of the controls, with a pooled odds ratio of 0.53 (exact 95% confidence limits 0.27-1.00) ( P = 0.05).

Chemotherapy Trials (Table 3)3'-43956-59): Survival: The survival data were expressed in various forms, including median survival and survival rates, in 1 1 of the trials. Five of the trials showed a trend toward improved survival, three showed a trend toward worse survival, and one reported a statistically significant worse survival in the TPN group. Two studies did not show any difference between groups. The pooled analysis of this data shows a slight decrease in survival in the TPN group, but this was not statistically significant (P = 0.30 by weighted Stouffer method).

Tumor Response: Eight of the 12 chemotherapy trials evaluated tumor response. In three of the eight trials, there was a trend toward improved response to chemotherapy, while in five there was a trend toward a worse response to chemotherapy in the TPN group. The pooled analysis suggests a decreased tumor response to chemotherapy in patients receiving TPN, but this was not statistically significant at the 5% level ( P = 0.08).

TABLE 2. TPN and Surgery Trials

Major complications Operative mortality (%)* Study

(reference) TPN Control TPN Control

Upper GI (23) 2/38 (5%) 3/36 (8%) 6/38 (16%) 8/36 (22%)

All GI (24) 4/30 ( I 3%) 5/26 ( I 9%) 2/30 (7%) 2/26 (8%)

All GI (25) 2/13 (15%) 2/13 (15%) O/l3 (0%) O/l3 (0%)

All GI (26) 1/10 (10%) 6/10 (60%) - -

Upper GI (27) 1/10 (10%) 4/10 (40%) 1/10 (10%) 2/10 (20%)

All GI (28) 11/66 (17%) 19/59 (32%) 3/66 ( 5 % ) 11/59 (19%)

Head and Neck (29) 8/30 (27%) 10/32 (31%) 2/34 (6%) 0/32 (0%)

All GI (30) 2/12(17%) 1/9(11%) 0/12(0%) 0/9(0%)

Upper GI ( 5 1 ) - - 1/25 (4%) 5/27 (19%)

Upper GI (53) 3/8 (38%) 4/7 (57%) 0/8 (0%) 0/7 (0%)

(54) - - 0/10 (0%) 1/10 (10%) Upper GI t

* Death in hospital within 30 days of surgery. t The group of patients randomized to receive only postoperative TPN were

TPN: total parenteral nutrition; GI: gastrointestinal. excluded.

Treatment Toxicity: Nine studies reported on hema- tologic toxicity. In six of these studies, there was less leu- kopenia in the TPN group, but in only one was this difference statistically significant. In this study, the benefit was limited to the first course of chemotherapy when TPN was given simultaneously. Two studies revealed no difference between TPN therapy and controls, and one of the nine studies demonstrated a slightly more severe de- cline in leukocyte count in the TPN group.

Infection: All seven trials that reported information on infection rates (usually sepsis or pneumonia) found that there was an increased number of infections in the TPN group, but none reached statistical significance. In one of these trials:' the data were not presented in a form that could be combined with the other studies and was excluded from Table 3 and the pooled analysis. An eighth trial,36 which did not report general infection rates, reported 3 episodes of catheter sepsis in the 21 patients receiving TPN. This trial was also excluded from Table 3 and the pooled analysis. A pooled analysis of the data (Table 3) shows that there is a statistically significant increase in infections in the TPN group ( P < 0.0001). The estimated odds of developing an infection in the TPN group is approximately 4 times that of the control group (exact 95% confidence limits 2.03-7.95).


TABLE 3. TPN and Chemotherapy Trials

Infection rate (70) Response rate (70) Survival Study

(reference) Avg no./arm TPN Control TPN Control Trend favors P value

Lung (small cell)

Lung (squamous)

Lung (adenoca)

(31, 42) 60 35 7 77 94 Control 0.78

(32) 13 - - 31 8 - -

(33) 22 32 8 12 30 Control 0.0 1

Colon (34) 23 5 4 15 12 Control 0.06

Lymphoma - - - - (35, 36, 43) 20 No difference

Testicular (37)

Sarcoma (38, 39, 43)

15 44 14 88 93 No difference

14 42 33 71 86 TPN NS

Lung (small cell) (40) 25 - - 62 61 TPN 0.70

Bone (41) - 10 50 30 - TPN NS

Acute leukemia (56) 12 - - - - TPN NS

(57) 14 - - 14 23 Control NS Lung (non-oat)

Lung (with mets) ( 5 8 ) 15 - - - - TPN NS

Pooled analysis Trend

Increased infections Decreased response Decreased survival with TPN rate with TPN with TPN

Pooled P value P < 0.0001 * P = 0.08* P = 0.30t

* Exact test for odds ratio = I . t Weighted Stouffer method for pooling P values.

Radiotherapy Trials44-49,60* . Survival: Two of the four trials demonstrated a decreased survival rate in the TPN group, while the other two showed that the TPN-treated patients had an increased survival rate. None of these differences, however, were statistically significant, and there are no obvious trends favoring either the TPN or control groups.

Treatment Tolerance: There was no obvious trend favoring the TPN or control groups. One trial showed a trend toward decreased tolerance, while another showed a trend towards increased tolerance to radiotherapy in the TPN group. The other two trials showed no difference between groups.

No the rap^^'.^^: Survival: In this single trial, the group of terminally ill patients receiving TPN survived a mean of 46 * 6 days compared to 7 +. 3 days for the control group. This is a statistically significant difference (P < 0.05).

TPN: total parenteral nutrition; AVG: average; adenoca: adenocarcinoma; mets: metastases; NS: not significant.

Sensitivity of the Pooled Analysis

The pooled P values obtained in evaluating tumor response and infections in chemotherapy trials and major complications in surgical trials (Table 4) remained statistically significant when the weights were changed from those based on sample size to those which are proportional to the quality-of-reporting index for each study. For surgical trials, however, the conclusions favoring TPN with respect to operative mortality (Table 4) was not as strongly supported when the P value was adjusted for quality of reporting. The P value for operative mortality became 0.07 (from 0.02).

The number of unreported null trials needed to make the pooled conclusions statistically insignificant was de- termined (Table 4). Only two additional unreported surgical trials are needed to make the pooled results from mortality insignificant at the 5% level, while seven are

No. 6 TOTAL PARENTERAL NUTRITION AND CANCER - Klein et al. 1383

TABLE 4. Pooled Analysis of TPN in Cancer Trials

Pooled P value

Common odds Weighted by No. of unreported null trials Major Trend ratio* estimate Exact quality of needed to make results

endpoints favors (95% CI) method reporting? statistically insignificant

Surgical trials Mortality TPN 0.44 (0.21-0.90) 0.02 0.07 Major complications TPN 0.50 (0.30-0.84) 0.0 1 0.02

Chemotherapy Trials Tumor response Control 0.61 (0.34-1.08) 0.08 0.09 Infection Control 3.93 (2.01-7.95) <o.ooo 1 0.0001

2 7

NA 18

* Results use exact methods. t Explained in the Appendix.

needed in the category of major complications. Eighteen unreported null studies are necessary to render the conclusion of a harmful effect of TPN in chemotherapy patients statistically insignificant.

Discussion

Twenty-eight prospective randomized controlled clinical trials evaluating the use of TPN in cancer patients have been identified through a computer search of the major indexing sources and by a manual bibliographic search of references found in pertinent articles. As a result of small sample size, the power of almost all these trials was insufficient to provide a reasonable assurance that a therapeutic effect would not be missed. The average sample size per treatment arm of these studies was 21 and only 2 of the 28 trials had more than 50 patients per treatment arm. A clinical trial of 20 patients per treatment arm would only have a 14% chance of detecting a reduc- tion in mortality rate from 20% to lo%, while 200 patients per treatment arm would be needed to have an 81% chance of detecting this difference. Pooling the results from several trials increases the ability to detect clinically important differences not apparent in individual studies. The failure to attain statistical significance does not rule out a therapeutic effect of TPN, but does make it less likely. If a difference is not found, it is possible that the power of the pooled data is still insufficient or that TPN only benefits certain subgroups of patients. For example, in seven of the trials, those patients who experienced severe weight loss were excluded from randomization. Therefore, the subgroups that may have demonstrated the most dra- matic benefits were not studied in randomized trials.

Although pooling results across several studies provides a more precise estimate of the treatment effects than each individual study, there are disadvantages to this approach. Pooling assumes that all studies combined are quite similar, with respect to the therapy received and the type of patient studied. If a significant treatment effect is found

NA: not applicable; TPN: total parenteral nutrition.

among a heterogeneous group of patients, we can conclude that the treatment may benefit all of the patients or at least a particular subgroup of patients. The test for heterogeneity62 found all of the pooled data were com- patible with a uniform effect. However, this does not completely exclude the possibility of variable effects for different tumor types or different treatment regimens.

Pooling studies can compound individual study biases which may have occurred if any randomized patients were excluded from analysis. A total of 82 randomized patients were excluded from analysis in the studies where statistically significant pooled results were found. Sixty-five of these patients were in the surgery trials and 17 in the chemotherapy trials where infection rates were evaluated. If TPN had the same effect in the excluded patients as in the studied patients, the pooled results would be even more significant than those reported. A large reversal of the observed TPN effect in the excluded group however, would negate the statistically significant effects found in the surgical trials. Since very few of the Chemotherapy patients were excluded from analysis, adjusting the pooled data for excluded patients would have very little impact on infection rate results.

This pooled analysis is also limited because it is possible to have missed trials not indexed within the sources reviewed. Furthermore, since clinical trials are often selected for publication on the basis of positive or interesting results, a pooled analysis based only on published trials may be severely biased.66968 For this reason, the tolerance of the pooled analysis to unpublished or unreviewed studies was assessed by calculating the number of unpublished or unreviewed null trials that would be necessary to reverse any significant conclusion. For example, the conclusion that TPN decreases postoperative mortality and wound infection is weakened by the fact that only two null trials are needed to make the conclusion statistically insignificant.

The assessment of the quality of reporting each study was included to improve our ability to judge the validity


of the conclusions reached in the pooled analysis.61369 This provides both a general measure of the quality of the published data and a means of weighting the information from individual trials in the combined analysis. It should be noted that there are some risks in using this approach, since the quality of reporting a study may not necessarily be closely related to the scientific quality of the study. The data on operative mortality were no longer statistically significant when the studies were weighted by the quality of reporting. Thus, the results were more favorable for the TPN group when the quality of reporting the study was poor. This again weakens the conclusion that TPN decreased operative mortality.

It is interesting to note that one surgical trial showed a trend toward an increase in mortality in the TPN In fact, when these patients were followed for more than 1 month, mortality in the TPN group was significantly worse than the controls. This was the only study involving head and neck cancer patients, and the control group in this study all received enteral tube feedings. Furthermore, while all patients in the TPN group received TPN post- operatively, less than 25% received preoperative TPN. In attempting to reduce operative complications, preoperative administration of TPN may be preferable to postoperative support, and there may be no benefit to intravenous nutrition when enteral feedings are possible. If this study is excluded from the analysis, the benefit from TPN becomes even more significant for operative mortality and major surgical complications. The retrospective exclusion of selected studies, however, can be misleading, so this information must be regarded with caution.

The role of TPN in patients with cancer, including evaluation of the randomized, controlled trials, has been reviewed p r e v i o ~ s l y . ~ , ~ ~ - ~ ~ Subjective analyses of the data, however, have resulted in divergent conclusions from different authors reviewing the same l i t e r a t ~ r e . ~ ~ - ~ ~ Since the majority of the TPN and cancer clinical trials were poorly reported, it is not surprising that differences in interpretation should occur. The method of evaluating the literature presented here decreases the influence of reviewer bias and provides an objective way to combine results from comparative clinical trials. Furthermore, this study also judges the quality of reporting these trials and tests the sensitivity of the pooled analysis to the quality of reporting, as well as to publication bias. It is our belief that this approach should be used to assess the efficacy of other controversial therapeutic modalities. This provides the reader with a better understanding of the deficiences of the trials reviewed, and presents a formalized assessment of the data which may better clarify the potential risks and benefits of a given therapy.

In conclusion, TPN may have a useful role in the surgical management of patients with cancer. It appears to be beneficial in decreasing major surgical complications

and operative mortality if used preoperatively in gastrointestinal tract cancer. No statistically significant benefit from TPN could be demonstrated in survival, treatment tolerance, treatment toxicity, or tumor response in patients treated with chemotherapy or radiotherapy. The increase in infections noted in the chemotherapy patients given TPN underscores the importance of using experienced teams when administering nutritional s u ~ p o r t ~ ~ , ~ ~ and argues against the routine use of TPN in all cancer patients. Our study does not rule out the possible benefit of TPN in cancer patients receiving chemotherapy or radiotherapy. The small sample size in individual studies and the inability to pool data on some endpoints results in a high probability of missing a therapeutic benefit. Fur- thermore, many trials excluded severely malnourished patients, so that the potential benefit of TPN in patients who have had significant weight loss, or who are unable to maintain adequate nutritional intake cannot be excluded. Other subgroups of patients who may benefit from TPN, such as those undergoing bone marrow transplan- t a t i ~ n , ~ ~ . ~ ’ were not studied in these trials.

Carefully planned prospective randomized trials are still needed to determine the appropriate role of TPN in the management of cancer patients. These should have adequate sample size and be aimed at specific groups of patients to avoid the pitfalls of previously reported studies.

APPENDIX

Combining Odds Ratios

By assuming that the study-specific odds ratios are constant, the common odds ratio has been estimated from the k published trials comparing TPN and control by taking a weighted average of the log odd ratios, as proposed by W 0 0 l f . ~ ~ An estimate of the odds ratio (OR) is given by

k k OR = EXP{ c wi In oR,/C w,}

where the index i refers to the trial number, In OR, denotes the estimated log ratio in the ith trial, and wi the weight assigned to the information in the ith trial. The log odds ratio for each trial has been estimated using modified empirical logits described by Cox.’’ The choice of weights is

(i) wi = l/Vi

(ii) wi = QJV, where Vi is the estimated variance of (In ORi),(?) and Qi is the quality- of-reporting index for the ith study. Since In OR is approximately nor- mally distributed, an approximate chi-square test of the null hypothesis Ho: OR = 1 may be based on the statistic

i= I i= I

k k

Xz = (2 wi In 0Ri)*/C: W;vi

where x2 has an approximate chi-square distribution with one degree of freedom.

i = l i= I

Unpublished Trials

If clinical trials are selected for publication on the basis of positive or interesting results, then a pooled analysis based only on published trials may be seriously biased. For example, all “statistically significant” trials

No. 6 TOTAL PARENTERAL NUTRITION AND CANCER - Klein et a/. 1385

but only a proportion of “statistically insignificant” trials may be published, and under the null hypothesis of no treatment effect, a false- positive result will be obtained from the pooled analysis more often than expected.

In assessing the impact of unpublished trials on the pooled analysis, we have modified Rosenthal’s method applied to combined P values‘” and assume that, in addition to the k published trials, there are m unpublished trials which on average show no difference between TPN and

controls (2 In OR, = 0). Suppose that the pooled analysis of k published

trials gives a statistically significant result at the 5% level using the first choice of weights (i) W, == l/V,. Then the number of unpublished null trials (of similar weight to the published studies) necessary to reverse this result and render the conclusion statistically insignificant at the 5% level is the smallest integer, m, greater than

m

,=,

kInOR 2 . . ( T I w - k

where W is the average weight ofthe k published studies. (A similar result can be obtained using the other choice of weights.)

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