parenteral nutrition in oncology - with last 10 years 08-17-2010-summary only

Oncology

Baxter HealthcareMedication Delivery IV Therapy

Nutrition Global Marketing Therapy Area Marketing TeamJune 2010

1

PARENTERAL NUTRITION IN CANCER: Summary of Clincial Evidence

Final Report

Baxter Confidential Information - For Internal Marketing and Medical Affairs Use Only

Cancer Types Included Bladder Breast Colorectal Endometrial Esophageal Laryngeal Liver Lung Non-Hodgkin’s Lymphoma Oral Ovarian Pancreatic Stomach / Gastric

Table of Contents

Executive Summary.........................................................................................................................................4

Executive Summary - Detailed.......................................................................................................................9Introduction....................................................................................................................................................9Economic findings and consensus guidelines................................................................................................9Bladder Cancer............................................................................................................................................11Breast Cancer...............................................................................................................................................13Colorectal cancer.........................................................................................................................................15Endometrial Cancer.....................................................................................................................................16Esophageal Cancer.......................................................................................................................................17Laryngeal Cancer.........................................................................................................................................19“Head and Neck” Cancer (Oral/Esoph. not specified)................................................................................21Liver Cancer................................................................................................................................................23Lung Cancer.................................................................................................................................................25Non-Hodgkin’s Lymphoma.........................................................................................................................27Oral Cancer..................................................................................................................................................29Ovarian Cancer............................................................................................................................................31Pancreatic cancer.........................................................................................................................................33Stomach / Gastric Cancer............................................................................................................................35“Upper GI” Cancer (Oral/Esoph./Gastric not specified).............................................................................37

Tabular Summary of Articles.......................................................................................................................39

Graded Articles- Parenteral Nutrition Only...............................................................................................46Bladder Cancer........................................................................................................................................46Breast Cancer...........................................................................................................................................47Colorectal Cancer....................................................................................................................................48Endometrial Cancer.................................................................................................................................52Esophageal Cancer...................................................................................................................................52Laryngeal Cancer.....................................................................................................................................55“Head and neck” Cancer..........................................................................................................................56Liver Cancer............................................................................................................................................57Lung Cancer.............................................................................................................................................58Non-Hodgkin Lymphoma........................................................................................................................60Oral Cancer..............................................................................................................................................61Ovarian Cancer........................................................................................................................................61Pancreatic Cancer....................................................................................................................................62Stomach/Gastric Cancer..........................................................................................................................65“Upper GI” Cancer (Oral/Esoph./Gastric not specified).........................................................................70

All Articles (PN, EN, General)......................................................................................................................72Bladder cancer.............................................................................................................................................72Breast cancer................................................................................................................................................74Colorectal cancer.........................................................................................................................................77

2Baxter confidential information. For internal use only

Baxter Confidential Information - For Internal Marketing and Medical Affairs Use Only

Endometrial cancer......................................................................................................................................84Esophageal cancer.......................................................................................................................................86Laryngeal cancer..........................................................................................................................................92“Head and neck” cancer...............................................................................................................................94Liver cancer.................................................................................................................................................98Lung cancer...............................................................................................................................................102Non-hodgkin lymphoma............................................................................................................................107Oral cancer.................................................................................................................................................108Ovarian cancer...........................................................................................................................................111Pancreatic cancer.......................................................................................................................................113Stomach/Gastric cancer.............................................................................................................................126“Upper GI” (Oral/esoph./gastric not specified).........................................................................................136Cancer- General.........................................................................................................................................138


THIS PAGE INTENTIONALLY LEFT BLANK


Executive Summary

BackgroundThis literature search was commissioned to identify articles that exist related to Nutrition and Oncology. The articles are classified alphabetically by cancer type, and then grouped into three treatment modalities (Medical/Non surgical, Radiation and Surgical). While this was a robust literature search, it was not exhaustive.

PurposeThe purpose of this research is to provide a foundation of information which facilitates discussions with marketing and medical affairs to prioritize areas of Oncology which are most compelling for Nutrition.

Results- The 13 cancer types included in the search criteria represent 75% of worldwide cancer incidences.

- 978 articles were identified during the search: PN & Oncology 316 articles EN & Oncology 212 Nutrition & Oncology 346 General Cancer 104

- PN Articles were grouped into three therapeutic modalities: 108 articles Medical Oncology / Chemotherapy / Non-surgical 20 articles Radiation Oncology 188 articles Surgical Oncology

- All PN related articles were graded based on a review of the abstract Grade A 5 articles Grade B 124 Grade C 102 N/A 80

- 37% (117) of the 316 PN related articles were published in the last 10 years.

- Figure 1 provides an overview of the quantity of existing evidence by therapeutic modality

- Figure 2 provides the quantity and grade of evidence in the last 10 years

- Table 1 provides a summary of the relative clinical strength (based on article design and positive evidence for PN) in each of the various cancer and treatment areas.

Conclusions

The strongest evidence for PN use in Oncology is concentrated in Colorectal, Esophageal and Stomach/Gastric cancer. Across these cancer types, the surgical modality exhibits the strongest positive evidence followed by medical oncology/non-surgical.

Colorectal, Esophageal and Stomach/Gastric cancer represent priority areas for further investigation and discussion.


Table 1. Clinical Evidence Summary for Parenteral Nutrition and Oncology

Bladder Breast Colorectal Endometrial Esophageal LaryngealHead & Neck

Liver LungNon-

Hodgkin’s

Oral Ovarian PancreaticStomach / Gastric

Upper GI

OverallMod.

Strong (11)

Mod. Strong

(6)

Strong (32)

Weak Strong (28) Weak WeakMod.

Strong (3)

ModerateMod.

Strong (6)

WeakMod.

Strong (6)

Moderate (18)

Strong (39)

Weak

NonSurg./ Medical

Oncology/ Chemo.

Mod. Strong

(3)

Mod. Strong

(3)

Mod. Strong (8)

Weak Strong (8) Weak Moderate WeakMod.

Strong (11)

Mod. Strong

(4)Weak

Mod. Strong

(4)

Mod. Strong (6)

Strong (14)

Moderate

Radiation ModerateMod.

Strong (2)

Weak Weak Moderate Weak Weak Weak WeakMod.

Strong (2)

WeakMod.

Strong (1)

Weak Weak Weak

SurgicalMod.

Strong (6)

Mod. Strong

(1)

Strong (23)

Weak Strong (19) Weak WeakMod.

Strong (3)

Weak Weak WeakMod.

Strong (1)

Moderate (12)

Strong (25)

Weak

Mod.=moderate.

(Numbers in parenthesis represent the number of articles with positive evidence supporting PN use)

The remaining sections of this report provide greater details on the analysis and articles identified through the research. Articles which received grade A or B are available in the Nutrition Global Marketing SharePoint site below.

IVT Business Information > Marketing > Shared Documents > Therapy Area Marketing > Oncology – Clinical Evidence Summary and Articles https://worksites.connect.inbaxter.com/sites/IVT/Marketing/Shared%20Documents/Forms/AllItems.aspx?RootFolder=%2Fsites%2FIVT%2FMarketing%2FShared%20Documents%2FTherapy%20Area%20Marketing&View=%7b5ABE4454%2d9329%2d4752%2d8199%2d0A842CB897D1%7d

For additional information please contact the Nutrition Global Marketing, Therapy Area Team.

7

https://worksites.connect.inbaxter.com/sites/IVT/Marketing/Shared%20Documents/Forms/AllItems.aspx?RootFolder=%2Fsites%2FIVT%2FMarketing%2FShared%20Documents%2FTherapy%20Area%20Marketing&View=%7B5ABE4454-9329-4752-8199-0A842CB897D1%7D



Table 2. Clinical Evidence Summary – Last 10 years, Positive Outcome for PN


Liver LungNon-

Hodgkin’s


Upper GI

Overall 2 0 24 0 3 1 0 0 1 2 0 5 9 18 0

NonSurg./ Medical

Oncology/ Chemo.

1 5 1 1 3 4 4

Radiation 1 1 1 1

Surgical 18 3 1 1 5 14

Numbers in parenthesis represent the number of articles with positive evidence supporting PN use)

Table 3. Clinical Evidence Summary – Last 10 years, all articles by Grade


Liver LungNon-

Hodgkin’s


Upper GI

Overall 2 0 34 0 10 1 4 0 4 2 1 7 17 26 0

Grade A 4 1

Grade B 1 19 5 1 1 2 5 11 10

Grade C 1 5 3 1 2 10

TDB/ NA 6 2 4 2 1 2 3 6


EXECUTIVE SUMMARY - DETAILED

INTRODUCTION

This summary presents the current status of literature regarding the use of parenteral nutrition (PN) in twelve types of cancer: oral, laryngeal, esophageal, lung, liver, gastric, colorectal, breast, endometrial, ovarian, bladder, and non-Hodgkin’s lymphoma. These cancers were identified in a survey of medical oncologists as being the most likely to employ PN in patient care and represent more than 75 % of world cancer incidences. In addition, each type of cancer has been grouped into three subcategories based on therapeutic modality: Non-Surgical/Medical Oncology/Chemotherapy, Radiation Oncology, and Surgical Oncology.

A PubMed search was performed to identify all clinically relevant publications. The following key search terms were used in a variety of combinations to maximize the retrieval rate of all published clinical articles to date: parenteral nutrition, enteral nutrition, nutrition, malnutrition, intravenous nutrition/feeding, malignancy, breast cancer/carcinoma, colorectal cancer/carcinoma, endometrial cancer/carcinoma, ovarian cancer/carcinoma, bladder cancer/carcinoma, non-Hodgkin’s lymphoma, hyperailmentation, hypercaloric, protein balance, and nitrogen balance. All primary articles of interest were considered for categorization and grading. Bibliographies of selected publications and related review articles were also scanned to ensure the inclusion of all relevant publications.

All Parenteral Nutriton related articles were categorized into the following therapeutic modalities: Non-Surgical/Medical Oncology/Chemotherapy, Radiation Oncology, and Surgical Oncology. The following grading scale was used to assign an alphabetical grade to the clinical publication:

TABLE 2: Grading CriteriaGrade Criteria

ARandomized controlled trial, statistical significance of results, clinically important outcomes, and top-tier journal.

B

Controlled but non-randomized trial that demonstrates clinically important outcomes; or, if randomized, less compelling results; lower-tier journal; or full text of article in another language and therefore not open to analysis beyond the abstract.

CNon-randomized trial; poor or non-significant statistics; inconclusive results; lower tier journal; or no results/statistics in the abstract with full text in another language.

Not relevant

Although the study mentioned the use of PN, it was not the focus of the paper and was not noted to influence outcomes.

ECONOMIC FINDINGS AND CONSENSUS GUIDELINES

In most cases, the consensus seems to be that PN is too expensive to justify its use in place of enteral nutrition (EN) except under certain circumstances. These circumstances include severe malnutrition and an inability of the patient to utilize EN or oral nutrition.

Esophageal CancerFor example, in esophageal cancer, Lim et al concluded that “gastrostomy feeding [EN] is preferred, as it is cheap,

simple and safe, and allows patients to be active, mobile and self dependent.1” They noted that:

“The cost of fluid alone is far higher for a full TPN regimen compared to gastrostomy or NG-tube enteral nutrition. TPN requires specialized nursing and medical care whereas patients on gastrostomy feeding are usually self sufficient. Furthermore, patients on TPN are generally confined to their beds and dependent upon i.v. lines. Although gastrostomy feeding is shown to be inferior to TPN in achieving positive nitrogen balance and weight gain within a 4-week period, it is still a simple and safe means of preoperative preparation of patients with cancer.1”

9Baxter Confidential – For Internal Use Only

Laryngeal CancerIn laryngeal cancer, Ryu et al (2009) found that the daily cost of EN via nasogastric tube was $11.81 cheaper per patient

than that of TPN.2

Upper GI CancerIn a 1986 review, Koretz3 analyzed weight-averaged data for cost/benefit of TPN in upper-gastrointestinal cancer patients

(esophageal and gastric). He concluded that, from a cost perspective, the overall result “makes little difference”. He notes,

however, that because the average rate of complications was nearly halved in the studies he reviewed, “for an extra $200 per

patient for TPN, substantial pain and suffering is avoided.” He derived these costs from the following calculation:

Costs of providing parenteral nutritional support to 100 patients:100 patients receiving 10 days each $800,000Reduction of 15% in minor complications -30,000Reduction of 15% in major complications -750,000 Net cost $20,000

1Lim ST, Choa RG, Lam KH, Wong J, Ong GB. Total parenteral nutrition versus gastrostomy in the preoperative preparation of patients with carcinoma of the oesophagus. Br J Surg. 1981 Feb;68(2):69-72. PubMed PMID: 6779888.2Ryu J, Nam BH, Jung YS. Clinical outcomes comparing parenteral and nasogastric tube nutrition after laryngeal and pharyngeal cancer surgery. Dysphagia. 2009 Dec;24(4):378-86. Epub 2009 Mar 3. PubMed PMID: 19255706.3Koretz RL. Nutritional support: how much for how much? Gut. 1986 Nov;27 Suppl 1:85-95. Review. PubMed PMID: 3098648.

Consensus Guidelines Given its increased cost, when is the use of PN justified? Despite the number of positive studies tallied below, recent

consensus tends to discourage the use of PN when EN can be tolerated. The exception is severe malnutrition in almost every

category of cancer. In discussing the most recent (2009) ESPEN guidelines on PN, Bozzetti et al1 note that:

In non-surgical, well-nourished oncologic patients routine parenteral nutrition is not recommended.

A benefit, however, is reported in patients undergoing hematopoietic stem cell transplantation.

Short-term parenteral nutrition is [also] commonly accepted in patients with acute gastrointestinal complications from chemotherapy and radiotherapy, and long-term (home) parenteral nutrition will sometimes be a life-saving maneuver in patients with sub acute/chronic radiation enteropathy.

In incurable cancer patients, home parenteral nutrition may be recommended in hypophagic/(sub)obstructed patients (if there is an acceptable performance status) if they are expected to die from starvation/under nutrition prior to tumor spread.

Supplemental PN is [also] recommended in patients if inadequate food and enteral intake (<60% of estimated energy expenditure) is anticipated for more than 10 days.

Perioperative PN is recommended in malnourished candidates, when EN is not possible. Peri-operative PN should not be used in well-nourished cancer patients. If for any reason peri-operative EN is not feasible, perioperative PN starting 7–10 days pre-operatively and continuing into the post-operative period, has been shown to be able to decrease complications and/or mortality.

1Bozzetti F, Arends J, Lundholm K, et al. ESPEN Guidelines on Parenteral Nutrition: Non-Surgical Oncology. Clin Nutr. 2009 Aug;28(4):445-54. PubMed PMID: 19477052.


BLADDER CANCER

Background/Outcomes: Figure 3 provides the overall number of clinical PN-related bladder cancer publications. All of

papers in the Surgical group were case reports limiting the interpretation and generalization of the results. Despite this limitation

in the study design, positive results were reported in the clinical outcomes assessed which included weight gain, nitrogen balance,

bone age, tumor growth, and survival. In the Radiation Oncology section, Blath et al. presented two case reports that

demonstrated low complication rates associated with PN.1 Last, 2 randomized trials in the Surgical category found that duration of

hospital stay was reduced and the metabolic profile was improved in bladder cancer patients receiving PN.2,3

Results:

In the Non-Surgical/Medical Oncology/Chemotherapy section, 3 articles were identified (all B-

grades).

In the Radiation category, 2 articles (1 rated as a B- and 1 as a C) were identified.

In the Surgical group, 2 B, 1 B-, and 5 C papers were reported.

Conclusions: Moderately Strong

TABLE 3: BLADDER CANCER

CategoryEvidence

supporting PNTotal

PapersPositive

Negative/No Benefit

OverallModerately

Strong14 11 3

Non-Surgical/Medical Oncology/ Chemotherapy

Moderately Strong

3 3 0

Radiation Moderate 2 2 0

SurgicalModerately

Strong9 6 3

1Blath RA, Bucy JG. Intravenous hyperalimentation in the treatment of difficult urologic problems. South Med J. Nov 1975;68(11):1366-1368. 2Askanazi J, Hensle TW, Starker PM, et al. Effect of immediate postoperative nutritional support on length of hospitalization. Ann Surg. Mar 1986;203(3):236-239.3Hensle TW, Askanazi J, Rosenbaum LH, Bernstein G, Kinney JM. Metabolic changes associated with radical cystectomy. J Urol. Nov 1985;134(5):1032-1036.


BREAST CANCER

Background/Outcomes: Very few articles in this area have been published. Figure 4 illustrates the tally of breast cancer PN-

related clinical publications by assigned grade. Breast cancer patients receiving PN had increased weight, required smaller or less

frequent medication, experienced leukocyte depression, and had no gastrointestinal symptoms.1-3 In addition, all patients

improved in performance as determined by activity and mental alertness and two patients were reported to have objective

improvements in lesion size within 3 weeks of chemotherapy.1 Approximately 54% of the patients (n=21) receiving radiation

therapy had a tumor response, defined as a >50% reduction in measurable tumor volume, without any serious complications.2,3

Further, patients undergoing surgical resections had improved weight gain, increase in strength, significant rises in serum

albumin (protein) concentrations, and returned to immunocompetence with PN administration.2 A low mortality rate of 4% (n=4)

was also reported despite the magnitude of the procedure and debilitated initial condition of the patients.2

Results:

In the Non-Surgical/Medical Oncology/Chemotherapy group, 4 breast cancer papers (1 rated as B, 2 as B-, and

1 as C) were identified. All were considered dated since the publication date was ≥25 years ago.

The Radiation Oncology group had 2 articles (grade B- and B). Both of these articles were considered dated as

well (≥30 years).

The Surgical group had 1 article which was assigned a grade B-.


TABLE 4: BREAST CANCER

CategoryEvidence

supporting PNTotal

PapersPositive

Negative/No Benefit

OverallModerately

Strong7 6 1


Moderately Strong

4 3 1

RadiationModerately

Strong2 2 0

SurgicalModerately

Strong1 1 0

1Schwartz GF, Green HL, Bendon ML, Graham WP, 3rd, Blakemore WS. Combined parenteral hyperalimentation and chemotherapy in the treatment of disseminated solid tumors. Am J Surg. Feb 1971;121(2):169-173.2Copeland EM, 3rd, Daly JM, Dudrick SJ. Nutrition as an adjunct to cancer treatment in the adult. Cancer Res. Jul 1977;37(7 Pt 2):2451-2456.3Tominaga T, Onodera T, Kitamura M, et al. Combined treatment by chemotherapy and intravenous hyperalimentation in Japanese patients with advanced breast cancer. Cancer. Aug 15 1980;46(4):642-646.


COLORECTAL CANCER

Background/Outcomes: Figure 5 displays the number of colorectal cancer PN-related publications by assigned grade. Most

of the studies identified were non-randomized and enrolled small sample sizes (<100) limiting accurate data interpretation of the

analysis. Patients taking PN demonstrating increased survival rates (P<0.001), improved quality of life as early as 18 weeks

(P<0.05), and reduced gastrointestinal symptoms (P<0.001) as demonstrated in Hasenberg article et al.1 PN was not associated

with cancer cell proliferation, metastasis, or recurrence.2 No major safety events were noted with PN, except in 1 case where

venous catheter-related bloodstream infections were observed.1,3 In addition, patients receiving PN had shorter hospital stays,4,5

improved and/or sustained nitrogen balance and lymphocyte recovery,5,6 enhanced immune response,7 lower mortality rates, and

very few PN-related complications.4,7,8

Results:

In the Non-Surgical/Medical Oncology/Chemotherapy group, 13 articles were identified (2 B+, 1 B, 5 B-, 1 C+,

2 C, and 2 Not Relevant).

For the Radiation Oncology category, there were 2 papers (both rated B-).

In the Surgical group, 41 articles (1 A, 1 A-, 2 B+, 4 B, 14 B-, 1, C+, 4 C, 1 C-, 10 Not Relevant) were

identified.


TABLE 5: COLORECTAL CANCER

CategoryEvidence

supporting PNTotal

PapersPositive

Negative/No Benefit

Overall Strong 56 32 24


Moderately Strong

13 8 5

Radiation Weak 2 1 1

Surgical Strong 41 23 18

1Hasenberg T, Essenbreis M, Herold A, Post S, Shang E. Early supplementation of parenteral nutrition is capable of improving quality of life, chemotherapy-related toxicity and body composition in patients with advanced colorectal carcinoma undergoing palliative treatment Results from a prospective, randomized clinical trial. Colorectal Dis. Nov 6 2009.2Liu Y, Tao KX, Wang GB. [Effects of perioperative total parenteral nutrition support on cyclin D1 expression, recurrence and metastasis of colorectal cancer cells]. Zhonghua Wei Chang Wai Ke Za Zhi. Jun 2010;13(6):433-435.3Ishizuka M, Nagata H, Takagi K, Kubota K. Total parenteral nutrition is a major risk factor for central venous catheter-related bloodstream infection in colorectal cancer patients receiving postoperative chemotherapy. Eur Surg Res. 2008;41(4):341-345.4Bozzetti F, Gavazzi C, Miceli R, et al. Perioperative total parenteral nutrition in malnourished, gastrointestinal cancer patients: a randomized, clinical trial. JPEN J Parenter Enteral Nutr. Jan-Feb 2000;24(1):7-14.


5Morlion BJ, Stehle P, Wachtler P, et al. Total parenteral nutrition with glutamine dipeptide after major abdominal surgery: a randomized, double-blind, controlled study. Ann Surg. Feb 1998;227(2):302-308.6Svanfeldt M, Thorell A, Nygren J, Ljungqvist O. Postoperative parenteral nutrition while proactively minimizing insulin resistance. Nutrition. May 2006;22(5):457-464. 7 Liang B, Wang S, Ye YJ, et al. Impact of postoperative omega-3 fatty acid-supplemented parenteral nutrition on clinical outcomes and immunomodulations in colorectal cancer patients. World J Gastroenterol. Apr 21 2008;14(15):2434-2439.8Wu GH, Liu ZH, Wu ZH, Wu ZG. Perioperative artificial nutrition in malnourished gastrointestinal cancer patients. World J Gastroenterol. Apr 21 2006;12(15):2441-2444.

ENDOMETRIAL CANCER

Background/Outcomes: No PN-related articles were identified in this area.

Conclusions: Weak


ESOPHAGEAL CANCER

Background/Outcomes: Figure 6 shows the Esophageal Cancer PN-related clinical publications by assigned grade. Patients

treated with PN were able to tolerate up to 26% more chemotherapy than controls, 1 while another study found that PN was

superior to ad lib. oral feeding and jejunostomy feeding [EN] in repleting plasma amino acid levels. 2 A study by Meuller et al of

esophageal and gastric cancer patients found that 9 patients died in the control group vs 2 in the PN group (p< 0.05); Significant

improvement of humoral and cellular immunocompetence and protein status were also found (p < 0,01). Muller et al found

reductions in postoperative mortality (19% v 5%) and major morbidity (22% v 11%) associated with parenteral nutrition.

Results:

There were no Grade A papers.

In the Non-Surgical/Medical Oncology/ Chemotherapy category, 5 out of 5 (100%) Grade B papers and 3 of 3 (100%) Grade C papers were positive for PN, while 1 was Negative/No Benefit.

In the Radiation category, the single Grade B paper was positive for PN.

In the Surgical category, 6 out of 10 (60%) Grade B papers were positive for PN, 8 out of 12 (67%) Grade C papers were positive for PN. Thirteen papers were not relevant, inconclusive, or were not rated due to lack of details.

Conclusion: Strong.

Overall, the evidence in favor of PN for esophageal cancer is strong. For the non-surgical and surgical categories, the

evidence is quite strong since 100% and ≥70% positive papers were found in each category, respectively.

TABLE 6: ESOPHAGEAL CANCER

CategoryEvidence

supporting PNTotal

PapersPositive

Negative/No Benefit



Strong 9 8 1

Radiation Moderate 1 1 0


1Sikora SS, Ribeiro U, Kane JM 3rd, Landreneau RJ, Lembersky B, Posner MC. Role of nutrition support during induction chemoradiation therapy in esophageal cancer. JPEN J Parenter Enteral Nutr. 1998 Jan-Feb;22(1):18-21. PubMed PMID: 9437649.2Pearlstone DB, Lee JI, Alexander RH, Chang TH, Brennan MF, Burt M. Effect of enteral and parenteral nutrition on amino acid levels in cancer patients. JPEN J Parenter Enteral Nutr. 1995 May-Jun;19(3):204-8. PubMed PMID: 8551648.


LARYNGEAL CANCER

Background/Outcomes: The Laryngeal Cancer PN-related clinical publications by assigned grade are demonstrated in

Figure 7. As with oral cancer, there were very few papers examining the role of PN in laryngeal cancer. A single Grade C study

by Ryu et al found that patients receiving post-operative PN experienced less discomfort than those receiving EN.1

Results:

There were no Grade A or Grade B papers.

Only two papers dealt directly with the use of PN in laryngeal cancer. While one of these was positive for PN, its quality was poor (Grade C).

Conclusion: Weak.

For all categories, the evidence in favor of PN in laryngeal cancer is quite weak.

1Ryu J, Nam BH, Jung YS. Clinical outcomes comparing parenteral and nasogastric tube nutrition after laryngeal and pharyngeal cancer surgery. Dysphagia.2009 Dec;24(4):378-86. Epub 2009 Mar 3. PubMed PMID: 19255706.

TABLE 7: LARYNGEAL CANCER

CategoryEvidence

supporting PNTotal

PapersPositive

Negative/No Benefit

Overall Weak 6 1 0


Weak 1 0 1


Surgical Weak 4 1 0


“HEAD AND NECK” CANCER (ORAL/ESOPH. NOT SPECIFIED)

Background/Outcomes: In Figure 8, the Head and Neck Cancer PN-related clinical publications by assigned grade is shown.

In the single Grade B study to support the use of PN in head and neck cancer by Veltri et al, patients who underwent a short

course of intravenous hyperalimentation prior to their treatment regimen demonstrated a transient decrease in the level of serum

immune complexes, as well as an increase in cell-mediated immune (CMI) correlates in vitro.1

Results:

There were no Grade A papers.

In the Non-Surgical/Medical Oncology/ Chemotherapy category, there were one Grade B paper and two Grade C papers (all Positive for PN).

In the Radiation Oncology category, there was one Grade C paper (Positive for PN).

In the Surgical category, there was one Grade C paper (Positive for PN).

Conclusion: Weak.

With the exception of a single Grade B paper in the Non-Surgical/Medical Oncology/ Chemotherapy category (Veltri et al),

the evidence in support of PN for head and neck cancer is quite weak.

TABLE 8: HEAD AND NECK CANCER

CategoryEvidence

supporting PNTotal

PapersPositive

Negative/No Benefit

Overall Weak 11 5 6


Moderate 6 3 3


Surgical Weak 1 1 3

1Veltri RW, Rodman SM, Maxim PE, Baseler MW, Sprinkle PM. Immune complexes, serum proteins, cell-mediated immunity, and immune regulation in patients with squamous cell carcinoma of the head and neck. Cancer. 1986 Jun 15;57(12):2295-308. PubMed PMID: 3084060.


LIVER CANCER

Background/Outcomes: In Figure 9, the Liver Cancer PN-related clinical publications are shown. Two Grade A papers

supported the use of PN in liver cancer patients. Both examined post-operative morbidity and mortality, including hepatic

function, sepsis, ascites, and immune function.1,2

Results:

In the Non-Surgical/Medical Oncology/ Chemotherapy category, the only two papers found were deemed “Not Relevant”.

There were no papers found in the Radiation Oncology category.

In the Surgical category, there were 2 Grade A papers (both Positive), no Grade B papers, and 3 Grade C papers (1 Positive; 2 Negative/No Benefit).

Conclusion: Moderately Strong (Surgical)

Although only 3 out of 5 relevant papers (60%) report positive results for PN, two of these are of Grade A caliber, which was

quite rare for any of the cancer types in this analysis. Thus evidence for the use of PN in liver cancer is moderately strong. (This

applies only to the Surgical category, however.)

TABLE 9: LIVER CANCER

CategoryEvidence supporting

PNTotal

PapersPositive

Negative/No Benefit

OverallModerately Strong

(Surgery only)10 3 7


Weak 2 0 2


Surgical Moderately Strong 8 3 2

1Ziegler TR. Perioperative nutritional support in patients undergoing hepatectomy for hepatocellular carcinoma. JPEN J Parenter Enteral Nutr. 1996 Jan-Feb;20(1):91-2. PubMed PMID: 8788271.2Fan ST, Lo CM, Lai EC, Chu KM, Liu CL, Wong J. Perioperative nutritional support in patients undergoing hepatectomy for hepatocellular carcinoma. N Engl J Med. 1994 Dec 8;331(23):1547-52. PubMed PMID: 7969324.


LUNG CANCER

Background/Outcomes: Figure 10 shows the Lung Cancer PN-related clinical publications by assigned grade. One Grade B

study found that PN conferred an increased tolerance to chemoimmunotherapy, as well as improved immune function, in lung

cancer patients.1 Three other Grade B studies found that PN increased energy balance, immune function, net fat synthesis, and

body-weight gain in lung cancer patients.2,3 However, Russell et al also observed concurrent hypercatabolism and fat

mobilization.2 Yin et al found that PN increased serum tryptophan and melatonin in lung cancer patients.4

Results:

In the Non-Surgical/Medical Oncology/ Chemotherapy category, there were 1 Grade A paper (Negative/No Benefit for PN); 6 Grade B papers (all Positive) and 12 Grade C papers (41% Positive, 58% Negative/No Benefit.)

In the Radiation Oncology category, there were no Grade A papers; no Grade B papers; and 2 Grade C papers (1 Positive; 1 Negative/No Benefit).

In the Surgical category, both papers found were deemed “Not Relevant”.

Conclusion: Moderate (for Non-Surgical/Medical Oncology/Chemotherapy)

Given that all of the Grade B papers (6 in total) were Positive, the evidence for the use of PN in lung cancer is moderately

strong. (This applies only to the Non-Surgical/Medical Oncology/Chemotherapy category, however.)

TABLE 10: LUNG CANCER

CategoryEvidence

supporting PNTotal

PapersPositive

Negative/No Benefit

Overall Moderate 29 12 17


Moderately Strong

24 11 13


Surgical Weak 2 0 2

1Issell BF, Valdivieso M, Zaren HA, Dudrick SJ, Freireich EJ, Copeland EW, Bodey GP. Protection against chemotherapy toxicity by IV hyperalimentation. Cancer Treat Rep. 1978 Aug;62(8):1139-43. PubMed PMID: 99235.

2Russell DM, Shike M, Marliss EB, Detsky AS, Shepherd FA, Feld R, Evans WK, Jeejeebhoy KN. Effects of total parenteral nutrition and chemotherapy on the metabolic derangements in small cell lung cancer. Cancer Res. 1984 Apr;44(4):1706-11. PubMed PMID: 6322985.


3Valdivieso M, Frankmann C, Murphy WK, Benjamin RS, Barkley HT Jr, McMurtrey MJ, Jeffries DG, Welch SR, Bodey GP. Long-term effects of intravenous hyperalimentation administered during intensive chemotherapy for small cell bronchogenic carcinoma. Cancer. 1987 Jan 15;59(2):362-9. PubMed PMID: 3026605.

4Yin S, Hu SL, Shen G, Wang WD, Hu B, Xu WP, Wang H, Zhang Q. [The effect of amino acid nutritional support on serum tryptophan and melatonin in lung cancer patients receiving chemotherapy]. Zhonghua Zhong Liu Za Zhi. 2006 Nov;28(11):840-3. Chinese. PubMed PMID: 17416006.


NON-HODGKIN’S LYMPHOMA

Background/Outcomes: Figure 11 illustrates the overall tally of PN-related publications for Non-Hodgkin’s Lymphoma. All

of the papers categorized in the Non-Surgical/Medical Oncology/Chemotherapy group demonstrated clinically positive outcomes

(weight gain, triglyceride kinetics, nitrogen balance, protein balance, safety). In particular, Barzaghi and colleagues evaluated

management, efficacy, and complications in a case series of 131 consecutive children who received total PN and 207 consecutive

children who did not receive total PN.1 Of the 131 consecutive children, only 1 case was Non-Hodgkin’s lymphoma and results

were reported in aggregate, not individually.1 Overall, the findings were positive with most of the complications being metabolic,

mild in nature, and easily controlled.1 In addition, very few complications associated with PN were reported in Non-Hodgkin’s

Lymphoma patients undergoing radiation therapy.2

Results:

In the Non-Surgical/Medical Oncology/Chemotherapy group, 4 articles (1 B+, 1 B, and 2 B-) were

identified.

In the Radiation group, 2 papers were identified (both B-).

No PN-articles were categorized in the Surgical group.


TABLE 11: NON-HODGKIN’S LYMPHOMA

CategoryEvidence

supporting PNTotal

PapersPositive

Negative/No Benefit

OverallModerately

Strong6 6 0


Moderately Strong

4 4 0

RadiationModerately

Strong2 2 0

Surgical Weak 0 0 0

1Barzaghi A, Rovelli A, Piroddi A, et al. Six years' experience of total parenteral nutrition in children with hematological malignancies at a single center: management, efficacy, and complications. Pediatr Hematol Oncol. Jul-Aug 1996;13(4):349-358.2Kellum JM, Jr., Jaffe BM, Calhoun TR, Ballinger WF, 2nd. Gastric complications after radiotherapy for Hodgkin's disease and other lymphomas. Am J Surg. Sep 1977;134(3):314-317.


ORAL CANCER

Background/Outcomes: In Figure 12, Oral Cancer PN-related clinical publications by assigned grade is shown. Given the

frequency of malnutrition in oral cancer patients, it was surprising that only two studies dealt with PN and oral cancer. A French

study found fewer complications for patients treated with TPN1, while a German study found that PN increased body mass, which

in turn improved survival.2 While both studies obtained a positive outcome for PN, both were small, non-randomized, and of

questionable quality (Grade C).

Results:

There were no Grade A or Grade B papers.

In the Non-Surgical/Medical Oncology/ Chemotherapy category, there was one Grade C paper (outcome Positive).

In the Surgical category, there was one Grade C paper (outcome Positive).

Conclusion: Weak.

The evidence supporting the use of PN in oral cancer is minimal and quite weak.

TABLE 12: ORAL CANCERCategory Evidence

Supporting PNTotal

PapersPositive

Negative/No Benefit

OverallWeak 4 2 2

Non-Surgical/Medical Oncology/ Chemotherapy Weak 1 1 0

RadiationWeak 1 0 1

SurgicalWeak 2 1 1

1Gillette JF, Susini J. [Improvement of the postoperative period in surgery for tumors of the mouth floor by parenteral nutrition]. Ann Otolaryngol Chir Cervicofac. 1982;99(9):435-8. French. PubMed PMID: 6817686.

2Klein C, Howaldt HP, Frenz M, Klein G. [High caloric parenteral nutrition in patients with mouth and oropharyngeal cancers--a clinical study]. Zentralbl Chir. 1994;119(1):28-36. German. PubMed PMID: 8147157.


OVARIAN CANCER

Background/Outcomes: The number of PN-related ovarian cancer publications by assigned grade is shown in Figure 13. In

the Non-Surgical/Medical Oncology/Chemotherapy article, survival rates improved in each of these studies when PN was

administered.1-4 Shang et al. was the only study that was randomized and also included an EN experimental arm.4 In this study, PN

and EN both positively influenced the quality of life and body composition in patients with advanced ovarian cancer.4 In the

Radiation Oncology and Surgical articles PN reduced the number of complications and improved survival rates in ovarian cancer

patients.2,5

Results:

In the Non-Surgical/Medical Oncology/Chemotherapy section, 6 articles (4 rated as B and 2 Not

relevant) were identified.

One article (rated B-) was reported in the Radiation group.

Of the 2 articles identified in the Surgical section, only 1 was relevant and was graded as a B.


TABLE 13: OVARIAN CANCER

CategoryEvidence

supporting PNTotal

PapersPositive

Negative/No Benefit

OverallModerately

Strong9 6 3


Moderately Strong

6 4 2

RadiationModerately

Strong1 1 0

SurgicalModerately

Strong2 1 1

1Abu-Rustum NR, Barakat RR, Venkatraman E, Spriggs D. Chemotherapy and total parenteral nutrition for advanced ovarian cancer with bowel obstruction. Gynecol Oncol. Mar 1997;64(3):493-495.2Brard L, Weitzen S, Strubel-Lagan SL, et al. The effect of total parenteral nutrition on the survival of terminally ill ovarian cancer patients. Gynecol Oncol. Oct 2006;103(1):176-180.3Hoda D, Jatoi A, Burnes J, Loprinzi C, Kelly D. Should patients with advanced, incurable cancers ever be sent home with total parenteral nutrition? A single institution's 20-year experience. Cancer. Feb 15 2005;103(4):863-868.4Shang E, Weiss C, Post S, Kaehler G. The influence of early supplementation of parenteral nutrition on quality of life and body composition in patients with advanced cancer. JPEN J Parenter Enteral Nutr. May-Jun 2006;30(3):222-230. 5Vidal A, de la Cuerda C, Luis Escat J, Breton I, Camblor M, Garcia-Peris P. Chronic radiation enteritis after ovarian cancer: from home parenteral nutrition to oral diet. Clin Nutr. Aug 2006;25(4):701-704.


PANCREATIC CANCER

Background/Outcomes: Figure 14 illustrates the overall tally of PN-related publications for Pancreatic Cancer. A total of 42

PN-related clinical articles were identified in the Pancreatic Cancer section. Clinical evidence was found to be weak in all three

modality areas, except the Non-Surgical/Medical Oncology/Chemotherapy group which was Moderately Strong. Of the total 42

papers, only 2 papers were assigned an A- grade.1,2 Both studies were randomized, controlled trials; however, patients receiving

PN demonstrated negative clinical outcomes (immunometabolic response, complication rate, length of hospital stay, morbidity,

mortality) compared with control counterparts.1,2

Results:

In the Non-Surgical/Medical Oncology/Chemotherapy group, 10 articles (1 B, 5 B-, 1 C) were

identified. Three articles were Not Relevant.

In the Radiation group, 1 paper was identified but it was Not Relevant.

Thirty-one PN-articles were categorized in the Surgical group, with the major ityof them having a

grade of B or higher (9 B-, 6 B, 2 A-). Seven article were Not Relevant.

Conclusions: Moderate

TABLE 14: PANCREATIC CANCER

CategoryEvidence

supporting PNTotal

PapersPositive

Negative/No Benefit

Overall Moderate 42 18 24


Moderately Strong

10 6 4


Surgical Moderate 31 12 19

1Brennan MF, Pisters PW, Posner M, Quesada O, Shike M. A prospective randomized trial of total parenteral nutrition after major pancreatic resection for malignancy. Ann Surg 1994; 220:436-44.2Gianotti L, Braga M, Gentilini O, Balzano G, Zerbi A, Di Carlo V. Artificial nutrition after pancreaticoduodenectomy. Pancreas 2000; 21:344-51. PubMed PMID: 11075988.


STOMACH / GASTRIC CANCER

Background/Outcomes: Figure 15 demonstrates the Stomach/Gastric cancer PN-related clinical publications. Bozzetti et al

(2000) used a stable amino acid isotope to study protein metabolism in three gastric-cancer patients. 1 They found that whole-body

protein synthesis nearly doubled with TPN (P<0.03), and that net protein balance became positive during TPN. In skeletal muscle,

protein synthesis almost quadrupled with TPN (P<0.015). The authors concluded that TPN triggers a positive metabolic response

in cachectic cancer patients. While this was a very small study (Grade B-), it suggests that TPN may confer significant benefit in

gastric cancer.

A study by Müller et al of esophageal and gastric cancer patients found that 9 patients died in the control group vs 2 in the

PN group (p< 0.05); Significant improvement of humoral and cellular immunocompetence and protein status were also found (p <

0,01). Müller et al found reductions in postoperative mortality (19% v 5%) and major morbidity (22% v 11%) associated with

parenteral nutrition.2

Yamada et al found that when gastric-cancer patients were treated with TPN during 5-FU administration, it restored

immunocompetence, increased their tolerance for 5-FU, and produced significant differences in the 3-year survival rates of

patients who underwent gastrectomy (54% for TPN-5-FU vs. 0% for non-TPN-5-FU; P< 0.05).3

Results:

There were no Grade A papers for gastric cancer.

In the Non-Surgical/Medical Oncology/Chemotherapy category, there were 4 Grade B papers (3 were Positive) and 16 Grade C papers (11 Positive; 2 Negative/No Benefit).


In the Surgical category, 11 out of 17 (65%) Grade B papers were Positive. For the Grade C papers, 12 out of 21 (57%) were Positive, while 4 out of 21 (19%) were Negative/No Benefit.

Conclusion: Strong

Because the majority of the Grade B and C papers were positive (75% and 69%, respectively), the evidence for Non-

Surgical/Medical Oncology/Chemotherapy is strong. Likewise, in the Surgical category, the majority of the B and C papers were

positive (22 of 38 total) were Positive. For gastric cancer overall, then, the evidence is strong.

1Bozzetti F, Gavazzi C, Ferrari P, Dworzak F. Effect of total parenteral nutrition on the protein kinetics of patients with cancer cachexia. Tumori. 2000 Sep-

Oct;86(5):408-11. PubMed PMID: 11130571.

2Müller MJ. [Hepatic complications in parenteral nutrition]. Z Gastroenterol. 1996 Jan;34(1):36-40. Review. German. PubMed PMID: 8776174.

3Yamada N, Koyama H, Hioki K, Yamada T, Yamamoto M. Effect of postoperative total parenteral nutrition (TPN) as an adjunct to gastrectomy for

advanced gastric carcinoma. Br J Surg. 1983 May;70(5):267-74. PubMed PMID: 6405838.


TABLE 15: STOMACH/GASTRIC CANCER

CategoryEvidence

supporting PNTotal

PapersPositive

Negative/No Benefit



Strong 24 14 10




“UPPER GI” CANCER (ORAL/ESOPH./GASTRIC NOT SPECIFIED)

Background/Outcomes: Shaw et al found that patients with advanced weight loss prior to treatment exhibited a significant

decrease in whole-body protein catabolism, coupled with increase in whole-body protein synthesis, when they were treated with

TPN (as measured via infusion of 15N- or 14C-urea).1 Figure 16 shows the Upper GI PN-related publications by assigned grade.

Results:

No Grade A papers were found for “upper GI” cancer.

In the Non-Surgical/Medical Oncology/Chemotherapy category, there was a single paper, Grade B- (Positive).


In the Surgical category, there were 5 relevant papers, 3 Grade C (1 Positive, 2 Negative/No Benefit), 1 Grade B positive, and 1 Grade B-.

Conclusion: Weak

A single, non-randomized trial (Grade B) offers “Moderately Strong” evidence in favor of TPN in “Upper GI” cancer, which

may be of some use. Overall, however, there is very little evidence to support TPN in this category.

TABLE 16: “UPPER GI” CANCER

CategoryEvidence

supporting PNTotal

PapersPositive

Negative/No Benefit

Overall Weak 10 3 7


Moderate 1 1 0


Surgical Weak 9 2 7

1Shaw JH, Wolfe RR. Whole-body protein kinetics in patients with early and advanced gastrointestinal cancer: the response to glucose infusion and total parenteral nutrition. Surgery. 1988 Feb;103(2):148-55. PubMed PMID: 3124279.
