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ONC: Chemotherapy (2007)

Citation:
 
Study Design:
Class:
- Click here for explanation of classification scheme.
Quality Rating:
Research Purpose:
To analyze the impact of enteral nutrition vs standard oral diet with regard to nutritional variables, tolerance of chemotherapy and radiation therapy, and final outcome (suitability for surgical resection and survival) in patients with esophageal cancer submitted to combined preoperative chemotherapy and radiation therapy.
Inclusion Criteria:
  • Histologically proven squamous cell cancer of the esophagus with local or locoregional disease
  • Enrolled in a prospective, non-randomized trial of combined chemotherapy and radiation therapy with or without surgery
  • Normal prestudy serum electrolytes, BUN (<50 gm/dL) and serum creatinine (<1.5 mg/dL) or creatinine clearance (<65 mL/min)
  • Initial leukocyte count exceeding 3.5 x 109 cells per liter
  • Initial platelet count exceeding 100 x 109 cells per liter
  • No metastatic disease
Exclusion Criteria:
None described
Description of Study Protocol:

Recruitment   Not described

 

Design

 Nutritional status as well as potential indications for enteral feeding were evaluated in a group of malnourished patients qualifying for a trial of combined chemo- and radiotherapy. All patients received an evaluation by an oncologist, a surgeon and a radiotherapist. Patients were divided into two groups based on severity of dysphagia, and all patients had a NG tube inserted.

  • Enteral nutrition group: severely dysphagic patients able to tolerate a NG tube
    • Provided 1.75% the REE as estimated by the Harris-Benedict equation
    • Full regimen was scheduled to be administered initially within a period of 3 or 4 days and to be continued throughout the two cycles of chemo- and radiotherapy for a total of 32 days.
    • Pump controlled administration during the 12-16 diurnal hours.
    • At discharge from the hospital, patients received enteral nutrition at home via gravity drip.
    • Formula used was Precision N (Novartis Nutrition) which contained 446 kcal/100g product powder having a calorie to nitrogen ratio of 110
  • Standard oral diet:
    • Received a normal hospital diet
    • Quantity based on individual preference
Chemo- and radiotherapy
  • All patients underwent 2 courses of induction chemotherapy with cisplatin and continuous infusion of 5-FU with concurrent external beam radiotherapy (30 Gy). Courses were repeated every 28 days.
  • Potentially resectable patients underwent surgery while non-surgical patients continued chemotherapy for 4-6 courses and a split course of radiotherapy (30 Gy + 20 Gy).
  • Dose reductions were described for side effects related to cisplatin and 5-FU

 

Blinding used (if applicable)  Not described

 

Intervention (if applicable)

 

Statistical Analysis

Statistical analysis was performed using either Student's t test or Fischer's exact test.

 

Data Collection Summary:

Timing of Measurements

 

Dependent Variables

  • Nutritional effects of enteral nutrition
  • Tolerance chemo- and radiotherapy
    • Assessed by analyzing the overall dose of drugs and Grays delivered, measuring the time required for completing therapy, assessing the bone marrow depression and mortality rate
  • Response to chemo- and radiotherapy
    • Tumor size: determined by its length at endoscopy or barium x-ray
    • Tumor location: measured from the upper front teeth
    • Tumor spread: physical exam, CT scan and/or MRI of the thorax, upper endoscopy with biopsy, double contrast barium x-ray, chest x-ray, ultrasonography and/or CT scan of the upper abdomen; bronchoscopy was performed only in patients with tumors located at or above the level of the carina; bone scan was done only in specific clinical situations
    • WHO criteria
  • Surgical mortality
  • Final survival

Independent Variables

Enteral nutrition

 

Control Variables

 

Description of Actual Data Sample:

 

Initial N:  50 men and women (43 men, 7 women)

Enteral Nutrition Group: N=29 (27 men, 2 women)

Standard Oral Diet: N=29 (16 men, 5 women)

  • 3 patients refused to use the nasogastric tube despite the onset of dysphagia of variable severity

Attrition (final N): 49 (1 death in the standard oral diet group)

Age: median (range)

  • Enteral nutrition group: 61 yr (43-77 yr)
  • Standard oral diet: 56 yr (44-70 yr)

Ethnicity:  not described

Other relevant demographics:

Karnofsky PS: median (range)

  • Enteral nutrition group: 80 (55-95)
  • Standard oral diet: 80 (65-90)
Oncologic:
  • Site:
    • cervical
      • enteral nutrition group: 3
      • standard oral diet: 3
    • thoracic
      • enteral nutrition: 23
      • standard oral diet: 15
    • multicentric
      • enteral nutrition: 3
      • standard oral diet: 3
  • Stage (UICC):
    • IIA
      • enteral nutrition: 12
      • standard oral diet: 8
    • IIB
      • enteral nutrition: 0
      • standard oral diet: 1
    • III
      • enteral nutrition: 17
      • standard oral diet: 12
Potential for resection
  • Enteral nutrition: 12
  • Standard oral diet: 9
  • 29 considered unresectable because of extensive extraesophageal involvement, regional lymph node spread or site of disease (cervical esophagus where resection would require a laryngectomy)
Nutritional/laboratory exams: median (range)
  • Total Protein (g/dL)
    • enteral nutrition: 7.2 (5.3-9.1)
    • standard oral diet: 6.9 (6.1-8.0)
  • Serum albumin (g/dL)
    • enteral nutrition: 3.9 (3.2-4.1)
    • standard oral diet: 4.0 (3.4-5.0)
  • Cholinesterase (mU/mL)
    • enteral nutrition: 1786 (1186-3605)
    • standard oral diet: 1920 (895-2726)
  • WBC (n/mm3)
    • enteral nutrition: 8510 (4350-13790)
    • standard oral diet: 8275 (4080-12400)
  • Platelets (n/mm3)
    • enteral nutrition: 274 (181-430)
    • standard oral diet: 248 (136-455)
  • Lymphocytes (n/mm3)
    • enteral nutrition: 1850 (450-3060)
    • standard oral diet: 1865 (390-3120)

Anthropometrics 

BMI

  • enteral nutrition: 19.5
  • standard oral diet: 20.7
% wt loss of usual body wt: median (range). Two groups were statistically different on this parameter.
  • enteral nutrition: 15.5 (7.3-30)
  • standard oral diet: 12.3 (5-28)
  • mean wt loss of the enteral nutrition group was 16.8% vs 12.8% in the standard oral diet group - statistically significant (P <0.02)

Location:

 Instituto Nazionale Tumori, Milan, Italy

Summary of Results:

 Nutitional Effects of Enteral Nutrition versus Standard Oral Diet Before and After Chemo- and Radiotherapy

Variable

 Enteral Nutrition

N=29

 

Standard Diet

N=21

  


Before

Mean±SD

 After

   Mean±SD

Before

Mean±SD

 After
Mean±SD

Body wt (kg)     

 55.0±8.9

 54.5±8.5

 56.2±7.3 

 54.4*±8.2

Total Proteins (g/dL)

 7.0±0.8

 6.8±0.6

 7.1±0.6

  6.6*±0.6
Serum albumin (g/dL)  3.9±0.4  3.8±0.4  4.0±0.4  3.5*±0.5
Serum cholinesterase (mU/mL)  1866±528  1955±756  1940±495  1869±584

 *Significantly different from before (P=0.01)

1. Enteral nutrition patients maintained stable body wt and unchanged levels of visceral proteins, while patients in the standard diet group had a significant decline in body wt, total proteins and serum albumin.


Nutritional Effects of Continuous Enteral Nutrition (EN) vs Discontinuous Enteral Nutrition Before and After Chemo- and Radiotherapy (means±SD)

Variable Continuous EN (n=22)   Discontinuous EN (n=7)  
  Before After Before After
Body wt (kg)  55±8 54±10
53.5±11
54.7±11
Total Proteins (g/dL) 6.9±0.7
6.9±0.5
6.8±1.2
6.2±0.5
Serum albumin (g/dL) 3.9±0.3
3.8±0.4
3.9±0.8
3.6±0.3
Serum cholinesterase (mU/mL) 1935±560
2052±821
1601±241
1742±230
Continuous EN: patients received EN for entire period
Discontinuous EN: patients who discontinued EN prior to the end of chemo- and radiotherapy due to remission of dysphagia (n=6) or tube intolerance (n=1).

1. Continuous enteral nutrition group received enteral feedings for a mean of 38 days while the discontinuous enteral nutrition group received feedings for a mean of 21 days.

2. The nutritional status of the 7 patients who discontinued enteral feeding was similar to that of patients receiving it for the entire period.


Tolerance to chemo- and radiotherapy

  Enteral Nutrition (n=29)     Standard Oral Diet
(n=21)		    
Total therapeutic dosage            
5-fluorouracil (g/m2)   7.35     7.4  
Cisplatin (mg/m2)   183     190  
Radiation (Gy)   31     31  
Duration of therapy (days)   38     39  
Blood cell count Before   After Before   After
White blood cells (n/mm3)  8790  
 5624
8236
  5337
Lymphocytes (n/mm3) 1841
  726
1960
  851
Platelets (n/mm3) 286
  249
260
 
  229
No. of deaths*    —      1  
*Mortality due to sepsis following severe bone marrow depression (grade 4 according to WHO grading of toxicity) and sepsis.


Surgery following chemo- and radiotherapy (Percentages in parentheses)

  Enteral Nutrition
(n=29)		 Standard Oral Diet
(n=20)*
Thoracotomy 11 (38) 14 (70)
radical resection 10 (34) 8 (40)
non-radical resection 0 3 (15)
explorative thoracotomy 1 (4) 3 (15)
Mortality 4/11 (36) 4/14 (28)
*1 patient was not considered because he died prematurely , prior to restaging due to iatrogenic toxicity

1. 25 of the original 50 patients underwent thoracotomy with an overall mortality of 36% and 28% in the enteral nutrition and standard diet groups, respectively.

2. For patients undergoing radical resection, mortality was 40% and 37% in the enteral nutrition and standard diet groups, respectively.

3. Three surgically eligible patients (one in enteral nutrition, 2 in standard diet) did not undergo thoracotomy because they had complete remission of the disease.


Response and Survival

1. Complete tumor regression was similar in the two groups

  • Enteral nutrition group: 10.3%
  • Standard diet group: 14.2%
2. Complete + partial regression was similar in the two groups with preoperative combined chemo- and radiotherapy.
  • Enteral nutrition group: 62%
  • Standard diet group: 66.6%
3. Discontinuance of enteral nutrition due to reduction of dysphagia was related to a favorable response to chemo- and radiotherapy. Five of the 7 patients had complete + partial regression of the disease while the remaining 2 had stable disease.

4. The median overall survival for both groups was 9.5 months.


Other Findings

1. Majority of patients reached the full enteral nutrition regimen within a period of 3-4 days. The regimen included 37 nonprotein kcal/kg/day and 2.0 gm/protein/kg/day, representing 86% of the total planned support.

2. Enteral nutrition was delivered relatively easily in patients receiving strong antiemetic treatment, and about 70% of the nutritional support was administered in the home setting.

Author Conclusion:
Enteral nutrition in patients with cancer of the esophagus undergoing chemotherapy and radiotherapy is well tolerated, feasible even in the home setting, prevents further nutritional deterioration and achieves the same oncological results in dysphagic patients as those achieved in non-dysphagic patients.
Funding Source:
Reviewer Comments:
Did not define severe dysphagia.
Quality Criteria Checklist: Primary Research
Relevance Questions
  1. Would implementing the studied intervention or procedure (if found successful) result in improved outcomes for the patients/clients/population group? (Not Applicable for some epidemiological studies) Yes
  2. Did the authors study an outcome (dependent variable) or topic that the patients/clients/population group would care about? Yes
  3. Is the focus of the intervention or procedure (independent variable) or topic of study a common issue of concern to dieteticspractice? Yes
  4. Is the intervention or procedure feasible? (NA for some epidemiological studies) Yes
 
Validity Questions
1. Was the research question clearly stated? Yes
  1.1. Was (were) the specific intervention(s) or procedure(s) [independent variable(s)] identified? Yes
  1.2. Was (were) the outcome(s) [dependent variable(s)] clearly indicated? Yes
  1.3. Were the target population and setting specified? Yes
2. Was the selection of study subjects/patients free from bias? N/A
  2.1. Were inclusion/exclusion criteria specified (e.g., risk, point in disease progression, diagnostic or prognosis criteria), and with sufficient detail and without omitting criteria critical to the study? Yes
  2.2. Were criteria applied equally to all study groups? Yes
  2.3. Were health, demographics, and other characteristics of subjects described? Yes
  2.4. Were the subjects/patients a representative sample of the relevant population? Yes
3. Were study groups comparable? Yes
  3.1. Was the method of assigning subjects/patients to groups described and unbiased? (Method of randomization identified if RCT) Yes
  3.2. Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline? No
  3.3. Were concurrent controls or comparisons used? (Concurrent preferred over historical control or comparison groups.) Yes
  3.4. If cohort study or cross-sectional study, were groups comparable on important confounding factors and/or were preexisting differences accounted for by using appropriate adjustments in statistical analysis? N/A
  3.5. If case control study, were potential confounding factors comparable for cases and controls? (If case series or trial with subjects serving as own control, this criterion is not applicable.) N/A
  3.6. If diagnostic test, was there an independent blind comparison with an appropriate reference standard (e.g., "gold standard")? N/A
4. Was method of handling withdrawals described? Yes
  4.1. Were follow-up methods described and the same for all groups? Yes
  4.2. Was the number, characteristics of withdrawals (i.e., dropouts, lost to follow up, attrition rate) and/or response rate (cross-sectional studies) described for each group? (Follow up goal for a strong study is 80%.) Yes
  4.3. Were all enrolled subjects/patients (in the original sample) accounted for? Yes
  4.4. Were reasons for withdrawals similar across groups? Yes
  4.5. If diagnostic test, was decision to perform reference test not dependent on results of test under study? N/A
5. Was blinding used to prevent introduction of bias? Yes
  5.1. In intervention study, were subjects, clinicians/practitioners, and investigators blinded to treatment group, as appropriate? No
  5.2. Were data collectors blinded for outcomes assessment? (If outcome is measured using an objective test, such as a lab value, this criterion is assumed to be met.) ???
  5.3. In cohort study or cross-sectional study, were measurements of outcomes and risk factors blinded? N/A
  5.4. In case control study, was case definition explicit and case ascertainment not influenced by exposure status? N/A
  5.5. In diagnostic study, were test results blinded to patient history and other test results? N/A
6. Were intervention/therapeutic regimens/exposure factor or procedure and any comparison(s) described in detail? Were interveningfactors described? Yes
  6.1. In RCT or other intervention trial, were protocols described for all regimens studied? Yes
  6.2. In observational study, were interventions, study settings, and clinicians/provider described? N/A
  6.3. Was the intensity and duration of the intervention or exposure factor sufficient to produce a meaningful effect? Yes
  6.4. Was the amount of exposure and, if relevant, subject/patient compliance measured? Yes
  6.5. Were co-interventions (e.g., ancillary treatments, other therapies) described? Yes
  6.6. Were extra or unplanned treatments described? Yes
  6.7. Was the information for 6.4, 6.5, and 6.6 assessed the same way for all groups? Yes
  6.8. In diagnostic study, were details of test administration and replication sufficient? N/A
7. Were outcomes clearly defined and the measurements valid and reliable? Yes
  7.1. Were primary and secondary endpoints described and relevant to the question? Yes
  7.2. Were nutrition measures appropriate to question and outcomes of concern? Yes
  7.3. Was the period of follow-up long enough for important outcome(s) to occur? Yes
  7.4. Were the observations and measurements based on standard, valid, and reliable data collection instruments/tests/procedures? Yes
  7.5. Was the measurement of effect at an appropriate level of precision? ???
  7.6. Were other factors accounted for (measured) that could affect outcomes? Yes
  7.7. Were the measurements conducted consistently across groups? Yes
8. Was the statistical analysis appropriate for the study design and type of outcome indicators? Yes
  8.1. Were statistical analyses adequately described and the results reported appropriately? Yes
  8.2. Were correct statistical tests used and assumptions of test not violated? Yes
  8.3. Were statistics reported with levels of significance and/or confidence intervals? Yes
  8.4. Was "intent to treat" analysis of outcomes done (and as appropriate, was there an analysis of outcomes for those maximally exposed or a dose-response analysis)? Yes
  8.5. Were adequate adjustments made for effects of confounding factors that might have affected the outcomes (e.g., multivariate analyses)? No
  8.6. Was clinical significance as well as statistical significance reported? Yes
  8.7. If negative findings, was a power calculation reported to address type 2 error? No
9. Are conclusions supported by results with biases and limitations taken into consideration? Yes
  9.1. Is there a discussion of findings? Yes
  9.2. Are biases and study limitations identified and discussed? Yes
10. Is bias due to study's funding or sponsorship unlikely? Yes
  10.1. Were sources of funding and investigators' affiliations described? No
  10.2. Was the study free from apparent conflict of interest? Yes