ONC: Arginine (2006)

- Treated in Departments of Surgery and Medical Oncology, Aberdeen Royal infirmary
- T2>cm,T3,T4 or N2 node status associated with a primary tumor of any size (UICC criteria)
- pre and post menopausal women
- Dx confirmed by mammography, breast ultrasonography, fine needle aspiration cytology and/or core biopsy
- Staged with serum biochemistry (urea, electrolytes, liver function tests),full blood counts and differentials and imaging modalities,
- All had echocardiography prior to study entry, were ambulatory, Estern Co-operative Oncology Group 0-1 and Karnofsky>80%.
- All received cyclophosphamide, 1g/m2 (maximum dose per cycle: 1.8 g); vincristine 1.5 mg/m2 (maximum dose per cycle: 2 mg); doxorubicin 50 mg/m2 (maximum dose per cycle; 90 mg), all given as i.v. bolus injections, followed by prednisolone 40mg orally for 5 days.
- Surgery performed 3 weeks after completion of chemotherapy; type determined by protocol. Received tamoxifen, 20mg/day,following surgery
- After surgery, radiotherapy given as 20 daily fractions (4500 cGy to breast and 4500 cGy to lymph draining areas).
- If patient had distant metastases
Recruitment Method not noted although all patients were treated in Departments of Surgery and Medical Oncology, Aberdeen Royal Infirmary.
Design 96 female patients (30-73 years of age, median age 50) with large or locally advanced breast cancer were randomized to 1 of 2 groups before being treated with chemotherapy (doxorubicin, cyclophosphamide, vincristine, prednisolone).
- Group 1(n=48) received 30g L-arginine per day for 3 days immediately prior to each round of chemotherapy, 6 pulses at 21-day intervals.
- Group 2 (n=48) received placebo per day for 3 days immediately prior to each round of chemotherapy, 6 pulses at 21 day intervals
- Protocol used to adjust or delay chemotherapy per blood white cell count (WCC) and platelet count(Plts)
Blinding used (if applicable)yes according to a stratified ( for menopausal status), permuted blocks design
Intervention (if applicable) L-arginine orally in dose of 30 g/day x 3 days immediately prior to each cycle of chemotherapy, 6 pulses.
Statistical Analysis
- Power calculations: 80% power of detecting 20% difference in clinical respone rates at .05 level of significance
- Analyses carried out on an intention to treat basis
- Tumor response rates between L-arginine and placebo group compared using Chi-square test, with p<0.05 accepted as statistically significant. All tests were two-tailed and data were analyzed using SPSS MS for Windows.
Timing of Measurements
- clinically measured tumor size prior to each cycle of chemotherapy (6 pulses)
- performed mammography and breast ultrasound at baseline and after 4th and 6th course of chemotheropy
- measured histological responses of excised breast tissue for tumor stage and clinical nodes after surgery (3 weeks after completion of chemotherapy cycles)
- Dependent Variables
- Variable 1: overall clinical response after 6 cycles of chemotherapy using standard UICC criteria (combined complete response and partial response together) using following measures to assess response:
- product of two maximal perpendicular diameters of tumor evaluated with calibrated skin callipers (four diameters, at 45 degree intervals)
- Product of two maximal perpendicular diameters of mammography
- reductions in tumor volume on ultrasound
- Variable 2: overall clinical response according to initial tumor size(<6 cm, 6-7 cm, > 7 cm) useing same measures as Variable 1 above.
- Variable 3: overall pathological response after 6 cycles of chemotherapy histologically examining excised tumors using previously described protocol (J. Brittenden et al. Br J Surg 69:918-921,1994),
- Type I: changes in tumor cells but tumor nests not destroyed; type II: tumor structure destroyed to minor degree; type III: tumor structure destroyed to moderate degree; type IV: tumor structure destroyed to severe degree; type V: no tumor cells in any specimens
- Variable 4: overall pathological response after 6 cycles of chemotherapy according to initial tumor size(<6 cm, 6-7 cm, > 7 cm)
- median split performed with
- a) type I and type II (minimal or minor degree of tumor cell destruction) grouped together
- b) types II, IV and V (moderate to complete destruction of tumor cells) grouped together.
- median split performed with
Independent Variables dietary supplementation with L-arginine
Control Variables randomized into 2 groups, blinded ( although protocol not described), same protocol for all with exception of L-arginine
Initial N: 96 women split into 2 randomized groups: L-arginine =48 and placebo group=48
Attrition (final N): 93 ( 3 patients died of MI's so were not included in pathological responses after surgery) 3% mortality.
Age: Mean of L-arginine group 49 (31-71) and Mean of Placebo group 50(30-72)
Ethnicity: unknown although treated in Scotland
Other relevant demographics: 93 participants assessed for pathology: tumor types: 74 invasive ductal carcinomas, 7 lobular and 2 tubular carcinomas, 10 not able to be assessed because of complete pathological response, 51 participants were node negative and 42 had positive nodes.
Anthropometrics No significant differences noted. See p 223, Table I in article for details on tumor stage, clinical nodal status, menopausal status, body weight, and body mass index if needed.
Location: Aberdeen Royal Infirmary in Scotland
Variables |
Treatment Group Measures and confidence intervals CI=p<0.05 |
Control group Measures and confidence intervals CI=p<0.05 |
Statistical Significance of Group Difference |
Dep var 1:overall clinical reponse( total tumor size reduction) (Mammography response ) (ultrasound response ) |
77% (23% CR and 54% PR)
56% (10& CR and 46%PR) 65% (13% CR and 52% PR)PR) |
71% (15% CR, 56% PR)
48% (8 % CR and 40% PR) 65% (17% CR and 48% PR |
p=ns
p=ns
p=>0.05 |
Dep var 2:clinical response by initial tumor size (<6 cm, 6-7 cm, or > 7 cm) |
89% ( no data provided for CR vs PR) for <6 cm no data provided on 6-7cm or > 7 cm |
80% ( no data provided for CR vs PR ) for <6 cm no data on provided on 6-7 cm or > 7 cm |
"trend toward better response in L-arginine group for <6 cm but p=ns stated p=ns |
Dep var 3:overall pathological response (all tumors classified by response Type I-V)
Dep Var 4: path response by <6 cm, 6-7 cm, > 7 cm |
Type I 12 Type II 8 Type III 14 Type IV 5 Type V 7 88% (Type III,IV and V) for < 6 cm no data provided on 6-7cm or > 7 cm |
Type I 8 Type II 17 Type III 11 Type IV 8 Type V 3 52% (Type III,IV and V) for < 6 cm no data provided on 6-7cm or > 7 cm
|
p=ns
p=0.04 p=ns |
Other Findings: Pathological responses by type for all tumors ( sum of both E and C groups):
Type I n=20, typeII n=25, type III n=25, type IV n =13, and type V n=10
- Well-designed and carefully implemented study
- Study was able to address the hypothesis; however no significant effect ws seen on clinical response or on pathological response in tumors of 6 or >cm.
- However, L-arginine supplementation significantly impacted pathological response in tumors < 6 cm (p=0.04) with better histopathological responses versus placebo group (88% vs 52%). This may have important implications for clinical practice since pathological response to treatment are best predictors of likelihood of overall survival.
- Better pathological response in tumors < 6 cm may have resulted, in part, because of an increased drug delivery as a result of a nitric oxide-induced increase in tumor blood flow. L-arginine is the precursor for nitric oxide synthesis. Changes may be dependent on tumor volume and explain lack of overt benefit in larger breast cancers.
-
Due to short length of follow-up, can't determine if L-arginine supplementation will result in increased survival but it is first human RCT study to show that administration of selected nutrients can modulate the response to chemotherapy.
- L-arginine is readily available, cheap and well tolerated when ingested in large doses by patients. ( diarrhea is only side effect directly attributed to it versus toxicities of other protocols).
University/Hospital: | Unversity of Aberdeen (UK) |
Quality Criteria Checklist: Primary Research
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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? | ??? | |
2.4. | Were the subjects/patients a representative sample of the relevant population? | ??? | |
3. | Were study groups comparable? | N/A | |
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? | Yes | |
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? | N/A | |
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%.) | ??? | |
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? | ??? | |
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? | ??? | |
6.5. | Were co-interventions (e.g., ancillary treatments, other therapies) described? | Yes | |
6.6. | Were extra or unplanned treatments described? | N/A | |
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? | N/A | |
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? | Yes | |
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? | ??? | |
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)? | N/A | |
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? | N/A | |
9. | Are conclusions supported by results with biases and limitations taken into consideration? | N/A | |
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 | |