Oncology

RTC (Randomized, double blind, placebo controlled trial)international, single center, with 96 initial breast cancer patients diagnosed with large or locally advanced breast cancer. Randomized to 1 of 2 groups. Experimental group (n=48) to receive L-arginine (30 g/day orally x 3 days) or control group (n=48) to receive placebo x 3 days before administration of chemotherapy (doxyrubicin, cyclophosphamide, vincristine, prednisolone), 6 pulses at 21 day intervals. Clinical and pathological responses were assessed in both groups after completion of chemotherapy as well as clinical and pathological response rates according to initial tumor size.

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POSITIVE: See Quality Criteria Checklist below.

Urgent need to greatly improve the response to chemotherapy without enhancing treatment morbidity. Purpose: determine if L-arginine supplementation is beneficial in patients with breast cancer undergoing neo-adjuvant therapy.

• 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. 

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)

This was a well-designed study.  However, the lack of critical data tables for raw data made it difficult to evaluate this article fully.