EAL

ONC: Radiation Therapy (2006)

Citation:

Study Design:

Class:

- Click here for explanation of classification scheme.

Quality Rating:

Research Purpose:

To assess if treatment combining pentoxifylline and vitamin E boosted by clodronate is effective in reversion osteoradionecrosis

Inclusion Criteria:

Patients who met clinical and radiographic criteria for head and neck cancer
Externiorized mandible ORN which failed to improve after at least 2 months of conventional conservative treatment
Patients treated with combination pentoxifylline and a-tocopherol between June 1995 and Jan 2000

Exclusion Criteria:

Evidence of recurrent or metastatic disease on entering the trial

Description of Study Protocol:

Recruitment

18 consecutive patients previously irradiated for head and neck cancer with exteriorized mandible osteoradionecrosis

Design

Recruitment
Patients treated with daily combination of pentoxifylline and vitamin E and clodronate
Clinical investigators assessed participants before, during and after treatment including
Length of superficial soft tissue necrosis describing the exposed bone
Completion of Subjective Objective Medical Management and Analytic Evaluation of Injury (SOMA) score
Patients were used as their own controls (paired data)

Blinding used (if applicable)

Not applicable

Intervention (if applicable)

Group I: Combination of pentoxifylline (800 mg/day) and vitamin E (1,000 IU/day) for 6 to 24 months.
Group 2: The above plus 1600 mg/day clodronate 5 days/week and 1 g/d ciprofloxacin and 16 mg/d methylprednisolone 2 d/week for at least 6 months until complete mucosal coverage was obtained

Statistical Analysis

A P<0.05 was considered significant
Comparisons were made using Student’s t-test for paired values or the chi-square test for hypothetical correlations
Data for length and SOMA score regression at 6 months were processed by single sample tests and bivariate plots
Median time to recovery was calculated by the Kaplan-Meier method

Data Collection Summary:

Timing of Measurements

Results of treatment were evaluated at baseline, 2, 4, 6, 9 and 12 months

Dependent Variables

Variable 1: Relative length (L) regression (measurement at x months - measurement at inclusion)/measurement at inclusion) correlated to the extent of recovery
Variable 2: Relative regression, expressed in Epstein stages and Subjective Objective Medical Management and Analytic Evaluation of Injury (SOMA) scores, according to the SOMA system devised in 1995 and modified recently, Cancer Terminology Criteria for Adverse Events, http://ctep.cancer.gov/reporting/ctc.html)

Independent Variables

Group I: Combination of twice-daily pentoxifylline 800 mg/day and vitamin E 500 1,000 IU/day
Group 2: Combination of twice-daily pentoxifylline 800 mg/day and vitamin E 500 1,000 IU/day week and 1 g/d ciprofloxacin and 16 mg/d methylprednisolone 2 d/week for at least 6 months until complete mucosal coverage was obtained

Control Variables

Just before inclusion in the study, all patients were given and oral antibiotic-corticoid treatment for 2 to 4 weeks, according to clinical signs of infection, consisting of 2 g/d amozicillin-clavulanate, 50 mg/d fluconazole, and 16 mg/d methylprednisolone

Description of Actual Data Sample:

Initial N:

18 (16 men, 2 women)

Characteristics:

Men had poor oral hygiene and excessive alcohol and tobacco consumption
Women with oral leukoplakia
Age range 35 – 70 years (mean ± standard deviation, 55 ± 9 years)
Mean latency period between the end of radiation and the incidence of ORN was 4.1 ± 4.3 years (range, 0.15 – 14 years)
ORN had been exteriorized without healing for 6.2 ± 5.7 months (range, 2 – 18 months)
7 patients had stage II ORN (chronic persistent); 11 patients had stage II ORN (active progressive)

Attrition (final N): 16

Location: Paris, France

Summary of Results:

Kinetics of the osteoradionecrosis response to treatment in 16 patients who recovered after combined pentoxifylline-vitamin E alone (group 1) or combined pentoxifylline-vitamin E and clodronate (group II)

	Baseline	2 mo	4 mo	6mo
Mean superficial necrosis L, mm	13.4 ± 8.0	8.8 ± 7.5	5.3 ± 6.7	2.1 ± 3.5
Mean % regression, total (group I/group II)		34 (50/21)	60 (75/57)	84 (86/79)
SOMA, mean % regression	12.4 ± 5.2	8.6 ± 5.8 31	5.3 ± 5.1 57	3.4 ± 4.7 73

All patients improved at 6 months and had a 67% mean SOMA score reduction
Sixteen of 18 patients achieved complete recovery, 14 in 5 ± 2.6 months
Remaining 2 patients exhibited 75% response in 6 months
Those patients who completely recovered had a mean % regression of 84% and SOMA mean % regression of 73%

Author Conclusion:

Combined pentoxifylline –vitamin E treatment boosted by clodronate is an effective treatment of mandible osteoradionecrosis, that induces mucosal and bone healing in a median period of 6 months.

Funding Source:

University/Hospital:

University of Nottingham, Southern Derbyshire Acute Hospitals, NHS Trust (UK)

Reviewer Comments:

Ethnicity of subjects not reported

Small sample size

Convenient sample of patients selected

No blinding of investigators

No placebo group

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?		No
	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?	No
	2.3.	Were health, demographics, and other characteristics of subjects described?	No
	2.4.	Were the subjects/patients a representative sample of the relevant population?	No
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)	N/A
	3.2.	Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline?	N/A
	3.3.	Were concurrent controls or comparisons used? (Concurrent preferred over historical control or comparison groups.)	N/A
	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?	N/A
	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?		No
	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.)	No
	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?	N/A
	6.2.	In observational study, were interventions, study settings, and clinicians/provider described?	Yes
	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?	N/A
	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?	N/A
	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?	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?	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)?	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?		Yes
	9.1.	Is there a discussion of findings?	Yes
	9.2.	Are biases and study limitations identified and discussed?	N/A
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