Non-randomised phase II trial of hyperbaric oxygen therapy in patients with chronic arm lymphoedema and tissue fibrosis after radiotherapy for early breast cancer.
ABSTRACT Radiation-induced arm lymphoedema is a common and distressing complication of curative treatment for early breast cancer. Hyperbaric oxygen (HBO(2)) therapy promotes healing in bone rendered ischaemic by radiotherapy, and may help some soft-tissue injuries too, but is untested in arm lymphoedema.
Twenty-one eligible research volunteers with a minimum 30% increase in arm volume in the years after axillary/supraclavicular radiotherapy (axillary surgery in 18/21 cases) were treated with HBO(2). The volunteers breathed 100% oxygen at 2.4 ATA for 100 min in a multiplace hyperbaric chamber on 30 occasions over a period of 6 weeks. The volume of the ipsilateral limb, measured opto-electronically by a perometer and expressed as a percentage of contralateral limb volume, was selected as the primary endpoint. A secondary endpoint was local lymph drainage expressed as fractional removal rate of radioisotopic tracer, measured using lymphoscintigraphy.
Three out of 19 evaluable patients experienced >20% reduction in arm volume at 12 months. Six out of 13 evaluable patients experienced a >25% improvement in (99)Tc-nanocolloid clearance rate from the ipsilateral forearm measured by quantitative lymphoscintigraphy at 12 months. Overall, there was a statistically significant, but clinically modest, reduction in ipsilateral arm volume at 12 months follow-up compared with baseline (P = 0.005). The mean percentage reduction in arm volume from baseline at 12 months was 7.51. Moderate or marked lessening of induration in the irradiated breast, pectoral fold and/or supraclavicular fossa was recorded clinically in 8/15 evaluable patients. Twelve out of 19 evaluable patients volunteered that their arms felt softer, and six reported improvements in shoulder mobility at 12 months. No significant improvements were noted in patient self-assessments of quality of life.
Interpretation is limited by the absence of a control group. However, measurement of limb volume by perometry is reportedly reliable, and lymphoscintigraphy is assumed to be operator-independent. Taking all data into account, there is sufficient evidence to justify a double-blind randomised controlled trial of hyperbaric oxygen in this group of patients.
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ABSTRACT: This article outlines the therapeutic mechanisms of hyperbaric oxygenation in acute stroke, based on information obtained from peer-reviewed medical literature. Hyperbaric oxygen is an approved treatment modality for ischemia-reperfusion injury in several conditions. It maintains the viability of the marginal tissue, reduces the mitochondrial dysfunction, metabolic penumbra, and blocks inflammatory cascades observed in acute stroke. Basic and clinical data suggest that hyperbaric oxygen could be a safe and effective treatment option in the management of acute stroke. Further work is needed to clarify its clinical utility when applied within the treatment window of "gold standard" treatments (<3-5 hours).Critical care nursing quarterly 36(3):290-8.
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ABSTRACT: The hypothesis being tested in this project is that a greater proportion of patients who develop radiation-induced subcutaneous late tissue morbidity possess a variant allele in the ATM gene compared with patients who do not suffer these complications. An additional objective is to determine the functional impact upon the protein encoded by the ATM gene for each genetic alteration identified and subsequent cellular radiosensitivity. The specific aims of this project are to (1) screen 50 breast cancer patients for ATM genetic alterations who developed radiation induced late subcutaneous tissue morbidity (2) establish a control group and screen 100 patients without evidence of this late radiation reaction and (3) perform functional studies using cells from patients identified as ATM carriers to determine to what extent each ATM variant identified affects radiosensitivity and normal activity of the protein produced by the ATM gene.06/2006;
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ABSTRACT: 1) Provide a critical analysis of the contemporary published research pertaining to complementary, alternative, and other non-Complete Decongestive Therapies (CDT) for treatment of lymphedema (LE); and 2) Provide practical applications of that evidence to improve care of patients with or at risk for LE. TYPE: This study meets the defining criteria as a systematic search and review since it includes varied study types. All studies that met the inclusion criteria were evaluated for weight of evidence and value. The systematic search and review includes manuscripts published in the contemporary literature (2004-2012). Publications published from 2004-2011 were retrieved from 11 major medical indices using search terms for LE and management approaches. Literature archives were examined through 2012. Data extraction included study design, objectives pertaining to LE, number and characteristics of participants, interventions, and outcomes. Study strengths and weaknesses were summarized. Study evidence was categorized according to the Oncology Nursing Society Putting Evidence into Practice (PEP) level-of-evidence guidelines after achieving consensus among the authors. No authors participated in development of nor benefitted from the review of these modality methods or devices. ology: Data extraction from 85 studies was reviewed in four sub-categories: Botanical, Pharmaceutical, Physical Agent Modality (PAM), and Modalities of Contemporary Value (MCV). After review, 47 articles were excluded, leaving 16 articles on botanicals and pharmaceuticals and 22 articles for PAM/MCV. Pharmaceuticals were later excluded. The authors concluded Botanicals had generated sufficient studies to support a second, more specific systematic review; thus, Botanicals are reported elsewhere. It was found that limited high-level evidence was available for all categories. Well-constructed randomized control trials (RCT) related specifically to LE were limited. Objective outcome measures over time were absent from several studies. Rationale for the use and benefits of the specific modality, as related to LE, was often anecdotal. Subject sizes were less than 50 for most studies. No interventions were ranked as "recommended for practice" based on the PEP guidelines. Two treatment modalities in three studies were ranked as "likely to be effective" in reducing LE, or in managing secondary LE complications. Consideration should be given that many of the PAM demonstrate long-standing support within the literature with broad parameters for therapeutic application and benefit for secondary conditions associated with LE. However, further investigation as to their individual, contributory value and the factors that contribute to their efficacy, specific to LE, have not been determined. It is also significant to mention that the majority of these studies focused on breast cancer-related lymphedema. Studies exploring treatment interventions for lymphedema-related vascular disorders (e.g., chronic venous insufficiency, congenital dysphasia, trauma) were sparse. Limitations of the literature support the recommendations for future research to further examine the level of evidence in these modalities for LE management.PM&R 09/2013; · 1.37 Impact Factor
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RADIOTHERAPY AND ONCOLOGY
L Gothard, A Stanton, J MacLaren, D Lawrence, E Hall, P
Mortimer, E Parkin, J Pritchard, J Risdall, R Sawyer, M
Woods, J Yarnold (2004) Non-randomised phase II trial of
hyperbaric oxygen therapy in patients with chronic arm
lymphoedema and tissue fibrosis after radiotherapy for early
breast cancer, Radiotherapy and Oncology, Vol. 70(3), 217-
Non-randomised Phase II Trial of Hyperbaric Oxygen Therapy in Patients
with Chronic Arm Lymphoedema and Tissue Fibrosis
after Radiotherapy for Early Breast Cancer
Lone Gothard , Anthony Stantonbc
, Julie MacLaren , David Lawrenced,
Emma Hall , Peter Mortimerc, Eileen Parkinee
, Joyce Pritchard ,
Jane Risdall , Robert Sawyer , Mary Woodsca,*
, John Yarnold
aDepartment of Radiotherapy, Royal Marsden Hospital NHS Trust, Sutton, Surrey, UK
bDivision of Physiological Medicine (Dermatology), St George's Hospital Medical School, London, UK
cLymphoedema Services, Royal Marsden Hospital NHS Trust, Sutton, Surrey, UK
dClinical Trials and Statistics Unit, Institute of Cancer Research, Sutton, Surrey, UK
eRadiotherapy Action Group Exposure, 24 Edgeborough Way, Bromley, Kent, UK
fInstitute of Naval Medicine, Alverstoke, Gosport, Hampshire, UK
* Corresponding author:
Professor John Yarnold, Consultant Clinical Oncologist
Academic Radiotherapy Unit, The Royal Marsden Hospital
Downs Road, Sutton, Surrey SM2 5PT, UK
Tel: 0044 20 8661 3388 / Fax: 0044 20 8661 3107 / Email: firstname.lastname@example.org
Total number of pages: 18, Tables: 2, Figures: 1
Running head: Hyperbaric oxygen therapy for chronic arm lymphoedema and tissue fibrosis
Key words: hyperbaric oxygen therapy, clinical trials, radiotherapy complications, lymphoedema
Radiation-induced arm lymphoedema is a common and distressing complication of curative treatment
for early breast cancer. Hyperbaric oxygen (HBO2) therapy promotes healing in bone rendered
ischemic by radiotherapy, and may help some soft-tissue injuries too, but is untested in arm
Twenty-one eligible research volunteers with a minimum 30% increase in arm volume in the years
after axillary/supraclavicular radiotherapy (axillary surgery in 18/21 cases) were treated with HBO2.
The volunteers breathed 100% oxygen at 2.4 ATA for 100 minutes in a multiplace hyperbaric chamber
on 30 occasions over a period of 6 weeks. The volume of the ipsilateral limb, measured opto-
electronically by a perometer and expressed as a percentage of contralateral limb volume, was selected
as the primary endpoint. A secondary endpoint was local lymph drainage expressed as fractional
removal rate of radioisotopic tracer, measured using lymphoscintigraphy.
Three out of 19 evaluable patients experienced >20% reduction in arm volume at 12 months. Six out
of 13 evaluable patients experienced a >25% improvement in 99Tc-nanocolloid clearance rate from the
ipsilateral forearm measured by quantitative lymphoscintigraphy at 12 months. Overall, there was a
statistically significant, but clinically modest, reduction in ipsilateral arm volume at 12 months follow
up compared with baseline (p = 0.005). The mean percentage reduction in arm volume from baseline
at 12 months was 7.51. Moderate or marked lessening of induration in the irradiated breast, pectoral
fold &/or supraclavicular fossa was recorded clinically in 8/15 evaluable patients. Twelve out of 19
evaluable patients volunteered that their arms felt softer, and six reported improvements in shoulder
mobility at 12 months. No significant improvements were noted in patient self-assessments of quality
Interpretation is limited by the absence of a control group. However, measurement of limb volume by
perometry is reportedly reliable, and lymphoscintigraphy is assumed to be operator-independent.
Taking all data into account, there is sufficient evidence to justify a double-blind randomised
controlled trial of hyperbaric oxygen in this group of patients.
Clinical syndromes associated with radiotherapy complications are variable, but all are progressive and
irreversible . The commonest indication for high dose radiotherapy in the UK is the management
of women with early breast cancer. A proportion of this population develop arm lymphoedema, painful
hardening and shrinkage of the breast, rib fracture, lung damage, cardiac injury and, rarely, nerve
damage . One of the commonest and most distressing of these consequences is lymphoedema of the
upper limb when the axilla has been irradiated, especially following axillary surgery [6,26]. In severe
cases, the volume of the limb is increased by 40% or more, causing disability by virtue of added
weight and impeded joint movement . In a population-based retrospective study in the South of
England, 28% of 1,077 women remaining disease-free after treatment of breast cancer reported some
degree of arm swelling . No reliable data exist on NHS workload related to this group of patients,
but the experience of patient advocate groups suggests that the need for rehabilitation services far
exceed the resources available . Conventional treatment consists of skin-care, exercises to maintain
and promote shoulder movement, massage (either self- or professionally-applied) and compression
garments to improve lymph drainage and soften the tissues. In many cases, the condition can be
managed with appropriate advice and compression sleeves for life . In a minority, compression
bandaging and other measures fail to prevent progression to a grossly swollen limb. In response to the
need for integrated management by a range of health professionals with appropriate expertise, clinical
oncologists, breast care nurses, pain specialists, physiotherapists, occupational therapists and
complementary therapists have been identified in each NHS Region .
Data from our own study testing HBO2 in patients with radiation-induced brachial plexopathy (RIBP)
 showed no reliable evidence to support the hypothesis that HBO2 therapy slows or reverses RIBP
in a substantial proportion of affected individuals, although improvements in warm sensory threshold
offered some suggestion of therapeutic effect. However, 2/6 cases with marked chronic arm
lymphoedema reported major and persistent improvements in arm volume for at least 12 months after
treatment with HBO2. This observation was not anticipated, and forms the basis of the current
hypothesis under test, namely that hyperbaric oxygen therapy improves long-standing arm
lymphoedema in a proportion of patients. The study was performed in collaboration with the patient
lobby group Radiotherapy Action Group Exposure (R.A.G.E.) and was funded by the UK Medical
Research Council. The protocol was approved by the Research Ethics Committees of the Royal
Marsden NHS Trust and the Institute of Naval Medicine.
Patients and Methods
Eligibility and pretreatment assessment
Inclusion criteria included ipsilateral arm lymphoedema following treatment for breast cancer causing
≥30% increase in arm volume, freedom from cancer recurrence, physical and psychological fitness for
HBO2, availability for follow up and written informed consent. Pretreatment baseline assessments
included magnetic resonance imaging (MRI) of the supraclavicular fossa, axilla and brachial plexus to
exclude cancer recurrence, clinical assessment of subcutaneous induration within the radiotherapy
volume, measurement of arm volume using a perometer, quantitative lymphoscintigraphy to assess
local lymph drainage in the forearm, clinical photographs and patient self-assessments using the
EORTC Quality of Life Questionnaires QLQ-C30 and BR23 .
Clinical examination was undertaken by an oncologist to confirm trial eligibility and grade induration
of the breast boost site, pectoral fold and supraclavicular fossa. The latter was done by palpation using
a scale 0-3 (0 = none, 1 = a little, 2 = quite a lot, 3 = very much) and was repeated at follow up
assessments by the same clinician to ensure consistency. Response was defined as an improvement of
at least 2 grades (e.g. 3→1, 3→0, 2→0) at 12 months, since this was regarded as a clinically
worthwhile improvement that could not easily be attributed to measurement error. Clinical
photographs were taken of the upper body (hands on hips and above head) and of both arms, but
response (change in photographic appearance at 12 months) was not predefined.
Measurement of arm volume
Arm volumes were measured in an operator-independent manner using a perometer (Model 400T,
Pero-System GmbH, Wuppertal, Germany [5,24]). The volume from wrist to axilla was determined by
placing the arm vertically inside a square measuring frame containing rows of infrared light-emitting
diodes on two adjacent sides. On moving the frame along the arm, volume was calculated from pairs
of diameter measurements every 3 mm, assuming a circular or elliptical cross-section. The volume of
the ipsilateral limb was expressed as a percentage of the contralateral (control) limb volume. Response
was defined in the protocol as a >20% reduction in ipsilateral arm volume on the grounds that this was
considered a clinically worthwhile improvement unlikely to be due to supportive measures or changes
Lymphoscintigrapy was performed on as many volunteers as possible. Patients were acclimatised to
their surroundings for at least 45 minutes before starting. The patient sat with both arms resting on a
table with palms facing up and the gamma camera (Starcam GE 400ACT, General Electric Medical
Systems, Milwaukee, WI, USA), wide-field-of-view, low energy, high resolution collimator)
positioned above the arms for ventral viewing. A site on the ventral surface of the ipsilateral forearm
particularly affected by swelling was selected for injection (typically one-third of the distance from the
antecubital crease to the wrist). The site was carefully marked and the distance to the outstretched
fingertip and to the olecranon process was measured in cm to enable relocation to the same position
for the repeat scan at 12 months. The corresponding site on the contralateral arm was also marked. 0.2
ml of 99mTc-Nanocoll in saline, containing approximately 35 MBq, was injected subcutaneously in
each forearm using a 1-ml syringe and a 23-gauge needle. The site was not massaged. The camera was
immediately lowered to 2 cm above the injection site and a 60-second static acquisition was
performed. Acquisitions were repeated at 30 min, 60 min, 90 min, 120 min and 180 min. In between
acquisitions the patient sat in the waiting room and read. No exercise was performed. The number of
counts recorded within a rectangular region of interest (area 54 cm2), encompassing the depot, was
obtained from the computer (GE acquisition computer). The removal rate constant for the radiotracer,
k (local lymph flow per unit volume of distribution of tracer, units: % min-1), was determined from the
regression slope of the plot of logn fraction of counts remaining at the depot against time . No
formal definition of response was agreed prior to the study.
Quality of life
The EORTC core questionnaire QLQ-C30 and breast module BR23 were chosen for the study. The
core questionnaire QLQ-C30 incorporates five functional scales (physical, role, cognitive, emotional,
and social), three symptom scales (fatigue, pain, and nausea and vomiting), a global health status/QoL
scale, and a number of single items assessing additional symptoms commonly reported by cancer
patients (dysphnoea, loss of appetite, insomnia, constipation and diarrhoea) and perceived financial
impact of the disease. The breast module BR23 comprises 23 questions assessing disease symptoms,
side effects of treatment (surgery, chemotherapy, radiotherapy and hormonal treatment), body image,
sexual functioning and future perspective . Volunteers were asked to complete set of a baseline
questionnaires before they started HBO therapy.
Hyperbaric oxygen therapy
Research volunteers were registered on the first day of treatment by a telephone call to the Clinical
Trials & Statistics Unit, Institute of Cancer Research. Volunteers were compressed to 2.4 ATA
(243 kba) in a multiplace Category 1 hyperbaric chamber at the Royal Hospital Haslar. Patients
breathed 100% oxygen at pressure via a transparent hood. The total time at 2.4 ATA was 100 minutes,
including two 5-minute ‘air breaks’. Each participant received a total of 30 pressure exposures,
treating five days a week for six weeks.
Clinical assessment and perometer measurement of arm volumes were repeated within 1 week of
completing six weeks of HBO2 therapy and 6 and 12 months after start of treatment. Self-assessments
of quality of life were completed at the same intervals plus3 and 9 months after start of treatment.
Lymphoscintigraphy and clinical photographs were repeated at 12 months only.
The primary endpoint was defined as an absolute change of >20% in the relative volume of the
ipsilateral arm vs. contralateral arm at 12 months. In addition, the relative change in excess arm
volume (arm swelling) between baseline and 12 months was analysed as an unplanned endpoint.
Planned secondary endpoints included i) lymphoscintigraphy, ii) patient self-assessments of arm
swelling, tissue hardness and physical functioning, and iii) physician assessments of photographic
appearance and palpable induration of the breast/chest wall, pectoral fold and/or supraclavicular fossa.
In addition, comments on arm softening and shoulder mobility volunteered by patients at clinical
assessment were incorporated as unplanned endpoints.
The appropriate size of the study group was determined by the feasibility of testing a complex
treatment as much as by statistical considerations. A sample size of 21 patients was judged to be large
enough to provide some indication of whether HBO has any effect on arm lymphoedema.
Change in ipsilateral arm volume was analysed on a continuous scale as the percentage change in
excess volume of the swollen arm as a percentage of the contralateral arm at baseline (bl) and after
therapy. In the protocol definition of response was an absolute change of >20% in the relative volume
of the ipsilateral arm vs. contralateral arm at 12 months (absdif = voldif12-voldifbl) e.g. for case 1 (see
Table 1) voldif12-voldifbl = 131-137 = -6 (minus sign indicates a reduction in volume). Change from
baseline at 12 months was examined using a paired t-test, since an inspection of the histogram and
normal probability plot suggested that a t-test was appropriate. In addition, the relative change in
excess arm volume (arm swelling) between baseline and 12 months was analysed using the formula
reldif = ((voldif12/voldifbl) x 100)-100 (where reldif is the relative difference in excess volume at 12
months e.g. for case 1 ((31/37) x 100)-100 = -16% relative change (reduction)). Health status scales
were derived from the questionnaires using standard methods . Change in lymphoscintigraphy,
breast induration (palpation), breast appearance (clinical photographs), arm softening and shoulder
mobility were recorded for each individual volunteer. No formal statistical analyses were planned of
the secondary endpoints, since the sample size was not large enough to provide reliable results on
multiple endpoints. However, it was felt appropriate to analyse the lymphoscintigraphy data formally.
Paired t-tests were used after confirming the normality of the data.
The median age of the 21 volunteers (20 female and 1 male) at the start of HBO2 was 64 years (range
53-76). The median time from primary therapy for breast cancer and onset of lymphoedema was 2
years (range 1 month-34 years). The median time from radiotherapy treatment to HBO2 was 14 years
(range 7-35). 10/21 volunteers had wide local excision as part of their primary treatment for breast
cancer, and 8 of these patients had some form of axillary surgery as well. Eleven out of 21 volunteers
underwent mastectomy, and 10 of these volunteers had some form of axillary surgery as well. The
level of axillary surgery performed was described in various terms, including “level I” and “axillary
clearance”, but the exact description was rarely available in the patients’ operation notes. All
volunteers had radiotherapy to the breast/chest wall and axilla +/- supraclavicular fossa.
Compliance with the treatment protocol was 100%. All planned 126 patient self-assessment
questionnaires were completed and returned on time, and only two individuals missed follow up
assessments (one moved away and declined her 12-month assessment; and another was hospitalised
with septicaemia and was advised by her medical practitioners not to travel). Hence, 81/84 (96%) of
perometer measurements and clinical assessments were completed as planned. Due to logistical
problems, only 15/21 (71%) patients entered the lymphoscintigraphy protocol. We found ourselves in
a situation where we were ready to start HBO2 therapy, but unable to fit in a sufficient number of
pretreatment lymphoscintigraphy scans. It was therefore decided to enter as many volunteers as
possible within the timeframe given, and the selection of individuals was entirely random. Fourteen
out of 15 (93%) completed the lymphoscintigraphy protocol (one volunteer did not attend for her 12-
month scan). Unfortunately, one follow up scan was accidentally erased from the computer system,
and this volunteer was therefore not evaluable for the study.
Results of arm volume measurements before HBO , one week post-HBO
22, at 6 months and 12 months
from study entry are listed in Table 1. Twenty-one out of 21 volunteers were assessed one week after
the end of therapy (7 weeks after start of HBO ), 20/21 at 6 months after start of HBO
22 and 19/21 at 12
months. For the purpose of the analysis only the 19 patients assessed at 12 months were included. The
median volume of the ipsilateral limb expressed as a percentage of contralateral limb volume at
baseline was 154% (range 131-213%). One week after the end of HBO2 therapy the median volume
was 159% (range 128-205%). 6 months after start of therapy this was reduced to 150% (range 114-
202%), and at 12 months the median volume of the ipsilateral limb expressed as a percentage of
contralateral limb volume was 144% (range 115-199%). The mean difference calculated at the same
time points changed from 157% at baseline to 149% 12 months after start of therapy.
In the trial protocol, a 'response' was defined as >20% reduction in arm volume at 12 months. This
level of improvement was considered to be both clinically significant and unlikely to be attributable to
supportive measures or change in lifestyle. 3 patients (volunteers 3, 14 and 15) were responders
according to this classification (range 21-29%), 16 patients were non-responders and 2 patients
(volunteers 7 and 21) could not be assessed, as they did not complete their 12-month clinical
assessments. Examining the relative reduction in arm swelling (excess arm volume rather than total
arm volume) as an unplanned secondary endpoint, 5/19 patients (volunteers 3, 6, 8, 14 and 15)
experienced >20% (range 25-66%) reduction in arm swelling at 12 months.
There was a statistically significant reduction in arm volume from baseline at 12 months (p = 0.005).
The mean percentage reduction in arm volume from baseline at 12 months was 7.68 (95% CI 2.65-
The lymphoscintigraphy outcome is shown graphically in Fig 1. Lymphoscintigraphy was performed
before HBO2 and 12 months after start of therapy as a planned secondary endpoint. This was not a
condition for participation in the study, but 13/21 volunteers consented and were evaluable. The mean
ratio between the lymphatic clearance rate in the arm affected by lymphoedema and the contralateral
arm (kipsilat/kcontralat) at baseline was 0.76, ie a reduction of 24% in the ipsilateral arm (constant with
published findings ). At 12 months after the start of HBO the mean value for k
2 ipsilat had increased
from 0.0244 to 0.0334 min (59%), whereas the mean value for k
contralat had increased from 0.0366 to
0.0386 min-1 (19%). As a result, the mean ratio kipsilat/kcontralat was increased to 0.92, i.e. an
improvement of 16% at 12 months post start of HBO .
There was a statistically significant difference between kipsilat and kcontralat at baseline (p = 0.05), but not
at 12 months after start of therapy (p = 0.20). Comparing kipsilat at baseline and kipsilat at 12 months
there was a statistically significant improvement (p = 0.03), whereas there was no significant
difference between k
at baseline and k
contralat contralat at 12 months (p = 0.71). Finally, when comparing
the ratio ipsilateral/contralateral baseline versus 12 months there was a significant difference (p =
Clinical assessments including tissue hardness and clinical photographs
The results of the serial clinical assessments of tissue hardness are summarised in Table 2. At baseline
17/19 patients had some degree of tissue hardness in irradiated areas of the breast/chest wall (n = 8),
pectoral fold (n = 16) and/or supraclavicular fossa (n = 12). Softening of a substantial number of these
sites was noted at the first post-therapy assessment one week after end of HBO2, and further softening
was recorded in some cases at 12 months post-therapy. The total improvement at 12 months were 1/8
(13%) sites on the breast/chest wall, 8/16 (50%) sites in the pectoral fold and 4/12 (33%) sites at the
supraclavicular fossa (total 13/36 (36%) sites in 8/17 (47%) patients). Clinical photographs were taken
of the volunteers at baseline and 12 months post start of HBO2, but these were not found to be
informative, recording no changes in appearance that were not recorded by perometry.
QLQ-C30 & BR23 and patient self-reports
The data were analysed but recorded no significant changes for better or worse over the study period
(data not shown). However, a proportion (12/19, 63%) of volunteers reported a definite softening in
the tissues of their affected arms. Six volunteers reported improvement in shoulder mobility and, in
cases of marked volume reduction, improved posture and less pain and feeling of heaviness, see Table
2. In Table 2, it is clear that there are no obvious associations between any of the endpoints reported.
Fibrosis is believed to contribute to the development of lymphoedema. The pathophysiology of
lymphoedema after radiotherapy and/or surgery involves obstruction of lymphatic flow causing an
imbalance between capillary filtration and lymph drainage [16,23]. Although physical removal of
lymphatic vessels at surgery offers a partial explanation, the variable onset, progression rate and
ultimate severity indicate that this is not the only mechanism. Radiotherapy to the axilla is a potent
cause of arm lymphoedema in its own right, more so after any kind of surgical disturbance of the axilla
. The continuous accumulation and contraction of scar tissue over many years is considered to be a
cause of progressive lymphatic obstruction in response to radiotherapy. The most vivid accounts of
fibrosis come from the surgical records of affected patients describing scar tissue infiltrating and
compressing axillary structures, especially the neurovascular sheath.
The traditional view regards radiation fibrosis as a passive phenomenon, representing the residual
extracellular matrix of a tissue depleted of cells. As such, fibrosis is regarded as an end-state beyond
effective therapeutic intervention. An alternative model considers radiation fibrosis in terms of
deregulated collagen metabolism with fibroblasts playing a central role [4,21]. The active model shares
features with other fibrotic states characterised by chronic imbalances between collagen deposition and
resorption . The significance of the active model is that it raises possibilities for reversing
Hyperbaric oxygen (HBO2) therapy currently provides the strongest proof of principle in support of an
active model for normal tissue responses to radiotherapy, with two comparative studies reported in
patients with heavily damaged tissues. The first study tested preoperative hyperbaric oxygen against
conventional penicillin cover in a randomised study of 74 patients requiring dental extraction
following radical mandibular irradiation . Only 5.4% of the patients in the hyperbaric oxygen
group compared to 30% of the patients in the penicillin-treated group experienced failure of wound
healing 6 months after surgery (p<0.05). In 160 patients treated by hyperbaric oxygen or standard
postoperative care following major soft tissue surgery for radiotherapy injury, four-fold reductions in
wound dehiscence, infection and delayed wound healing were seen in the hyperbaric oxygen treated
group (p<0.01) . The pathological correlates of the response to hyperbaric oxygen in irradiated
tissues have been studied in animals, and include neovascularisation, organisation and marked
reductions in fibrous tissue . However, it is not currently clear how these relate to the clinical
effects reported in humans.
There are several reports of HBO2 in the treatment of patients with haemorrhagic cystitis following
pelvic radiation and refractory to conventional measures. Bevers et al. describe 40 patients treated for
20 sessions of HBO2 for severe haematuria . Thirty-seven of the 40 patients showed improvement in
symptoms and no adverse effects were reported. Lee et al. treated 20 similar patients from 1989-1992
and again showed improvement of haematuria in 90% . Schoenrock and Cianci reported a patient
with severe haemorrhagic cystitis and a vesicocutaneous fistula which healed with HBO2 . Nakada
et al. gave 6 patients with radiation cystitis HBO2 and also found improvement in all but one patient
. Similar reports on small patient numbers are given by Kindwall, Weiss and Norkool [8,19,28].
No adverse effects of HBO were reported in any of these studies.
Turning to the current data, the evidence is highly suggestive of a therapeutic effect, but falls short of
providing reliable evidence for clinical benefit. Assuming HBO2 has reduced lymphoedema, it is not
possible to say if this relates to the changes induced by surgery, radiotherapy or both. Where
experimental design is concerned, the important decision to conduct a non-randomised study was
determined by the assumptions i) that perometry offers an operator-independent measure of arm
volume and ii) that a sustained reduction of >20% in arm volume could not occur spontaneously, or in
response to other interventions such as more intensive arm care by lymphoedema clinics. The average
reduction in arm volume reported was just below 10%, with only 3/19 patients recording >20%
reductions in arm volume (5/19 with >20% reductions in arm swelling) at 12 months. Although this
reproduces our previous observations, the modest level of effect makes it difficult to be certain that
responses were HBO2-induced, rather than seasonal fluctuation (this appears to be ruled out by
reviewing the calendar months of measurements), changes in life-style and/or more intense interest
shown by lymphoedema clinics responsible for routine management (we have no evidence for either
of these effects).
Despite these uncertainties, quantitative lymphoscintigraphy offers strong supportive evidence for a
durable effect attributable to HBO2. The robustness of the technique is indicated by the similarity of
the pre-HBO2 difference (24%) with published data . The baseline clearance rate of radioactive
tracer was <0.9 (ratio of kipsilat to kcontralat) in the ipsilateral arm compared to the contralateral limb in
9/13 patients before treatment and in only 4/13 patients 12 months later, a statistically significant, and
highly clinically significant, improvement. It is difficult to ignore the softening of the ipsilateral arm
reported by so many (12/19) evaluable patients, not considered as a planned endpoint, but mentioned
by so many patients without prompting. Assuming the recorded changes in arm volume, 99Tc-Nanocoll
clearance rate and arm hardness to be consequences of HBO2, it is possible to speculate that limb
tissues can be insufficiently elastic to respond to restoration of normal clearance rates by volume
The physician assessments of tissue softening recorded in Table 2 were planned secondary endpoints.
Whilst these are highly subjective, it is considered unlikely that improvements of 2 grades represent
measurement errors or spontaneous change. The pathological changes underlying induration are not
clear, although tissue fibrosis and oedema are likely to be important. The same pathological features
may be relevant to the pathogenesis of arm lymphoedema after lymphatic surgery and radiotherapy to
HBO2. If so, the response at one site might be expected to be associated with a response at another.
Possibly due to the very small sample size, these associations are not apparent.