ABSTRACT: This report was prepared by a special committee of the Royal College of Radiologists. It provides a British perspective on how to manage this potential complication of breast irradiation. Portions of the report are summarized or, where indicated, reproduced in their entirety, with the permission of the College. [ONCOLOGY 10(5):685-700, 1996]
Patients treated for breast cancer may suffer a range of upper limb problems, from mild edema and changes in inner arm sensation related to surgery, to the rare, but severely disabling brachial plexus neuropathy associated with radiation damage. Public attention focused on the latter problem by a group of British patients, the Radiation Action Group Exposure (RAGE), led to a House of Lords debate (May 1994). As a result of that debate, a multidisciplinary committee was set up in July 1994, under the auspices of the Royal College of Radiologists, to consider how women with axillary tunnel damage associated with radiation should be managed. The 14-member committee, which was chaired by Dr. E.J. Maher, Consultant Oncologist, Mount Vernon Centre for Cancer Treatment, included patients as well as oncology professionals. The committee's report was presented to the Board of the Faculty of Clinical Oncology of the Royal College of Radiologists on February 3, 1995.
The committee had the following objectives:
1. To assess the optimum management of women who have suffered axillary tunnel damage following radio therapy for breast cancer and the current availability of specialist services for such management.
2. To make recommendations on how services for this group of women can best be organized.
3. To report through the Faculty Board of the Royal College of Radiologists, the Joint Council of Clinical Oncology, and then to the Chief Medical Officer. The report would then be submitted to the Clinical Outcomes Group of the Department of Health.
What is Axillary Tunnel Damage?
For their report, the committee members used the term "axillary tunnel damage" to describe the spectrum of problems associated with damage to tissues adjacent to the clavicle and under the armpit due to treatment with ionizing radiation. The most serious complication is generally acknowledged to be damage to the nerve cords, ie, radiation-induced brachial plexopathy (RIBP).
The committee based its assessment of optimal management of axillary tunnel damage and current availability of specialist services on three sources of information: (1) consultation with RAGE (including results of a survey conducted by that organization), (2) a literature review, and (3) consultation with individual experts and organizations.
The committee found no completely unambiguous guidelines on the diagnosis or management of RIBP and associated problems in the literature. Also, most studies were based on small selected series of cases considered retrospectively rather than large prospective randomized trials. Thus, there is no solid research base. The committee took the view that, despite these acknowledged limitations, the views of sufferers, as represented by RAGE, should be paramount in recommendation of services and was guided by the priorities identified by the RAGE members.
Assessment of Need and Available Services
The chief problems reported were unrelieved pain, characteristically neuropathic in character, and paralysis of the hand and then of the whole arm. Further complications included bone pain and necrosis, lung damage, severe fibrosis, and lymphoedema.
For RAGE members one of the worst deficiencies was denial of the problem, which compounded the real anger they felt at not being warned of the possible dangers of radiotherapy.
Patients reported difficulties in obtaining a diagnosis or even information about the condition. There appeared to be no structured management plan, with problems in gaining access to expert help at the different stages of progression of the condition, in particular, pain management and access to occupational therapy, including aids to daily living. There was also a failure to provide psychological support.
The RAGE survey reported some good practice. In particular, pools of expertise were found in cancer treatment units, palliative care units, and pain clinics, but there was poor communication among them, no clear protocols, and difficulties in patient access. Based on perceived shortfalls, information was collated on the following topics:
• Organization of a coordinated professional network
• Role of neurologist in diagnosis
• Role of neurophysiologist in diagnosis
• Role of breast care nurse
• Management of neuropathic pain
• Role of occupational therapies
• Management of lymphoedema interest group
• Role of specialist surgical intervention
• Role of pain clinic
These papers were used to inform the work of the committee. Draft guidelines, completed on December 31, 1994, were widely circulated before presentation to the Board of the Faculty of Clinical Oncology of the Royal College of Radiologists on February 3, 1995.
The following is the full text of this portion of the Royal College report. It is reproduced, with permission, from Management of Adverse Effects Following Breast Radiotherapy. London, The Royal College of Radiologists, 1995. The full texts of this report and the complementary report by Thelma Bates and R.G.B. Evans, Brachial Plexus Neuropathy Following Radiotherapy for Breast Carcinoma (London: RCR, 1995. ISBN 1 872599 18 4) are available from: http://www.rcr.ac.uk/Enquiries.
The committee recognizes that there is a difficult balance to be struck between the benefits of postoperative radiotherapy in reducing the risks of recurrence and death and the risks of serious morbidity. A relatively high dose of radiation is necessary to sterilize microscopic deposits of breast cancer. Survival may be prolonged by postoperative radiotherapy in selected patients. However, at these levels of dose, there is a relatively steep increase in the risk of complications. The price of reducing dose in order to reduce the risk of major morbidity is an increase in the risk of loco-regional recurrence and possibly an increase in cancer related plexopathy.
It is anticipated that the peak incidence of RIBP in the UK has been reached, possibly related to changes in technique over the late 70s and early 80s, but this is only conjecture and will be examined by the formal audit being conducted by Dr. Bates and Dr. Evans for the Royal College of Radiologists; however, it is also possible that the trend away from supraclavicular fossa and axillary radiotherapy could lead to more cancer related plexopathy. In view of the uncertainty as to which patients benefit from nodal radiotherapy, it is essential that treatment options are discussed carefully with appropriate specialists.
In a minority of patients, supraclavicular and/or axillary irradiation may cause edema and fibrous tissue to constrict the brachial plexus. Substantial loss of myelin occurs with disappearance of the axis cylinders. The neurolemmal sheath itself undergoes varying degrees of fibrous thickening. Hyalinization and obliteration of blood vessels causes further ischemia of nerve fibers. The precise mechanisms of damage are still incompletely understood.
More recently it has become recognized that individual variations in radiosensitivity to the same total dose and fractionation may be, in part, genetically determined. It has been estimated that up to 20% of patients may be heterozygous for the ataxia-telangiectasia gene which confers substantial enhancement in radiation reactions. This may account for the abnormally intense axillary fibrosis following post operative radiotherapy in some patients. However, at the time of writing this report, there is no reliable test to determine whether an individual is heterozygous for the ataxia-telangiectasia gene or not and other genes may be equally important. While this is a promising area of research, there is no evidence that genetic factors are responsible for the injuries reported by RAGE.
Reports of the incidence of RIBP among women who have undergone postoperative axillary irradiation vary widely. This probably reflects differing criteria for the diagnosis of RIBP and the range of dose and fractionation schedules described in the literature. However, it is a rare complication probably affecting less than 1% of treated patients. Its rarity means that a general practitioner is unlikely to see a single case during his or her professional lifetime. Similarly, many health care professionals involved in the treatment of breast cancer may be unfamiliar with the clinical features of RIBP.
The most common presenting symptoms of RIBP are:
• Tingling and numbness of the thumb and forefinger.
• Wasting and weakness of the small muscles of the hand.
• Persistent pain in the shoulder region.
These symptoms appear from 6 months to over 20 years after treatment with the most commonly reported incidence between the 2nd and the 5th year after radiotherapy. It should be emphasised that such symptoms may be caused by a variety of unrelated conditions and, if related to cancer and its treatment, are more likely to be due to recurrent cancer than RIBP.
Typically, a patient will present with numbness of the fingers. Wasting of the small muscles of the hand will follow within months or years. Pain will follow a variable course: characteristically it follows the distribution of nerves supplied by C5 and C6, although it may involve the whole brachial plexus; the features of the pain vary not only in different individuals but also within the same individuals at different times. Such neuropathic pain is notoriously difficult to manage. Between one third and two thirds of patients with RIBP will develop progressive loss of function of the hand and arm over a period of months or years. In a minority, progression may arrest without significant loss of function. As paralysis becomes complete the severity of pain may recede but in other cases persistent causalgic pain remains.
There is a variable incidence of other associated problems including bone necrosis/fracture, lymphoedema and circulation problems. Persistent pain and increasing disability may result in clinical depression and non-specific stress-related illness.
Diagnosis may involve the following and their teams:
• Consultant oncologist.
• Breast care nurse.
• Breast surgeon.
RIBP is a diagnosis of exclusion based on the demonstration of a brachial plexopathy in an irradiated site in the absence of other causes, in particular recurrent cancer.
At the time of presenting symptoms and signs it is usually (but not always) possible to confirm a brachial plexopathy, but there are no completely reliable criteria for distinguishing the cause to be radiation rather than recurrent cancer.
Diagnosis rests on:
• Recognition of the significance of the common presenting symptoms
• Competent history and physical examination to identify a neurological deficit and to detect obvious recurrent cancer. This may require assessment by a neurologist as well as clinical oncologist.
-Chest x-ray, cervical spine x-ray.
-CT/MRI axilla SCF and cervical spine.
-Biopsy of suspicious areas (preferably under CT control).
-Neurophysiological tests: nerveconduction and needle studies toidentify a lesion in the brachialplexus.
-Screen for metastatic disease: liver ultrasound, bone scan.
The committee proposes the consultant oncologist as best placed to recognize the significance of symptoms and coordinate diagnosis. There was, however, debate among the members of the committee and outside experts consulted as to the appropriate sequence of investigation. Some recommended CT and MRI before neurophysiological tests; others that referral to a neurologist was essential before proceeding to either MRI or neurophysiological studies; others that it would be within the competence of a clinical oncologist to coordinate all these investigations. Much depends on local expertise and the committee recommends that a local coordinating clinician makes appropriate recommendations; however, this committee would expect that, in the face of persistent symptoms (more than 3 months) and/ or objective signs suggesting a brachial plexus neuropathy, patients should have at least:
• CT/MRI scan axilla, supraclavicular fossa (with biopsy under CT control of suspicious areas).
• Neurophysiological studies (nerve conduction and needle studies).
A diagnosis of cancer related plexopathy is suggested by:
• Rapid progression of weakness (particularly involving muscles supplied by lower plexus).
• Abnormal supraclavicular/axillary nodes.
• Evidence of metastatic disease elsewhere.
• Horner's syndrome.
Initial absence of these does not exclude the possibility of tumor, as demonstrable cancer has been reported many years after initial symptoms. Abnormal masses should be biopsied, ideally under local anaesthetic, but open exploration may be required. Even then negative findings do not completely exclude cancer.
Plexopathy related to cancer may respond to systemic chemotherapy and/ or a second course of radiotherapy; in the presence of rapidly progressive weakness and a negative biopsy patients may consider a trial of chemotherapy in combination with high dose steroids.
Surgery—Operations have been described to decompress the brachial plexus and revascularize nerves and surrounding tissues, but there is no treatment which will reliably reverse or change the natural history of RIBP. In general, the most successful results will be obtained with a team of a surgeon with skills in the management of brachial plexus injury (generally an orthopaedic or neurosurgeon) and a vascular and/or reconstructive surgeon used to placing vascularized flaps within heavily irradiated tissues.
The success rates vary both in the literature and amongst reports from individual RAGE members who have undergone surgery. Some have noted improvement of motor function and others improvement of pain; however, others have reported deterioration as a result of such surgery. It is possible such surgery may delay vascular insufficiency and avoid progression to complete loss of motor function in selected cases. In general, most value is obtained within 12 months of presenting symptoms. Patients with severe vascular problems have eventually required amputation. It should be noted that this is not an effective measure to relieve pain.
Mr R Birch was consulted by this committee and comments that operations are hazardous and difficult and should not be attempted by the occasional surgeon, but that teams with appropriate skills are available in several parts of the UK. The committee feels that further research is required before producing recommendation for the use of such surgery. Mr Birch, who is prepared to be consulted by health care professionals managing cases, feels there is a need for significant investment in those centers dealing with brachial plexus injury of all sorts, if more surgery and/or research is to go forward.
Medication—Thyroxine and salicylates, eg, phentoxyphylene have been proposed to inhibit development of radiation fibrosis in selected cases. Recently, the antioxidant agent Cu/Zn superoxide dismutase (Lipsod) has been successfully used to reduce fibrosis, in a French study (Delanian et al 1994). Again more research is required before recommendations can be made.
The key to effective management is a collaborative multidisciplinary approach with honest explanation and communication with the patient, as well as all health care professionals involved. It must be acknowledged that RIBP is essentially an incurable condition, as unrealistic expectations reduce the chances of producing useful improvements in quality of life.
In the absence of definitive treatment, management should be directed towards optimizing symptom control and function to maintain as good a quality of life as possible. This should be combined with careful surveillance to detect and treat recurrent cancer, particularly in the first 2 years after presentation.
The committee considered various health care professionals to coordinate the management of patients with RIBP but concluded that a clinical oncologist is the best placed to recognize the condition, to give an honest explanation both of uncertainties and possible prognosis, and to recognize and treat recurrent cancer.
The committee would expect a coordinating consultant oncologist in each center to liaise with the following health care professionals and teams in the management of such patients:
• Anesthetist and psychologist/psychiatrist, as part of pain clinic.
• Breast Care Nurse.
• GP and District Nurse.
• Lymphoedema clinic.
• Occupational therapist.
• Palliative care clinic.
In addition, a range of complementary therapists (aromatherapists, masseurs, acupuncturists, reflexologists) have been helpful to RAGE members, particularly for those who have been recognized late and have had little or no psychological support. The committee feels more research is needed both in the contribution of complementary therapies and the management of those patients with multiple problems related to axillary tunnel damage, but is not able to make specific recommendations at present.
The key elements of management include:
• Information and explanation to empower patients to help themselves to cope with the condition.
• Systematic management of pain. In view of the emphasis placed by RAGE on this detailed guidelines are included in [the Appendix].
• Assistance with the functions of daily living, in particular access to the recommended aids listed in [the Appendix].
• Psychological support including access to a nurse counselor, information on voluntary organizations and self help groups and regular evaluation for clinical depression.• Regular surveillance to detect and treat recurrent cancer, particularly in the first 2 years.
The committee recommends that one oncologist in every cancer unit and cancer center is responsible for identifying and briefing each member of the team to allow coordinated care, following the guidelines in pain management documented in the Appendices, Symptomatic Management of Neuropathic Pain, and Occupational Aids.
The committee has identified a provisional list of named oncologists in every radiotherapy treatment center in the UK. Ninety percent of these have access to occupational therapy, physiotherapy, pain clinic, breast care nurse, lymphoedema clinic, palliative care clinic and complementary therapy.
The committee proposes that the audit of breast cancer treatment includes key symptoms suspicious of brachial plexopathy in order to facilitate future follow up and management of such cases.
The committee recommends that all those patients with a provisional diagnosis of RIBP are followed by a clinical oncologist at least 3-monthly for 2 years to evaluate:
• Evidence of recurrent cancer.
• Evidence of clinical depression.
• Other complications, eg, lymphoedema; pathological fractures; vascular insufficiency.
Thereafter they should be seen 6-12 monthly indefinitely depending on their symptoms.
If problems arise in between, the GP is an important point of contact; however, given the rarity of RIBP it is not a condition that they would readily recognize and patients should also be able to have access to a key nurse, ideally a breast care nurse, but failing that, an identified community Macmillan (palliative care) nurse to facilitate speedy referral for re-evaluation.
The committee recognizes that, in some cases involving suspected iatrogenic damage, relationships break down with the treating oncologist, in which case it proposes that the breast care nurse should act as key worker to facilitate discussion with the treating oncologist and allow referral to an alternative oncologist in the same center or the identified regional specialist.
The committee has identified a directory of oncologists in each cancer center and cancer unit...and the services to which they have access. It proposes that this information be made available to all breast care nurses through their regional coordinators and, ideally, also to voluntary groups.
The committee proposes that further education of breast care nurses in identification and management of RIBP and associated problems is included in their training, possibly with the addition of regional seminars under the auspices of CRMF. If a patient has no breast care nurse, advice should be available from regional breast care nurse coordinators. The committee has identified a list of these....
The committee recognizes that many health care professionals will not have seen a case of RIBP. It has not been possible within the time frame and resources of this committee to identify all those with expertise in, each discipline but, as a step in the right direction, a group of specialists, including an experienced occupational therapist, physiotherapist, anesthetist, neurologist, specialist surgeon, neurosurgeon, orthopedic surgeon, radiologist, palliative care doctor, all of whom have advised the committee, have indicated that they are willing to act in an advisory capacity to their colleagues faced with such cases.... A more expanded directory will be prepared, if funds become available.
An unacceptable burden is currently falling on RAGE committee members and the committee proposes that written information for patients is produced by a collaboration between BACUP, CancerLink and Breast Cancer Care and a more extended directory of advisory services made available.
In addition the Committee has liaised with BACUP and CancerLink to facilitate formal counseling and help to RAGE committee members in their work in supporting patients. This committee feels that the supportive as well as the campaigning role of RAGE should be acknowledged.