I am including this page on the complications associated with breast cancer radiation therapy after a discussion in one of the lymphedema support groups. Arm lymphedema has long been an easily identifiable complications of this treatment, but there are numerous other ones as well. These include many shoulder, elbow and joint problems.
I especially want to thank Bob Weiss, who is a lymphedema treatment advocate and has done extensive work in advocacy, assisting patients with Medicare and in helping patients in a number of support groups understand and overcome lymphedema problems.
An important article written in 2011 is What is Radiation Induced Brachial Plexopathy? (RIBP), the full text can be read: Radiation-Induced Brachial Plexopathy
by E. Senkus-Konefka, J. Jassem Department of Oncology and Radiotherapy, Medical University of Gdan´sk, Gdan´sk, Poland
Published in Clinical Oncology (2006) 18: 229-235
Although the beneficial effect of postoperative radiotherapy for breast cancer is well documented, this treatment may be related to a number of complications, which may affect patient quality of life and possibly survival.
Among significant long-term irradiation sequelae are cardiac and lung damage, lymphoedema, brachial plexopathy, impaired shoulder mobility and second malignancies.
The risk of these complications, particularly high with old, suboptimal irradiation techniques, has decreased with the introduction of modern technologies. In this paper, we review the contemporary knowledge on the toxicity of b reast-cancer radiotherapy and discuss possible preventive measures.
Shoulder and arm complications are among the most troublesome sequelae of breast-cancer treatment [25,57,58]. Some arm problems are estimated to occur in up to 90% of women with breast cancer [58,59]. Most important complications include arm lymphoedema, brachial plexus neuropathy and impaired shoulder mobility [25,57]. These morbidities often appear together and, to some extent, share common pathogenic elements (e.g. neural damage leads to restricted mobility, which in turn may aggravate lymphoedema) [25,58,60]. These complications may be related to muscular and subcutaneous fibrosis or to vascular injury . All of these symptoms influence the ability to carry out common daily activities . They may lead to change in clothing habits or may require job change . The gross effect in particular women is, however, the product of severity of symptoms and individual’s ability to cope .
Lymphedema is considered a most significant complication of locoregional treatment of breast cancer . It may result in significant psychological and functional morbidity, and markedly worsens quality of life [20,62]. Once established, in most cases it cannot be cured. It is thus essential to prevent or minimise this condition . Chronic lymphoedema is often associated with skin changes, the socalled ‘brawny oedema’ . In most women, it is also accompanied by pain, numbness and shoulder stiffness . It may also predispose to development of cellulitis and limits the arm mobility [20,25,57].
The pathogenesis of lymphoedema includes radiation-induced fibrosis, causing venous and lymphatic vessel obstruction and lymphocyte depletion with fatty replacement and local fibrosis . These factors strongly interact with surgery, possibly due to reduced lymphatic regeneration after surgical interruption . The contribution of haemodynamic factors is also relevant .
The incidence of lymphoedema in particular studies varied greatly between 4% and 39% [20,57,61,64]. This is partially due to different definitions of increased arm dimensions: volume increase greater than 200 ml, circumference increase greater than 2 cm or increase of diameter greater than 5% [20,63,64]. The median latency is usually in the range of 1.5e4 years [20,25,61,65]. As lymphoedema may develop as many as 10 years after radiotherapy, its observed incidence depends also on the length and completeness of follow-up [61,63].
The risk of lymphoedema is mainly related to the treatment applied . The risk after surgery only varies between 1% and 30% [20,25,63], and depends primarily on the extent of lymph node dissection [20,22,25,58,61,64]. Radiotherapy to the axilla considerably increases incidence and severity of this complication, with relative risk ratio reaching 4.6 [20,57,61,64]. It is estimated that these two treatment modalities contribute to the development of lymphoedema to a similar degree . The effect of radiotherapy is highly dependent on the size of dose per fraction (low a/b value). The doseeresponse relationship is strongly affected by surgery and, similarly to other late end points, is very steep (which translates to large effects of small changes of fractionation and dose distribution) . Concomitant use of tamoxifen or chemotherapy may increase the risk of lymphoedema [25,63], although a bias associated with the selection of patients with more advanced disease cannot be excluded .
Other risk factors can be divided into patient-related and disease-related factors. The first group includes obesity, older age, lower education, history of hypertension and infection or inflammatory process within the arm [20,22,25,58,61,63,64]. Disease-related factors include stage and, in particular, pathological nodal (N) status [61,63]. The mechanism involved here may be lymphostasis secondary to malignant involvement of lymphatic channels and scarring caused by successful eradication of disease . It is hoped that widespread use of the sentinel node technique will significantly decrease the risk of lymphoedema . Ongoing studies are testing whether full lymph-node dissection in node-positive patients can be replaced by axillary radiotherapy (European Organisation for Research and Treatment of Cancer ‘‘After Mapping of the Axilla: Radiotherapy Or Surgery’’ EORTC AMAROS study). On the other hand, the need for nodal irradiation after adequate lymph-node dissection is questionable [64,66].
Brachial plexus neuropathy is a relatively rare complication of modern radiotherapy, although, in the past, its incidence was much higher [60,65e69]. It has been predominantly observed in women treated with high dose per fraction or with overlapping fields [60,68]. The most remarkable data on this complication come from the Umea series, in which, over 30 years after hypofractionated radiotherapy with possible field overlapping, more than 90% of women developed complete paralysis of the arm . The estimated biologically equivalent dose in 2 Gy fractions in these women was 85e92 Gy . Interestingly, the damage continued to progress up to 30 years after radiotherapy [67,68,70]. The latency period for this complication ranges from 1.5 to 10 years (7e14 years for complete paralysis), and is similar for motor and sensory impairment [25,60,65,67,68,70]. The late presentation of damage results from slow turnover of tissues, which attempt cell division many years after injury. Lost tissue is then replaced by fibrosis, leading to formation of dense, inelastic and constricting tissue .
Brachial plexus neuropathy is defined as motor or sensory symptoms or physical signs, with or without accompanying pain in a nerve-root distribution in the arm. Neurological manifestations may include paresthesia in the fingers or hands, hypoesthesia, hypoalgesia, disesthesia, paresis, hyporeflexia and muscular atrophy [25,60,67,68,70]. The limb weakness may be selectively distal, global with more marked distal deficits or a complete flaccid paralysis . Most women have abnormal neurophysiology findings: absent sensory nerve action potential, axonal changes, myokymia and prolonged F-waves . Magnetic resonance imaging studies show only soft-tissue fibrosis . Brachial plexopathy is strongly correlated with late fibrosis and muscle atrophy within the shoulder region [60,65]. The damage may encompass the whole plexus or only its lower part . Plexopathy is irreversible . Its incidence depends on total dose, dose per fraction (low a/b value), patient age and concomitant use of chemotherapy [25,64,65,68,70]. Frequently, the toxicity results from unplanned overdosage originating from field overlap caused by changing the woman’s position between treatment fields or from ‘matchline’ problems [25,60,65,67,68]. One of the suggested pathomechanisms of radiationinduced neuropathy is nerve entrapment by radiationinduced fibrosis, chronic oedema, or both [25,67,68].
Another postulated cause was direct damage to neurones or glial cells and ischaemic damage resulting from microvascular injury [25,65,68]. There are probably two phases of radiation-induced neuropathy: the first includes more direct changes in electrophysiology and histochemistry, whereas the second involves fibrotic changes around the nerves and injury of the adjacent vessels [25,71].
A proportion of women with breast cancer experience some degree of post-surgery shoulder stiffness, which may further be aggravated by the use of axillary radiotherapy . Symptoms usually include reduced flexion, external rotation and abduction, and pain at movement or at rest [25,57]. In some women, this leads to reduced working ability .
Shoulder stiffness is usually caused by fibrosis of the major pectoralis muscle and damage to vasculature or to the joints . Movement range may also be decreased as a result of lymphoedema or neural damage . Symptoms usually appear after a median latency of 4 years . Increased risk of radiation-related impaired shoulder mobility is related to the use of large doses per fraction (low a/b value), older age, use of concomitant systemic treatment, co-existence of subcutaneous fibrosis and degree of movement impairment at the start of radiotherapy [25,72].
To diminish the consequences of shoulder and arm problems, women should be recommended physical exercise programmes [25,64]. However, some women with oedema or neurological deficits may not be able to follow these programmes .
Radiotherapy and Oncology Volume 82, Issue 3, Pages 308-316 (March 2007)
Tiziana Rancatia, Berit Wennbergbc, Pehr Lindcd, Gunilla Svanee, Giovanna Gagliardif
Received 17 May 2006; received in revised form 4 December 2006; accepted 8 December 2006. published online 17 January 2007
To fit four different NTCP (Normal Tissue Complication Probability) models to prospectively collected data on short-term pulmonary complications following breast cancer radiotherapy (RT).
Four hundred and seventy-five breast cancer patients, referred to the Radiotherapy Department at Stockholm Söder Hospital (1994–1998) for adjuvant post-operative RT were prospectively followed for pulmonary complications 1, 4 and 7 months after the completion of RT. Eighty-seven patients with complete dose–volume histogram (DVH) of the ipsilateral lung were selected for the present analysis. Mean dose to the ipsilateral lateral lung ranged from 2.5 to 18Gy (median 12Gy). Three different endpoints were considered: (1) clinical pneumonitis scored according to CTC-NCIC criteria: asymptomatic (grade 0) vs grade 1 and grade 2; (2) radiological changes assessed with diagnostic chest X-ray: no/slight radiological changes vs moderate/severe; (3) radiological changes assessed with CT: no/slight vs moderate/severe.
Four NTCP models were used: the Lyman model with DVH reduced to the equivalent uniform dose (LEUD), the Logit model with DVH reduced to EUD, the Mean Lung Dose (MLD) model and the Relative Seriality (RS) model. The data fitting procedure was done using the maximum likelihood analysis. The analysis was done on the entire population (n=87) and on a subgroup of patients treated with loco-regional RT (n=44).
24/87 patients (28%) developed clinical pneumonitis; 28/81 patients (35%) had radiological side effects on chest X-rays and 11/75 patients (15%) showed radiological density changes on Computed Tomography (CT). The analysis showed that the risk of clinical pneumonitis was a smooth function of EUD (calculated from DVH using n=0.86±0.10, best fit result). With LEUD, the relationship between EUD and NTCP could be described with a D50 of 16.4Gy±1.1Gy and a steepness parameter m of 0.36±0.7. The results found in the overall population were substantially confirmed in the subgroup of patients treated with loco-regional RT.
Conclusions A large group of prospective patient data (87 pts), including grade 1 pneumonitis, were analysed. The four NTCP models fit quite accurately the considered endpoints. EUD or the mean lung dose are robust and simple parameters correlated with the risk of pneumonitis. For all endpoints the D50 values ranged in an interval between 10 and 20Gy.
Keywords: Pulmonary complications, Breast cancer, Radiation therapy, NTCP-models
18 September 2007
MedWire News: Women who receive radiation therapy for breast cancer may experience cardiac symptoms up to 6 years after their initial treatment, suggests a small study.
On average, 52% of 160 women had a cardiac perfusion abnormality 3 years after treatment with radiotherapy, rising to 71% after 4 years, and staying high at 67% and 57% after 5 and 6 years, respectively.
The women, aged a median of 55 years, were diagnosed with left-sided breast cancer between 1998 and 2006. All of the patients received tangential radiation to the left breast or chest wall at a dose of 46-50 Gy and given as 1.8-2.0 Gy fractions.
Cardiac symptoms were assessed using single-photon emission computed tomography (SPECT) to measure changes in regional cardiac perfusion, wall motion, and ejection fraction.
Overall, 68% of women had cardiac perfusion defects between 3 and 6 years after initial treatment. The cumulative incidence of ever having a perfusion defect was 60% at 3 years and 90% at 6 years.
Notably, 12 (63%) of 19 women who had normal scans during the first 2 years of follow-up developed new perfusion defects 3 to 6 years after initial treatment. Meanwhile, eight (80%) of 10 patients who had abnormal scans during the first 2 years after initial treatment continued to have abnormal scans 3 to 6 years post-radiotherapy.
Despite the prevalence of cardiac perfusion defects, the researchers did not find significant levels of cardiac wall motion abnormalities or a decrease in ejection fraction during the study, as predicted.
Robert Prosnitz (Duke University Medical Center, North Caroline, USA) and colleagues point out that radiotherapy techniques may differ with regard to levels of cardiotoxicity and additional follow-up is needed to better understand the consequences of radiotherapy.
While the researchers acknowledge the benefit of radiotherapy in terms of survival and local recurrence, they insist that this needs to be weighed up against possible cardiac mortality.
They comment in the journal Cancer: “Every effort should be made to minimize incidental irradiation of the heart while maintaining adequate coverage of target volumes.”
Coen JJ, Taghian AG, Kachnic LA, Assaad SI, Powell SN.
Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA. firstname.lastname@example.org
Erratum in Int J Radiat Oncol Biol Phys. 2003 Jun 1;56(2):604.
Keywords: Radiation, Breast cancer, Lymphedema, Axillary surgery
PURPOSE: To evaluate the risk factors for lymphedema in patients receiving breast conservation therapy for early-stage breast cancer.
METHODS AND MATERIALS: Between 1982 and 1995, 727 Stage I-II breast cancer patients were treated with breast conservation therapy at Massachusetts General Hospital. A retrospective analysis of the development of persistent arm edema was performed. Lymphedema was defined as a >2-cm difference in forearm circumference compared with the untreated side. The median follow-up was 72 months. Breast and regional nodal irradiation (BRNI) was administered in 32% of the cases and breast irradiation alone in 68%.
RESULTS: Persistent arm lymphedema was documented in 21 patients. The 10-year actuarial incidence was 4.1%. The median time to edema was 39 months. The only significant risk factor for lymphedema was BRNI. The 10-year risk was 1.8% for breast irradiation alone vs. 8.9% for BRNI (p = 0.001). The extent of axillary dissection did not predict for lymphedema even within the subgroups of patients defined by the extent of irradiation. Most patients underwent Level I or II dissection. In this subgroup, the lymphedema risk at 10 years was 10.7% for BRNI vs. 1.0% for breast irradiation alone (p = 0.0003).
CONCLUSION: Nodal irradiation was the only significant risk factor for arm lymphedema in patients receiving breast conservation therapy for early-stage breast cancer. Our data suggest that this risk is low with Level I/II dissection and breast irradiation. However, even after the addition of radiotherapy to the axilla and supraclavicular fossa, the development of lymphedema was only 1 in 10, lower than generally recognized.
Complications from radiotherapy for breast cancer Sao Paulo Medical Journal Mar 2011