PAIN SYNDROMES IN SURVIVORS WITH BREAST CANCER Sebastiano Mercadante, MD Director Anesthesia and Intensive Care Unit Pain Relief and Palliative Care Unit La Maddalena Cancer Center Palermo – Italy Professor of Palliative Medicine University of Palermo
Pain in the different stages of disease At any stage 40-50% Advanced disease 72% Survivors ?
A large number of disease-free cancer survivors live with pain or neuropathies induced by treatment or by the cancer itself. Sometimes these conditions resolve over time, but irreversible damage to tissue and nerves can cause pain and neuropathy to progress and persist indefinitely. Because health care professionals may not recognize these as delayed problems or know how to identify those at greatest risk, many of these conditions go undiagnosed and untreated.
Pain and other symptoms during the first year after radical and conservative surgery for breast cancer.
Tasmuth T , Br J Cancer. 1996
Pain, neurological symptoms, oedema of the ipsilateral arm, anxiety and depression occurring in women treated surgically for breast cancer,
One year after surgery, 80% of the women had treatment-related symptoms in the breast scar region and virtually all pts had symptoms in the ipsilateral arm . The incidence of chronic post-treatment pain was higher after conservative surgery than after radical surgery
Numbness occurred in 75% and oedema of the ipsilateral arm in over 30% of the pts after both radical and conservative surgery. Phantom sensations in the breast were reported by 25% of the patients.
No difference in psychic morbidity was detected after the two types of surgery . Both the anxiety and depression scores were highest before surgery, decreasing with time, and were significantly correlated with preoperative stressful events.
Have women operated in high volume surgical units have less chronic symptoms than women operated in smaller volume units?
Chronic symptoms were less common in HVU than in LVU: chronic pain (56 vs. 43%) or strange sensations (45 vs. 26%) in the ipsilateral arm or phantom sensations in the removed breast (66 vs. 26%, P<0.001).
The risk factors chronic pain in the breast:
intensity of acute post-operative pain
For chronic arm pain:
low volume unit
More careful surgical technique seems to reduce the risk of chronic pain following treatment of breast cancer . Chronic pain is associated with more intense post-operative pain and depression
Chronic post-treatment symptoms in pts with breast cancer operated in different surgical units. Tasmuth et al, Eur J Surg Oncol 1999
Long-term morbidity following axillary dissection in breast cancer pts: clinical assessment, significance for QoL and the impact of demographic, oncologic and therapeutic factors.
Kuehn T , Breast Cancer Res Treat. 2000
396 pts retrospectively using a self-report questionnaire and a clinical examination.
Shoulder-arm morbidity and fear of cancer recurrence were the most important long-term sources of distress following breast cancer surgery in our study population.
Shoulder-arm morbidity following axillary dissection is a frustrating polysymptomatic disease that seems to be relatively unaffected by therapeutic measures.
The surgical trauma necessary for adequate tumor staging (removal of 10 lymph nodes) seems decisive for the postsurgery syndrome following axillary dissection. For node-positive patients complete axillary clearing may improve tumor control without worsening long-term morbidity.
New techniques, such as the sentinel-node-biopsy, that selects patients with negative axillary status while preserving the integrity of axillary structures, may improve the overall morbidity.
Shoulder and arm problems after radiotherapy for primary breast cancer. Deutsch M , Flickinger JC .
Am J Clin Oncol. 2001
331 seen during a 6-month period for follow-up after radiotherapy postlumpectomy or mastectomy for primary breast cancer. Local treatment included lumpectomy and breast irradiation with or without axillary dissection.
There is a low incidence of arm edema, decreased range of motion of the ipsilateral shoulder, and shoulder-arm pain in patients undergoing postlumpectomy or postmastectomy radiotherapy. Ipsilateral arm edema occurred in 20 women (6.0%), limited ipsilateral shoulder motion in 5 (1.5%), and ipsilateral shoulder pain in 5 (1.5%). Edema was mild (1+) in 15 patients and moderate (2+) in five patients.
Multivariate analysis revealed that the risk of arm edema was significantly increased in black women and with mastectomy
Results of a questionnaire survey for symptom of late complications caused by radiotherapy in breast conserving therapy. Ishiyama H , Breast Cancer 2006
A cross-sectional survey was conducted on 247 patients who had had early breast cancer and who were free of recurrence after BCT.
Common perceptions of late complications included shrinking in size (85%), pain (73%), firmness (65%), thickening of the arm (34%), and changes in skin color (19%). However, high-grade toxicity (above Grade 2) was perceived in only 0.52-7.8% of patients.
In multivariate models, pain was associated with additional boost irradiation
Late complications as perceived by the patient herself after BCT are common, but tend to be of minimal severity. Most predictive factors are inevitably associated with late complications. However, the boost irradiation may not be indicated for every patient from a QOL perspective.
Pain after QUART and RT for early-stage breast cancer: incidence, characteristics and influence on quality of life. Results from a retrospective study. Amichetti M , Caffo O . Oncology. 2003
Conservative breast surgery has clearly improved the impact of local treatment on postoperative body image adjustment, but the effect on patients' quality of life (QL) is similar to that observed after mastectomy.
Retrospective study of 348 pts treated with CBS and RT, who completed a questionnaire (72%)
141/348 pts reported pain as a consequence of treatment .
It generally started within 3 months after the completion of therapy, was localized in the axillary region and was intermittent.
The pain was mainly described as aching (59%), tender (51%) and cramping (43%). Compared to the pts who did not experience pain, those who suffered from pain had significantly worse scores in physical, psychological, autonomy,and relational subscales.
Such symptoms can cause postoperative psychosocial distress,
Concurrent administration of adjuvant chemotherapy and RT after breast-conservative surgery enhances late toxicities . Toledano A , Cancer Radiother. 2006 214 pts were eligible for late toxicity. After breast-conserving surgery with axillary dissection, pts were treated either with sequential treatment with CT first followed by RT (arm A) or CT administered concurrently with RT (arm B). Following breast conserving surgery, the concurrent use of CT with RT is significantly associated with an increase incidence of grade 2 or greater late side effects. No statistical difference was observed between the two arms concerning grade superior or equal to 2 pain, breast oedema, and lymphoedema .
Long-term morbidity of pts with early breast cancer after sentinel lymph node biopsy compared to axillary lymph node dissection.
Schulze T , J Surg Oncol. 2006
Sentinel lymph node biopsy (SLNB) requires less traumatic surgery to the axilla than axillary lymph node dissection (ALND).
134: pts SNLB only, 103 pts had SLNB followed by ALND or ALND only.
Loss of strength and hypaesthesia were less frequent after SLNB . No lymph oedema occurred after SNLB without adjuvant radiotherapy. Subjective complaints concerning pain, hypoesthesia, and paresthesia were more common in the ALND group . No axillary recurrence developed in either group.
Isolated SLNB in node-negative is a highly efficient tool to reduce postoperative long-term morbidity without compromising the local control of the disease.
Effects of chronic widespread pain on the health status and quality of life of women after breast cancer surgery. Burckhardt CS , Jones KD . Health Qual Life Outcomes. 2005
A cross-sectional, descriptive design compared two groups of women with chronic pain that began after surgery: regional pain (n = 11) and widespread pain (n = 12).
A majority of both groups described their pain as aching, tender, and sharp on the MPQ-SF.
Women who experienced widespread pain after breast cancer surgery had significantly more severity of pain, pain impact and lower physical health status than those with regional pain.
Long-term follow-up of breast cancer survivors with post-mastectomy pain syndrome. Macdonald L , Br J Cancer. 2005
The aim of this study was to assess long-term outcome at 7-12 yrs postoperatively
Of 175 women reporting PMPS in 1996, 138 were eligible for questionnaire follow-up in 2002. Mean time since surgery was 9 yrs
52% women reported continued PMPS since the previous survey in 1996.
QoL scores were significantly lower in women with persistent PMPS compared to those women whose pain had resolved. However, for women with persistent PMPS, SF-36 scores had improved over time.
Risk factors for persistent PMPS included younger age and heavier weight .
SURGERY-RELATED PAIN AND NEUROPATHY Breast surgery
Chronic pain after mastectomy or lumpectomy with axillary node dissection is reported in about 20% of women. Believed to be related to intercostobrachial nerve trauma, this pain, often called postmastectomy pain syndrome (PMPS), is characterized by burning, shooting, and electric shock–like sensations in the skin around the surgical sites.
Recent data suggest that it may be more common among younger, overweight, and black, being single, and having a short education .
Risk factors for acute pain and its persistence following breast cancer surgery. Katz J , Pain. 2005
Identify risk factors for acute pain and its persistence one month following breast cancer surgery in 114 women scheduled for breast cancer surgery
In univariate analyses, the risk of clinically meaningful acute pain was increased among women who were younger, unmarried, had more invasive surgeries, and had greater preoperative emotional distress .
In multiple logistic regression analyses, greater preoperative anxiety was the only variable that made an independent contribution to predicting clinically meaningful acute pain at 2 days after surgery whereas younger age, being unmarried, and preoperative anxiety each made an independent contribution to predicting clinically meaningful acute pain that persisted from 2 to 30 days after surgery.
These results increase understanding of neurobiologic mechanisms and psychosocial processes that contribute to the development of acute pain following breast cancer surgery and have implications for the development of interventions to prevent it.
Factors related to post-treatment chronic pain in breast cancer survivors: the interference of pain with life functions. Gulluoglu Int J Fertil Womens Med. 2006 Treatments completed at least 6 months before and were free of disease . The factors related to chronic pain were compared between pts with and without chronic pain. 85 eligible pts were included in the study. 39 ( 46%) pts declared that they had chronic pain. The mean VAS scale score was 4.1 . Younger age and receiving radiotherapy were found to be significant contributing factors. The interference of post-treatment chronic pain with life functions was small. Overall, mood was found to be the most affected life function among all.
Risk factors for chronic pain following breast cancer surgery: a prospective study. Poleshuck EL , J Pain. 2006
Chronic pain following breast cancer surgery is associated with decreased health-related quality of life and is a source of additional psychosocial distress in women who are already confronting the multiple stresses of cancer.
95 women scheduled for breast cancer surgery.
In a multivariate analysis of the presence of chronic pain, only younger age was associated with a significantly increased risk of developing chronic pain 3 months after surgery. In an analysis of the intensity of chronic pain, more invasive surgery, radiation therapy after surgery, and clinically meaningful acute postoperative pain each independently predicted more intense chronic pain 3 months after surgery.
Preoperative emotional functioning variables did not independently contribute to the prediction of either the presence or the intensity of chronic pain after breast cancer surgery.
Clinical variables and severe acute pain were risk factors for chronic pain following breast cancer surgery, but psychosocial distress was not, which provides a basis for hypothesizing that aggressive management of acute postoperative pain may reduce chronic pain.
Neurologic examinations should be conducted, which include identifying the presence of sensitivity to touch or numbness of the affected areas, motor weakness, abnormal reflexes in deep tendons, disturbances in gait and balance, and orthostatic hypotension
Have you had any pain or discomfort in the area where you had surgery or radiation therapy; discomfort, pain, or unusual sensations in your hands or feet; weakness in your legs or arms; or problems moving around?
How much pain are you experiencing? What does it feel like? What makes it better or worse?
Preincisional paravertebral block reduces the prevalence of chronic pain after breast surgery. Kairaluoma PM , Bachmann MS , Anesth Analg. 2006 - In addition to providing acute postoperative pain relief, preoperative paravertebral block reduces the prevalence of chronic pain 1 yr after breast cancer surgery
Regional block and mexiletine: the effect on pain after cancer breast surgery.- Fassoulaki A , Reg Anesth Pain Med. 2001- Regional block reduced the analgesic requirements in the early postoperative period, while mexiletine combined with regional block reduced the total analgesic requirements during the next 5 postoperative days. Although chronic pain was not affected by these treatments late-abnormal sensation may be diminished by combination of these treatments
The analgesic effect of gabapentin and mexiletine after breast surgery for cancer. Fassoulaki A , Anesth Analg. 2002 - Mexiletine and gabapentin reduced the postoperative analgesic requirements, and particularly, gabapentin reduced pain after movement. The overall incidence of chronic pain was unaffected except for burning pain .
EMLA reduces acute and chronic pain after breast surgery for cancer. Fassoulaki A , Reg Anesth Pain Med. 2000 - The application of EMLA to patients undergoing breast surgery for cancer reduced the postoperative analgesic requirements and the incidence and intensity of chronic pain
Multimodal analgesia with gabapentin and local anesthetics prevents acute and chronic pain after breast surgery for cancer. Fassoulaki A , Anesth Analg. 2005 - M ultimodal analgesia on acute and chronic pain after breast surgery for cancer. Gabapentin, eutectic mixture of local anesthetics cream, and ropivacaine in the wound or three placebos. Multimodal analgesia reduced acute and chronic pain after breast surgery for cancer.
Multimodal Analgesia with Gabapentin and Local Anesthetics prevents Acute and Chronic Pain After Breast Surgery Fassoulaki et al, Anesth Analg 2005
50 pts scheduled for breast cancer surgery blindly randomized to receive gabapentin, eutectic mixture of local anesthetics cream, and ropivacaine in the wound or three placebos .
The treatment group consumed less analgesics than the controls, exhibited lower visual analog scale scores at rest in the PACU and on postoperatively (1,3,5, days), and after movement in the PACU and on postoperative Days 2, 4, and 8.
3 and 6 mo after surgery, 18 of 22 (82%) and 12 of 21 (57%) of the controls reported chronic pain versus 10 of 22 (45%) and 6 of 20 (30%) in the treatment group;
5 of 22 and 4 of 21 of the controls required analgesics versus 0 of 22 and 0 of 20 of those treated
Multimodal analgesia reduced acute and chronic pain after breast surgery for cancer.
Evaluation of efficacy of the perioperative administration of venlafaxine XR in the prevention of postmastectomy pain syndrome . Reuben SS , J Pain Symptom Manage. 2004
Perioperative administration of venlafaxine beginning the night prior to surgery significantly reduces the incidence of PMPS following breast cancer surgery .
Venlafaxine in neuropathic pain following treatment of breast cancer. Tasmuth T , Eur J Pain. 2002
Evaluation of the effectiveness of venlafaxine in neuropathic pain. The average daily pain intensity not significantly reduced by venlafaxine compared with placebo. Poor responders had low venlafaxine concentrations
Amitriptyline effectively relieves neuropathic pain following treatment of breast cancer.
Kalso E , Pain. 1996
The effectiveness of amitriptyline in relieving neuropathic pain following treatment of breast cancer was studied in 15 patients in a RC DB CO study. The dose was escalated from 25 mg to 100 mg per day in 4 weeks.
Amitriptyline significantly relieved neuropathic pain both in the arm and around the breast scar. 8 out of 15 patients had a more than 50% decrease in the pain intensity ('good responders') with a median dose of 50 mg of amitriptyline.
The 7 patients who had a less than 50% effect had drug concentrations equaling those of the good responders. The 'poor responders' reported significantly more adverse effects with amitriptyline and placebo than the good responders.
It is concluded that amitriptyline effectively reduced neuropathic pain following treatment of breast cancer. However, the adverse effects of amitriptyline put most of the patients off from using the drug regularly
GABAPENTIN FOR NEUROPATHIC CANCER PAIN. A RC TRIAL. Caraceni et al, J Clin Oncol 2004
121 pts with neuropathic pain due to cancer partially controlled with systemic opioids.
Symptomatic hypogonadism in male survivors of cancer with chronic exposure to opioids.
Rajagopal A et al , Cancer 2004 .
Profound hypogonadism has been noted in patients receiving intrathecal opioids.
Determine whether chronic consumption of oral opioids by male survivors of cancer also would lead to central hypogonadism
20 pts chronically consuming opioids were compared with 20 matched controls.
18 of the 20 pts (90%) exhibited hypogonadism, compared with 8 of the 20 control patients (40%)
Testosterone was 145 versus 399.5 ng/dL, FSH l was 2.85 versus 5.3 mIU/mL, LH was 1.8 versus 4.2 mIU/mL,
Survivors of cancer who chronically consumed opioids experienced symptomatic hypogonadism with significantly higher levels of depression, fatigue, and sexual dysfunction. With the increasing use of opioids among patients with cancer, further research in improving quality-of-life outcomes is warranted.
Failing to Plan Is Planning to Fail: Improving the Quality of Care With Survivorship Care Plans. Craig C. Earle, J Clin Oncol, 2006
"From Cancer Patient to Cancer Survivor: Lost in Transition"
Any previously existing follow-up guidelines for cancer survivors have been largely restricted to surveillance for recurrence of the primary disease.
An important message of the Institute of Medicine report is that survivorship care plans must surpass this and address the chronic effects of cancer ( pain, fatigue, premature menopause, depression/anxiety), monitoring for and preventing late effects like osteoporosis, heart disease, and second malignancies, and promoting healthy lifestyles.
Improvement in sexual function after reduction of chronic high-dose opioid medication in a cancer survivor.
Rajagopal A & Bruera E . Pain Med 2003
A 58-year-old male, free of cancer for 12 years, with chronic low back pain from a prior retroperitoneal mass.
A decrease in morphine-equivalent daily dose from 690 mg to 20 mg resulted in a significant increase in sexual function. Reduction in opioid consumption can dramatically increase libido and sexual function. A possible mechanism involves opioid-related effects on the hypothalamic-pituitary-gonadal axis
Hypogonadism and sexual dysfunction in male cancer survivors receiving chronic opioid therapy. Rajagopal A , JPSM 2003
Prevalence of central hypogonadism and sexual dysfunction in male cancer survivors exposed to chronic high-dose oral opioid therapy.
20 male pts with cancer-related chronic pain who were disease-free for at least one year. At least 200 mg-equivalent of morphine on a daily basis for at least one year.
Serum testosterone levels were reduced, no compensatory increase in FSH and LH. The sexual desire score was reduced .
Chronic exposure to high-dose oral opioid therapy may result in marked central hypogonadism and sexual dysfunction . Given the increasing use of long-term opioid therapy for chronic pain syndromes, further investigation into these findings is warranted.
Chronic pain, lymphoedema, post-irradiation neuropathy and other symptoms are reported in as many as 75% of women following breast cancer treatment. This study examined pain and sensory abnormalities in women following breast cancer surgery.
Sensory threshold to pinprick and thermal stimuli was significantly higher on the operated side in both groups while pressure pain threshold was significantly lower in pain patients on the operated side compared to the contralateral side. No side to side difference was seen in pressure pain threshold in the pain-free group.
Evoked pain intensity to repetitive stimuli was significantly higher on the operated side in pain patients compared to the control area while no such difference was seen in pain-free patients.
Cutaneous blood flow was significantly higher on the operated side compared to contralaterally in pain patients, while no side to side difference was seen in pain-free patients.
Sensitization seems to be a feature in breast cancer-operated women with pain, but not in pain-free women.
Health-related quality of life in long-term breast cancer survivors: Nationwide survey in Denmark. Peuckmann V , et al, Breast Cancer Res Treat. 2006
An age-stratified random sample of 2,000 female BCS >/= 5 years after primary surgery without recurrence compared with 3,104 women.
HRQOL was similar between BCS and women of the general population.
However, predictors for worse HRQOL in BCS were being single, and having a short education .
Full-Dose IORT with Electrons in Breast Cancer : First Report on Late Toxicity and Cosmetic Results from a Single-Institution Experience Mussari S , Strahlenther Onkol. 2006
Exclusive adjuvant IORT after conservative surgery to evaluate late effects and cosmetic results after this new conservative treatment.
47 consecutive pts , after a follow-up of a median of, 48 months.
15 pts developed breast fibrosis (grade 2 in 14 patients, grade 3 in one patient), 2 pts presented with grade 3 skin changes, 1 pt developed a clinically relevant fat necrosis, and 1 pt showed breast edema and pain. 2 pts developed contralateral breast cancer and 1 distant mts; no local relapses occurred.
Asymptomatic findings of fat necrosis were observed at mammography in 12 pts (25.5%), while an hypoechoic area was revealed by sonography in 10 pts (21.5%). In 4 pts (8%), mammographic and sonographic findings suggested malignant lesions and required a rebiopsy to confirm the benign nature of the lesion.
Jung BF , Pain. 2003 Neuropathic pain following breast cancer surgery: proposed classification and research update. Edwards RR , Raja S J Pain Symptom Manage. 2006 The laterality of long-term pain following mastectomy. Pain. 2005 Nov;118(1-2):10-4. Epub 2005 Oct 4. Links Neuropathic pain associated with non-surgical treatment of breast cancer. Jung BF , Herrmann D , Griggs J , Oaklander AL , Dworkin RH .
Pain and quality of life after surgery for breast cancer. Caffo O , Breast Cancer Res Treat. 2003
Regardless of the type of operation, BC patients may feel pain even without recurrent disease with poor adjustment in terms of quality of life (QL).
A questionnaire was mailed to a consecutive series of 757 disease-free pts
Analysis of 529 pts who underwent axillary dissection.
Pain after surgery for BC distress almost one-third of patients, regardless of the type of treatment, and had a negative effect on patients' QL. The different surgical procedures may marginally influence the quantitative characteristics of pain.
Risk factors for pain after mastectomy/lumpectomy.
Carpenter JS , Cancer Pract. 1999
Potential risk factors for PMP including demographic, disease, and treatment variables, as well as surgical factors, such as surgical technique and number of lymph nodes removed..
Contrary to expectation, PMP was found in women postlumpectomy without axillary dissection, women whose intercostobrachial nerve was spared, and women without documented postoperative complications.
Cases of PMP cannot uniformly be identified based on the presence or absence of certain factors . Findings also underscore the need to screen all women for PMP after breast cancer surgery, particularly given the availability of effective pain management therapies