This large cohort study analyzed the factors and pain characteristics of postoperative persistent breast cancer in three hospitals. These three hospitals can fully reflect the breast treatment level of China's national, provincial and municipal hospitals. And because the number of patients we followed up was sufficient and the statistical content was comprehensive, it can be considered that this study represents the occurrence of PMPS after breast cancer surgery in China. And this study further divided PMPS into groups according to the degree of pain, analyzed the situation of PMPS during movement and at rest, and determined the risk factors of moderate and severe pain. This is relatively rare in previous reports and articles.
4.1 Incidence
The prevalence of PMPS was 16.9% after 1790 breast cancer patients were investigated, which is slightly lower than that observed in other studies before. This difference is caused by many reasons, such as different patient choices, different tools and methods to measure the degree of pain, and different follow-up periods and methods. Persistent pain after mastectomy was first reported in 1978[10]. In 1986, the international Pain Research Council defined PMPS as persistent pain in the anterior chest, armpit and / or medial upper arm, which occurred shortly after mastectomy or mass resection[35]. Previous studies did not clearly define the duration of pain, and many other terms attempted to better describe PMPS, including post-axillary dissection pain[36], postoperative neuropathic pain after mastectomy[37], chronic pain after breast cancer treatment, persistent pain after mastectomy[38], and persistent postmastectomy pain[12]. This may lead to the widespread occurrence of PMPS and the expansion of the reporting scope. In 2021, Chang and Smith proposed a new definition[5]. This study was followed up with reference to this new definition, so the prevalence rate may be slightly lower than previously reported.
4.2 Risk factors
4.2.1 Age
In 2006, a study showed that youth was often considered a predictor of postoperative pain[39]. Recent studies also show that younger breast cancer patients are more likely to develop PMPS than older breast cancer patients[40-42]. In our study, patients in the PMPS group were also younger than those in the non-PMPS group. However, in the analysis of patients in PMPS group during rest and movement, we found that older patients were more likely to have moderate or severe pain. The specific reason may be related to the physiological changes of pain perception system, through the subjective expression of pain or the changes of physical activities[43, 44]. We believe that younger patients are more likely to perceive the occurrence of pain, while older patients are more sensitive to the degree of pain.
4.2.2 Intraoperative Factors
Many studies have compared the effects of surgical methods on PMPs and found no difference between breast conserving surgery, mastectomy and breast reconstruction surgery[17, 23, 45-49]. In our study, we found that the risk of PMPS in patients after breast conserving surgery was lower than that in patients with total mastectomy. At the same time, the mode of operation had no significant effect on the degree of pain. This may be related to the formation of intercostal and intercostal cutaneous neuroma. Neuroma is formed when the peripheral nerve is damaged and cannot heal normally during operation[50]. The two main types of neuromas include end-stage neuromas that occur when the nerve is completely severed, or continuous neuromas with intact nerves[51]. Intercostal nerve T3 – T6 and its anterior and lateral cutaneous branches innervating the chest wall skin are vulnerable to direct injury and neuroma formation[52]. Total mastectomy has a wide range of surgery, and the probability of neuroma is high, so PMPS is more likely to occur. Such pain is usually manifested as swelling pain or numbness in the surgical area, and may show Tinel sign, accompanied by radial symptoms distributed along the nerve. Meanwhile, phantom breast pain may occur after mastectomy[53]. Similar to distending pain during amputation, phantom breast pain is also considered to be caused by changes in the central nervous system, and peripheral and psychological factors also play a role[54]. The diagnosis of phantom breast pain requires the exclusion of other sources of pain, and the pain comes from the mastectomy area. Injury to the pectoralis major, pectoralis minor or its surrounding fascia during surgery may lead to myofascial pain. The most common feature of myofascial pain is the presence of trigger points[55]. One study showed that patients who underwent mastectomy had significantly more trigger points than those who did not[56].
However, this result may be affected by radiotherapy, because radiotherapy for residual breast tissue is the standard treatment for breast conserving patients. Since radiotherapy is also a risk factor, it is recommended to consider breast surgery and radiotherapy comprehensively when analyzing the results. Any comparison of surgery must be made with patients receiving similar radiotherapy and chemotherapy, and all other risk factors must be evaluated.
Many studies have shown that the staging of axillary lymph nodes is very important for PMPS, that is, patients with ALND have a higher risk of pain than patients with SLNB. Fabro et al. found that PMPS was positively correlated with the number of axillary lymph node dissections[45], while some studies showed that it was not related to the number of lymph nodes, but related to the size of the surgical area[57, 58]. Our study also shows that patients with ALND are more prone to PMPS than patients with SLNB, and the type of axillary surgery has no significant effect on the degree of pain of PMPS. This may be related to intercostal brachial nerve (ICBN) injury. The ICBN usually originates from the lateral cutaneous branch of the second intercostal nerve[59, 60]. It passes through the armpit into the upper arm, providing nerves and feelings for the skin of the armpit and the posterior medial upper arm. Anatomical variation may cause symptoms to spread to the distal elbow, including the extensor muscle of the forearm. Because of this localization, intercostal brachial nerves are easily damaged directly during axillary lymph node dissection. Intercostal brachial nerve injury is related, mainly manifested as burning sensation, tingling sensation and electric shock sensation in axillary or upper arm area. And there may be Tinel sign at the proximal and medial sides of the ipsilateral upper arm[61]. Lymphedema in the axillary region also causes PMPS[5]. Axillary lymphedema is associated with ALND or radiotherapy, with an incidence rate of about 19.9%[62, 63].Lymphedema occurs due to damage to the lymphatic system, mainly manifested in the feeling of limb filling and swelling.
4.2.3 Adjuvant Therapy
It is well known that radiotherapy can lead to neuropathy and neuropathic pain[64, 65]. Patients with conservative breast surgery or mastectomy at high risk of recurrence need radiotherapy. Radiotherapy for residual breast or chest wall and radiotherapy for axillary and clavicle are the main treatments for postoperative radiotherapy after breast cancer surgery. The scope of radiotherapy is related to the scope of operation and condition. Studies have shown if the radiotherapy area needs to include the armpit, it may lead to brachial plexus neuropathy[66, 67]. Pectoralis minor syndrome / neurogenic thoracic outlet syndrome may be related to PMPs after radiotherapy[68, 69]. After breast cancer surgery, the reduction of pectoralis minor muscle is common[70]. This muscle shortening, coupled with further shortening and hardening that may occur in patients undergoing radiotherapy, may lead to compression of the brachial plexus, resulting in pectoralis minor syndrome. Patients often show weakness and tingling in the distribution of pectoralis minor muscle, shoulder, upper arm, forearm and hand. In our study, we also found that there was a positive correlation between radiotherapy and PMPS, and it would aggravate the feeling of pain during activity. As mentioned above, breast conserving surgery and radiotherapy are considered as a complex factor in predicting the incidence of postoperative PMPs. Because radiotherapy may be performed within a few months after surgery. In addition, brachial plexus neuropathy caused by radiotherapy may develop after many years of treatment. It is very important to clarify the relative importance of surgery and radiotherapy in the development of PMPS.
Chemotherapeutic agents such as taxanes, platinum drugs and Changchun flower alkaloids breast cancer can be neurotoxic[71-73]. A study reported that three months after taxane treatment, breast cancer survivors still had chemotherapy-induced peripheral neuropathy[74]. Another study found that neuropathic pain after chemotherapy was related to paclitaxel dose, osteoarthritis, diabetes and chemotherapy induced peripheral neuropathy[75]. However, most studies on PMPs recorded the chemotherapy regimen by dichotomy, and did not record the changes of pain after chemotherapy. In our study, we found that chemotherapy is not directly related to the occurrence of PMPS, but may lead to increased pain during movement. In clarifying whether chemotherapy is a risk factor for PMPS, we should pay more attention to the use of chemotherapy drugs, cumulative dose, administration time and the changes of patients' pain.
Endocrine therapy and HER2-targeted therapy are also common adjuvant treatments after breast cancer surgery. Endocrine therapy includes tamoxifen and aromatase inhibitors, both of which can cause musculoskeletal pain[76]. Aromatase inhibitors can also cause joint pain and affect our diagnosis of PMPs[76-78]. The relationship between HER2-targeted therapy and postoperative pain has not been reported in the literature. In our study, endocrine therapy and targeted therapy are not risk factors for PMPS.
4.2.4 Obesity
Some studies found a positive correlation between BMI and PMPs[79], but at the same time, some studies showed no correlation between them[17, 46]. In patients with high BMI, axillary clearance is more challenging due to more adipose tissue, which may affect the treatment of intercostal brachial nerve, so the patients may face a higher risk of pain and sensory impairment. Obesity can also cause lymphatic pain and arm swelling in breast cancer patients[80]. However, in our study, there was no correlation between PMPS and BMI, and obesity did not increase the degree of PMPS. In conclusion, BMI still needs to be included in the future research on PMPS, especially the research on axillary surgery.
4.2.5 Ethnicity
Experimental studies show that people of different races have different sensory thresholds for pain[81]. Some studies have found that breast cancer survivors from different races differ in their survival experience[82, 83]. In our study, we distinguished the Han nationality from other nationalities and found no difference in PMPS between the two groups. In future studies of breast cancer patients, we need to consider the subracial differences in cultural attitudes, values and beliefs.
4.2.6 Physical and psychological conditions
According to the literature, the physical and psychological conditions before operation will affect the occurrence of PMPS[5, 42, 84-86]. Preoperative pain is considered to be one of the risk factors of postoperative persistent pain. One study found a positive correlation between preoperative pain and PMPS[87]. In a large national study, the incidence of persistent pain in the surgical area was higher in patients with pain elsewhere, which was consistent with the study of other surgical procedures[88]. In our study, the past history of patients was counted, including whether they had breast history, cancer history, or other surgical history. It was found that there was no clear correlation with PMPS. Studies have shown that diabetes is positively correlated with postoperative pain[89, 90], which may be related to diabetes induced neuropathy. But in our research, we have statistics on hypertension, diabetes, heart disease, menarche time, menstrual period and allergy history. We found that underlying diseases are not related to the occurrence of PMPS, and do not aggravate the pain.
4.3 Prevention and treatment
According to the researches, long term postoperative pain can cause anxiety and seriously affect the quality of life of patients after operation[91-93]. And the more severe the pain, the more serious the anxiety. In our study, we found that the HADS-A score of patients with painless or mild pain was much lower than that of patients in the moderate and severe pian group, indicating that pain had a great impact on the psychology of patients. At the same time, moderate and severe pain will lead to the decline of patients' satisfaction with their breasts and the weakening of psychosocial well-being. Further, patients with moderate to severe PMPS will think they are in a state of disease for a long time and are more dissatisfied with the surgeon. This will form a vicious circle, resulting in great physical and psychological trauma to patients. However, in our PMPs patients, only about 10% of patients have received relevant pain management treatment, and other patients have not received standardized treatment, resulting in long-term pain and affecting life. Therefore, we should actively prevent and treat PMPS.
4.3.1 Pain prevention
For patients with high risk factors of PMPS, we need to pay more attention to the prevention of pain. A meta-analysis showed that psychosocial intervention had a good effect on reducing pain intensity and pain interference in ordinary cancer patients[94]. There are also psychological studies that show that actively giving psychological counseling to patients before operation can reduce postoperative pain and anxiety[95, 96]. Therefore, medical staff and patients' families need to actively help patients to create a comfortable and happy mood.
During the operation, the surgeon should avoid damage to the pectoralis major, pectoralis minor and its fascia[97]. Especially in axillary surgery, it is necessary to protect the intercostal brachial nerve (ICBN) from injury. At the same time, some studies have shown that nerve block during operation can avoid the occurrence of PMPS[98-101]. On the premise of ensuring the complete removal of the focus during the operation, it is recommended to protect the skin, residual breast tissue, lymphoid tissue and nerve tissue as much as possible to avoid damage. A study has shown that complete resection of the injured intercostal nerve can also reduce the occurrence of neuroma and postoperative pain[102].
More attention should be paid to the prevention of PMPS after operation. According to our study, even six months after surgery, patients are still likely to have PMPS, with a probability of about 20%. Physiotherapy is an integral part of PMPS management, especially in maintaining glenohumeral and scapular chest movement, strength and normal neuromuscular recruitment patterns, and minimizing upper limb dysfunction[6]. According to the clinical practice guidelines[103, 104], it is generally recommended that patients start physical therapy and small-scale movement of the surgical side forearm on the second day after surgery. After removing the surgical drainage tube, the patient can carry out one-step mild range of motion exercise and gradually carry out active stretching. Then perform intensive exercise within 6-8 weeks until the full range of motion of the upper limb is reached. Studies have shown that patients' postoperative active movement has been proved to be effective in improving shoulder range of motion and reducing postoperative pain. Studies have shown that patients' postoperative active movement has been proved to be effective in improving shoulder range of motion and reducing postoperative pain[105].
4.3.2 Pain treatment
Oral pharmacological agents are the most common way of pain treatment, which has the advantages of conservative and noninvasive. Considering the good prognosis of breast cancer treatment, we must consider the long-term consequences of analgesic treatment. At present, there is no report on specific analgesic pharmacological agents for PMPS. Generally speaking, indications for pharmacological therapy for breast cancer survivors are similar to those of non-cancer patients. A double-blind randomized controlled trial showed that oral pregabalin 75mg two times a day for a week from the beginning of operation can reduce the incidence of postoperative pain syndrome in breast cancer[106].A multicenter, factorial, randomized, controlled trial also showed that perioperative oral pregabalin and intraoperative lidocaine infusion can reduce persistent neuropathic pain after breast cancer surgery[98]. An earlier study reported the effect of levetiracetam on postoperative pain syndrome in breast cancer patients[107]. At present, there are still few studies on the drug treatment of PMPS, and there are some limitations, including insufficient research, small sample research and single center research, which limit the universality and hinder its wide application in clinical practice
Local anesthetics and regional anesthesia are possible treatments for patients with persistent pain after breast cancer surgery[108]. At present, a large number of literatures have reported that interventional therapy can significantly alleviate the acute pain after breast surgery[109-111]. Meanwhile, interventional techniques have also made progress in the study of chronic pain after breast cancer surgery. In 2014, a randomized controlled trial was conducted to compare the effects of paravertebral block and local anesthesia on pain management after 1 years of breast cancer surgery[112]. The nerve block areas seen include thoracic nerves, serratus plane blocks, intercostal brachial nerves and parathoracic nerves. One literature studied the effect of regional anesthesia on persistent pain after mastectomy and found that regional anesthesia was related to the reduction of pain severity and pain effect at 3, 6 and 12 months after mastectomy[91]. Local anesthetics and regional anesthesia are effective in relieving and treating chronic pain, but it should be noted that it is generally recommended to operate under the guidance of ultrasound to avoid further damage to patients.
Multidisciplinary combination therapy can also alleviate PMPS. There is strong evidence that multidisciplinary treatment of chronic pain can accelerate patients' recovery and improve their quality of life[113]. Multidisciplinary treatment often includes surgeons, pain physicians, nurses, psychologists, pharmacists and physiotherapists according to the actual situation. One piece of literature describes the development of transitional pain services (TPS) as a model of postoperative pian care.[114]. Another study has shown that reviewing TPS can minimize the risk of postoperative chronic pain[115].
Other treatments such as music, aromatherapy and acupuncture treatment seem to be effective in reducing preoperative anxiety and postoperative pain in breast cancer[116].
4.3 Study limitations.
Because it is a retrospective study, this study lacks the statistics of patients' psychological state before operation. Therefore, further research on PMPS needs to be designed as a comprehensive and prospective study.