Prevalence of persistent pain after breast cancer treatment by detection mode among participants in population-based screening programs

Breast cancer is the most frequent malignancy among Spanish women, with an estimated 25,215 new cases in 2012 [1]. Screening programs and improved treatments have reduced mortality from this disease [2]. Early detection allows more effective treatment, but the treatment itself is not free of complications in the short term or sequels in the long term. Women with interval cancer (cancers detected clinically after a negative screening round and before the following screening invitation) may not benefit from early detection because of a delay in diagnosis and less favourable biological tumor characteristics [3].

To date, complications have not been evaluated by according to the detection method. Among complications, persistent pain, defined by some authors as pain in the breast area, axilla, shoulder or arm for more than 3 months after breast cancer surgery, has been reported as one of the most frequent long-term complications [4]. Among patients treated surgically for breast cancer, the prevalence of persistent pain may range from 10 % to 50 % or more, depending on the characteristics of the population studied, as well as on the definition of persistent pain [4‐16]. Several factors have been associated with the risk of developing persistent pain: young age [5‐7, 10, 12, 14, 16, 17] adjuvant therapies (chemotherapy or radiotherapy) [5, 11], axillary lymph node dissection (ALND) [5‐7, 10, 12], and the presence of comorbidities [5, 16], among others, but the evidence remains inconclusive.

Given that a substantial number of women are diagnosed with breast cancer and that most are treated surgically, a large number of women can be expected to experience persistent pain, which may negatively affect their quality of life and psychosocial well-being. Therefore, from the perspective of public health, persistent pain in women treated for breast cancer is an important health problem. To date, study of the risks and benefits of breast cancer screening has not included the onset of complications and sequels after breast cancer treatment within the context of population-based screening programs. Women with screen-detected breast cancer benefit from early detection and have better survival [18, 19]. However, no studies have evaluated whether these women also benefit from fewer complications and have less persistent pain in the long term. The risk-benefit analysis of breast cancer screening should include information on complications in women with screen-detected breast cancer.

We aimed to investigate the prevalence of persistent pain and associated factors in women diagnosed with breast cancer (screening or interval) in the context of a population-based breast cancer screening program in Spain.

Of the 1,086 women included in the CAMISS cohort, most were treated surgically (n = 1,057, 97.3 %) and were included in the analysis. Breast cancer was detected during routine screening mammograms in 732 women (69.3 %) and emerged as interval cancer in 325 (30.7 %). The characteristics of the women and detected tumors by detection mode, as well as the treatments provided, are shown in Table 1. Women with interval cancers had larger tumors, with a higher percentage of positive lymph node involvement (44.4 % vs. 25.8 %; P < 0.001). The percentage of ductal in situ tumors was higher among women with screen-detected tumors (11.1 % vs. 3.8 %; P < 0.001). Histological grade III was more frequent among women with interval cancers (42.3 % vs. 24.2 %; P < 0.001), as well as among those with triple negative phenotype (16.1 % vs. 8.1 %; P < 0.001). Women with interval cancer were younger than those with screen-detected cancers (P < 0.001). No differences in the Charlson index were observed according to the detection method. Most women underwent conservative surgery (n = 829, 78.6 %). According to the detection method, radical surgery was more common among women with interval cancers (33.0 %) than in those with screen-detected cancers (16.3 %) (P < 0.001). ALND was more common in women with interval cancers than in those with screen-detected tumors (78.4 % vs. 70.6 % P < 0.05). Neoadjuvant therapy was more frequent in women in the interval cancer group than in the screening group (24.0 % vs. 4.2 % P < 0.001).

A total of 313 women (29.6 % 95 % CI: 27.4 –33.0) experienced at least one complication during follow-up. Among all the complications reported, the most frequent was persistent pain, which was present in 118 women (11.3 % 95 % CI: 9.4 –13.2). Women who were diagnosed in routine screening reported a higher prevalence of persistent pain (12.9 % 95 % CI: 10.4 –15.3) than those with tumors that emerged as interval cancers between two screening rounds (7.8 % 95 % CI: 4.8 –10.7) (P < 0.05) (Table 1).

Table 2 shows the prevalence of persistent pain according to women’s characteristics, the detection method and tumor characteristics. Women aged 65–70 years had a lower prevalence of persistent pain (8.7 %) than those from other age groups (50–54 years: 11.8 %, 55–59 years: 13.2 %, 60–64 years: 10.5 %). However, these differences were not statistically significant (P = 0.483). A gradient was observed in the prevalence of persistent pain, according to the Charlson index. Women without other comorbidities (Charlson index = 0) had the lowest prevalence of persistent pain (8.5 %), whereas those with a Charlson index > =2 had the highest prevalence of persistent pain (21.9 %) (P < 0.001). According to the detection method, women with screen-detected tumors had a higher prevalence of persistent pain than women with interval tumors (12.9 % vs. 7.8 % P < 0.05). When tumor characteristics were analyzed, the prevalence of persistent pain was higher among women with lobular histological type tumors (14.3 %) (P < 0.05). No statistically significant differences in the prevalence of persistent pain were observed by tumor size, lymph node involvement, focality, histology or phenotype.

Table 3 shows the prevalence of persistent pain according to the treatments provided. The prevalence of persistent pain was higher among women who underwent ALND than in those who underwent SLNB only (13.7 % vs. 6.7 % P < 0.001). The prevalence was also higher in women who received chemotherapy after surgery than those who did not (14.5 % vs. 8.4 % P < 0.01). No statistically significant differences in persistent pain prevalence were observed according to the type of surgery, neoadjuvant therapy, radiotherapy, hormone therapy or Her2 treatment after surgery.

The factors associated with persistent pain were described using univariate and multivariate logistic regression models (Table 4). In the univariate analysis, five factors were associated with persistent pain (detection method, Charlson index, histological type, axillary treatment and chemotherapy after surgery). In the multivariate model, only the Charlson index remained statistically significant, with the highest odds ratio (OR). Women with a Charlson index > =2 had an OR of 4.5 (95 % CI: 2.1 –9.5) with respect to women without comorbidities (Charlson index = 0). Persistent pain was also more frequent among patients with ALND than in those with SLNB only, although this result was at the limit of statistical significance (OR: 2.0 95 % CI: 1.0 – 4.0).

The prevalence of persistent pain was higher in women diagnosed within the screening program than in those with interval cancers. Our first hypothesis was that, given the benefits of screening (early diagnosis, with less aggressive tumors), the treatment of screen-detected cancer would be less intensive and, therefore, have fewer complications. Surprisingly, we observed that women diagnosed within the screening program did not benefit from fewer complications; on the contrary, they initially seemed to have more persistent pain. However, in the multivariate analysis only two factors showed a clear association with the onset of persistent pain: the presence of other comorbidities and the performance of an ALND.

The prevalence of persistent pain in our study was 11.3 %. This prevalence is relatively low compared with that in other studies, which include all diagnostic methods and women of different ages, with values ranging from 10 % to 50 % or more [4, 5, 7‐12, 14, 16]. In our study, information on the presence of persistent pain was extracted through the medical records review. Women were considered to have persistent pain if they had pain (either in the arm, breast area or shoulder) 3 months after surgery, but this information had to have been registered by the physician during the clinical course. If women had been asked the question “Do you have any pain?” the prevalence could possibly have been higher than 11.3 %. Our results might be interpreted as follows: 11.3 % of women treated for breast cancer had clinically relevant pain, since pain was recorded in the medical record. In addition, some cultural differences may exist in pain perception. In a European survey of chronic pain, Spanish participants reported the lowest prevalence of chronic pain (12 %) [26]. Another possible reason for the low prevalence of persistent pain is that our patients came from screening and, therefore, had less aggressive tumors and less use of ALND than women with breast cancer of all ages, including those with a symptomatic diagnosis.

Among the risk factors described in the literature, young age is usually reported to be a risk factor for developing persistent pain [5‐7, 10, 12, 14, 17]. In our study population, women aged 65–70 years had the lowest prevalence of persistent pain, but the differences were not statistically significant. Since our study population only comprised women participating in population-based breast cancer screening programs, we were unable to investigate persistent pain among women of younger ages (50 years or younger) or older ages (more than 70 years).

The presence of other comorbidities has been proposed as an associated factor in the development of persistent pain [5, 16]. In our study, we investigated the presence of other comorbidities by using the Charlson index. Women with a Charlson index equal to 2 or higher had a much higher risk of developing persistent pain. It is well established that previous painful conditions predispose patients to persistent pain after surgery [5, 7, 16]. In addition, women with several comorbidities may have more depression, anxiety and other psychosocial factors that may also be risk factors for persistent pain [5, 27].

The use of ALND has been described in the literature as a risk factor for developing persistent pain [6, 7, 10, 12, 14] and in our study remained a risk factor at the limit of statistical significance in the multivariate analysis. These studies report that women with an ALND had OR values between 2.0 and up to 7.7 and, in our study, women with an ALND had an OR of 2.0. This variability may be partly due to differences in the reference population: some studies take women without ALND as the reference, whereas others take those with SLNB as the reference category.

Some studies have found that chemotherapy is related to persistent pain [5, 11]. In our study, the univariate analysis showed that women who received chemotherapy after surgery had a higher risk of persistent pain than those who did not but this result was not statistically significant in the multivariate analysis. Therefore, chemotherapy may be associated with the onset of persistent pain, but other factors are more strongly associated with to pain.

Our study has some limitations. Pain was not evaluated with validated instruments such the Visual Analogue Scale, Numerical Rating Scale or specific pain questionnaires, and could be underestimated. Most published evidence is based on pain measurement with validated instruments and therefore our results are not directly comparable to those of studies using these instruments. However, the value of reporting pain recorded in the medical record is a valid measure for clinically relevant pain, which could be comparable to the prevalence of moderate/severe pain reported in other studies. Moreover, our study did not collect women’s height and weight, the two variables used to calculate the body mass index, a variable that has been proposed as a risk factor for developing persistent pain [14, 16]. Equally, variables related to psychosocial factors were not collected, which are well-established risk factors for persistent pain [5, 7, 9, 14]. Finally, another limitation of our study is the lack of information on previous chronic pain conditions (such as low back pain, osteoarthritis, arthritis or fibromyalgia) [5, 16] or breast pain immediately before surgery [11, 14, 16]; all of these factors have been found to be related to the onset of persistent pain. Equally, no information was gathered on the presence of acute postoperative pain, another factor that it has been proposed as a risk factor for persistent pain [7]. However, the absence of these variables might not change our results on the effect of the detection method on the development of persistent pain.

This study has some important strengths. It is the first to evaluate the onset of complications and, specifically, persistent pain among women diagnosed with breast cancer participating in population-based screening programs in Spain. Our cohort study has a long follow-up period, with a median of 8.7 (Interquartile Range: 7.2 –10.6) years.

Our study shows that the detection mode (screening or interval) has no direct effect on the prevalence of complications and specifically on the onset of persistent pain. Although women with screen-detected cancer had a higher prevalence of persistent pain, the multivariate analysis showed that other factors were also associated with its onset, namely, Charlson index > =2 and the performance of an ALND.

In conclusion, the prevalence of persistent pain in our population of screened women was relatively low, and women with screen-detected cancers did not benefit from less persistent pain than women with interval cancer.