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Pain Medicine 2014; 15: 233–240 Wiley Periodicals, Inc.
Brief Research Report Widespread Pressure Pain Hypersensitivity and Ultrasound Imaging Evaluation of Abdominal Area after Colon Cancer Treatment
Antonio Sánchez-Jiménez, MsC,* Irene Cantarero-Villanueva, PhD,* Rocio Molina-Barea, MD,† Carolina Fernández-Lao, PhD,* Noelia Galiano-Castillo, MsC,* and Manuel Arroyo-Morales, MD, PhD* *Physical Therapy Department, Instituto de Investigación Biosanitaria (IBS), University of Granada; †
Department of General and Digestive Surgery, San Cecilio University Hospital, Granada, Spain Reprint requests to: Manuel Arroyo-Morales, MD, PhD, Physical Therapy Department, Faculty of Health Sciences, University of Granada, Avda. Madrid s/n, 18071 Granada, Spain. Tel: 00 34 958 24 80 30; Fax: 00 34 958 24 23 57; E-mail: [email protected]. Conflict of interest statement: None declared.
Abstract Objective. To investigate the presence of widespread pressure pain sensitivity in cancer patients following partial colorectal resection in the abdominal and lower back area and to describe the presence of abnormalities in abdominal and lower back muscle morphology. Methods. Twenty colon cancer survivors (eight females, mean age 56.60 ± 7.76 years) and 20 matched healthy controls (10 females, mean age 54.22 ± 8.12 years) participated. Abdominal and lower back pain was assessed after undergoing surgery using a Visual Analogue Scale (VAS) and Brief Pain Inventory (BPI). Pressure pain thresholds (PPTs) were bilaterally assessed over the supraumbilical, infraumbilical, and lower back areas and the second metacarpal. Ultrasound imaging was used to measure the depth of the abdominal muscles, the width of the midline abdominal fascia and the width of the lumbar multifidus.
Results. Ten months after finishing oncological treatments, patients who underwent partial colorectal resection reported significantly higher pain levels in the low-back area (P = 0.003) but not in the abdominal area (P = 0.426) compared with the matched controls. After surgery, the colon patients reported significantly higher BPI-intensity (P < 0.001) and BPI-interference scores (P = 0.009) compared with the matched controls. An analysis of variance (ANOVA) revealed significant betweengroups difference in dominant-side lumbar, supraumbilical and infraumbilical (P ≥ 0.01), and second-metacarpal (P < 0.05) PPT levels. A significant between-groups difference was found by the ANOVA in ultrasound imaging of the depth of the internal oblique muscle (F = 4.887, P = 0.035) but not in the other ultrasound imaging measurements. Conclusions. Ten months after oncology treatment, colon cancer survivors show widespread pressure pain muscle hyperalgesia and reduced depths of dominant-side internal oblique muscles compared with matched controls. Key Words. Neoplasm; Colon; Pain; Abdominal Muscles; Ultrasound
Introduction Recent statistical data show that cancer surpassed heart disease as the leading cause of death in several population groups in the United States [1]. Colorectal cancer is the third most common cancer in the United States when considering both genders [2], with more than 147,000 new cases per year, while the incidence in the United States is decreasing, it increases in economically transitioning countries [3]. Fortunately, the improvements in diagnosis and treatment have increased the mean 5-year survival rate up to 56% in Europe [4]. The aging process and increased survival rate have contributed to the fact that colorectal cancer (CRC) survivors comprise a major portion of the 28 million cancer survivors worldwide [5]. 233
Sánchez-Jiménez et al. CRC treatments include surgery and chemotherapy; in combination with the effects of the condition itself, these treatments often result in pain and fatigue (two common cancer-related symptoms) [6]. The prevalence of cancer pain in gastrointestinal cancers is approximately 60% [7]. Quality of life in CRC survivors could be affected by these symptoms [6]. Incidence and epidemiological data concerning the presence of pain in CRC survivors is scarce. In the past decade, only anecdotal evidence has focused on examining chronic pain syndromes in this patient population [8]. Data extracted from epidemiological studies have suggested that chronic cancer pain could have multifaceted origins, including arising from the oncological process itself, as a complication of anticancer treatment, or from concomitant disease [9]. Previous evidence has shown that chronic cancer pain is associated with widespread pressure pain muscle hyperalgesia in breast cancer survivors [10] (independent of the type of surgery) [11], which suggest that both peripheral and central sensitization mechanisms are present in this population. To the best of the authors’ knowledge, no studies have investigated the presence of widespread pressure pain hypersensitivity in other groups of cancer survivors. The presence of this adaptation of the central nervous system [12] could provide relevant information to help understand the chronic pain processes in cancer survivors. Rehabilitative ultrasound imaging (RUSI) has become a popular diagnostic tool for soft tissue pathology because of its high resolution, dynamic imaging that allows comparative and repeatable analyses of the musculoskeletal anatomy [13]. Reduced thickness in the cross-sectional area of the rectus abdominis has recently been reported in breast cancer survivors after mastectomy using a musclesparing procedure which could generate weakness of the abdominal muscles [14]. Resection surgery is a typical colon cancer treatment choice. The surgeon enters the abdomen through a large incision in the abdominal wall. Postoperative immobilization, which is common after breast and colon cancer surgeries, could be associated with previously reported changes in the muscles of the abdominal wall [14]. Changes that are induced in the abdominal wall after resection surgery in colon cancer patients have not previously been studied. We hypothesize that resection surgery could alter abdominal muscle functions. Alterations in muscle function could be associated with the pain process in colon cancer survivors. This study is focused on to clarify an actual research gap referred to possible physical impairments associated to pain suffered by this growing population which could help clinicians to promote strategies to reduce the influence of these handicaps in quality of life of CRC survivors. This study has two principal aims: 1) to investigate the presence of pain and widespread pressure pain hyperalgesia in patients after curative colon cancer surgery in the abdominal and low-back areas and 2) to describe the presence of abnormalities in ultrasound imaging of muscles in the abdominal and lower back areas that are 234
susceptible to affect abdominal muscle function in colon cancer survivors. We hypothesize that CRC patients receiving surgery resection would have greater widespread pressure pain hypersensitivity than paired matched healthy controls. Materials and Methods Participants Patients were recruited from the Department of Surgery at the University Hospital San Cecilio, Granada (Spain). The study protocol was revised and approved by the hospital’s ethics committee. The inclusion criteria were as follows: 1) patients had undergone partial colorectal resection to treat colon cancer, 2) patients ranged in age from 30 to 75 years, 3) patients had a first-time primary diagnosis of colon cancer (grades I to IIIA), 4) patients presented with cancer-related symptoms, such as fatigue or abdominal/ lower back pain, and had considered beginning a rehabilitation program to eliminate these symptoms, 5) at least 6 months had elapsed after finishing all oncological treatments (e.g., radiotherapy and chemotherapy), and 6) at least 3 months had elapsed after colorectal resection. Participants were excluded if they presented with cancer recurrence or if they had undergone previous abdominal surgeries or were diagnosed with concomitant conditions, such as previous lower back pain or musculoskeletal conditions (e.g., osteoarthritis, fibromyalgia, or chronic fatigue syndrome). Volunteers who responded to a university announcement seeking research participants were selected as age and gender-matched controls. Control group participants were excluded from this study if they presented with any musculoskeletal condition or chronic disease or had previous histories of lower back or pelvic pain. The patients and matched healthy controls all signed informed consent forms prior to being enrolled in the study. The research team followed the Helsinki Declaration to carry out this study. Both patient groups followed the same order and sequence of measurements. The sample size determination (Tamaño de la Muestra 1.1, Spain) was based on detecting a minimal difference of 20% in the pressure pain threshold between groups [15] with an α-level of 0.05 and a desired power of 80%, an estimated interindividual coefficient of variation for pressure pain threshold (PPT) measures of 18%. Assuming a 20% possible dropout rate, we chose 20 participants for each group. Visual Analogue Scale (VAS) and Brief Pain Inventory (BPI) The participants completed a VAS to assess the presence of lower back and/or abdominal pain. A 100 mm line with two end points representing “no pain” and “worst pain imaginable” was used [16]. Patients did not ingest analgesics or muscle relaxants for 2 days prior to the study.
Pain in Colon Cancer Survivors The BPI is a reliable [17] and accepted tool to assess pain interference [18]. The BPI consists of nine items; item 9 consists of seven questions measuring interference with different life activities (e.g., general activities, sleep, mood, relationships, walking normally, work, and enjoyment of life). Pain severity is obtained using the mean of the four severity items. Scores are assigned on a scale ranging from 0 (does not interfere) to 10 (completely interferes). PPTs Measurements An electronic algometer (Somedic AB, Farsta, Sweden) was used to determine the PPT, which was defined as the lowest pressure able to elicit a sensation of pain after pressure [19]. The methodology was reported elsewhere [10]. Briefly, the mean of three trials, with a 30-second resting period between trials, was used for the main analysis. The pressure was applied at an approximate rate of 30 kPa/s with a 1 cm2 probe. The abdominal wall was assessed using four points marked bilaterally. Localized PPT points were established following previously reported methodologies [20]. The supraumbilical point was assessed 3 cm above the umbilical point inside the hemiclavicular line (the lateral border of each rectus muscle). The infraumbilical point was assessed 3 cm below the umbilical point inside the hemiclavicular line (Figure 1A). The lower back area was assessed bilaterally, referencing the spinous process of the fifth lumbar vertebrae, verified by ultrasound imaging, and placing the algometer in the paraspinal area in the middle of halfway on the belly of the erector spinae muscle (i.e., approximately 3 cm to the right or left of the marked spinae) [21]. (Figure 1B). Finally, the second metacarpals of both sides were assessed as a distant point to the affected area [10]. Ultrasound Imaging All ultrasound imaging quantitative measurements were taken at the dominant side following previously described
methodologies [22]. An ultrasound device (MyLab 25, Esaote Medical Systems, Genova, Italy) and a 12 MHz linear probe were used in this study. Three measurements were taken, with 2-minute intervals between the trials. The average of three trials was used in this study. All images were captured when the patient was relaxed at the end of the expiration movement. Depth of Internal and External Oblique and Transversus Abdominis The subject was placed in a supine position with a bolster under the legs. The hip and knee flexion angles were fixed during all measurements. The ultrasound probe was situated in the abdomen midway between the iliac crest and the inferior border of the rib cage, inside the medial axillary line. When the muscles were identified, the probe was adjusted to ensure that the anterior medial edge of the transversus abdominis was 2 cm from the medial edge of the ultrasound image. Once the image was captured, calipers were used to measure the distance from the most superficial to the deepest hypoechoic portion of the external oblique, internal oblique, and transversus abdominis (Figure 2). Medial Width of Midline Abdominal Fascia The patient position was similar to that described in the previous measurement. To standardize the midline transverse probe location, it was positioned below the inferior border of the xiphoid process. When the medial borders of the rectus abdominis were identified, the image was captured, and the ultrasound’s calipers were used to measure the distance from the most medial hypoechoic portion of the right rectus abdominis belly to the most medial hypoechoic portion of the left rectus (Figure 3). Depth of Lumbar Multifidus The patient was placed in a prone position with the lordosis corrected using pillows below the abdominal area.
Figure 1 A: Pressure pain thresholds measurements localization in abdominal area. B: Pressure pain thresholds measurements localization in lower back area. 235
Sánchez-Jiménez et al. distribution of the variables was analyzed using the Kolmogorov–Smirnov test (P > 0.05). A group of quantitative data without normal distribution (lower back and abdominal pain intensity and BPI variables) were analyzed using the nonparametric Mann–Whitney U-test. The remaining quantitative data followed a normal distribution and were used in two-way analysis of variance (ANOVA) with group (colon cancer and healthy controls) as the between-patients factor and side as a within-patient factor. We used the Pearson correlation test to assess the association between low back and abdominal pain intensity areas and algometry measurements over each selected pressure point and each study group.
Figure 2 Ultrasound imaging: Depth of internal and external oblique and transversus abdominis.
Results Demographic and Clinical Data The study included 20 patients who underwent partial colorectal resection for colon cancer (eight females), ranging in age from 45 to 70 years (mean ± SD 56.60 ± 7.76 years) and 20 matched controls (10 females) ranging in age from 43 to 64 years (mean ± SD 54.22 ± 8.12 years). All participants were Caucasian. No differences between age (t = 0.992, P = 0.364) or gender (χ2 = 0.404, P = 0.376) were observed between groups. The mean time from the curative surgery treatment was 10.1 ± 5.0 months. Table 1 shows a summary of the demographic and clinical data of the patients. VAS and BPI Results
Figure 3 Ultrasound imaging: Medial width of midline abdominal fascia. The spinal process of the fifth lumbar vertebra was marked on the patient’s skin to ensure an appropriate spinal level measurement. The measurement was taken at the greatest perpendicular anteroposterior distance from the processus transversus to posterior layer of the lumbar fascia (Figure 4).
Using the VAS, patients who had undergone curative colon cancer surgery reported significantly higher pain levels in the lower back area compared with the matched controls (3.00 vs 0.88, Z = 3.032, P = 0.003) but not in the abdominal area (0.85 vs 0.33, Z = 0.272, P = 0.426). After surgery, the colon patients reported significantly higher scores in BPI intensity (3.07 vs 0.81, Z = 3.417, P < 0.001) and BPI interference (1.90 vs 0.20, Z = 2.889, P = 0.009). Pressure Pain Threshold Measurements The ANOVA revealed a significant between-group difference in PPT levels of the lumbar (dominant side F = 6.017,
Width of Lumbar Multifidus A position similar to the previous exploration was used. The dominant side of each participant was used to establish this measurement. The multifidus was encapsulated by the spinous process medially and the lamina anteriorly. The fascial layer delineated the multifidus from the longissimus laterally and from subcutaneous tissue posteriorly. The measurement was taken using the ultrasound’s calipers to determine the greatest horizontal distance between the lateral aspects of the spinous process to the fascial boundary of the longissimus muscle (Figure 4). Statistical Analysis Mean and standard deviation and 95% CI were used to present the descriptive results of this study. The normal 236
Figure 4 Ultrasound imaging: Depth and width of lumbar multifidus.
Pain in Colon Cancer Survivors
Table 1 Demographic and clinical data score in cancer colon group (N = 20) Variable
Value
Age (years), mean ± SD* Gender, N (%) Female Male Marital status, N (%) Married Divorced Employment status, N (%) On sick leave Retired Active working Educational level, N (%) University level Secondary level Primary level Tumor stage, N (%) II IIIa Type of surgery treatment, N (%) Right hemicolectomies Left hemicolectomies Sigmoid colectomies Anterior resections Treatment, N (%) Only surgery Others treatments: Radiotherapy Chemotherapy Radiotherapy + Chemotherapy Time since surgery treatment (months) mean ± SD*
56.60 ± 7.76 8 (40) 12 (60) 18 (90) 2 (10) 9 (65) 5 (25) 2 (10) 5 (25) 6 (30) 9 (45) 1 (5) 19 (95)
sound imaging (F = 4.887, P = 0.035). Patients showed a lower depth of the internal oblique muscle than the healthy subjects. There was nonsignificant between-group difference in the depth of the external oblique muscle (F = 2.800, P = 0.105), the depth of the transversus abdominis (F = 0.726, P = 0.401), the medial width of the midline abdominal fascia (F = 0.059, P = 0.811), and the length (F = 0.002, P = 0.065) and the depth (F = 2.867, P = 0.101) of the lumbar multifidus muscle between colon cancer patients and healthy controls (Table 3). PPT and Pain Intensity There was no significant association between the lumbar or abdominal pain intensity and PPTs at any points (P > 0.156) in the control group. On the other hand, in the CRC patients group, lower back pain was negatively associated with PPT measurements over the dominant side in lumbar multifidus (Rs = −0.492; P = 0.028) and metacarpal bone (rs = −0.479; P = 0.032). In summary, the greater the low back pain, the lower the PPTs over these points. Discussion
6 (30) 7 (35) 2 (10) 5 (25) 3 (15) 17 (85) 6 (30) 8 (40) 3 (15) 10.1 ± 5.0
* Values ± SD are expressed as mean (95% confidence interval).
P = 0.019; nondominant side F = 11.129, P = 0.002), supraumbilical (dominant side F = 10.210, P = 0.003; nondominant side F = 5.545, P = 0.024), infraumbilical dominant side (F = 5.996, P = 0.019), and second metacarpal (dominant side F = 4.859, P = 0.034; nondominant side F = 8.172, P = 0.007). An insignificant difference was found in the infraumbilical nondominant side (F = 2.469, P = 0.125). Over all the studied points, the patients showed lower PPT levels compared with the healthy paired controls. Table 2 shows the PPT measurements of the lumbar multifidus (low back area), supraumbilical and infraumbilical sites (abdominal wall area), and second metacarpal (distant point to surgery) for both sides in each study group. Ultrasound Imaging in Abdominal Wall and Low Back Area A significant between-group difference was revealed by the ANOVA in the depth of internal oblique muscle ultra-
The principal findings of this study are the existence of widespread muscle pressure pain hyperalgesia in colon cancer patients during the first year after oncological treatment. The PPT levels in all selected sites in this study, except infraumbilical in the nondominant side, were significantly lower in the colon cancer patients compared
Table 2 Pressure pain thresholds (kPa) in colon cancer patients and healthy controls
PPT Measurements (kPa)
Colon Cancer Healthy Patients Control N = 20 N = 20
266.1 ± 172.2 (185.4–246.7) Lumbar nondominant 248.1 ± 141.6 side* (181.8–314.3) Supraumbilical dominant 149.7 ± 77.9 side* (113.2–186.2) Supraumbilical 163.3 ± 101.3 nondominant side* (115.8–210.7) Infraumbilical dominant 161.6 ± 92.1 side* (118.5–204.8) Infraumbilical 185.2 ± 109.9 nondominant side (133.8–236.7) Second metacarpal 193.3 ± 71.1 dominant side* (160.0–226.6) Second metacarpal 171. 7 ± 63.5 nondominant side* (142.0–201.4)
Lumbar dominant side*
411.2 ± 192.5 (315.5–507.0) 416.8 ± 170.0 (332.2–501.4) 263.9 ± 137.2 (195.70–332.19) 244.63 ± 111.48 (189.2–300.0) 246.0 ± 119.7 (185.5–305.6) 242.9 ± 116.3 (185.1–300.8) 255.4 ± 101.2 (205.0–305.7) 237.9 ± 78.9 (198.6–277.2)
Values ± SD are expressed as mean (95% confidence interval). * Significant differences between patients and controls (analysis of variance test).
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Sánchez-Jiménez et al.
Table 3 Ultrasound imaging measurements of abdominal muscle wall and lumbar multifidus in colon cancer patients and healthy controls
Ultrasound imaging measurements (cm) Depth internal oblique* Depth external oblique Depth transversus abdominalis Medial width of the midline abdominal fascia Depth lumbar multifidus Width lumbar multifidus
Colon Cancer Patients N = 20
Healthy Control N = 20
0.6 ± 0.1 (0.5–0.7) 0.4 ± 0.1 (0.3–0.5) 0.4 ± 0.1 (0.3–0.4) 0.7 ± 0.2 (0.5–0.9)
0.7 ± 0.1 (0.6–0.8) 0.5 ± 0.2 (0.4–0.6) 0.3 ± 0.1 (0.3–0.4) 0.7 ± 0.1 (0.6–0.8)
3.9 ± 0.5 (3.6–4.1) 3.4 ± 0.5 (3.2–3.7)
3.9 ± 0.4 (3.6–4.1) 3.4 ± 0.8 (2.9–3.9)
Values ± SD are expressed as mean (95% confidence interval). * Significant differences between patients and controls (analysis of variance test).
with the healthy controls. A lower PPTs values in multifidus and metacarpal bone were related to greater intensity of lower back pain: the greater the pain intensity, the lower the PPTs values. These results suggested that both peripheral and central sensitization mechanisms are present in this patient group. A greater degree of sensitization in the affected abdominal area was found in this study. It suggests a greater sensitization in the surgical area joined to a reduced algometry levels in second metacarpal and supports the presence of secondary sensitization mechanisms in a similar way to breast cancer survivors [11]. The PPT values for abdominal wall muscles in colon cancer survivors were lower than previously reported in healthy women [20]. The magnitude of PPT differences between the colon cancer patients and healthy controls in our study was slightly higher in the supraumbilical site than the infraumbilical and lumbar areas. However, these differences values in the metacarpal point were quite similar to those obtained from the infraumbilical area. Peripheral and central sensitization processes have been previously reported in breast cancer survivors [10]. Nevertheless, the levels reported in breast cancer (range 37 to 49%) and colon cancer patients (range 56 to 75%) were greater than those reported by healthy people, which could suggest the magnitude of widespread pressure pain sensitivity in breast and colon cancer survivors. We found a greater difference in the supraumbilical site but not in the infraumbilical in the nondominant side compared with healthy people, suggesting a greater sensitization in the most affected area by the surgical procedures. Our sample of colon cancer survivors reported significant differences in the intensity of lower back pain compared 238
with the healthy controls. Lower back pain has been associated with the presence of generalized sensitization [23]. Lower back pain and other possible pain syndromes, such as pelvic pain [24], could explain the initiation of central sensitization [25]. In addition, other possible sources that generate this type of change in the central nervous system could be explained by the nociception from damaged nerve fibers during abdominal surgery [26] or the immobilization process after major surgery [27], which has been associated with changes in sensory inputs from immobilized areas. Another relevant finding of this study was the decrease in the depth of the internal oblique muscle in the cancer patients compared with the healthy controls. Results similar to ours have been described in relation to breast cancer surgery [14,28]. We did not find any differences in the abdominal midline with respect to the control group, which does not support the possibility that the decreased depth of the internal oblique muscle is explained by excessive tension in the deep abdominal muscles caused by the fascial suture technique used during surgery. We speculate that the decrease in the depth of the internal oblique muscle is a consequence of changes in muscle contraction and an indirect sign of atrophy and reduced strength [14]. Fear of pain to possible complications after surgery and immobilization of the affected area, which is ausual recommendation after surgery, could influence the inhibition of deep abdominal muscles, thereby decreasing the activity of these muscles and changing muscle thickness [29]. Several limitations should be recognized in this novel but preliminary study. No prospective data were obtained from the patients prior to surgery. The study design used also did not provide information about the possible cause– effect relationship between widespread pressure pain hyperalgesia and the RUSI changes detected in this population. Additional RUSI analysis with follow-ups of muscle use during different activities or a qualitative analysis of the muscle architectural based on echogenicity could increase understanding of the changes that occur in the abdominal wall muscles after colon cancer surgery. These changes in abdominal wall muscles could reduce lumbopelvic stabilization of CRC survivors which could increase the risk to suffer different musculoskeletal disorders [30]. Finally, a larger follow-up could provide more information about the changes in pain processes and muscle function that are associated with colon cancer treatment. Nevertheless, this study is the first to analyze the possible rehabilitation implications in colon cancer survivors, which could help health care professionals, to manage this patient population and promote exercise based on interventions to improve muscle function and attenuate pain processes produced as consequence of oncological treatment in CRC survivors. Conclusions In summary, the findings of this study show that during the first year after surgery, colon cancer survivors develop
Pain in Colon Cancer Survivors widespread pressure pain muscle. These results support the presence of possible peripheral and central sensitization mechanisms in patients after partial colectomies. In addition, this patient population presents a decreased depth of the internal oblique dominant-side muscle, which could affect changes in muscle contraction decreasing lumbopelvic stabilization. These results show a gap in colon cancer survivor research in relation to support programs that are based on exercise or rehabilitation strategies to improve physical impairments of these patients. Acknowledgments The authors are indebted to all participants, without whom this work would not have been possible. This study was supported by a grant from the Education Ministry and Economy, Innovation, Science and Employment Counseling through the University of Granada CEI-BioTic, as well as a grant (Program FPU AP2010-6075) from the Education Ministry, Madrid, and Spanish Government. References 1 Siegel R, Naishadham D, Jemal A. Cancer statistics for Hispanics/Latinos, 2012. CA Cancer J Clin 2012;62:283–98. 2 Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin 2010;60:277–300. 3 Edwards BK, Ward E, Kohler BA, et al. Annual report to the nation on the status of cancer, 1975–2006, featuring colorectal cancer trends and impact of interventions (risk factors, screening, and treatment) to reduce future rates. Cancer 2010;116:544–73.
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Pain Medicine 2014; 15: 233–240 Wiley Periodicals, Inc.
Brief Research Report Widespread Pressure Pain Hypersensitivity and Ultrasound Imaging Evaluation of Abdominal Area after Colon Cancer Treatment
Antonio Sánchez-Jiménez, MsC,* Irene Cantarero-Villanueva, PhD,* Rocio Molina-Barea, MD,† Carolina Fernández-Lao, PhD,* Noelia Galiano-Castillo, MsC,* and Manuel Arroyo-Morales, MD, PhD* *Physical Therapy Department, Instituto de Investigación Biosanitaria (IBS), University of Granada; †
Department of General and Digestive Surgery, San Cecilio University Hospital, Granada, Spain Reprint requests to: Manuel Arroyo-Morales, MD, PhD, Physical Therapy Department, Faculty of Health Sciences, University of Granada, Avda. Madrid s/n, 18071 Granada, Spain. Tel: 00 34 958 24 80 30; Fax: 00 34 958 24 23 57; E-mail: [email protected]. Conflict of interest statement: None declared.
Abstract Objective. To investigate the presence of widespread pressure pain sensitivity in cancer patients following partial colorectal resection in the abdominal and lower back area and to describe the presence of abnormalities in abdominal and lower back muscle morphology. Methods. Twenty colon cancer survivors (eight females, mean age 56.60 ± 7.76 years) and 20 matched healthy controls (10 females, mean age 54.22 ± 8.12 years) participated. Abdominal and lower back pain was assessed after undergoing surgery using a Visual Analogue Scale (VAS) and Brief Pain Inventory (BPI). Pressure pain thresholds (PPTs) were bilaterally assessed over the supraumbilical, infraumbilical, and lower back areas and the second metacarpal. Ultrasound imaging was used to measure the depth of the abdominal muscles, the width of the midline abdominal fascia and the width of the lumbar multifidus.
Results. Ten months after finishing oncological treatments, patients who underwent partial colorectal resection reported significantly higher pain levels in the low-back area (P = 0.003) but not in the abdominal area (P = 0.426) compared with the matched controls. After surgery, the colon patients reported significantly higher BPI-intensity (P < 0.001) and BPI-interference scores (P = 0.009) compared with the matched controls. An analysis of variance (ANOVA) revealed significant betweengroups difference in dominant-side lumbar, supraumbilical and infraumbilical (P ≥ 0.01), and second-metacarpal (P < 0.05) PPT levels. A significant between-groups difference was found by the ANOVA in ultrasound imaging of the depth of the internal oblique muscle (F = 4.887, P = 0.035) but not in the other ultrasound imaging measurements. Conclusions. Ten months after oncology treatment, colon cancer survivors show widespread pressure pain muscle hyperalgesia and reduced depths of dominant-side internal oblique muscles compared with matched controls. Key Words. Neoplasm; Colon; Pain; Abdominal Muscles; Ultrasound
Introduction Recent statistical data show that cancer surpassed heart disease as the leading cause of death in several population groups in the United States [1]. Colorectal cancer is the third most common cancer in the United States when considering both genders [2], with more than 147,000 new cases per year, while the incidence in the United States is decreasing, it increases in economically transitioning countries [3]. Fortunately, the improvements in diagnosis and treatment have increased the mean 5-year survival rate up to 56% in Europe [4]. The aging process and increased survival rate have contributed to the fact that colorectal cancer (CRC) survivors comprise a major portion of the 28 million cancer survivors worldwide [5]. 233
Sánchez-Jiménez et al. CRC treatments include surgery and chemotherapy; in combination with the effects of the condition itself, these treatments often result in pain and fatigue (two common cancer-related symptoms) [6]. The prevalence of cancer pain in gastrointestinal cancers is approximately 60% [7]. Quality of life in CRC survivors could be affected by these symptoms [6]. Incidence and epidemiological data concerning the presence of pain in CRC survivors is scarce. In the past decade, only anecdotal evidence has focused on examining chronic pain syndromes in this patient population [8]. Data extracted from epidemiological studies have suggested that chronic cancer pain could have multifaceted origins, including arising from the oncological process itself, as a complication of anticancer treatment, or from concomitant disease [9]. Previous evidence has shown that chronic cancer pain is associated with widespread pressure pain muscle hyperalgesia in breast cancer survivors [10] (independent of the type of surgery) [11], which suggest that both peripheral and central sensitization mechanisms are present in this population. To the best of the authors’ knowledge, no studies have investigated the presence of widespread pressure pain hypersensitivity in other groups of cancer survivors. The presence of this adaptation of the central nervous system [12] could provide relevant information to help understand the chronic pain processes in cancer survivors. Rehabilitative ultrasound imaging (RUSI) has become a popular diagnostic tool for soft tissue pathology because of its high resolution, dynamic imaging that allows comparative and repeatable analyses of the musculoskeletal anatomy [13]. Reduced thickness in the cross-sectional area of the rectus abdominis has recently been reported in breast cancer survivors after mastectomy using a musclesparing procedure which could generate weakness of the abdominal muscles [14]. Resection surgery is a typical colon cancer treatment choice. The surgeon enters the abdomen through a large incision in the abdominal wall. Postoperative immobilization, which is common after breast and colon cancer surgeries, could be associated with previously reported changes in the muscles of the abdominal wall [14]. Changes that are induced in the abdominal wall after resection surgery in colon cancer patients have not previously been studied. We hypothesize that resection surgery could alter abdominal muscle functions. Alterations in muscle function could be associated with the pain process in colon cancer survivors. This study is focused on to clarify an actual research gap referred to possible physical impairments associated to pain suffered by this growing population which could help clinicians to promote strategies to reduce the influence of these handicaps in quality of life of CRC survivors. This study has two principal aims: 1) to investigate the presence of pain and widespread pressure pain hyperalgesia in patients after curative colon cancer surgery in the abdominal and low-back areas and 2) to describe the presence of abnormalities in ultrasound imaging of muscles in the abdominal and lower back areas that are 234
susceptible to affect abdominal muscle function in colon cancer survivors. We hypothesize that CRC patients receiving surgery resection would have greater widespread pressure pain hypersensitivity than paired matched healthy controls. Materials and Methods Participants Patients were recruited from the Department of Surgery at the University Hospital San Cecilio, Granada (Spain). The study protocol was revised and approved by the hospital’s ethics committee. The inclusion criteria were as follows: 1) patients had undergone partial colorectal resection to treat colon cancer, 2) patients ranged in age from 30 to 75 years, 3) patients had a first-time primary diagnosis of colon cancer (grades I to IIIA), 4) patients presented with cancer-related symptoms, such as fatigue or abdominal/ lower back pain, and had considered beginning a rehabilitation program to eliminate these symptoms, 5) at least 6 months had elapsed after finishing all oncological treatments (e.g., radiotherapy and chemotherapy), and 6) at least 3 months had elapsed after colorectal resection. Participants were excluded if they presented with cancer recurrence or if they had undergone previous abdominal surgeries or were diagnosed with concomitant conditions, such as previous lower back pain or musculoskeletal conditions (e.g., osteoarthritis, fibromyalgia, or chronic fatigue syndrome). Volunteers who responded to a university announcement seeking research participants were selected as age and gender-matched controls. Control group participants were excluded from this study if they presented with any musculoskeletal condition or chronic disease or had previous histories of lower back or pelvic pain. The patients and matched healthy controls all signed informed consent forms prior to being enrolled in the study. The research team followed the Helsinki Declaration to carry out this study. Both patient groups followed the same order and sequence of measurements. The sample size determination (Tamaño de la Muestra 1.1, Spain) was based on detecting a minimal difference of 20% in the pressure pain threshold between groups [15] with an α-level of 0.05 and a desired power of 80%, an estimated interindividual coefficient of variation for pressure pain threshold (PPT) measures of 18%. Assuming a 20% possible dropout rate, we chose 20 participants for each group. Visual Analogue Scale (VAS) and Brief Pain Inventory (BPI) The participants completed a VAS to assess the presence of lower back and/or abdominal pain. A 100 mm line with two end points representing “no pain” and “worst pain imaginable” was used [16]. Patients did not ingest analgesics or muscle relaxants for 2 days prior to the study.
Pain in Colon Cancer Survivors The BPI is a reliable [17] and accepted tool to assess pain interference [18]. The BPI consists of nine items; item 9 consists of seven questions measuring interference with different life activities (e.g., general activities, sleep, mood, relationships, walking normally, work, and enjoyment of life). Pain severity is obtained using the mean of the four severity items. Scores are assigned on a scale ranging from 0 (does not interfere) to 10 (completely interferes). PPTs Measurements An electronic algometer (Somedic AB, Farsta, Sweden) was used to determine the PPT, which was defined as the lowest pressure able to elicit a sensation of pain after pressure [19]. The methodology was reported elsewhere [10]. Briefly, the mean of three trials, with a 30-second resting period between trials, was used for the main analysis. The pressure was applied at an approximate rate of 30 kPa/s with a 1 cm2 probe. The abdominal wall was assessed using four points marked bilaterally. Localized PPT points were established following previously reported methodologies [20]. The supraumbilical point was assessed 3 cm above the umbilical point inside the hemiclavicular line (the lateral border of each rectus muscle). The infraumbilical point was assessed 3 cm below the umbilical point inside the hemiclavicular line (Figure 1A). The lower back area was assessed bilaterally, referencing the spinous process of the fifth lumbar vertebrae, verified by ultrasound imaging, and placing the algometer in the paraspinal area in the middle of halfway on the belly of the erector spinae muscle (i.e., approximately 3 cm to the right or left of the marked spinae) [21]. (Figure 1B). Finally, the second metacarpals of both sides were assessed as a distant point to the affected area [10]. Ultrasound Imaging All ultrasound imaging quantitative measurements were taken at the dominant side following previously described
methodologies [22]. An ultrasound device (MyLab 25, Esaote Medical Systems, Genova, Italy) and a 12 MHz linear probe were used in this study. Three measurements were taken, with 2-minute intervals between the trials. The average of three trials was used in this study. All images were captured when the patient was relaxed at the end of the expiration movement. Depth of Internal and External Oblique and Transversus Abdominis The subject was placed in a supine position with a bolster under the legs. The hip and knee flexion angles were fixed during all measurements. The ultrasound probe was situated in the abdomen midway between the iliac crest and the inferior border of the rib cage, inside the medial axillary line. When the muscles were identified, the probe was adjusted to ensure that the anterior medial edge of the transversus abdominis was 2 cm from the medial edge of the ultrasound image. Once the image was captured, calipers were used to measure the distance from the most superficial to the deepest hypoechoic portion of the external oblique, internal oblique, and transversus abdominis (Figure 2). Medial Width of Midline Abdominal Fascia The patient position was similar to that described in the previous measurement. To standardize the midline transverse probe location, it was positioned below the inferior border of the xiphoid process. When the medial borders of the rectus abdominis were identified, the image was captured, and the ultrasound’s calipers were used to measure the distance from the most medial hypoechoic portion of the right rectus abdominis belly to the most medial hypoechoic portion of the left rectus (Figure 3). Depth of Lumbar Multifidus The patient was placed in a prone position with the lordosis corrected using pillows below the abdominal area.
Figure 1 A: Pressure pain thresholds measurements localization in abdominal area. B: Pressure pain thresholds measurements localization in lower back area. 235
Sánchez-Jiménez et al. distribution of the variables was analyzed using the Kolmogorov–Smirnov test (P > 0.05). A group of quantitative data without normal distribution (lower back and abdominal pain intensity and BPI variables) were analyzed using the nonparametric Mann–Whitney U-test. The remaining quantitative data followed a normal distribution and were used in two-way analysis of variance (ANOVA) with group (colon cancer and healthy controls) as the between-patients factor and side as a within-patient factor. We used the Pearson correlation test to assess the association between low back and abdominal pain intensity areas and algometry measurements over each selected pressure point and each study group.
Figure 2 Ultrasound imaging: Depth of internal and external oblique and transversus abdominis.
Results Demographic and Clinical Data The study included 20 patients who underwent partial colorectal resection for colon cancer (eight females), ranging in age from 45 to 70 years (mean ± SD 56.60 ± 7.76 years) and 20 matched controls (10 females) ranging in age from 43 to 64 years (mean ± SD 54.22 ± 8.12 years). All participants were Caucasian. No differences between age (t = 0.992, P = 0.364) or gender (χ2 = 0.404, P = 0.376) were observed between groups. The mean time from the curative surgery treatment was 10.1 ± 5.0 months. Table 1 shows a summary of the demographic and clinical data of the patients. VAS and BPI Results
Figure 3 Ultrasound imaging: Medial width of midline abdominal fascia. The spinal process of the fifth lumbar vertebra was marked on the patient’s skin to ensure an appropriate spinal level measurement. The measurement was taken at the greatest perpendicular anteroposterior distance from the processus transversus to posterior layer of the lumbar fascia (Figure 4).
Using the VAS, patients who had undergone curative colon cancer surgery reported significantly higher pain levels in the lower back area compared with the matched controls (3.00 vs 0.88, Z = 3.032, P = 0.003) but not in the abdominal area (0.85 vs 0.33, Z = 0.272, P = 0.426). After surgery, the colon patients reported significantly higher scores in BPI intensity (3.07 vs 0.81, Z = 3.417, P < 0.001) and BPI interference (1.90 vs 0.20, Z = 2.889, P = 0.009). Pressure Pain Threshold Measurements The ANOVA revealed a significant between-group difference in PPT levels of the lumbar (dominant side F = 6.017,
Width of Lumbar Multifidus A position similar to the previous exploration was used. The dominant side of each participant was used to establish this measurement. The multifidus was encapsulated by the spinous process medially and the lamina anteriorly. The fascial layer delineated the multifidus from the longissimus laterally and from subcutaneous tissue posteriorly. The measurement was taken using the ultrasound’s calipers to determine the greatest horizontal distance between the lateral aspects of the spinous process to the fascial boundary of the longissimus muscle (Figure 4). Statistical Analysis Mean and standard deviation and 95% CI were used to present the descriptive results of this study. The normal 236
Figure 4 Ultrasound imaging: Depth and width of lumbar multifidus.
Pain in Colon Cancer Survivors
Table 1 Demographic and clinical data score in cancer colon group (N = 20) Variable
Value
Age (years), mean ± SD* Gender, N (%) Female Male Marital status, N (%) Married Divorced Employment status, N (%) On sick leave Retired Active working Educational level, N (%) University level Secondary level Primary level Tumor stage, N (%) II IIIa Type of surgery treatment, N (%) Right hemicolectomies Left hemicolectomies Sigmoid colectomies Anterior resections Treatment, N (%) Only surgery Others treatments: Radiotherapy Chemotherapy Radiotherapy + Chemotherapy Time since surgery treatment (months) mean ± SD*
56.60 ± 7.76 8 (40) 12 (60) 18 (90) 2 (10) 9 (65) 5 (25) 2 (10) 5 (25) 6 (30) 9 (45) 1 (5) 19 (95)
sound imaging (F = 4.887, P = 0.035). Patients showed a lower depth of the internal oblique muscle than the healthy subjects. There was nonsignificant between-group difference in the depth of the external oblique muscle (F = 2.800, P = 0.105), the depth of the transversus abdominis (F = 0.726, P = 0.401), the medial width of the midline abdominal fascia (F = 0.059, P = 0.811), and the length (F = 0.002, P = 0.065) and the depth (F = 2.867, P = 0.101) of the lumbar multifidus muscle between colon cancer patients and healthy controls (Table 3). PPT and Pain Intensity There was no significant association between the lumbar or abdominal pain intensity and PPTs at any points (P > 0.156) in the control group. On the other hand, in the CRC patients group, lower back pain was negatively associated with PPT measurements over the dominant side in lumbar multifidus (Rs = −0.492; P = 0.028) and metacarpal bone (rs = −0.479; P = 0.032). In summary, the greater the low back pain, the lower the PPTs over these points. Discussion
6 (30) 7 (35) 2 (10) 5 (25) 3 (15) 17 (85) 6 (30) 8 (40) 3 (15) 10.1 ± 5.0
* Values ± SD are expressed as mean (95% confidence interval).
P = 0.019; nondominant side F = 11.129, P = 0.002), supraumbilical (dominant side F = 10.210, P = 0.003; nondominant side F = 5.545, P = 0.024), infraumbilical dominant side (F = 5.996, P = 0.019), and second metacarpal (dominant side F = 4.859, P = 0.034; nondominant side F = 8.172, P = 0.007). An insignificant difference was found in the infraumbilical nondominant side (F = 2.469, P = 0.125). Over all the studied points, the patients showed lower PPT levels compared with the healthy paired controls. Table 2 shows the PPT measurements of the lumbar multifidus (low back area), supraumbilical and infraumbilical sites (abdominal wall area), and second metacarpal (distant point to surgery) for both sides in each study group. Ultrasound Imaging in Abdominal Wall and Low Back Area A significant between-group difference was revealed by the ANOVA in the depth of internal oblique muscle ultra-
The principal findings of this study are the existence of widespread muscle pressure pain hyperalgesia in colon cancer patients during the first year after oncological treatment. The PPT levels in all selected sites in this study, except infraumbilical in the nondominant side, were significantly lower in the colon cancer patients compared
Table 2 Pressure pain thresholds (kPa) in colon cancer patients and healthy controls
PPT Measurements (kPa)
Colon Cancer Healthy Patients Control N = 20 N = 20
266.1 ± 172.2 (185.4–246.7) Lumbar nondominant 248.1 ± 141.6 side* (181.8–314.3) Supraumbilical dominant 149.7 ± 77.9 side* (113.2–186.2) Supraumbilical 163.3 ± 101.3 nondominant side* (115.8–210.7) Infraumbilical dominant 161.6 ± 92.1 side* (118.5–204.8) Infraumbilical 185.2 ± 109.9 nondominant side (133.8–236.7) Second metacarpal 193.3 ± 71.1 dominant side* (160.0–226.6) Second metacarpal 171. 7 ± 63.5 nondominant side* (142.0–201.4)
Lumbar dominant side*
411.2 ± 192.5 (315.5–507.0) 416.8 ± 170.0 (332.2–501.4) 263.9 ± 137.2 (195.70–332.19) 244.63 ± 111.48 (189.2–300.0) 246.0 ± 119.7 (185.5–305.6) 242.9 ± 116.3 (185.1–300.8) 255.4 ± 101.2 (205.0–305.7) 237.9 ± 78.9 (198.6–277.2)
Values ± SD are expressed as mean (95% confidence interval). * Significant differences between patients and controls (analysis of variance test).
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Sánchez-Jiménez et al.
Table 3 Ultrasound imaging measurements of abdominal muscle wall and lumbar multifidus in colon cancer patients and healthy controls
Ultrasound imaging measurements (cm) Depth internal oblique* Depth external oblique Depth transversus abdominalis Medial width of the midline abdominal fascia Depth lumbar multifidus Width lumbar multifidus
Colon Cancer Patients N = 20
Healthy Control N = 20
0.6 ± 0.1 (0.5–0.7) 0.4 ± 0.1 (0.3–0.5) 0.4 ± 0.1 (0.3–0.4) 0.7 ± 0.2 (0.5–0.9)
0.7 ± 0.1 (0.6–0.8) 0.5 ± 0.2 (0.4–0.6) 0.3 ± 0.1 (0.3–0.4) 0.7 ± 0.1 (0.6–0.8)
3.9 ± 0.5 (3.6–4.1) 3.4 ± 0.5 (3.2–3.7)
3.9 ± 0.4 (3.6–4.1) 3.4 ± 0.8 (2.9–3.9)
Values ± SD are expressed as mean (95% confidence interval). * Significant differences between patients and controls (analysis of variance test).
with the healthy controls. A lower PPTs values in multifidus and metacarpal bone were related to greater intensity of lower back pain: the greater the pain intensity, the lower the PPTs values. These results suggested that both peripheral and central sensitization mechanisms are present in this patient group. A greater degree of sensitization in the affected abdominal area was found in this study. It suggests a greater sensitization in the surgical area joined to a reduced algometry levels in second metacarpal and supports the presence of secondary sensitization mechanisms in a similar way to breast cancer survivors [11]. The PPT values for abdominal wall muscles in colon cancer survivors were lower than previously reported in healthy women [20]. The magnitude of PPT differences between the colon cancer patients and healthy controls in our study was slightly higher in the supraumbilical site than the infraumbilical and lumbar areas. However, these differences values in the metacarpal point were quite similar to those obtained from the infraumbilical area. Peripheral and central sensitization processes have been previously reported in breast cancer survivors [10]. Nevertheless, the levels reported in breast cancer (range 37 to 49%) and colon cancer patients (range 56 to 75%) were greater than those reported by healthy people, which could suggest the magnitude of widespread pressure pain sensitivity in breast and colon cancer survivors. We found a greater difference in the supraumbilical site but not in the infraumbilical in the nondominant side compared with healthy people, suggesting a greater sensitization in the most affected area by the surgical procedures. Our sample of colon cancer survivors reported significant differences in the intensity of lower back pain compared 238
with the healthy controls. Lower back pain has been associated with the presence of generalized sensitization [23]. Lower back pain and other possible pain syndromes, such as pelvic pain [24], could explain the initiation of central sensitization [25]. In addition, other possible sources that generate this type of change in the central nervous system could be explained by the nociception from damaged nerve fibers during abdominal surgery [26] or the immobilization process after major surgery [27], which has been associated with changes in sensory inputs from immobilized areas. Another relevant finding of this study was the decrease in the depth of the internal oblique muscle in the cancer patients compared with the healthy controls. Results similar to ours have been described in relation to breast cancer surgery [14,28]. We did not find any differences in the abdominal midline with respect to the control group, which does not support the possibility that the decreased depth of the internal oblique muscle is explained by excessive tension in the deep abdominal muscles caused by the fascial suture technique used during surgery. We speculate that the decrease in the depth of the internal oblique muscle is a consequence of changes in muscle contraction and an indirect sign of atrophy and reduced strength [14]. Fear of pain to possible complications after surgery and immobilization of the affected area, which is ausual recommendation after surgery, could influence the inhibition of deep abdominal muscles, thereby decreasing the activity of these muscles and changing muscle thickness [29]. Several limitations should be recognized in this novel but preliminary study. No prospective data were obtained from the patients prior to surgery. The study design used also did not provide information about the possible cause– effect relationship between widespread pressure pain hyperalgesia and the RUSI changes detected in this population. Additional RUSI analysis with follow-ups of muscle use during different activities or a qualitative analysis of the muscle architectural based on echogenicity could increase understanding of the changes that occur in the abdominal wall muscles after colon cancer surgery. These changes in abdominal wall muscles could reduce lumbopelvic stabilization of CRC survivors which could increase the risk to suffer different musculoskeletal disorders [30]. Finally, a larger follow-up could provide more information about the changes in pain processes and muscle function that are associated with colon cancer treatment. Nevertheless, this study is the first to analyze the possible rehabilitation implications in colon cancer survivors, which could help health care professionals, to manage this patient population and promote exercise based on interventions to improve muscle function and attenuate pain processes produced as consequence of oncological treatment in CRC survivors. Conclusions In summary, the findings of this study show that during the first year after surgery, colon cancer survivors develop
Pain in Colon Cancer Survivors widespread pressure pain muscle. These results support the presence of possible peripheral and central sensitization mechanisms in patients after partial colectomies. In addition, this patient population presents a decreased depth of the internal oblique dominant-side muscle, which could affect changes in muscle contraction decreasing lumbopelvic stabilization. These results show a gap in colon cancer survivor research in relation to support programs that are based on exercise or rehabilitation strategies to improve physical impairments of these patients. Acknowledgments The authors are indebted to all participants, without whom this work would not have been possible. This study was supported by a grant from the Education Ministry and Economy, Innovation, Science and Employment Counseling through the University of Granada CEI-BioTic, as well as a grant (Program FPU AP2010-6075) from the Education Ministry, Madrid, and Spanish Government. References 1 Siegel R, Naishadham D, Jemal A. Cancer statistics for Hispanics/Latinos, 2012. CA Cancer J Clin 2012;62:283–98. 2 Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin 2010;60:277–300. 3 Edwards BK, Ward E, Kohler BA, et al. Annual report to the nation on the status of cancer, 1975–2006, featuring colorectal cancer trends and impact of interventions (risk factors, screening, and treatment) to reduce future rates. Cancer 2010;116:544–73.
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