Review article 93
Persistent postoperative pain and sensory changes following lymph node excision in melanoma patients: a topical review Charlotte Slagelsea, Karin L. Petersena, Jørgen B. Dahlc, Kenneth Finnerupf, Kaitlin Greenea, Stanley P. Leonga, Jon Levineb, Michael Rowbothama, Mads U. Wernere and Nanna B. Finnerupd Studies on complications related to chronic nerve injury following sentinel lymph node biopsy (SLNB) and complete lymph node dissection (CLND) for melanoma are sparse. This review summarizes the existing literature on pain and neuropathic complications in melanoma patients undergoing SLNB with or without CLND. The Cochrane Central Register of Controlled Trials and the Embase and PubMed databases were searched. Full-text English language articles published before June 2013 were included. Prospective and retrospective studies assessing persistent (> 1 month) sensory nerve injury, postoperative pain, neuropathic pain, and sensory disturbances following SLNB with or without CLND in melanoma patients were eligible. Nine studies (six prospective and three retrospective) including data for 3632 patients met our inclusion criteria. Outcome parameters were too heterogeneous to conduct a quantitative analysis, and few studies systematically evaluated pain and sensory abnormalities. Persistent postoperative pain was reported in 1–14% of patients following SLNB and in 6–34% following CLND and sensory abnormalities in 0.1–32 and 2–82%, respectively. In the one study that assessed the type of pain, neuropathic pain was suggested to
explain persistent pain in 31–66% of patients with SLNB and 82–89% of patients with CLND. Sensory-nerve-related complications in melanoma patients seem to be less pronounced following SLNB compared with CLND. Prospective observational studies are necessary to identify predictors of persistent pain, to evaluate the prevalence and impact of pain and sensory abnormalities, and to develop strategies for prevention of long-term c 2014 Wolters complications. Melanoma Res 24:93–98 Kluwer Health | Lippincott Williams & Wilkins.
Introduction
lymphedema, and wound infection [7,11,12]. Although most complications resolve, little is known about longterm complications. Both excisions of the melanoma, CLND and SLNB, may be associated with persistent and occasionally severe and disabling neuropathic pain in the area of surgery [13–15]. Studies on the development of persistent pain after these procedures have primarily been conducted in breast cancer patients, among whom about 55% report persistent pain and 77% report persistent sensory disturbances following treatment [16]. Treatment for breast cancer often includes multiple concomitant or subsequent interventions such as lumpectomy, mastectomy, radiation, and chemotherapy, making it more difficult to assess pain following SLNB and CLND procedures per se [17]. As pain and regional nerve injury are rarely present before SLNB or CLND in melanoma patients, it is possible to study the natural history of nerve injury pain following lymph node surgery. The purpose of this systematic review was to analyze the literature describing pain and sensory abnormalities in melanoma patients undergoing SLNB with or without CLND.
Malignant melanoma causes more than 75% of skin cancer deaths. In 2008, there were 85 927 new cases in Europe and 68 100 in Northern America, and it is estimated that there will be 76 690 new cases in the American population in 2013 (http://www.cancer.gov/cancertopics/types/melanoma) [1,2]. Melanoma is currently the fourth most common cancer in the USA [1,3]. The 2008 age-standardized world standard population incidence per 100 000 individuals was 36.7 in Australia, 18.0 in Denmark, and 14.2 in the USA [2]. The initial treatment for melanoma consists of local resection of the melanoma skin lesion for diagnosis. Depending on the histology, this may be followed by wide excision of the melanoma and sentinel lymph node biopsy (SLNB) to determine whether cancer cells have metastasized. In the case of a positive SLNB with malignant cells, the current standard treatment is complete lymph node dissection (CLND) in the region [4,5]. The morbidity associated with SLNB and CLND is considerable, with overall complication rates ranging from 10 to 65% [6–10]. Common complications of the procedures are seroma, c 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins 0960-8931
Melanoma Research 2014, 24:93–98 Keywords: malignant melanoma, neuropathy, persistent postsurgical pain, sensory changes, sentinel lymph node a California Pacific Medical Center Research Institute, bDepartment of Medicine, Division of Rheumatology, University of California at San Francisco, San Francisco, California, USA, cDepartment of Anaesthesia, Rigshospitalet and Copenhagen University, dMultidisciplinary Pain Center, Neuroscience Center, Rigshospitalet, Copenhagen, eDanish Pain Research Center, Aarhus University, Aarhus and fDepartment of Plastic Surgery, Aalborg University Hospital, Aalborg, Denmark
Correspondence to Charlotte Slagelse, MD, California Pacific Medical Center Research Institute, San Francisco, CA 94107, USA Tel: + 1 45 61688615; e-mail: [email protected] Received 7 July 2013 Accepted 12 November 2013
DOI: 10.1097/CMR.0000000000000041
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Methods
Study results
Studies assessing pain and sensory nerve injury-related complications following SLNB and CLND for melanoma were searched by the first author (C.S.). A nonrestrictive systematic search of the published literature, including prospective and retrospective, randomized and nonrandomized, observational studies, as well as reports on patients with malignant melanoma undergoing SLNB and/or CLND, was conducted in the Cochrane, Embase, and PubMed databases. Free text combinations including the following search terms were used: ‘axillary/groin dissection’, ‘complete lymph node dissection’, ‘complications’, ‘functional deficits’, ‘lymph node excision’, ‘melanoma’, ‘melanoma and surgery’, ‘morbidity’, ‘pain and melanoma’, ‘neuropathic pain’, ‘neuropathy’, ‘radical lymph node dissection’, ‘sensory disturbances’, ‘sentinel lymph node’, ‘sentinel node biopsy’, ‘shoulder mobility’, and ‘quality of life’. The reference lists from the retrieved articles were searched for additional papers. The last search was conducted on 3 June 2013. Articles were considered for inclusion if one of the following outcome parameters were evaluated: functional deficit/shoulder mobility, sensory disturbances, sensory dysfunction/pain, sensory nerve injury, pain elsewhere, and postoperative pain. We limited the search to full journal publications or reports in the English language. Abstracts were not included. Each of the identified articles was independently read and assessed for eligibility by the authors (C.S., N.B.F., and K.L.P.), and disagreements were solved by discussion or, if persistent, by a fourth review author. Studies were included if they reported the occurrence of long-term (> 1 month) pain or sensory abnormalities following SLNB or CLND in melanoma patients. The preferred reporting items for systematic reviews and meta-analyses, the PRISMA statement, were followed to the extent possible with the included material [18].
Study quality
Results Search results and study selection
Performing the database search resulted in 30 abstracts. Three studies were in duplicate and were excluded. Twenty-seven studies were retrieved for further review on the basis of initial abstract evaluation. Nine studies were excluded because the study population included breast cancer patients, six studies because of lack of assessment of parameters required for inclusion, and three studies because they did not assess long-term complications. Nine studies met our inclusion criteria and were included in the review (Fig. 1; flowchart). Baseline data from the included studies were extracted into a datasheet (Table 1). Review limitations
Because of the scarcity of literature evaluating long-term pain and sensory disturbances and with heterogeneous outcome measures, a meta-analysis was not possible and only a systematic qualitative analysis was carried out.
The included studies were a combination of retrospective and prospective studies, questionnaire-based and clinical follow-up studies, and medical chart reports. Quality assessment and relevance scores [24] are presented in Table 1. In seven studies, pain and sensory disturbances were not the primary outcome, and no definitions were given for pain and sensory disturbances (Table 1). Baseline data
In total, nine studies evaluating 3632 patients were included in the review (Table 1). Baseline data were comparable across study populations. A total of 3148 SLNBs and 1056 CLNDs were included in the review. The study populations ranged from 60 to 2120 patients. The female/male ratio was 0.96 and the mean age was between 40 and 59 years. Breslow thickness (depth of tumor invasion) of the primary melanoma lesion was 0.8–10 mm (Table 1). The mean follow-up period ranged from 1 to 39 months. The type of anesthesia was reported in three studies, all of which reported general anesthesia [10,19,23]. General anesthesia was specified as propofol and remifentanil in one study [19]. Postoperative analgesics were assessed in two trials and included paracetamol and/or opioids [19] or nonopioids for moderate pain and opioids for severe pain [9]. Outcome measures Sensory abnormalities
Sensory abnormalities were evaluated in five studies [15,19,20,22,23] (Table 1). The definition of sensory abnormality ranged from changed sensation to touch, which was assessed in all patients [19], to extensive sensory nerve dysfunction [15], which was recorded in medical charts for legal purposes and not systematically assessed [22,23] (Table 1). In one study, numbness and/ or paresthesia was not considered a complication as the intercostobrachial nerves were not spared, thus making it an expected event [15]. One study described sensory abnormality in more detail [19]. In the questionnaire, part of the study, 22% of patients undergoing SLNB and 78% undergoing CLND experienced hyposensitivity, whereas 13% reported hypersensitivity after SLNB and 34% after CLND. Twelve percent of the SLNB patients and 26% of the CLND patients reported impact of sensory abnormalities on quality of life (QOL). Postoperative pain
Five studies evaluated long-term (> 1 month) postoperative pain (Table 1). Pain was more common after CLND than after SNLB. Pain was defined as pain during the previous month in the area of surgery [19] or pain with no further definition [9]. In two studies, pain and other sensory disturbances or nerve dysfunctions were combined [10,14]. Only one study provided details on
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Persistent postoperative pain in melanoma patients Slagelse et al. 95
Fig. 1
30 abstracts and 1 editorial identified through database searching
27 records after duplicates removed
27 full-text articles assessed for eligibility
18 studies were excluded: 9 included breast cancer patients 6 did not assess required outcome measures 3 only assessed short-term complications
9 studies included in qualitative synthesis Flowchart.
pain; in this study, the chronic postoperative pain was suggested to be neuropathic in 31–66% of patients with SLNB and 82–89% of patients with CLND, depending on the criteria used [19]. In patients with SLNB, 2% reported at least moderate pain and 2% reported that the pain had an impact on their QOL. After CLND, 12% reported at least moderate pain and 14% reported that pain had an impact on their QOL 3–48 months after surgery [19]. Other long-term complications
Four studies included functional deficits as a parameter in their assessments [9,10,14,15]. Functional deficits included the following terms: motor nerve injury, functional deficit, mobility limitations, and functional limitation. In the studies, 0–2% of SLNB patients and 0.5–17% of CLND patients showed functional deficits. The incidence of lymphedema was reported in eight studies and ranged between 4 and 24% for SLNB and 1 and 37% for CLND [9,10,14,15,20–23]. The presence of lymphedema may contribute independently to pain and discomfort after surgery and may also influence the patient’s sensory perception. To our knowledge, no studies have examined the effect of lymphedema on sensory thresholds, nor the degree to which postoperative pain is due to lymphedema.
Discussion SLNB and CLND for melanoma involve tissues with a very high density of nerve fibers, including superficial
and small fibers in the skin, as well as the deeper located brachial and lumbar nerve plexuses. Hence, there is a considerable risk for nerve damage and subsequent development of sensory/motor dysfunction and pain. This qualitative review shows that there is a void in the literature with regard to systematically assessed outcome measures. Further, the studies have variable follow-up periods and intervals, which makes it difficult to adequately describe the incidence of symptoms after melanoma surgery. Despite these limitations, our review suggests that pain after CLND is more severe and longer lasting compared with that after SLND. Most of the studies did not define how they recorded pain and sensory abnormalities, and some did not record sensory abnormalities in territories innervated by nerves that were likely to be damaged during surgery. Hence, there is a considerable risk of reporting bias. In the only study in which pain and sensory abnormalities were the primary outcome [19], the prevalence of pain (14% after SLND and 34% after CLND) and sensory abnormalities (32 and 82%, respectively) was higher than that in the other studies. It is, however, important to note that a considerable number of patients experienced mild complications that may not be clinically relevant, and such questionnaire studies may overestimate the prevalence. Nevertheless, in a subgroup of patients, the sensory changes and pain were severe enough to impact the patients’ QOL; sensory abnormalities were reported to affect QOL in 12% of patients after SLNB and in 26% of patients after CLND, and pain affected QOL in 2 and 14% of patients, respectively [19].
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A, 3 A, 3 A, 3 A, 2 A, 2 B, 1 B, 1 B, 0
Prospective clinical follow-up Prospective clinical follow-up
Prospective clinical follow-up
Prospective clinical follow-up
Retrospective medical chart review
Retrospective case note review
Retrospective case note review
0 1056
3148
208
42
17
0
204 444
90
51
100
0
197
60
250
0 2120
297
124
SLNB CLND
No. of procedures
3632
100
208
197
60
250
204 2120
315
175
No.
Patients
49
55
NA
51
53
49
40 44
49
50
Female %
Sex
NA
47 (15–86)
57 (16–89)
56
54 (28–83)
57 (17–84)
48 (15–79) 50
58 (17–88)
59 (22–86)
Mean (range)
Age (years)
NA
NA
85.1
65.4
73.3
48.0
76.5 43.1
NA
40.0
Extremity
NA
2.1 (0.5–5)
NA
NA
(0.8–5)
2.4 (0.8–10)
> 0.8 2.5
NA
2.0 (0.3–10)
Mean/median (range)
Primary site Breslow thickness (%) (mm)
NA
(9–30)
>1
39.5 (5–97)
32
35 (2–98)
>6 16
(3–6)
23 (3–48)
Mean/median (range)
Follow-up (months)
1.0g,m
3.3j
0.1e,g,h
31.5
a
SLNB
6.7m
1.8e,g,h
82.4
a
CLND
Sensory abnormalities
2.6i,g
0.9d,e
13.8
b
SNLB
4.7g,k
6.0f
8.9d,e
34.0b
CLND
Pain
Percentage of patients undergoing surgery
Quality assessment: types of studies: A, prospective assessment, no group comparison; B, retrospective assessment, no group comparison. Relevance score: the following score, consisting of four questions, was applied to each study to assess its relevance in assessing neuropathic PPSP: (1) Was the study prospective? yes/no; (2) Was prevalence of pain and sensory abnormalities among the main outcomes of the study? yes/no; (3) Was assessment of pain and sensory abnormalities performed? yes/no; (4) Was follow-up clearly defined? yes/no. Yes = 1, No = 0. A score between 0 and 4 was assigned to each study, indicating the score of lowest and highest relevance, respectively. The relevance score does not provide an estimate of the overall methodological quality of the study. The studies have been prioritized on the basis of the quality assessment. CLND, complete lymph node dissection; NA, not applicable; PPSP, persistent postsurgical pain; SLNB, sentinel lymph node biopsy. a Any changed sensation (hypoesthesia or hyperesthesia) to touch in the surgical area. b Pain within the past month in the surgical area. c Lymphedema was assessed. d Nerve dysfunction/pain with no further description/definition. e Numbness or paresthesia was not considered a complication, as the intercostobrachial nerves were not spared, thus making it an expected event. f Pain, not defined. g Time of complication not specified; it may thus be an early complication. h Extensive sensory nerve dysfunction (with no further definition). i Postoperative pain and/or other sensory disturbances. j Wound pain with neuropathy, time not specified. k Adverse events as recorded in medical charts. l Primary cancer includes melanoma, squamous cell, thyroid, and salivary gland carcinoma. m Paresthesia, not defined.
Kretschmer et al. [14]c Urist et al. [9]c Wrightson et al. [15]c Wasserberg et al. [10]c Blumenthal et al. [20]c Biver-Dalle et al. [21]c Shaw and Rumball [22]l,c Heittiaratchy et al. [23]c Total
B, 4
Study quality
Retrospective postal questionnaire clinical examination in a subgroup Prospective interview clinical examination
Study design
Demographics and outcome data
Hoimyr et al. [19]
Table 1
96 Melanoma Research 2014, Vol 24 No 2
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Persistent postoperative pain in melanoma patients Slagelse et al. 97
For comparison, persistent postsurgical pain is present in about 20–40% of patients after breast and thoracic surgery, with 5–10% having severe disabling pain, and in 10% of patients after inguinal hernia repair, with 2–4% reporting severe pain [24,25]. Wound infection and seroma/hematoma formation were common postoperative complications but were often resolved [15]. Lymphedema, functional deficits with, for example, range of motion restrictions, and nerve injury-related complications may, however, become chronic. As neuropathic pain results in a severe impact on QOL in some patients [19], it is important to identify this type of pain and initiate appropriate treatment. Axillary and inguinal CLND are extensive surgical procedures that may directly or indirectly affect nerves in the surgical field. When SLNB or CLND is performed in the axilla, the potentially affected nerves include the long thoracic nerve, the intercostobrachial nerves, the pectoral nerves, and the thoracodorsal nerves. Inguinal SLNB and CLND may affect the lateral femoral cutaneous nerve, the branches of the femoral nerve, as well as the femoral branches of the genitofemoral nerve. In deep inguinal CLND, the sartorius muscle is dissected and transposed and repositioned before closure, which can result in loss of muscle function. Nerve injury-related complications after SLNB are primarily in the area around the surgical incision [19]. The axillary dissections, however, often result in sensory changes and pain in the upper lateral thoracic part of the T2–T3 dermatomes and the C6–C7 dermatomes in the posterior area of the upper arm [19]. Groin dissections mainly show involvement of the L2–L4 dermatomes in the anterior and anterolateral sides of the thigh extending distally in varying degrees. In addition, the length of the incision is 15–20 cm in inguinal CLND and 7–10 cm in head/neck and axillary CLND, which in itself represents a bigger area at risk of developing complications. Radical neck dissection involves the risk of nerve damage as lymph nodes are excised from the mandible to the clavicle [26]. Injury during surgery may thus lead to motor and sensory changes, including pain, in the innervation territory of the injured nerve. The pain immediately following surgery is likely due to a combination of inflammation and nerve injury, whereas chronic pain is more likely to be of neuropathic character [19]. The prevalence of neuropathic pain after surgery varies depending on the likelihood of surgical iatrogenic nerve injury. Neuropathic pain is present in up to 68% of patients with persistent postoperative pain following breast and thoracic surgeries and in only 6% of patients with persistent pain following hip or knee arthroplasty [24]. Patients may also develop pain after the excision of the melanoma [13]. It has been reported that 9.7% of patients develop persistent pain and 1.7% have moderate-to-severe pain following melanoma excision
[13]. In some cases, it can be difficult to distinguish between the pain following melanoma excision and that following lymph node excision. The development and testing of adjuvant therapy, such as ipilimumab, vemurafenib, and chemotherapy, for melanoma patients with the intention of improving their long-term survival is progressing rapidly [27,28]. Ipilimumab and, to a lesser extent, vemurafenib have been associated with the development of peripheral neuropathy. Given the increased utilization of these novel agents, it is critical to evaluate and monitor complications related to nerve damage in patients undergoing treatment for melanoma. More high-quality studies are needed to determine the prevalence and impact of persistent pain and sensory abnormalities following SLNB and CLND in melanoma patients, preferably prospective studies with designs that will allow identification of possible risk factors [29]. Validated questionnaires should be used and a clinical examination should be included to determine the type of pain [30]. There is, however, no doubt that some patients will develop persistent pain following these procedures. Improved surgical techniques with preservation of major nerves and more aggressive perioperative analgesia may prevent and/or reduce the incidence and severity of persistent postoperative pain [31,32]. Conclusion
CLND is a more invasive procedure than SLNB and is associated with more complications overall, including chronic neuropathic pain and sensory abnormalities. Our systematic review showed wide heterogeneity of outcome parameters and results in the literature, which limits further conclusions. Prospective studies are needed to evaluate the prevalence, prognosis, and impact of pain and sensory abnormalities following CLND and SLNB, to identify pain predictors, and to develop strategies for prevention of long-term complications.
Acknowledgements This review has been financially supported by the CPMC Foundation and the Danish Ministry of Foreign Affairs (the Trade Council) and the Danish Ministry of Science, Innovation and Higher Education. Conflicts of interest
There are no conflicts of interest.
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Persistent postoperative pain and sensory changes following lymph node excision in melanoma patients: a topical review Charlotte Slagelsea, Karin L. Petersena, Jørgen B. Dahlc, Kenneth Finnerupf, Kaitlin Greenea, Stanley P. Leonga, Jon Levineb, Michael Rowbothama, Mads U. Wernere and Nanna B. Finnerupd Studies on complications related to chronic nerve injury following sentinel lymph node biopsy (SLNB) and complete lymph node dissection (CLND) for melanoma are sparse. This review summarizes the existing literature on pain and neuropathic complications in melanoma patients undergoing SLNB with or without CLND. The Cochrane Central Register of Controlled Trials and the Embase and PubMed databases were searched. Full-text English language articles published before June 2013 were included. Prospective and retrospective studies assessing persistent (> 1 month) sensory nerve injury, postoperative pain, neuropathic pain, and sensory disturbances following SLNB with or without CLND in melanoma patients were eligible. Nine studies (six prospective and three retrospective) including data for 3632 patients met our inclusion criteria. Outcome parameters were too heterogeneous to conduct a quantitative analysis, and few studies systematically evaluated pain and sensory abnormalities. Persistent postoperative pain was reported in 1–14% of patients following SLNB and in 6–34% following CLND and sensory abnormalities in 0.1–32 and 2–82%, respectively. In the one study that assessed the type of pain, neuropathic pain was suggested to
explain persistent pain in 31–66% of patients with SLNB and 82–89% of patients with CLND. Sensory-nerve-related complications in melanoma patients seem to be less pronounced following SLNB compared with CLND. Prospective observational studies are necessary to identify predictors of persistent pain, to evaluate the prevalence and impact of pain and sensory abnormalities, and to develop strategies for prevention of long-term c 2014 Wolters complications. Melanoma Res 24:93–98 Kluwer Health | Lippincott Williams & Wilkins.
Introduction
lymphedema, and wound infection [7,11,12]. Although most complications resolve, little is known about longterm complications. Both excisions of the melanoma, CLND and SLNB, may be associated with persistent and occasionally severe and disabling neuropathic pain in the area of surgery [13–15]. Studies on the development of persistent pain after these procedures have primarily been conducted in breast cancer patients, among whom about 55% report persistent pain and 77% report persistent sensory disturbances following treatment [16]. Treatment for breast cancer often includes multiple concomitant or subsequent interventions such as lumpectomy, mastectomy, radiation, and chemotherapy, making it more difficult to assess pain following SLNB and CLND procedures per se [17]. As pain and regional nerve injury are rarely present before SLNB or CLND in melanoma patients, it is possible to study the natural history of nerve injury pain following lymph node surgery. The purpose of this systematic review was to analyze the literature describing pain and sensory abnormalities in melanoma patients undergoing SLNB with or without CLND.
Malignant melanoma causes more than 75% of skin cancer deaths. In 2008, there were 85 927 new cases in Europe and 68 100 in Northern America, and it is estimated that there will be 76 690 new cases in the American population in 2013 (http://www.cancer.gov/cancertopics/types/melanoma) [1,2]. Melanoma is currently the fourth most common cancer in the USA [1,3]. The 2008 age-standardized world standard population incidence per 100 000 individuals was 36.7 in Australia, 18.0 in Denmark, and 14.2 in the USA [2]. The initial treatment for melanoma consists of local resection of the melanoma skin lesion for diagnosis. Depending on the histology, this may be followed by wide excision of the melanoma and sentinel lymph node biopsy (SLNB) to determine whether cancer cells have metastasized. In the case of a positive SLNB with malignant cells, the current standard treatment is complete lymph node dissection (CLND) in the region [4,5]. The morbidity associated with SLNB and CLND is considerable, with overall complication rates ranging from 10 to 65% [6–10]. Common complications of the procedures are seroma, c 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins 0960-8931
Melanoma Research 2014, 24:93–98 Keywords: malignant melanoma, neuropathy, persistent postsurgical pain, sensory changes, sentinel lymph node a California Pacific Medical Center Research Institute, bDepartment of Medicine, Division of Rheumatology, University of California at San Francisco, San Francisco, California, USA, cDepartment of Anaesthesia, Rigshospitalet and Copenhagen University, dMultidisciplinary Pain Center, Neuroscience Center, Rigshospitalet, Copenhagen, eDanish Pain Research Center, Aarhus University, Aarhus and fDepartment of Plastic Surgery, Aalborg University Hospital, Aalborg, Denmark
Correspondence to Charlotte Slagelse, MD, California Pacific Medical Center Research Institute, San Francisco, CA 94107, USA Tel: + 1 45 61688615; e-mail: [email protected] Received 7 July 2013 Accepted 12 November 2013
DOI: 10.1097/CMR.0000000000000041
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Melanoma Research 2014, Vol 24 No 2
Methods
Study results
Studies assessing pain and sensory nerve injury-related complications following SLNB and CLND for melanoma were searched by the first author (C.S.). A nonrestrictive systematic search of the published literature, including prospective and retrospective, randomized and nonrandomized, observational studies, as well as reports on patients with malignant melanoma undergoing SLNB and/or CLND, was conducted in the Cochrane, Embase, and PubMed databases. Free text combinations including the following search terms were used: ‘axillary/groin dissection’, ‘complete lymph node dissection’, ‘complications’, ‘functional deficits’, ‘lymph node excision’, ‘melanoma’, ‘melanoma and surgery’, ‘morbidity’, ‘pain and melanoma’, ‘neuropathic pain’, ‘neuropathy’, ‘radical lymph node dissection’, ‘sensory disturbances’, ‘sentinel lymph node’, ‘sentinel node biopsy’, ‘shoulder mobility’, and ‘quality of life’. The reference lists from the retrieved articles were searched for additional papers. The last search was conducted on 3 June 2013. Articles were considered for inclusion if one of the following outcome parameters were evaluated: functional deficit/shoulder mobility, sensory disturbances, sensory dysfunction/pain, sensory nerve injury, pain elsewhere, and postoperative pain. We limited the search to full journal publications or reports in the English language. Abstracts were not included. Each of the identified articles was independently read and assessed for eligibility by the authors (C.S., N.B.F., and K.L.P.), and disagreements were solved by discussion or, if persistent, by a fourth review author. Studies were included if they reported the occurrence of long-term (> 1 month) pain or sensory abnormalities following SLNB or CLND in melanoma patients. The preferred reporting items for systematic reviews and meta-analyses, the PRISMA statement, were followed to the extent possible with the included material [18].
Study quality
Results Search results and study selection
Performing the database search resulted in 30 abstracts. Three studies were in duplicate and were excluded. Twenty-seven studies were retrieved for further review on the basis of initial abstract evaluation. Nine studies were excluded because the study population included breast cancer patients, six studies because of lack of assessment of parameters required for inclusion, and three studies because they did not assess long-term complications. Nine studies met our inclusion criteria and were included in the review (Fig. 1; flowchart). Baseline data from the included studies were extracted into a datasheet (Table 1). Review limitations
Because of the scarcity of literature evaluating long-term pain and sensory disturbances and with heterogeneous outcome measures, a meta-analysis was not possible and only a systematic qualitative analysis was carried out.
The included studies were a combination of retrospective and prospective studies, questionnaire-based and clinical follow-up studies, and medical chart reports. Quality assessment and relevance scores [24] are presented in Table 1. In seven studies, pain and sensory disturbances were not the primary outcome, and no definitions were given for pain and sensory disturbances (Table 1). Baseline data
In total, nine studies evaluating 3632 patients were included in the review (Table 1). Baseline data were comparable across study populations. A total of 3148 SLNBs and 1056 CLNDs were included in the review. The study populations ranged from 60 to 2120 patients. The female/male ratio was 0.96 and the mean age was between 40 and 59 years. Breslow thickness (depth of tumor invasion) of the primary melanoma lesion was 0.8–10 mm (Table 1). The mean follow-up period ranged from 1 to 39 months. The type of anesthesia was reported in three studies, all of which reported general anesthesia [10,19,23]. General anesthesia was specified as propofol and remifentanil in one study [19]. Postoperative analgesics were assessed in two trials and included paracetamol and/or opioids [19] or nonopioids for moderate pain and opioids for severe pain [9]. Outcome measures Sensory abnormalities
Sensory abnormalities were evaluated in five studies [15,19,20,22,23] (Table 1). The definition of sensory abnormality ranged from changed sensation to touch, which was assessed in all patients [19], to extensive sensory nerve dysfunction [15], which was recorded in medical charts for legal purposes and not systematically assessed [22,23] (Table 1). In one study, numbness and/ or paresthesia was not considered a complication as the intercostobrachial nerves were not spared, thus making it an expected event [15]. One study described sensory abnormality in more detail [19]. In the questionnaire, part of the study, 22% of patients undergoing SLNB and 78% undergoing CLND experienced hyposensitivity, whereas 13% reported hypersensitivity after SLNB and 34% after CLND. Twelve percent of the SLNB patients and 26% of the CLND patients reported impact of sensory abnormalities on quality of life (QOL). Postoperative pain
Five studies evaluated long-term (> 1 month) postoperative pain (Table 1). Pain was more common after CLND than after SNLB. Pain was defined as pain during the previous month in the area of surgery [19] or pain with no further definition [9]. In two studies, pain and other sensory disturbances or nerve dysfunctions were combined [10,14]. Only one study provided details on
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Persistent postoperative pain in melanoma patients Slagelse et al. 95
Fig. 1
30 abstracts and 1 editorial identified through database searching
27 records after duplicates removed
27 full-text articles assessed for eligibility
18 studies were excluded: 9 included breast cancer patients 6 did not assess required outcome measures 3 only assessed short-term complications
9 studies included in qualitative synthesis Flowchart.
pain; in this study, the chronic postoperative pain was suggested to be neuropathic in 31–66% of patients with SLNB and 82–89% of patients with CLND, depending on the criteria used [19]. In patients with SLNB, 2% reported at least moderate pain and 2% reported that the pain had an impact on their QOL. After CLND, 12% reported at least moderate pain and 14% reported that pain had an impact on their QOL 3–48 months after surgery [19]. Other long-term complications
Four studies included functional deficits as a parameter in their assessments [9,10,14,15]. Functional deficits included the following terms: motor nerve injury, functional deficit, mobility limitations, and functional limitation. In the studies, 0–2% of SLNB patients and 0.5–17% of CLND patients showed functional deficits. The incidence of lymphedema was reported in eight studies and ranged between 4 and 24% for SLNB and 1 and 37% for CLND [9,10,14,15,20–23]. The presence of lymphedema may contribute independently to pain and discomfort after surgery and may also influence the patient’s sensory perception. To our knowledge, no studies have examined the effect of lymphedema on sensory thresholds, nor the degree to which postoperative pain is due to lymphedema.
Discussion SLNB and CLND for melanoma involve tissues with a very high density of nerve fibers, including superficial
and small fibers in the skin, as well as the deeper located brachial and lumbar nerve plexuses. Hence, there is a considerable risk for nerve damage and subsequent development of sensory/motor dysfunction and pain. This qualitative review shows that there is a void in the literature with regard to systematically assessed outcome measures. Further, the studies have variable follow-up periods and intervals, which makes it difficult to adequately describe the incidence of symptoms after melanoma surgery. Despite these limitations, our review suggests that pain after CLND is more severe and longer lasting compared with that after SLND. Most of the studies did not define how they recorded pain and sensory abnormalities, and some did not record sensory abnormalities in territories innervated by nerves that were likely to be damaged during surgery. Hence, there is a considerable risk of reporting bias. In the only study in which pain and sensory abnormalities were the primary outcome [19], the prevalence of pain (14% after SLND and 34% after CLND) and sensory abnormalities (32 and 82%, respectively) was higher than that in the other studies. It is, however, important to note that a considerable number of patients experienced mild complications that may not be clinically relevant, and such questionnaire studies may overestimate the prevalence. Nevertheless, in a subgroup of patients, the sensory changes and pain were severe enough to impact the patients’ QOL; sensory abnormalities were reported to affect QOL in 12% of patients after SLNB and in 26% of patients after CLND, and pain affected QOL in 2 and 14% of patients, respectively [19].
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A, 3 A, 3 A, 3 A, 2 A, 2 B, 1 B, 1 B, 0
Prospective clinical follow-up Prospective clinical follow-up
Prospective clinical follow-up
Prospective clinical follow-up
Retrospective medical chart review
Retrospective case note review
Retrospective case note review
0 1056
3148
208
42
17
0
204 444
90
51
100
0
197
60
250
0 2120
297
124
SLNB CLND
No. of procedures
3632
100
208
197
60
250
204 2120
315
175
No.
Patients
49
55
NA
51
53
49
40 44
49
50
Female %
Sex
NA
47 (15–86)
57 (16–89)
56
54 (28–83)
57 (17–84)
48 (15–79) 50
58 (17–88)
59 (22–86)
Mean (range)
Age (years)
NA
NA
85.1
65.4
73.3
48.0
76.5 43.1
NA
40.0
Extremity
NA
2.1 (0.5–5)
NA
NA
(0.8–5)
2.4 (0.8–10)
> 0.8 2.5
NA
2.0 (0.3–10)
Mean/median (range)
Primary site Breslow thickness (%) (mm)
NA
(9–30)
>1
39.5 (5–97)
32
35 (2–98)
>6 16
(3–6)
23 (3–48)
Mean/median (range)
Follow-up (months)
1.0g,m
3.3j
0.1e,g,h
31.5
a
SLNB
6.7m
1.8e,g,h
82.4
a
CLND
Sensory abnormalities
2.6i,g
0.9d,e
13.8
b
SNLB
4.7g,k
6.0f
8.9d,e
34.0b
CLND
Pain
Percentage of patients undergoing surgery
Quality assessment: types of studies: A, prospective assessment, no group comparison; B, retrospective assessment, no group comparison. Relevance score: the following score, consisting of four questions, was applied to each study to assess its relevance in assessing neuropathic PPSP: (1) Was the study prospective? yes/no; (2) Was prevalence of pain and sensory abnormalities among the main outcomes of the study? yes/no; (3) Was assessment of pain and sensory abnormalities performed? yes/no; (4) Was follow-up clearly defined? yes/no. Yes = 1, No = 0. A score between 0 and 4 was assigned to each study, indicating the score of lowest and highest relevance, respectively. The relevance score does not provide an estimate of the overall methodological quality of the study. The studies have been prioritized on the basis of the quality assessment. CLND, complete lymph node dissection; NA, not applicable; PPSP, persistent postsurgical pain; SLNB, sentinel lymph node biopsy. a Any changed sensation (hypoesthesia or hyperesthesia) to touch in the surgical area. b Pain within the past month in the surgical area. c Lymphedema was assessed. d Nerve dysfunction/pain with no further description/definition. e Numbness or paresthesia was not considered a complication, as the intercostobrachial nerves were not spared, thus making it an expected event. f Pain, not defined. g Time of complication not specified; it may thus be an early complication. h Extensive sensory nerve dysfunction (with no further definition). i Postoperative pain and/or other sensory disturbances. j Wound pain with neuropathy, time not specified. k Adverse events as recorded in medical charts. l Primary cancer includes melanoma, squamous cell, thyroid, and salivary gland carcinoma. m Paresthesia, not defined.
Kretschmer et al. [14]c Urist et al. [9]c Wrightson et al. [15]c Wasserberg et al. [10]c Blumenthal et al. [20]c Biver-Dalle et al. [21]c Shaw and Rumball [22]l,c Heittiaratchy et al. [23]c Total
B, 4
Study quality
Retrospective postal questionnaire clinical examination in a subgroup Prospective interview clinical examination
Study design
Demographics and outcome data
Hoimyr et al. [19]
Table 1
96 Melanoma Research 2014, Vol 24 No 2
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Persistent postoperative pain in melanoma patients Slagelse et al. 97
For comparison, persistent postsurgical pain is present in about 20–40% of patients after breast and thoracic surgery, with 5–10% having severe disabling pain, and in 10% of patients after inguinal hernia repair, with 2–4% reporting severe pain [24,25]. Wound infection and seroma/hematoma formation were common postoperative complications but were often resolved [15]. Lymphedema, functional deficits with, for example, range of motion restrictions, and nerve injury-related complications may, however, become chronic. As neuropathic pain results in a severe impact on QOL in some patients [19], it is important to identify this type of pain and initiate appropriate treatment. Axillary and inguinal CLND are extensive surgical procedures that may directly or indirectly affect nerves in the surgical field. When SLNB or CLND is performed in the axilla, the potentially affected nerves include the long thoracic nerve, the intercostobrachial nerves, the pectoral nerves, and the thoracodorsal nerves. Inguinal SLNB and CLND may affect the lateral femoral cutaneous nerve, the branches of the femoral nerve, as well as the femoral branches of the genitofemoral nerve. In deep inguinal CLND, the sartorius muscle is dissected and transposed and repositioned before closure, which can result in loss of muscle function. Nerve injury-related complications after SLNB are primarily in the area around the surgical incision [19]. The axillary dissections, however, often result in sensory changes and pain in the upper lateral thoracic part of the T2–T3 dermatomes and the C6–C7 dermatomes in the posterior area of the upper arm [19]. Groin dissections mainly show involvement of the L2–L4 dermatomes in the anterior and anterolateral sides of the thigh extending distally in varying degrees. In addition, the length of the incision is 15–20 cm in inguinal CLND and 7–10 cm in head/neck and axillary CLND, which in itself represents a bigger area at risk of developing complications. Radical neck dissection involves the risk of nerve damage as lymph nodes are excised from the mandible to the clavicle [26]. Injury during surgery may thus lead to motor and sensory changes, including pain, in the innervation territory of the injured nerve. The pain immediately following surgery is likely due to a combination of inflammation and nerve injury, whereas chronic pain is more likely to be of neuropathic character [19]. The prevalence of neuropathic pain after surgery varies depending on the likelihood of surgical iatrogenic nerve injury. Neuropathic pain is present in up to 68% of patients with persistent postoperative pain following breast and thoracic surgeries and in only 6% of patients with persistent pain following hip or knee arthroplasty [24]. Patients may also develop pain after the excision of the melanoma [13]. It has been reported that 9.7% of patients develop persistent pain and 1.7% have moderate-to-severe pain following melanoma excision
[13]. In some cases, it can be difficult to distinguish between the pain following melanoma excision and that following lymph node excision. The development and testing of adjuvant therapy, such as ipilimumab, vemurafenib, and chemotherapy, for melanoma patients with the intention of improving their long-term survival is progressing rapidly [27,28]. Ipilimumab and, to a lesser extent, vemurafenib have been associated with the development of peripheral neuropathy. Given the increased utilization of these novel agents, it is critical to evaluate and monitor complications related to nerve damage in patients undergoing treatment for melanoma. More high-quality studies are needed to determine the prevalence and impact of persistent pain and sensory abnormalities following SLNB and CLND in melanoma patients, preferably prospective studies with designs that will allow identification of possible risk factors [29]. Validated questionnaires should be used and a clinical examination should be included to determine the type of pain [30]. There is, however, no doubt that some patients will develop persistent pain following these procedures. Improved surgical techniques with preservation of major nerves and more aggressive perioperative analgesia may prevent and/or reduce the incidence and severity of persistent postoperative pain [31,32]. Conclusion
CLND is a more invasive procedure than SLNB and is associated with more complications overall, including chronic neuropathic pain and sensory abnormalities. Our systematic review showed wide heterogeneity of outcome parameters and results in the literature, which limits further conclusions. Prospective studies are needed to evaluate the prevalence, prognosis, and impact of pain and sensory abnormalities following CLND and SLNB, to identify pain predictors, and to develop strategies for prevention of long-term complications.
Acknowledgements This review has been financially supported by the CPMC Foundation and the Danish Ministry of Foreign Affairs (the Trade Council) and the Danish Ministry of Science, Innovation and Higher Education. Conflicts of interest
There are no conflicts of interest.
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