Int J Clin Oncol (2011) 16:238–243 DOI 10.1007/s10147-010-0171-5
ORIGINAL ARTICLE
Risk factors for lower-limb lymphedema after surgery for cervical cancer Yoko Ohba • Yukiharu Todo • Noriko Kobayashi • Masanori Kaneuchi Hidemichi Watari • Mahito Takeda • Satoko Sudo • Masataka Kudo • Hidenori Kato • Noriaki Sakuragi
•
Received: 1 November 2010 / Accepted: 26 November 2010 / Published online: 7 January 2011 Ó Japan Society of Clinical Oncology 2011
Abstract Background Lower-limb lymphedema (LLL) is a prevalent complication that is encountered after treatment for gynecological malignancies. The aim of this study was to evaluate the risk factors for postoperative LLL in patients with cervical cancer. Methods We conducted a retrospective chart review for patients who had undergone surgery, including systematic lymphadenectomy, for cervical cancer. Patients who died of cancer, were evaluated for short periods of time (\2 years), had missing medical records, or were suffering from deep venous thrombosis were excluded. We utilized the International Society of Lymphology staging of lymphedema severity as the diagnostic criteria for LLL, and patients with stage II or III lymphedema, as objectively determined by physicians, were included in the group of patients with LLL. Multivariate analysis was performed to confirm independent risk factors. Results A total of 155 patients with cervical cancer were evaluated. Thirty-one patients (20.0%) contracted LLL with a median follow-up of 6.1 years. Suprafemoral node dissection (odds ratio, 9.5; 95% confidence interval, 1.2–73.3; P = 0.031) and adjuvant radiotherapy (3.7;
Y. Ohba N. Kobayashi M. Kaneuchi H. Watari M. Takeda S. Sudo M. Kudo N. Sakuragi (&) Department of Gynecology, Hokkaido University Graduate School of Medicine, N15W7 Kita-ku, Sapporo 060-8638, Japan e-mail:
[email protected] Y. Ohba Y. Todo H. Kato Division of Gynecologic Oncology, National Hospital Organization, Hokkaido Cancer Center, 3-54, Kikusui 4-jo 2-chome, Shiroishi-ku, Sapporo 003-0804, Japan
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1.2–10.9; P = 0.019) were identified as independent risk factors. Conclusion Given that the effectiveness of the above two therapeutic options for cervical cancer is currently controversial, the clinical benefits of these therapies should be reevaluated specifically to conserve the quality of life for patients with this disease. Keywords Cervical cancer Lower-limb lymphedema Surgery Risk factor
Introduction Lower-limb lymphedema (LLL) is a common complication after lymph node dissection and is associated with surgery for gynecological cancers; it is characterized by abnormal absorption of protein-rich fluid from the interstitium as a result of an obstruction of lymphatic vessels in the lower limbs after lymphadenectomy. Because of its chronic and incurable nature, lymphedema causes problems for gynecological cancer survivors in the form of functional and aesthetic defects as well as psychological sequelae, thereby reducing their quality of life [1–3]. Cervical cancer is one of the leading causes of death from malignant tumors among women worldwide, and in Japan, 8,500 women contract this malignancy each year [4]. The majority of cervical cancer patients are diagnosed between young adulthood and middle age, with an average age at diagnosis of approximately 40 years old [4]. LLL after cervical cancer surgery results in severe sequelae for patients. It is particularly important that the rest of the life of such young women affected by cervical cancer is much longer than those with other malignancies. Moreover, the incidence of cervical cancer has recently been increasing
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among younger women, which has caused gynecological oncologists to carefully consider patients’ quality of life after treatment. In this study, we conducted a retrospective chart review to highlight the risk factors for LLL associated with cervical cancer surgery. Among the clinical factors evaluated, postoperative radiotherapy and dissection of suprafemoral nodes (SFNs) were identified as independent risk factors. Whether these treatments are truly required for the management of individual cervical cancer patients should be evaluated. Furthermore, we should establish strategies for preventing and managing LLL, which would consequently lead to improved quality of life.
Materials and methods Patients We performed a retrospective chart review of 216 patients with uterine cervical cancer treated with systematic lymphadenectomy at the Hokkaido University Hospital from January 1995 to February 2008. This study was approved by the Institutional Review Board of Hokkaido University Hospital and has been disclosed on its official website. Sixty-one patients were excluded for the following reasons: incomplete medical information (32), short observation periods (\2 years) (10), death from cancer (15), and the development of deep venous thrombosis (4). Finally, 155 living patients were enrolled in the study. A retrospective chart review was undertaken to obtain the following clinical information: patient age, body mass index, International Federation of Gynecology and Obstetrics (FIGO) clinical stage, lymph node metastasis, variations in surgical procedures [i.e., number of resected lymph nodes, extent of lymph node dissection (paraaortic lymph node dissection in addition to pelvic nodes and SFN dissection), retroperitoneal closure (closure or nonclosure), and the type of hysterectomy performed], the presence of postoperative lymphoceles, and postoperative adjuvant therapy, including chemotherapy and radiotherapy.
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mesenteric artery. Dissection of PANs and/or SFNs occurs at the surgeon’s discretion. At the Hokkaido University Hospital, the retroperitoneal approach was changed in 2003, and retroperitoneal closure has not been used after 2003. Assessment of lymphedema We utilized the grading of LLL severity proposed by the International Society of Lymphology [6]. Briefly, stage I lymphedema represents swelling caused by protein-rich fluid that can be temporarily reduced by simple elevation of the limbs. At stage II, the swelling becomes irreversible and develops into pitting edema, which will regress consequent to a progressive hardening of the affected tissues at late stage II. Stage III lymphedema is characterized by a tremendous increase in volume, hardening of the dermal tissues, hyperkeratosis, and papillomas of the skin. On the basis of medical records, we identified patients with postoperative LLL. Unilateral or bilateral lower-limb edema, as objectively determined by a physician, was defined as LLL, whereas patients with subjective complaints of swelling in their legs without an objective assessment were not included in the LLL group. Therefore, the severity of lymphedema defined in this study corresponds to stage II or III lymphedema, which is not reduced by limb elevation and greatly influences patients’ quality of life. Statistical analysis The primary endpoint of this study was the occurrence of LLL. The aforementioned factors that might contribute to the development of LLL were analyzed using the chisquared test. Multivariate logistic regression analysis was used to further assess whether the risk factors evaluated therein were independent for postoperative LLL. Statistical significance was set at P \ 0.05. All the statistical calculations were executed using Stat View J-5.0 PPC software (SAS Institute, Cary, NC, USA).
Surgical procedures
Results
Systematic lymphadenectomy is defined as surgery to remove regional lymph nodes from the retroperitoneum, which include pelvic and paraaortic lymph nodes (PLNs and PANs, respectively). The nomenclature for retroperitoneal lymph nodes in the current study was essentially adopted from a previous report [5]. PLNs consist of common iliac, external iliac, internal iliac, obturator, suprafemoral, parametrial, and sacral nodes. PANs comprise lymph nodes that are inferior and/or superior to the inferior
Patient characteristics and the details of treatment are shown in Table 1. All 155 patients were diagnosed with stage I or II cervical cancer according to the International Federation of Gynecology and Obstetrics (FIGO) as follows: 110 patients (71.0%) had stage I disease [Ia: 9 (5.8%); Ib: 101 (65.1%)], and 45 patients (29.0%) had stage II disease [IIa: 8 (5.2%); IIb: 37 (23.9%)]. The majority of patients [139 (89.7%)] underwent radical hysterectomy, whereas 8 patients (5.2%) with FIGO stage Ia
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Table 1 Clinical characteristics of 155 patients in this study
Table 2 Influence of factors on the incidence of lower-limb lymphedema (LLL)
Age (years), mean ± SD
53 ± 12
BMI (kg/m2), mean ± SD
22.8 ± 3.8
N
FIGO stage, N (%) Ia and Ib
110 (71.0)
IIa and IIb
45 (29.0)
Age (years) \50
Surgical procedure (lymphadenectomy was combined in all cases)
C50 BMI (kg/m2)
Type of hysterectomy, N (%)
\25
Radical hysterectomy
139 (89.7)
Modified radical hysterectomy
8 (5.2)
FIGO stage
Total hysterectomy
1 (0.6)
Ia and Ib
7 (4.5) 85 (38–172)
IIa and IIb
Conization Number of lymph nodes dissected, mean (range) Extent of lymphadenectomy, N (%)
No. of patients Incidence P value* with LLL (%)
C25
100 22 55
22.0
9
16.4
118 23
19.5
37
8
21.6
110 19
17.3
45 12
26.7
139 30
21.6
RH
PLN ? PAN
136 (87.7)
MRH, TH, Conization
Adjuvant chemotherapy, N (%)
16
1
Number of lymph nodes dissected 70 (45.2)
\90
97 18
18.6
-
85 (54.8)
C90
58 13
22.4
Adjuvant radiotherapy, N (%) 16 (10.3)
-
139 (89.7)
BMI body mass index, FIGO International Federation of Gynecology and Obstetrics, PLN pelvic lymph node, PAN para-aortic lymph node
PLN only PLN ? PAN
4
80
3
60
2
40
1
20
Cumulative percentage
Numb er of patients
5
100
0
0 4
5
6
7
8
9
10
Years after operation Fig. 1 Number and incidence of lower-limb lymphedema (LLL) after lymphadenectomy. The number (columnar graph) and cumulative percentage (line graph) of patients are plotted against time (in years) from surgery to the onset of LLL. Percentages at the top of the graph indicate the cumulative percentages within 2 and 4 years after surgery
and Ib underwent modified radical hysterectomy, and 7 patients (4.5%) received conization and systematic lymphadenectomy to spare their uteri for future fertility. The total number of lymph nodes dissected per patient ranged from 38 to 172 (85 ± 26, mean ± SD). Seventy-six patients (49.0%) underwent operations with retroperitoneal
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5.3 22.1
0.087
?
119 30
25.2
0.003
36
1
2.8
Opening
76 12
15.8
Closing
79 19
24.1
Retroperitoneal closure
120
77%
19 1 136 30
SFN dissection -
3
0.561
Extent of lymphadenectomy
?
2
0.147
6.3
?
1
0.185
Type of hysterectomy 19 (12.3)
40%
0.778
Surgical procedure
PLN only
6
0.401
0.199
Postoperative lymphocele formation ?
41 10
24.4
-
114 21
18.4
0.413
Lymph node metastasis ? -
32
9
28.1
123 22
17.9
70 16
22.9
85 15
17.6
16
8
50.0
139 23
16.5
0.197
Adjuvant chemotherapy ? Adjuvant radiotherapy ? -
0.420
0.002
* Chi-squared test RH radical hysterectomy, MRH modified-radical hysterectomy, TH total hysterectomy, PLN pelvic lymph node, PAN para-aortic lymph node, SFN suprafemoral node
nonclosure, whereas 79 patients (51.0%) underwent operations with surgical closure. The median follow-up was 6.1 years (range, 2.0–14.9 years). LLL was observed in 31 of the 155 patients (20.0%) throughout the follow-up period. The median time from operation to the onset of LLL was
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Table 3 Logistic regression analysis of factors related to lower-limb lymphedema (LLL) after systematic lymphadenectomy for cervical cancer Factor
N
No. of patients with LLL
Incidence (%)
Odds ratio (95% CI)
P value
0.031
SFN dissection ?
119
30
25.2
9.5 (1.2–73.3)
-
36
1
2.8
1.0
Adjuvant radiotherapy ?
16
8
50.0
3.7 (1.2–10.9)
-
139
23
16.5
1.0
0.019
CI confidence interval, SFN suprafemoral node
2.5 years (range, 0.5–10.8 years). Most of the LLL (77%) cases occurred within 4 years of the operation, and the remaining cases developed sporadically beyond 5 years after the operation (Fig. 1). The chi-squared test revealed that, among the clinical variables tested, postoperative radiotherapy (P = 0.002) and SFN dissection (P = 0.003) were significantly associated with the occurrence of LLL, whereas none of the other treatment protocols, including surgical procedures (the number of resected lymph nodes or paraaortic lymph node dissection in addition to pelvic nodes) and postoperative chemotherapy, was a risk factor for LLL (Table 2). Age, body mass index, FIGO stage, type of hysterectomy, handling of the retroperitoneum, and the presence of lymphoceles showed no relationship to LLL. A multivariate logistic regression model that included PAN dissection, postoperative adjuvant radiotherapy, and SFN dissection further demonstrated that postoperative radiotherapy [odds ratio (OR), 3.7; P = 0.019] and SFN dissection (OR, 9.5; P = 0.031) were independent risk factors for the occurrence of LLL (Table 3). The presence of PAN dissection was not an independent risk factor for LLL [OR, 1.7; 95% confidence interval (CI), 0.2–15.0; P = 0.656].
Discussion Lymphedema is a common complication after systematic lymphadenectomy for the treatment of cervical cancer; however, the detailed mechanism of pathogenesis or appropriate prophylaxis remains unidentified. Several reports have documented risk factors for LLL associated with surgical treatment of gynecological malignancies, which include the number of dissected lymph nodes [7–9], postoperative adjuvant radiotherapy [9–11], and SFN dissection [9]. In our study, adjuvant radiotherapy and SFN dissection were also revealed as risk factors for LLL,
whereas the number of dissected lymph nodes was not. This inconsistency regarding the dissected lymph node number may be accounted for by a difference in the number of dissected lymph nodes per operation among institutions. The average number of dissected lymph nodes in this study was 85 (range, 38–172), which is substantially more than that of other institutions, as reported in previous studies; in fact, our minimum (i.e., 38) exceeds thresholds for obtaining significance in other studies (usually 10–31). Therefore, the number of dissected lymph nodes may be a risk factor in an all-or-none manner, and there does not appear to be a direct correlation between an increased number of dissected lymph nodes and an increased risk for LLL. In this study, the values for the number of dissected lymph nodes were already supraliminal, which reduced the likelihood of delineating an influence on the LLL onset. In the present study, we reported a 20% incidence of LLL among 155 patients who underwent systematic lymphadenectomy for cervical cancer. As reported in the literature, LLL incidence after surgery for gynecological malignancies ranges from 1.2% to 37.8% [7, 9, 10, 12], and in patients with cervical cancer, similar values (3.6–30.2%) have been reported by independent research groups [8, 10, 13, 14]. These variations in incidence among reports may be attributed to a lack of criteria for evaluating lymphedema. In fact, different definitions [objective judgment by physicians, subjective complaints from patients (‘‘symptomatic’’ lymphedema), or a mixture of both] have been arbitrarily utilized in previous studies. Thus, the aforementioned studies may have included substantial numbers of patients with stage I or milder lymphedema. In contrast, our study adopted stage II or III lymphedema as a criterion because lymphedema at these stages is obvious to the physician and is clearly distinguishable from edema from other causes. The lower incidence rate in the present study as compared to that in other reports may result from this difference in the lymphedema inclusion criteria. A similar difference among studies is observed regarding the onset of lymphedema. Again, the onset in our study (median, 2.5 years; range, 0.5–10.8 years) is substantially later than that observed in other reports (median, 4.2–11 months), which appears to be related to the difference in criteria for the severity of lymphedema. Adjuvant radiotherapy and SFN dissection were identified as independent risk factors, which is consistent with a previous endometrial cancer report by Todo et al. [9]. The influence of the extent of lymph node dissection on the treatment of cervical cancer has been a matter of debate, although it is generally accepted that systematic lymphadenectomy should be incorporated into hysterectomy procedures [15]. The lymph node metastatic pathways associated with cervical cancer are believed to depend on the pattern of the lymphatic vessel network and the
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proximity of the draining nodes [16, 17]. Lymphatic drainage from the uterine cervix follows three routes: the lateral, anterior, and posterior routes. SFNs are located in the adipose tissue that is most distal to the external iliac nodes, which is a hub for the anterior route [16, 17], which may explain why SFNs have commonly been included in the regional lymph nodes for cervical cancer. On the other hand, the lymph nodes most frequently involved in cervical malignancies are reported to be internal iliac, obturator, external iliac, and common iliac nodes [17–19]. More importantly, solitary lymph node metastases are detected in very limited nodes: obturator, internal iliac, cardinal ligament, and common iliac nodes; SFN metastases are rarely encountered in operative cases [17, 18, 20, 21]. Indeed, it has been reported that SFN metastases are accompanied with multiple lymph node metastases, and only 8% of patients with any positive regional nodes have SFN metastases [18]. Moreover, SFNs are seldom identified as sentinel lymph nodes in cervical cancer [22–26]. It would be worthwhile to conduct a randomized control study to evaluate whether SFN dissection is essential to improve disease-free survival and overall survival and to design a strategy to assess the necessity of SFN dissection for individual patients. Abu-Rustum and Barakat [20] also suggested that the dissection of SFNs, which are the draining lymph nodes of the lower limbs, contributes to an increase in the risk for postoperative LLL in cervical and uterine corpus cancers. Therefore, at present, although SFN dissection may still remain appropriate for cases with multiple metastases, it may not be required for the majority of cervical cancer patients. Because irradiation per se can cause lymphedema by preventing the formation of collateral circulation of the lymphatic system and accelerating skin fibrosis [27], adjuvant radiotherapy has been implicated in postoperative lymphedema [9–11, 28–31]. We found that LLL affected 50% of patients who had received radiotherapy, whereas the frequency of LLL in those without radiotherapy was 16%. Adjuvant radiotherapy has been generally introduced for stage I–II cervical cancer patients who are at high risk for recurrence; these cases include characteristics such as deep stromal invasion, parametrial invasion, lymph vascular space involvement, lymph node metastasis, and bulky tumors (C4 cm). To date, several guidelines for cervical cancer treatment, including those launched by the American Congress of Obstetricians and Gynecologists and the Japan Society of Gynecologic Oncology, recommend radiotherapy as a first-line postoperative adjuvant therapy for patients with a high risk for recurrence. In 1998, a prospective randomized study conducted by the Gynecologic Oncology Group to investigate the efficacy of adjuvant radiotherapy for stage I cervical cancer cases at risk
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for recurrence showed that adjuvant radiotherapy significantly reduces cancer recurrence by 44% [32]. Similar results have been demonstrated by several retrospective studies [14, 33, 34]; however, it has not yet been demonstrated by randomized controlled trials that adjuvant radiotherapy prolongs overall survival. Therefore, a careful assessment of the clinical significance of this therapy for individual patients is ultimately envisaged. In this regard, chemotherapy could be considered as adjuvant therapy for cervical cancer. In fact, one of the aforementioned retrospective studies demonstrated that, compared to radiotherapy, adjuvant chemotherapy resulted in a lower frequency of complications, including lymphedema, bowel obstruction, and urinary disturbance, and had an equivalent effect on disease-free survival [14]. Given that radiotherapy is still indispensable for a substantial number of patients, gynecological oncologists may need to carefully monitor for the occurrence of LLL and prepare effective countermeasures for patients who receive this adjuvant therapy. Recent studies have been designed to evaluate the effectiveness of physiotherapy as prophylaxis against LLL. Lacomba and colleagues conducted a randomized controlled trial that assessed the effectiveness of early physiotherapy for prophylaxis of secondary lymphedema in 120 women who underwent surgery for breast cancer (including axillary lymph node dissection) and showed that significantly fewer women who received physiotherapy developed clinically significant lymphedema at 1 year as compared with controls (25% vs. 7%; risk ratio, 0.28; 95% CI, 0.10–0.79) [35]. At our hospital, since 2008, we have also provided physiotherapy-based lifestyle guidance for patients receiving lymph node dissection for gynecological malignancies; these include self-manual lymph drainage and wearing of compression garments. The effectiveness of these approaches, in particular, their longterm efficacy, should be evaluated by prospective studies in the near future. Moreover, we may need to develop coping strategies, including more intensive interventions (e.g., lymphatic drainage by trained therapists), for patients with risk factors for LLL. In this study, we focused on stage II or III LLL after systematic lymphadenectomy for cervical cancer and found SFN dissection and adjuvant radiotherapy to be independent risk factors. Stage I lymphedema was excluded because it is easily overlooked by physicians. Given that lymphedema obviously exacerbates the patients’ quality of life even in stage I [2], and because immediate intervention is particularly important in preventing lymphedema progression, it may be worthwhile to include stage I cases in a reevaluation of the risk factors for LLL while incorporating methods to quantitatively evaluate mild lymphedema, such as volume measurement.
Int J Clin Oncol (2011) 16:238–243 Acknowledgments The authors thank Yusuke Ohba (Hokkaido University) for drafting the manuscript and Drs. M. Nakatani, Y. Suzuki, S. Minobe, and K. Okamoto (Hokkaido Cancer Center) for helpful discussion. This work was supported in part by grants from the Japan Society for the Promotion of Science (KAKENHI: 22591843, 22591844). Conflict of interest
No author has any conflict of interest.
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