Of the 8766 articles that were retrieved, 1,231 articles were excluded due to duplication. The remaining 7,535 articles were evaluated, and 7,109 were excluded based on their title and abstract. Next, 426 full-text articles were assessed and 389 were excluded, leaving 36 articles for inclusion reporting 36 studies (Refer to Figure 1).
[Insert Figure 1]
Characteristics of included studies
The majority of studies (n=34) focused on women (n=12145), while two studies (20, 21) involved both men and women. All studies were conducted between 2001 and 2019 and three studies (22-24) were reported in non-English language publications (Refer to table 2).
While the majority of studies were conducted in Brazil (n=12) and Turkey (n=9), most other regions with LMIC were represented, including: South America (n=12) (5, 20, 24-33), Europe (n=11) (21, 23, 34-42), Southern Asia (n=6) (43-48), West Africa (n=3) (22, 49, 50), Middle East (n=3) (51-53) and East Asia and Pacific (n=1) (54).
[Insert Table 2]
Most studies were cross-sectional (n=21), with a smaller number of prospective cohort (n=8), retrospective cohort (n=3) and case-control studies (n=4). The majority of studies (n=34) reported exclusively on either arm (n=30) or leg (n=4) lymphedema, while two (20, 50) reported on both. One study reported on lymphedema of the chest and arm secondary to breast cancer treatment (28). This study was the only study to use bioelectric impedance to diagnose lymphedema (28). Other methods used for measuring and defining lymphedema included: tape measurement (n=16) (21, 25, 32-34, 38, 39, 41-45, 48, 51-53); patient self-report (n= 8) (22, 26, 30, 40, 46, 47, 49, 54); water volumeter (n=2) (27, 35); palpation and clinical diagnosis (n=2) (29, 50); and perometer (n=1) (31).
Twenty-five studies reported lymphedema prevalence and 11 studies reported incidence.
Of the three studies that explored the risk of developing lymphedema associated with cancer staging both in the leg and arm, two involved women with breast cancer (41, 45) and the other, women with vulvar cancer (29). Four studies reported on the risk of developing arm lymphedema associated with breast cancer treatment among women who had sentinel lymph node biopsy (5, 21, 32, 42). Variations in the timing or the onset of cancer related lymphedema ranged from three months to over five years post diagnosis and treatment. The type of management received by women with cancer related lymphedema included: lymphatic drainage (42), physiotherapeutic modalities such as care for the affected limb, home exercises and self-lymphatic drainage (24, 26, 34), hormonal therapy (51) and neo-adjuvant therapy including radiotherapy and chemotherapy (25, 31).
Arm Lymphedema Following Breast Cancer Treatment
The majority of studies (n=31) reported arm lymphedema secondary to breast cancer treatment. However, lymphedema was defined differently based on the method of measurement used. Half of these studies (n=16) used circumferential measurements (21, 25, 32-34, 38, 39, 41-45, 48, 51-53). The remainder either used self-reports of swelling in the arms (n=5) (26, 30, 46, 47, 54), volumetric measurement (n=2) (27, 35), perimetry (n=1) (31) and/or bioimpedance spectrometry (n=1) (37). Six studies used more than one method of arm lymphedema diagnosis (5, 20, 23, 24, 27, 36).
Eleven studies (n=11) compared circumferential measurement in bilateral limbs using a range difference of ≥2 cm as indicative of lymphedema. One study from Brazil only used a difference of ≥1 cm circumferential measurement in the presence of any other two lymphedema symptoms of heaviness, swelling, tightness or firmness in the affected limb (5). Another study (23) which examined the upper extremity disorders among breast cancer women undergoing surgery measured lymphedema as circumferential measurement difference ≥1.5 cm in the affected limb. There was only one large population study involving Turkish women with breast cancer (n=5064), which used a cut-off difference of ≥5 cm in the affected limb as a diagnosis for lymphedema (34). All Turkish studies (n=7) measured arm lymphedema by the circumferential method, while the Brazilian (n=3) (24, 26, 30) and Indian (n=2) (46, 47) studies used patients’ self-reports.
Studies which used the volumetric measurement defined lymphedema to be a cut-off difference in volume based on circumferential measurements of both limbs > 10% percent (27, 35). Lymphedema was diagnosed as an impedance ratio of greater than 10 in the affected limb using the bioimpedance spectrometer (37).
Prevalence of arm lymphedema following breast cancer treatment
The most common method of arm lymphedema measurement was arm circumference (n=16), while several studies (n=9) also used more than just one lymphedema measurement. One study used lymphoscintigraphy as a technique in the measurement of lymphedema among Brazilian post-breast cancer women (32). All studies included in this review reported prevalence of arm lymphedema secondary to breast cancer treatment. Twenty-five studies reported prevalence estimates (5, 22, 23, 25-33, 35, 36, 38-40, 43, 44, 49-54). The prevalence estimate among post breast cancer treated women varied from 0.4% in Papua New Guinea (54) to 92.5% reported by a Brazilian study (35). The lowest estimate of 0.4% was reported by self-report of lymphedema(54). Of the two studies that reported on sentinel lymph node biopsy, the prevalence estimates were relatively low compared with other studies; 4.4% (95% CI 1.0 – 15.0) (32) and 17.0% (95% CI 11.0 – 27.0) (5).
Using data abstracted from 13 studies the pooled estimate for prevalence of breast cancer related lymphedema was 30 % (95% CI 24 – 37). There was considerable heterogeneity among studies (I2=91.66%, p=0.001) (refer to Figure 2). Heterogeneity was not reduced in a subgroup analysis of studies grouped by a single country, Brazil (pooled prevalence = 31%, 95% CI 19.0 – 43.0, I2 = 87.21%, n = 5 studies). Studies from the Middle East (i.e. Iran (51), Jordan (53) and Turkey (23)) demonstrated considerable heterogeneity (I2= 94.69%, p=0.001), which increased to considerable heterogeneity when a second Turkish study (39) was included (I2= 99.67%, p=0.001). The pooled prevalence recorded by the two Turkish studies was 37% (95% CI 32 – 42) among breast cancer women receiving treatment in cancer units (refer to Figure 3).
[Insert Figures 2 and 3]
Incidence of arm lymphedema following breast cancer treatment
Eleven (11) studies reported incidence of unilateral arm lymphedema (20, 21, 24, 34, 37, 41, 42, 45-48), while one study reported lymphedema of both arm and leg (20). The follow up periods varied among studies from 6 months to over 5 years post- cancer treatment.
The lowest incidence was 5.9% after breast cancer treatment in Romania (21) with a mean follow up period of 24 months, who received sentinel lymph node biopsy. The highest incidence was 56.7% recorded in an Indian study with 6-month follow up after modified radical mastectomy treatment for breast cancer patients (47). Breast cancer related lymphedema incidence in Turkey ranged from 7.2% recorded within a population sample with a median follow up of 64 months with a median follow up of 30 months after breast cancer treatment (41). The incidence of arm lymphedema reported by the Brazilian studies ranged from 17.5% to 23.2% (20, 24). The pooled incidence was 21% (95% CI 15.0 – 26.0, I2 = 95.29%, n=11 studies) with considerable heterogeneity, while that reported by circumferential measurement was 16% (95% CI 9.0 – 23.0, I2=96.54%, n=6 studies) (refer to Figure 4). The estimated pooled incidence by all other methods of assessment was between 16.0% (circumferential measurement) and 26.0% (self-report).
[Insert Figure 4]
Risk factors of lymphedema following breast cancer treatment
Ten of the 11 studies reporting on lymphedema risk factors, focused on the risk of developing arm lymphedema following breast cancer treatment (21, 31, 34, 38, 41-43, 45, 48, 52). One study (34) reported that individuals with body mass index (BMI) of ≥30 were 6.64 times more likely to develop arm lymphedema than those with BMI ≤17.9. The risk of developing arm lymphedema among breast cancer women with BMI ≥25 ranges from the odds ratio (OR) of 1.5 to 5.9 compared to participants with BMI < 25 (34, 38, 41, 48, 52). We obtained a pooled effect estimate OR of 1.98, 95% confidence interval (CI): 1.45 to 2.70 (P < 0.0001; I2 = 84.0%) in a random effect meta-analysis (refer to figure 5).
[Insert Figure 5]
Axillary radiotherapy treatment is a significant risk with an OR ranging from 2.7 to 4.4 (21, 38, 42). Four studies examined the risk of developing arm lymphedema associated with higher number of lymph node removal among breast cancer survivors (21, 38, 48, 52). The removal of lymph nodes of >25 during mastectomy was associated with a risk of developing arm lymphedema [4.88 (OR2.25–10.58)] among breast cancer woman compared with when less number of lymph nodes were removed (21). Higher nodal ratio [1.135 (Hazard ratio (HR) 1.037‑1.243)] was also found to be associated with higher risk of arm lymphedema (48). Lumpectomy was not a significant risk factor for arm lymphedema (38).
Modified radical mastectomy was associated with an OR of 4.3 (95% CIs: 2.3 – 7.9) risk than those who did not and participants who received radiotherapy had an OR of 3.9 (95% CIs: 1.8 – 8.2) risk of developing arm lymphedema compared with those who did not (52). The length of time after surgery for breast cancer was also reported to be 9.7 times higher among breast cancer women who had surgery more than 5 years as compared to those with less years (31).
Other risk factors identified to significantly affect lymphedema among breast cancer survivors include: past history of limb damage had an OR of 1.7 (95% CIs: 0.9 – 3.1) (52), presence of a co-morbid condition with a HR of 0.1593 (95% CIs: 1.1441 – 2.9369) (43), post radiotherapy moist desquamation had an OR of 4.34 (95% CIs: 1.07–17.65) (45), and presence of seroma after breast cancer surgery (31). Women with breast cancer tumour invasion were 13.7 times at risk of developing arm lymphedema compared to those women who did not receive tumour invasion (52). Cancer stage was not significant in arm lymphedema following breast cancer treatment (31, 45) (refer to Table 3).
[Insert Table 3]
Leg lymphedema following gynecological cancer treatment
All five studies that reported leg lymphedema used either patient self-report (n=3) or palpation or clinical diagnosis (n=2). Studies which used the self-report method of lymphedema diagnosis only used either palpation or observation methods of identifying lymphedema in the affected limbs of the patients (22, 40, 49). These were based on patients’ reports of swelling in the legs alone. In the case of the clinical diagnosis, lymphedema was identified as present when a positive Stemmer’s sign was recorded (50).
Prevalence of leg lymphedema following gynecological cancer treatment
Of the five studies reporting on leg lymphedema, three focused on the prevalence of leg lymphedema secondary to cervical cancer treatment; two West African and one Romanian (22, 40, 50). The prevalence estimates were similar; 7.0% (95% CI 3 – 15) (22), 11.0% (95% CI 8 – 15) (40) and 13% (95% CI 7 – 23) (50). The three studies (22, 40, 50) that reported on leg lymphedema following cervical cancer reported a pooled prevalence of 10% (95% CI 7 – 13) with considerable heterogeneity. The method of measurement of lymphedema was self-report and none of these studies explored leg lymphedema risk factors.
Two studies reported leg lymphedema prevalence based on clinical diagnosis among women who received vulvectomy (29, 49). The prevalence varied widely from 60.1% in the Brazilian study to 9.1% in the Nigerian study (49).
The incidence of leg lymphedema was reported in only one study, which focused on patients following inguinal and ilioinguinal lymphadenectomies in Brazil and identified an incidence of 59.1% (20).
Risk factors of lymphedema following vulvar cancer treatment
One study reported the risk of developing leg lymphedema following vulvar cancer treatment (29). The risk of leg lymphedema following vulvar cancer included age associated with an OR of 1.09 (95% CIs: 1.00 – 1.18) and a BMI with an OR of 1.34 (1.01 -1.77) (29) (refer to Table 3).
Planned sub-group analyses failed to significantly reduce heterogeneity. Heterogeneity based on: country of study publication and the type of cancer was 95.29%; study region was 93.85%; sample size, the type of measurement of lymphedema, and the design of the study were 94.69%. The level of heterogeneity was 97.2% (n=5 studies) for incidence and 94.89% (n=6 studies) for prevalence when focusing on low risk of bias studies (refer to table 4).
[Insert Table 4]
A post-hoc subgroup analysis was also conducted in which we removed from the meta-analyses all studies that had less than 24 months follow up (n = 5). This too resulted in minimal improvement in heterogeneity.