Symptoms and their Relationship to Disability Following Treatment for Lower Extremity Tumours

Purpose. The aims of this study were to describe the symptoms experienced by patients in the first year following treatment for lower extremity sarcoma by limb conservation and to describe the relationship between symptoms and physical disability. Subjects. Eighty consecutive patients treated for primary bone or soft tissue sarcoma (STS) of the lower limb who were treated with limb preservation surgery. Methods. Subjects were evaluated by questionnaire at 6 weeks, and 3, 6, and 12 months post surgery. They identified whether they experienced any of the following symptoms: pain, stiffness, fatigue, weakness, limited range of motion, or swelling.The Toronto Extremity Salvage Score (TESS), a measure of physical disability, was also completed. Frequency of symptoms over time was calculated and change was evaluated using the Cochrane test. The relationship of symptoms to disability was analyzed with regression methods. Results. The mean age was 43.0, SD=20.4 with a gender ratio of 1:1. There were 38 bone tumours and 42 STS.The most frequently reported symptoms were: stiffness 48 (60%), weakness 41 (51%), fatigue 26 (33%), and pain 25 (31%) at 6 weeks. Stiffness and fatigue decreased and plateaued by 3 months. Complaints of weakness and pain continued to decrease over time. At 6 weeks, pain, stiffness, weakness and limited motion predicted disability in both univariate and multivariate analyses. At 12 months, pain, stiffness, fatigue, weakness and limited motion were significant predictors of the TESS in univariate analysis with only pain, stiffness and limited motion significant predictors in the multivariate model. Discussion. Pain, stiffness, fatigue, weakness and limited motion are common symptoms with stiffness and weakness decreasing significantly over time. The symptoms predictive of disability differ between the acute and late phases of recovery.


Introduction
O ver the past two decades, lim b conservation surgery for patients with extremity sarcom a has becom e the accepted standard of treatment. T his standard has been attainable m ainly due to the advent of m odern im ag ing techniques and advances in surgical reconstructive techniques.T he outcom es of patients treated by lim b conservation have been reported in term s of survival and local control with few studies addressing the sym ptom s and disability experienced by patients following treatment. 1± 4 O f these published studies reporting m orbidity outcom es, m any include patients treated in the 1970s and early 1980s, such that the outcomes related to treatment morbidity do not reflect current advances in treatment. 1± 3 The aim s of the cu r ren t stu d y w ere: to d esc r ib e the sym p to m s experienced by patients in the ® rst year following treatm ent by lim b conservation for lower extremity sarcom a; to evaluate how the reported sym ptom s change over time; and to describe the relationship between symptoms and physical disab ility.

M ethods
F rom Ju n e 1994 to Ju ly 1995, 9 7 co n se cu tive , consenting patients w ith prim ar y bone or soft tissue (STS) sarcom a of the lower extremity were entered in the stu d y. A ll patients were treated by lim b conser vation surgery. U se of adjuvant therapy, radiation or chem otherapy, was determ ined by the m ultidisciplinary team on a case by case basis. Adjuvant radiotherapy for soft tissue sarcom a was delivered as previously described by our group 5 and chemotherapy for patients with bone tumours varied according to th e tu m o u r h ist o lo gy. Patien ts p resen tin g w ith m etastatic disease, or w ho could not com plete the questionnaires for reasons of language or cognition were excluded from the study. S y m p to m s a n d the d isa bility exp er ien ced b y patients were collected by questionnaire at 6 weeks, and 3, 6 and 12 m onths post-operatively. Previous pilot interviews 6 identi® ed that patients thought that pain, stiffn ess, fatigue, lim ited range of motion, weakness, swelling and abnorm al sensation were im portant sym ptom s. C onsequently, subjects were ask ed to indicate all sym ptom s that they experienced from the above list and they were also able to add additional sym ptom s. Physical disab ility was evaluated by the patient using the Toronto Extremity Salvage Score (TESS). 7,8 T he T ESS is a reliable and valid m easure of physical disab ility developed for the extrem ity sarcom a population in which patients rate their ability to perform routine daily activities. 7 Sym ptom data were analyzed by frequency at each point in time and change over time was evaluated graph ically and using the Cochrane test.T he relationship of sym ptom s to disability as m easured by the TESS was evaluated in the im m ediate post-operative period (6 weeks) and then at 12 m onths post surgery when m ost patients had reached their m axim al level of functioning. T his relationship was evaluated using regression m ethods.
O f the 97 consecutive patients for whom functional outcom e (TESS) data and sym ptoms data was available, only 80 had sym ptom data for all the time points. The data from these 80 subjects with complete data at all evaluation times form ed the sam ple for analysis. The 17 subjects excluded from the analysis did not differ on any descriptive variables or their outcom e from the sam ple of 80 (data not shown).

Results
The subjects had a m ean age of 43 years (± 20) and 41 were m ale. T he sam ple included 38 subjects with primar y bone tum ours and the rem aining 42 had primar y soft tissue sarcom as. As anticipated in lower extrem ity m u sculoskeletal tum our patien ts, m o st tum ours were proxim al, speci® cally with 36 located in the area of the pelvis and hip, 35 at the knee and nine in the distal leg, foot and ankle. O f the bone tum ou r su bje cts, 11 w ere tre ated w ith ad ju vant chem otherapy and 35 of the soft tissu e sarcom a subjects received adjuvant radiotherapy.
At 6 weeks post surgery, pain (31% ), stiffn ess (60% ), fatigue (33% ), weakness (51% ) and lim ited range of m otion (29% ), were com m on symptoms experienced by patients (Table 1).W ith the exception of com plaints of pain and swelling, the frequency of these sym ptom s decreased as the interval of time following surgery increased. Com plaints of pain were relatively constant in frequency across patients until 6 m onths post surger y and then declined. Swelling was present in app roxim ately 10% of cases at a given point in time. W hile appearing constant in frequency across time, the num bers actually re¯ect different subjects reporting swelling at a single point in time for half the cases. For instance, only a sm all num ber of cases (n=8), showed signs of swelling 6 weeks after surger y, and of these, less than half (n=3) showed signs of swelling at other time points. Hence, the num ber of subjects w ith persistent swelling across time was very small (3 of 80). O f par ticular note is the increasing frequency of subjects who have no sym ptom com plaints in the year post surger y. By 12 m o n th s p o st-op erative ly, ap proxim ately 25% o f subjects report no symptoms limiting their daily activities.
Considering that patients m ay not experience a single sym ptom in isolation, the data were analyzed to determ ine whether there were consistent sym ptom com plexes reported. Speci® cally, we a priori evaluated th e freq u en cies o f th ree co m bin an ts o f sym ptom s: (1) stiffn ess and weakness; (2) pain, stiffness and weakness; and (3) stiffn ess and lim ited range of m otion. However, there d id not app ear to be consistent sym ptom com plexes as the frequencies were 5% or less at all times for this patient sam ple.
The change in sym ptom s over time is shown graphically in Fig. 1a,b. There appear to be two patterns of sym ptom variation over time follow ing treatm ent for lower extremity tum ours. F irst, as shown in Fig. 1a, stiffness, fatigue and lim ited ROM show a plateautype pattern. Stiffness is present to a great extent initially (60% of patients at 6 weeks) but then plateaus to approxim ately 45% of patien ts. Fatigu e also plateaus after 3 m onths w ith approxim ately 23% (n=18) of patients subsequently experiencing this sym ptom . T he data suggest that com plaints of weakness and pain, however, do not plateau. Both pain and weakness are constant through 3 m onths and decline progressively through 6 and 12 m onths post surger y (Fig. 1b).
Statistical analysis of the change in frequency of sym ptom s over time using the Cochrane test and then M cNemar' s test post hoc to determ ine the specific T here was a trend towards decreasing stiffn ess from 6 weeks post surgery to 6 m onths (p=0.04). There was also a trend towards decreasing com plaints of weakness from 3 to 6 m onths (p=0.04), with a m ore signi® cant decrease in com plaints of weakness by 12 m onths from any of the earlier times (p values rang ing from 0.0 04 to 0.002). D ecreasing com plaints of lim itation of range of m otion were signi® cant for all times com pared to 6 week (p-values ranging from 0.03 to 0.01). Physical disab ility was evaluated by the T ESS. At 6 weeks post surgery, the m ean TE SS score was 64.3 (SD =23.9). Correlating the presence of each of pain, stiffn ess, fatigue, weakness, lim ited ROM or swelling w ith the T ESS score, the correlation coefficients ranged from ± 0.31 to ± 0.39 (Spearm an's r ) indicating that the presence of the speci® c sym ptom resulted in lower T ESS scores. All correlations were significantly different from zero. At 12 m onths, the m ean TESS score was 83.9 (SD=15.8). Again the presence or absence of each sym ptom was correlated with the TESS score with the correlation coefficients ranging from ± 0.39 to ± 0.51. All correlations were significantly different than zero.
Regression analysis controlling for whether the patient had a bone or soft tissue sarcom a was used to evaluate the relationship of symptoms to physic al disability as m easured by the T ESS. Table 2 shows that, at 6 weeks, com plaints of pain, stiffness, weakness and lim ited RO M are signi® cant predictors of disability in both univariate and multivariate analyses. In m ultivariate analysis, these sym ptom s explained 40% of the variance in the TE SS score after controlling for whether the subject was treated for a bone or soft tissue tum our. At   signi® cance in the m ultivariate m odel. After controlling for bone versus soft tissue tum our, pain, stiffness, and lim ited ROM explained 51% of the variation in the T ESS score of patients.

Discussion
This study has con ® rm ed that sym ptom s are an im portant outcom e experienced by patients who und ergo lim b preser vation surger y for extrem ity tum ours. At least 80% of patients continue to experience som e sym ptom s at 1 year post surgery. T he sym ptom s m ost frequently reported include: stiffness (60% ), weakness (51% ), fatigue (33% ), pain (31% ), lim ited RO M (29% ) and swelling (10% ). T hese ® ndings are sim ilar to work of other authors w ho reported pain, swelling and weakness in soft tissue sarcom a patients 1± 4 and pain and weakness in bone tum our patients.
To our know ledge, the current study is the ® rst to evalu ate how sym ptom s chan ge ove r tim e. Tw o patterns were identi® ed, one that shows that stiffn ess, fatigue and lim ited RO M rem ain quite constant after 3 m onths and another that suggests that pain and weakness continue to decrease in frequency 6 and 12 months post treatm ent. These patterns re¯ect tissue healing physio logy. Soft tissue healing by scarring occurs in the ® rst 3 to 6 weeks under norm al conditio n s, bu t h ealin g is p ro lo n ged in the f ace o f radiotherapy and chem otherapy. Consequently, the ® rst 3 months following surgery is the period during which rehabilitation is directed towards im proving soft tissue lengthening and gaining joint m otion by breaking soft tissue adhesions. Although strengthening is im por tant in the early phases of rehabilitation, the m o st sign i® can t gain s are o bser ve d later w h en strengthening can occur through the functional range of a jo in t. F u r th er m o re, stren gth en in g is m ore functionally based in the later stages of recover y as activity and endurance are emphasiz ed.
T he persistence of pain and weakness from 6 weeks to 3 months m ay also result from patients attem pting more activities as they m ove further from their surgery.
Sim ilarly, patients m ay report feeling weaker due to increased exertion. It is possible that patients cannot perform as m any physical tasks as they attem pt to do and therefore report weakness.
As noted above, the plateau in stiffness and ROM can be explained based on an understanding of tissue healing. However, the plateau in complaints of fatigue from 3 m onths is somewhat surprising. Fatigue was experienced by 33% of subjects at 6 weeks and at 3, 6 and 12 m onths reduced to approximately 23%. We wo u ld h ave anticipated th at fa tigu e wo uld have decreased as patients m oved further from their treatm ent and improved their endurance. However, work in other cancers su ggests that o ngoin g fatigue is a phenom enon associated with the cancer diagnosis. Speci® cally, in breast cancer, numerous authors 9± 12 have found that fatigue is a frequent and persistent symptom .
The relationship between the presence of sym ptom s and the level of patient reported physic al disab ility suggests that these two phenom ena are m oderately related with correlations in the range of m agnitude of 0.30± 0.50. T he presence of sym ptom s accounts for up to 50% of the varian ce in the disability scores reported by patients in this sam ple. Although the im pact of sym ptom s on physical disab ility has not previously been reported in the sarcom a population, work by Rigby et al. 13 in arthritic populations and M cC arthy et al. 14 with injured workers would support these ® ndings. This study is the ® rst to evaluate the trajectory of symptoms experienced by patients who undergo lim b preser vation for lower extrem ity sarcom a and the first to attempt to understand the relationship of these sym ptom s to the ability of patients to continue to perform their daily activities. Previous authors 1± 4 have reported sym ptoms experienced by patients at a single point in time but m any of these studies do not reflect current surgical or adjuvant therapy techniques. T he recent trend in evaluating patient outcom es as a m easure of treatm ent effectiveness has emphasized evaluation of functional status and quality of life. It is im portant that we recognize the com ponent outcomes that re¯ect patient's status and how these outcom es relate to each other in order that new treatment interventions can be rigorously evaluated.

A cknow ledgem ent
T his work was supported in part by funding from the N ational C ancer Institute of CanadaÐ Clinical Trials G roup.