Cancer Therapy Vol 4, 241-248, 2006

Muscle strength and functional ability in children during and after treatment for acute lymphoblastic leukemia or T-cell Non-Hodgkin lymphoma: a pilot study

Research Article

Marja Schoenmakers¹, Tim Takken^1,*, Vincent AM Gulmans¹, Nico LU Van Meeteren^{2, 3}, Marrie CA Bruin⁴, Tom Révész⁴, Paul JM Helders¹

¹Department of Pediatric Physical Therapy & Exercise Physiology, Wilhelmina Children’s Hospital, University Medical Center, Utrecht, The Netherlands,

²Rudolf Magnus Institute of Neuroscience, Department of Neuroscience, Section Rehabilitation, University Medical Center, Utrecht, The Netherlands,

³Department of Physiotherapy, Academy of Health Sciences, Utrecht, The Netherlands,

⁴Department of Pediatric Hematology, Wilhelmina Children’s Hospital, University Medical Center, Utrecht, The Netherlands

__________________________________________________________________________________

*Correspondence: Tim Takken, Department of Pediatric Physical Therapy & Exercise Physiology, University Medical Center, Wilhelmina Children’s Hospital, RM KB 02. 056.0, P.O. Box 85090, 3508 AB Utrecht, The Netherlands; Phone: +31302504030; Fax: +31302505333 ; E-mail: t.takken@umcutrecht.nl

Key words: leukemia; children; muscle strength; functional skills; motor performance

Abbreviations: 6 months after diagnosis, (T3); 6 months after the end of treatment, (T5); 6-mercaptopurine, (6MP); 6-thioguanine, (6TG); acute lymphoblastic leukemia, (ALL); at diagnosis, (T1); at the end of treatment, (T4); cytosine-arabinoside, (Ara-C); daunorubicine, (DNR); dexamethasone, (dexa); dose of intrathecal medications is based on age, (*); doxorubicine, (Adria); Dutch Childhood Leukemia Study Group, (DCLSG); event-free survival, (EFS); following induction, (T2); intrathecal, (i.th)); L-asparaginase, (L-Asp); methotrexate, (MTX); Pediatric Evaluation of Disability Inventory, (PEDI); prednisone, (Pred); T-cell non-Hodgkin Lymphoma, (T-NHL); vincristine, (VCR)

Received: 15 March 2006; Revised: 24 March 2006

Accepted: 31 July 2006; electronically published: August 2006

Summary

The aim of this pilotstudy was to explore the course of muscular strength, functional skills, and motor performance in children during and after treatment for acute lymphoblastic leukemia (ALL) or T-cell non-Hodgkin Lymphoma (T-NHL). Eighteen children and adolescents, aged between 0-18 years, with standard-risk ALL or with T-NHL were included in this prospective descriptive study. Nine were treated according to a BFM-based protocol (ALL-8), and 9 with protocol ALL-9 which is an antimetabolite-based treatment and uses high doses of dexamethasone and vincristine. Since there were no statistically significant differences between these two groups, the data were pooled for analysis. Muscle strength and functional skills were measured during and after treatment. Motor performance was measured only after treatment. Muscle weakness occurred in all patients, and was most severe during the first two months of treatment. After cessation of treatment, muscle strength recovered towards normal for most muscle groups, although knee- and foot extensors were still decreased as compared to reference values. Similarly, functional skills were also deficient in the first two months, mainly concerning transfers, walking, and going up- and down stairs. After cessation of treatment, these basic skills normalized. Six months after treatment, fine motor problems were present in 2 patients, and gross motor problems in 4 of the 18 patients. Muscle weakness and mobility problems were most severe in the first two months of treatment. These problems were reversible in most patients. However, in some children muscle weakness and fine and motor deficits were present after treatment.

I. Introduction

The treatment results in childhood acute lymphoblastic leukemia (ALL) are much improved due to the use of intensive combination chemotherapy. However, these results come at a cost: short and long-term side effects of chemotherapy. Among other complications, muscle weakness is increasingly recognized as a problem in children treated for ALL (Hovi et al, 1993)

In 1984 the Dutch Childhood Leukemia Study Group (DCLSG) developed a relatively non-toxic, antimetabolite-based treatment protocol (ALL-6) with high cumulative doses of vincristine and dexamethasone for standard-risk ALL patients (Veerman et al, 1996). The 8-year event-free survival (EFS) on this protocol was 80%. During and after treatment with this protocol, many children had significant gross- and fine motor difficulties, thought to be due to a vincristine-induced neuropathy (Ryan and Emami, 1983; Postma et al, 1993; Reinders-Messelink et al, 1996). Between 1991 and 1996 the DCLSG followed a slightly modified BFM protocol (DCLSG-ALL 8) which included lower doses of vincristine and steroids (Kamps et al, 1999). Since 1997 all Dutch children with ALL are treated with protocol ALL-9, which again is based on the ALL-6 protocol that includes vincristine and dexamethasone pulses during the whole treatment period of two years.

Vainionpää, (1993) and Reinders-Messelink et al, (1996, 1999) described motor problems in children during and after treatment for ALL. In these studies, motor problems like gait disturbances, clumsiness and fine motor problems are mainly attributed to peripheral neuropathy, which is thought to be a neurotoxic side effect of vincristine. Although Reinders-Messelink and colleagues, systematically investigated in 1999 the relationship between motor problems and vincristine, possible toxic effects of other medications could not be excluded.

To our knowledge, the course of muscular weakness, motor performance and activities of daily living, has sparsely been explored before in children treated for ALL. The aim of this pilotstudy was to explore the clinical course of muscle strength, functional skills and motor performance as well as the reversibility of these symptoms in children treated according to protocol ALL-8 or ALL-9.

II. Methods and Patients

A. Patients

Nineteen patients, aged between 0-18 years, who started treatment for ALL or T-NHL at the Pediatric Hematology-Oncology Clinic of the Wilhelmina Children’s Hospital, University Medical Center Utrecht, the Netherlands from January 1996 to December 1998, were included in this study. Informed consent was obtained from their parents and also from the children if they were older than 12 years of age. Of these 19 children, one was excluded, because in this child complete remission of the disease was not achieved. Of the remaining 18 children, 9 were treated according to protocol ALL-8 including three children with T-cell Non-Hodgkin lymphoma, and 9 according to protocol ALL-9. There was a change of treatment protocols on 1-1-1997. The last 9 consecutive patients treated prior to this date and according to the DCLSG protocol ALL-8 were included in the study, along with the first 9 consecutive patients on the new ALL-9 protocol. All patients were evaluated during and after treatment.

The outline of treatment according to the two protocols is shown in Table 1. Children treated with protocol ALL-8 received 8 x 1.5 mg/m² vincristine in two periods of four weeks. Children treated with protocol ALL-9 received 34 x 2.5 mg/dose vincristine during the whole treatment period of two years (Table 2). In protocol 8 both dexamethasone and prednisone were used as corticosteriod-therapy, in protocol 9 this was dexamethasone. The equivalent doses of steroids were also 5-6 times higher in protocol 9 than protocol 8. On the other hand, the latter protocol contained more cystostatic agents (daunorubicine, ara-C, 6-thioguanine). Both protocols did not include cranial irradiation.

B. Measurements

Muscle strength and functional skills were evaluated prospectively at the time of diagnosis (T1=week 0), twice during treatment (T2 = week 7 and T3 = week 28), at the end of treatment (T4 = week 105) and 6 months after treatment (T5 = week 131) (Table 2). Motor performance and hand-held myometry were evaluated 6 months after treatment (T5). All measurements were performed by the same pediatric physical therapist (MS).

C. Muscle strength

Strength of the upper and lower extremity muscles was scored according to the manual muscle testing criteria of the Medical Research Council, using a 6-point scale (range 0-5) (Medical Research Council, 1950). As manual muscle testing is a less reliable method measuring strength for grade 4 or 5 (Wadsworth et al, 1987), a hand-held myometer (Penny and Giles Biometrics Ltd., Blackwood, Gwent, UK.) was used in children with strength ³ grade 4, to evaluate upper and lower extremity muscles on the non-dominant side, according to Bäckman et al (1989). The following muscles were assessed: shoulder abductors, elbow flexors, wrist extensors, hip flexors, hip abductors, hip extensors, knee extensors, and dorsal extensors of the foot. The scores of these muscle groups were compared with published reference values for healthy children (Backman et al, 1989).

D. Functional skills

Functional skills were measured with the adapted Dutch version of the ‘Pediatric Evaluation of Disability Inventory’ (PEDI) (Haley et al, 1992; Custers et al, 2002). The PEDI is a validated and reliable parental questionnaire which measures functional skills and the amount of caregiver assistance in three domains: self-care, mobility and social function (Haley et al, 1992). With this reference-based instrument, discrimination can be made between disabled and non-disabled children (Haley et al, 1992). The domain of self-care includes eating, grooming, dressing, bathing and toileting skills. The mobility domain includes transfers, indoor and outdoor mobility, and capability to climb stairs, walking distance and walking speed. The social domain includes communication, social-interaction, and household and community tasks. Reference values are provided for children between 0.5-7.5 years. Normal values are defined in the range of 2 SD score (50 ± 20). In children over the age of 7.5 years, all functional skills should be mastered leading to a scale score of 100, which is considered to be normal (Haley et al, 1992).

E. Motor performance

In children from 4 years of age and up, motor performance was measured with the Movement Assessment Battery for Children (Henderson and Sugden, 1992). The Movement-ABC is a valid and reliable instrument that has been developed to evaluate gross and fine motor function in children from 4 years of age (Henderson and Sugden, 1992). Percentile scores of the child’s motor abilities can be compared with a normative age-matched sample of children. A score below the 5th percentile indicates that the child has significant movement difficulties. In scores between the 5th and 15th percentile, the child is at risk for these difficulties. The motor performance is adequate in scores above the 15^th percentile (Henderson and Sugden, 1992).

F. Statistical analysis

Our original intention was to compare the results of the two groups. However, due to the small number of patients and the individual variability in response, there were no statistically significant differences between the two groups with respect to any of the variables. Therefore, the data of both groups were pooled and used together in the statistical analysis.

Descriptive statistics were used to explore the course of the measures. Z-scores or percentile scores were calculated when reference values in a healthy population were available. The non-parametric Friedman test (Friedman, 1937) was used for analyzing repeated measurements. When the differences between the groups appeared to be significant (P < 0.05), the Wilcoxon signed-rank test was used to detect the significant differences. Differences in percentages were tested using Fishers exact test. All data were analyzed using SPSS 11.5 for Windows.

III. Results

Eighteen patients were examined in this study. Data concerning gender, age and type of leukemia are presented in Table 1.

The percentage of muscle groups with impaired muscle strength (MRC £ grade 4) during and after treatment is shown in Figure 1. One patient has already received 1 dose of vincristine at the time of first examination (T1); therefore his scores were not included. One four year old girl did not co-operate on muscle testing, while 5 children were less than four years old and were too young to be co-operative for adequate muscle testing. At T2 and T3 there are missing data due to the fact that some children were too ill to co-operate. At T4, 2 patients did not show up for the follow-up examination.

As can be appreciated from Figure 1, muscle weakness was most apparent 7 weeks following chemotherapy induction (T2). All patients had muscle strength £ 4 in at least one muscle group. Muscle weakness occurred both in upper and lower limbs, and proximal as well as distal. Six months after the end of

Table 1. Patient characteristics and outline of treatment according to protocol ALL-8 and ALL-9

	ALL-8	ALL-9
Number	9	9
Male to female ratio	5:4	4:5
Age, mean (range)	8.7 (1-16)	7.5 (2-15)
Medication Induction Intensification Reinduction Maintenance	VCR/Pred/DNR/L-Asp + MTX/Ara-C/Pred i.th. MD-MTX/6MP + MTX/ Ara-C/Pred i.th. VCR/Dexa/Adria/L-Asp/ 6MP, Ara-C, 6TG + MTX/Ara-C/Pred i.th. 6MP/MTX	VCR/Pred/L-Asp + MTX/Ara-C/Pred i.th. MD-MTX/6MP + MTX/Ara-C/Pred i.th. none 6MP/MTX + Q5 weeks: VCR/Dexa

Abbreviations: 6-mercaptopurine, (6MP); 6-thioguanine, (6TG); cytosine-arabinoside, (Ara-C); daunorubicine, (DNR); dexamethasone, (dexa); doxorubicine, (Adria); intrathecal, (i.th)); L-asparaginase, (L-Asp); methotrexate, (MTX); prednisone, (Pred); vincristine, (VCR)

Table 2. Test periods and cumulative doses of vincristine and steroids

Assessments	T1	T2	T3	T4	T5
Weeks after diagnosis	0	6-8	28	105	131
Cumulative dose vincristine (mg/m²) ALL-8 ALL-9	0 0	6 21.25	12 42.5	12 85	12 85
Cumulative dose of corticosteroids ALL-8: prednisone (mg/m²) prednisone intrathecal (mg/age)* ALL-9: dexamethasone (mg/m²) prednisone intrathecal (mg/age)*	0 0 0 0	1600 12-24 210 16-24	1600 36-72 462 64-96	1600 48-84 1386 104-156	1600 48-84 1386 104-156

Abbreviations: 6 months after diagnosis, (T3); 6 months after the end of treatment, (T5); at diagnosis, (T1); at the end of treatment, (T4); dose of intrathecal medications is based on age, (*); following induction, (T2)

Figure 1. Percentage of muscle groups with impaired strength (MRC £ grade 4) during and after treatment (T1-T5). Legend; hip: hip muscles (hip flexors, hip abductors, hip extensors); leg: lower extremity (knee extensors, dorsal extensors of the foot), ue: upper extremity (shoulder abductors, elbow flexors, wrist extensors,). The number behind the muscle region denotes the measurement; 1: at diagnosis (N=11), 2: following induction (N=14), 3: 6 months after diagnosis (N=13), 4: at the end of treatment (N=16), 5: 6 months after the end of treatment (N=18).

Five children were younger than 4 years of age at the time of diagnosis. Six months after the end of treatment (T5), weakness of hip-extensor or hip-abductor muscles (MRC grade 4) was seen in 2 of these children. All five had normal functional skills in all the PEDI-domains, ranging from 35.1-72.1. Scores on motor performance were normal in 4 of these children, ranging from the 38^th to the 93^rd percentile. One boy, the youngest patient at time of diagnosis, had significant fine and gross motor difficulties after treatment (1^st percentile).

Severe vincristine neurotoxicity occurred in 1 patient. This child was younger than 4 years of age at time of diagnosis. She was treated according to protocol ALL-9. She showed severe ptosis and very severe constipation after a few weeks of treatment. Her vincristine dose had to be lowered temporarily. At T5, her PEDI-scores on self-care, mobility and social function were within normal ranges (48.1-54.5), as well as her motor performance (46^th percentile score).

This pilot study shows that muscle weakness, and mobility problems occurred in almost all patients during treatment for ALL. These problems were reversible in most patients; whereas gross and as well as fine motor problems were present in some patients after treatment. Although muscle strength recovered towards normal for most muscle groups, knee- and foot extensors were still decreased as compared to reference values.

Over the last decade more attention has been paid to the consequences of chemotherapy on motor performance in children during and after treatment for ALL (Vainionpaa, 1993; Reinders-Messelink et al, 1996, 1999; Wright et al, 1998). In these studies, motor problems and muscle weakness, are mainly attributed to peripheral neuropathy. However, during intensive vincristine/ corticosteroid-based treatment protocols, steroid induced myopathy may also occur (DeAngelis et al, 1991).

DeAngelis et al, (1991) described the course of muscle weakness due to either vincristine neuropathy or steroid myopathy in 27 adults during treatment for Non-Hodgkin’s lymphoma. In their study, all patients had moderate to severe signs of muscle weakness. They suggested that muscle weakness due to steroid use was typically proximal in location and primarily affected lower extremities. Weakness caused by vincristine was in their opinion mostly distal in location and affected hands and feet equally, resulting in problems with fine manipulative abilities. Our data on muscle strength in children are in part in agreement with DeAngelis et al, (1991). In the first two months of treatment, we found muscle weakness in at least one muscle group in all patients. It occurred in both proximal as well as distal muscle groups. After treatment, muscle strength improved to scores > 4 in almost all of our patients. Since manual muscle testing is less reliable in scores ³ 4, hand-held myometry was also performed in these patients. Mean Z-scores for muscle strength using myometry were within normal ranges (> 2SD). However, knee extensors and foot extensors were still significantly decreased compared to references values. Recently, Gocha Marchese and colleagues also found a decreased muscle strength in ALL patients during treatment (Gocha Marchese et al, 2003). Moreover, Hovi et al, (1993) investigated the late sequelae of leukemia treatment and found a decreased muscle strength in ALL patients off therapy for 1 to 19 years. They also found a decreased muscle endurance in these patients (Hovi et al, 1993), which is a frequent complaint in ALL patients after therapy (Jenney et al, 1995; Turner-Gomes et al, 1996; Warner et al, 1997). The observed muscle weakness might be due to a combination of steroid myopathy and vincristine myopathy and neuropathy.

Wright and colleagues, studied in 1998 the long-term effects of cancer treatment on musculoskeletal function and gross motor skills in 36 children and compared their outcome with healthy peers. They found that survivors of ALL were able to perform most basic motor functions, such as walking, running and climbing stairs, but their levels of gross motor proficiency and performance (balance and running speed) were significantly lower than those of their school-aged peers.

We found in fraction of our patients, deviant scores on PEDI before as well as during treatment for ALL. Initially, patients had deviant scores in the mobility domain (transfers, walking abilities) of the PEDI. The scores in self-care domain were also low at this time, but they were still within normal ranges. This might be biased due to the fact that 5 children in our study were younger than 4 years of age, and 3 were aged between 4-5 years. Caregiver-assistance in self-care skills is normal at this age. Eight of 18 children were unable to perform functional skills in the mobility domain during treatment. After treatment PEDI-scores normalized, however motor performance as measured on the Movement-ABC, was still deviant in 5 children, mainly concerning ball-handling and balance skills.

Reinders-Messelink and colleagues, studied in 1999 motor performance in 17 children during and after chemotherapy. They found balance problems to be most severe during treatment: 50% (7/14) at the start of treatment, 69% (11/16) during treatment, and 27% (4/15) after treatment. An opposite pattern was seen in fine motor skills. The percentage of patients with fine motor problems was higher after treatment then at start, 33% (5/15) and 14% (2/14) respectively. Reinders-Messelink and colleagues, (1996, 1999, 2000) stated that a relation between these motor problems and vincristine-induced neurotoxicity seemed plausible but the effect of other neurotoxic drugs, like methotrexate and steroids could not be ruled out. The number of patients with fine motor problems in our study (2/18) is not significantly different from the number of patients (5/15) reported by Reinders-Messelink and colleagues, (1996, 1999). We found gross motor disturbances more frequently than fine motor problems. This is in agreement with Vainionpää, (1993), who found gross motor disturbances in 30% (10/33) and fine motor problems in 18% (6/33) of the patients.

Why some children seem never fully able to recover after cytostatic/corticosteroid treatment might depend more on their individual sensitivity to these agents and their pharmacokinetic variability than the actual doses of vincristine and corticosteroids.

It is generally thought that children treated for ALL benefit from programs that promote physical activity to improve gross motor function (Wright et al, 1998; Reinders-Messelink et al, 1999). Further studies are needed to clarify to what extent physical therapy can prevent, or improve disturbed muscle and motor function. Marchese et al, (2004) found significant improvement of muscle strength in children who received physical therapy intervention early in treatment for ALL. In an other small pilot study, it was found that exercise improved endurance, mood state and body fat levels (Shore and Shepard, 1999).

IV. Conclusions

Severe muscle weakness and mobility problems (such as transfers, walking, navigating stairs) occurred in children treated for standard risk ALL or T-NHL. These problems were most severe in the first two months of treatment, but they were mainly reversible, whereas gross and fine motor deficits were still present six months after treatment in some patients. Although muscle strength recovered towards normal for most muscle groups, knee- and foot extensors were still decreased as compared to reference values. Muscle weakness occurred in both proximal and distal muscles and could be due to a combination of steroid myopathy, vincristine myopathy and neuropathy and inactivity. However, a more precisely planned prospective multi-center study with sufficient numbers of patients is indicated to study the effects of and recovery after chemotherapy in this patient group.

Further studies are needed to clarify to what extent physical therapy can prevent, or improve disturbed muscle function during and after treatment for childhood leukaemia.

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Tim Takken