Abstract
Background: One of the biological characteristics of melanoma is the locoregional development of metastases that are difficult to treat by conventional tumour mass reduction. Locoregionally metastasised melanoma of the limb can effectively be treated by hyperthermic isolated limb perfusion (HILP). Postoperative complication rates are acceptable. Only few studies have examined long-term complications. This is the reason why we followed up patients in respect of long-term physical and psychological complications after HILP.
Materials and methods: 312 patients with melanoma of the limb underwent HILP in our department between 1977 and 1983.
Eighty-two patients that were still alive and no older than 80 years at the time of follow-up were contacted and invited to a physical examination. On average, follow-up took place 20 years after HILP. Thirty-nine patients were willing to participate in the study. Twelve of these patients were male and 27 female. The average age was 63.1 years (range 41 to 79). The average age at the point of perfusion was 42.1 years (range 19 to 59). In 10 cases the upper extremity was involved, in 29 patients the lower extremity. Patients were questioned on impairment of daily life and their health status using a standardised questionnaire. A physical examination was performed to document the impairments quantitatively. Ranges of motion, circumference and neurological deficits of the operated limbs were compared to the healthy limbs.
Results: At the time of follow-up examination all patients were without recurrent disease. A definite correlation between impairment of the general health condition and the operation could only be found in one patient with persisting lymph oedema. Thirteen patients still wore elastic stockings during the day, 9 of which regularly underwent lymphatic drainage. Most of the patients (58%) saw an improvement of their condition due to the treatment. 67% of the patients reported not having any or only slight impairment of everyday life. Only a few cases had disadvantages in their social and working life due to the perfusion. The physical examination of the upper limb showed an impaired range of motion of the shoulder in all planes in 50% of the patients. Relevant decrease in range of motion in the elbow was seen in two patients. The other examination results showed no significant differences in comparison to the healthy arm. The analysis of the lower limb showed relevant clinical reduction of range of motion in all three major joints. Significant differences were also found in the circumference of the leg compared to the healthy side.
Summary: According to our results and results from the literature it was possible to show that hyperthermic isolated limb perfusion is associated with an elevated risk of persisting impairment of range of motion of the treated limb. The impaired function is due to a persistent swelling of the limb because of lymph oedema on the one hand and local toxicity to the ligaments of the joints on the other. Response rates and results of HILP have greatly improved in the last years due to numerous modifications so that this treatment is the method of choice in locoregionally metastasised melanoma of the limb in spite of the long-term complication rate.
Background
Melanoma is a tumour entity with one of the highest growth rates in the last decades. In central Europe every seventieth citizen develops melanoma in his life time.
In over 80% of the cases the tumour metastasises lymphogenously to the regional lymph nodes first and then develops organ metastases via the blood stream secondarily. One of the biological characteristics of melanoma is the locoregional development of metastases (so-called satellite or in-transit metastases) that are difficult to treat by conventional tumour mass reduction. An effective way to treat locoregionally metastasised melanoma of the limb is hyperthermic isolated limb perfusion (HILP) that was first described in 1957 Citation[1]. This procedure was first performed in Germany in our department in 1975.
The therapeutic results of HILP have greatly improved in the last years due to numerous modifications of the perfusion regimen. Data from the literature including our own studies showed that HILP is not a palliative procedure, but can be curative in a subset of patients. The postoperative complication rates are acceptable in spite of the relevant toxicity administered to the non-tumoural tissue by the application of heat and cytostatic drugs Citation[2–5].
Till now, only a few studies have examined the functional outcome of the limb after HILP. The results from other studies in respect of the long-term complications were very diverse and the follow-up took place in a time span of a few months to a maximum of 4 years. For this reason we followed up patients from our department who had undergone HILP for malignant melanoma 20 years before.
Materials and methods
Patients
Three hundred and twelve patients with melanoma of the limb underwent HILP in our department between 1977 and 1983. The perfusion technique used during this time period has been reported by Tonak et al. Citation[6].
At the time of follow-up 122 patients were still alive. All the patients (n = 82) that were no more than 80 years were contacted and invited to a physical examination. Thirty-nine patients were willing to participate in the study. Twelve of these patients were male and 27 female. The average age was 63.1 years (range 41 to 79). The average age at the time of perfusion was 42.1 years (range 19 to 59). In 10 cases the upper extremity was involved, in 29 patients the lower extremity. One patient presented with satellite metastases at the point of undergoing HILP. In the other patients, HILP was indicated as an adjuvant treatment following local excision of a primary high risk melanoma. In all cases axillary or inguinal lymph node dissections were performed during the operation. Lymph node metastases were found histologically in five patients. In 25 cases additional fasciotomy was performed. Mesh graft was used for wound closure in 31 cases. Twice the wound was closed primarily, in two other cases a sliding flap was used and four patients underwent secondary wound closure with mesh graft.
Follow-up
A standardised questionnaire was used for the patients’ complaints. Patients were asked to describe impairment of motility, pain, etc. in private and working life present at the time of follow-up. Additionally, a rating of the momentary health status and life quality was asked for. Apart from standardised questions patients were given the chance to express postoperative problems or general health statements in open questions. Furthermore the initial and present tumour stages as well as absolved or current adjuvant therapies were documented.
The physical examination of the perfused extremities was compared to the healthy side. Muscle strength against resistance was rated in six grades; 6/6 being the normal strength. Muscular tone was divided into the parameters normal, too low and too high. The biceps, triceps and brachioradialis reflex on the upper extremity as well as knee and Achilles jerk on the lower limb were examined. The passive range of motion was measured using the neutral-0 method and rounded to the nearest five degrees. A difference of ten degrees in big joints and five in small joints was rated as pathological. Sensitivity was tested by evaluating epicritic sensibility and proprioception as well as sensitivity to temperature and vibration. The circumferences of the upper and lower limb were measured at five and eight specific points respectively. A difference of 1 cm on the upper extremity and 2 cm on the lower extremity was defined as pathological.
Peripheral pulses of the perfused extremity as well as of the healthy side were also documented, but there was no difference between both sides concerning the vascular condition due to impairment by the HILP procedure (data not shown).
Statistics
The statistical tests were performed with the Wilcoxon test. The statistical level of significance was defined as p < 0.05. The p values for multiple testing were corrected using Bonferroni's method.
Results
On average, follow-up took place 20 years after HILP. At this stage all patients were without recurrent disease. One patient had to undergo further tumour mass reduction due to recurrence in 1989 and 1990 as well as a second limb perfusion. Another patient developed a metastasis of the skull which was excised. The other 37 patients remained without tumour during the whole period that was followed up.
Questionnaire
Two patients (5%) rated their general health status as ‘bad’. One of these patients ascribed this fact to the impaired range of motion due to persisting lymph oedema after HILP. The other one reported suffering from depressive episodes since the operation and being psychologically strained by the diagnosis of melanoma. 58% described their situation as ‘good’ or ‘very good’ ().
Figure 1. General health status.
Again, 58% of the patients described the postoperative condition as ‘similar’ to the preoperative one. Thirteen patients reported a slight deterioration due to the perfusion or persisting lymph oedema. Those patients that saw themselves in a better health condition related this to the reduction of stress after tumour control ().
Figure 2. Comparison between preoperative and postoperative health status.
Thirteen patients (33%) described impairment of everyday life. The problems occurred mainly in strenuous tasks such as sports, heavy lifting or walking further than 1 km and activities of medium difficulty like cycling, swimming or walking up to 1 km.
Restrictions in social life were mentioned by five patients especially due to complications of wound healing. The patients felt restricted in respect to the choice of clothes or did not dare to go swimming. Working life was impaired in seven patients (18%). Two patients had to give up their occupation completely or change job after the procedure. The others could continue working in their previous jobs.
Asked about persisting tenderness, 21 patients (54%) reported having regular episodes of pain. Five patients (13%) had permanent pain in the operated limbs which necessitated treatment with pain killers in four of them ().
Figure 3. Pain at the time of follow-up.
Some patients reported on distressing symptoms difficult to verify such as ‘meteorosensitivity’, ‘tension’ or ‘itching’ in the limb. Seven patients (18%) described having recurrent muscle cramps and eight patients had recurrent erysipelas. Thirteen (45%) of the 29 patients that underwent HILP of the lower limb had to wear elastic stockings during the day, 9 of which still regularly undergo lymphatic drainage.
Physical examination results of the upper limb
Abduction of the shoulder joint was considerably reduced (from 10 to 85 degrees) in five patients (50%). Adduction was impaired by ten degrees in two patients (20%). Retroversion showed a reduction in two patients (20%) of 20 and 35 degrees respectively, whereas the anteversion was impaired in half of the patients (n = 5) by 10 to 30 degrees. The external rotation measured in 90 degrees of abduction and in the neutral position showed no pathological findings. Internal rotation showed a reduction of the range of motion (15 degrees in abduction, 50 degrees in neutral position) in one patient (10%). Extension in the elbow showed no pathological findings. The flexion was impaired in two patients (20%) by 10 and 110 degrees respectively. Pronation and supination were impaired by 70 and 80 degrees respectively in one patient. Examination of the wrist revealed impaired flexion (by 10 degrees) and extension (by 10 and 30 degrees) in two patients (20%). Ulnar abduction was also reduced by 10 degrees in these patients while radial abduction was normal.
Measurements of the circumference of the arm were taken at five specific points. Differences larger than 1 cm were rated as pathological. The first measurement was taken 15 cm above the lateral epicondylus humeri and revealed that one patient had a larger circumference here than on the healthy arm by 1.2 cm. Three patients showed a reduction of circumference by 2.1 cm to 2.5 cm.
Measurements at the elbow showed an increase of the circumference in two patients (1.2 and 1.5 cm). Ten cm below the lateral epicondylus humeri two patients had increased circumferences of their operated arms (1.1 cm and 2.9 cm). No atrophies were found at this position. The relevant results are displayed in .
Table I. Summary results of physical examination of the upper extremity.
Physical examination results of the lower limb
The range of motion of the hip showed a difference of ten degrees in extension between the operated and the healthy leg in one patient. Flexion of the hip was reduced by over 10 to 40 degrees in nine patients (31%). Abduction was also reduced by 15 and 25 degrees in two patients (7%). The adduction and internal and external rotation showed no differences.
Nine patients (31%) revealed impairment of flexion in the knee up to 35 degrees. Extension was normal.
Seventeen patients (59%) showed a reduction of extension in the ankle of up to 20 degrees, while only five patients had reduced flexion (maximum 20 degrees). Slight impairment of rotation was found in ten patients. Toe movement was normal.
Measurements of the circumference of the leg were taken at eight specific points. Sixteen patients (55%) had a significantly enlarged circumference (median 3.23 cm, maximum 16.6 cm) on the operated limb at 20 cm above knee. Nineteen patients (66%) showed a difference of up to 13.8 cm at 10 cm above the knee. Measurement at the height of the knee joint showed a circumference increased by 1 cm in ten patients. All other measurements on the lower limb showed no significant differences. The relevant results are displayed in .
Table II. Summary results of physical examination of the lower extremity.
Summary of the results
A definite correlation between impairment of the general health condition and the operation could only be found in one patient with persisting lymph oedema. Most of the patients (58%) saw an improvement of their condition due to the treatment.
Only about 33% of the patients reported difficulties with strenuous or medium difficulty tasks. The other 67% reported on not having any or only slight impairment of everyday life. Only a few cases had problems due to the operation in their social and working lives. Thirteen patients had to wear elastic stockings during the day, 9 of which still regularly undergo lymphatic drainage.
The physical examination of the upper limb showed impaired range of motion of the shoulder in all directions in 50% of the patients. Clinically relevant decrease in the range of motion of the elbow was found in two patients. The other examination results showed no substantial differences between the operated and the healthy side.
The examination results of the lower extremities showed relevant restrictions in the range of motion of all three major joints. Measuring the circumferences also showed significant differences between the two sides.
Discussion
The follow-up of our patients revealed important facts in respect to long-term physical and psychological sequelae after HILP. Subjective impairments of the patients’ everyday life as well as objective restrictions in the range of motion of the limbs were found. All patients confirmed that daily tasks were easy to handle. Only two patients had to change their occupation because it involved heavy work and long walking distances.
Constant pain was reported in one patient only. Occasional pain in the area of the wound, especially during periods of changing weather, which was not rated as restricting, was reported by several patients.
Slight loss of muscle strength of the lower limb was often associated with difficulty to walk long distances. The physical examination of the passive range of motion showed significant losses for all joints in the vertical plane (flexion/extension). This is partly due to persisting lymph oedema of the limb. Seven out of nine patients with impaired hip motility had an enlarged circumference of their thighs. The other reason could be a local toxic effect to the elastic structures of the articular ligaments and capsules. No correlation between impaired range of motion of the ankle and swelling was found. Other studies found impaired range of motion of the ankle without performing lymph node dissection Citation[7–9].
According to our policy, lymph node dissection is an integral part of the treatment strategy that precedes HILP during the same operation – for staging reasons, technical reasons (access to vessels for cannulation) or even for oncological reasons in clinically evident lymph node metastases.
According to our experience Citation[10], lymphoedema is particularly related to lymph node dissection, especially to the dissection of the inguinal nodes. HILP itself, without any doubt, contributes to treatment-related oedema but there is no possibility to discriminate the effect on lymph oedema between both operative procedures. Finally, patients who are candidates for lymph node dissection only do not suffer from in-transit or subcutaneous metastases that nowadays constitute the primary indication for HILP. So a suitable patient control group that can be matched adequately can hardly be defined.
Patients with malignant melanoma in stage I, treated either with ILP and wide excision (WE) or WE alone, were compared in a prospective randomised study by the European Organisation for Research and Treatment of Cancer. The follow-up after twelve months showed no differences between the two groups in the function of the treated limb. The ILP + WE group reported on having subjective ailments like meteorosensitivity and paraesthesia more often than the other group Citation[11].
Our results and the results from the literature were able to show that HILP can cause impaired function of the perfused limb. Hence, prophylactic HILP with or without lymph node dissection should only be performed in exceptional situations and after detailed information of the patient, since prospective randomised studies showed no improvement of prognosis after prophylactic HILP Citation[12].
In summary, we can state that hyperthermic isolated limb perfusion has an elevated risk for persisting reduction of range of motion of the treated limb. On the other hand the impaired motility hardly impacts the tasks of everyday life. The impaired function is due to a persistent swelling of the limb because of lymph oedema on the one hand and local toxicity to the articular ligaments and capsules on the other. Since HILP is the only alternative to amputation in the event of numerous tumour nodules on the limb Citation[13], and response rates and results have greatly improved in recent years due to various modifications this treatment is the method of choice in locoregionally metastasised melanoma of the limb in spite of the long-term complication rate.
Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
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