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Annals of Surgical Oncology 9:968-974 (2002)
© 2002 Society of Surgical Oncology

ORIGINAL ARTICLES

Safety and Efficacy of Isolated Limb Perfusion in Elderly Melanoma Patients

E.M. Noorda, MD, B.C. Vrouenraets, MD, PhD, O.E. Nieweg, MD, PhD, A.N. van Geel, MD, PhD, A.M. M. Eggermont, MD, PhD and B.B. R. Kroon, MD, PhD

From the Department of Surgery (EMN, BCV, OEN, BBRK), The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands; and Department of Surgery (ANV, AMME), University Hospital Rotterdam/Daniel den Hoed Cancer Center, Rotterdam, The Netherlands.

Correspondence: Address correspondence and reprint requests to: E. M. Noorda, MD, Department of Surgery, The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands; Fax: 31-20-5122554; E-mail: e.noorda{at}nki.nl


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: Older patients are assumed to have a higher risk of complications from isolated limb perfusion (ILP). A study was performed evaluating the safety and efficacy of ILP in patients older than 75 years with advanced melanoma of the limbs.

Methods: A total of 218 therapeutic ILPs with melphalan with or without tumor necrosis factor {alpha} were performed in 202 patients with advanced measurable melanoma and were analyzed retrospectively. Fifty-three patients (28%) were 75 years or older.

Results: Complete response rates were 56% for those older than 75 years and 58% for the younger group (P = .79). Locoregional relapse occurred in 56% of the older group versus 51% in the younger group (P = .61). Limb toxicity, systemic toxicity, local complications, and long-term morbidity were similar in both age groups. Perioperative mortality was low, with one procedure-related death in the older group. Older patients stayed in the hospital for a median of 23 days (younger patients, 19 days; P < .01).

Conclusions: ILP results in similar response rates in the elderly with recurrent melanoma, without increased toxicity, complications, or long-term morbidity compared with younger patients. Older age in itself is not a contraindication for ILP.

Key Words: Melanoma • Regional perfusion • Chemotherapy • Aged • Drug toxicity


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Isolated limb perfusion (ILP) with melphalan is an accepted treatment modality to achieve locoregional control in advanced melanoma of extremities.1 The principle of ILP is that a high dose of chemotherapy can be administered to a melanoma-bearing limb without systemic adverse effects. Since the introduction of recombinant tumor necrosis factor {alpha} (TNF-{alpha}) in ILP, this procedure has also been applied successfully to irresectable limb sarcoma and bulky or melphalan-resistant melanoma.2–5

Nowadays, operative mortality from ILP is low, regional toxicity is mild, and systemic leakage of the cytostatic drug(s) is negligible.6–8 Still, many surgeons are reluctant to refer patients at an advanced age for ILP because the perioperative mortality for major surgical procedures increases with age,9 the perioperative complication rate is higher in patients older than 70 years of age, and the hospital stay is generally longer.10–12 A fear of long-term functional morbidity due to severe acute limb toxicity,13 increased systemic adverse effects from melphalan,6 and a severe systemic cardiovascular response to TNF-{alpha} is felt when the elderly are concerned.14 To assess whether these assumptions are true, we studied the safety and efficacy of ILP in melanoma patients older than 75 years who were treated for advanced locoregional melanoma.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
From 1978 to 2001, 218 single therapeutic ILPs were performed with either melphalan (n = 84) or the combination of TNF-{alpha} and melphalan (n = 134) under normothermic (37°C–38°C) or mild hyperthermic (38°C–40°C) conditions for advanced unexcised melanoma of a limb. Patients were included if they had measurable disease at the time of ILP. These procedures were performed in 202 patients. A group of 53 patients (27.6%) was >=75 years old (mean, 79 years; range, 75–90 years) at the time of ILP, and they underwent 58 ILPs. Results from this older age group were compared with those from patients younger than 75 years of age. Patient characteristics of both age groups are listed in Table 1. Stage of disease was classified according to the M. D. Anderson classification system Table 2. A few patients with stage IV disease (n = 8) were treated with palliative intent only, because of distressing symptoms of bulky, irresectable locoregional metastases. Patients were all considered fit for operation by a regular preoperative screening procedure, including electrocardiogram, chest x-ray, lung function tests, standard hematological and chemical laboratory tests, and screening for distant metastatic disease.


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  		TABLE 1. Patient characteristics in the two age groups
 

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  		TABLE 2. M. D. Anderson classification (adapted for stage II)30
 
During ILP, the major artery and vein are clamped at the desired level, collateral vessels are ligated, and a tourniquet is applied around the limb proximal to the region of ILP. After insertion of the catheters, the isolated limb is perfused by extracorporeal circulation, oxygenated, and propelled by a heart-lung machine. A melphalan dose of 13 mg/L of perfused tissue in the upper limb and 10 mg/L for the lower limb is added to the perfusate. For TNF-{alpha}, this is 3 and 4 mg, respectively, irrespective of limb volume. Adequate tissue temperatures are achieved and maintained by heating the heparinized perfusate and applying a warm blanket around the limb. Limb temperatures are kept between 37°C and 38°C (normothermia) or between 38°C and 40°C (mild hyperthermia) in case of ILP with TNF-{alpha}. ILP with melphalan lasts 1 hour, and when TNF-{alpha} is used, it lasts 90 minutes. At termination of the ILP, the perfusate is drained out, and the limb is rinsed with an electrolyte solution. The tourniquet is then released, and catheters are removed.

In our routine, to limit the surgical dissection and total melphalan dose, lower-limb ILP in older patients is usually performed at the femoral level instead of the iliac level, unless the disease extends up to the femoral region. This is reflected in our data, which show significantly fewer iliac and more femoral ILPs being performed in patients older than age 75 than in younger patients (Table 1; P = .002). There was no difference in the use of TNF-{alpha} between older and younger patients. Regional toxicity after ILP was graded according to Wieberdink et al.15 (Table 3). After surgery, patients stay in bed with the leg elevated until acute toxic limb reactions subside. Systemic toxicity and tumor response were measured by World Health Organization criteria.16 Patients were gradually mobilized with the help of a physiotherapist and were discharged when fully mobile. Long-term morbidity was routinely scored by identifying the following signs or symptoms: edema, venous thrombosis, arterial thrombosis, nerve injury, muscle atrophy or fibrosis, recurrent erysipelas, and subjective complaints of pain and malfunction in the perfused limb. All were scored at 1 month, 3 months, 1 year, and 2 years after ILP, and morbidity was considered irreversible if complaints were persistent longer than 2 years after ILP.


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  		TABLE 3. Classification of acute regional toxicity reactions after ILP15
 
The median follow-up was 6 years (25%–75% interval, 3–10 years). Some patients had an amputation of the limb despite the effort of limb-sparing surgery. This was only performed in the case of locally irresectable progressive recurrences that could not be excised without severely compromising limb function, could not be ablated by CO2 laser, and had previously shown no or little response to ILP, so that repeat ILP was not an option.

The following tests were used for statistical analysis: proportions were compared by using the {chi}2 test. Survival and limb recurrence-free intervals were analyzed with Kaplan-Meier analyses, with the log-rank test assessing equality of distributions. Multivariate linear regression analysis was performed to determine the most important factors leading to increased hospital stay. A P value of <.05 was considered significant. The following independent variables were tested in this analysis: age, sex, level of ILP, time period in which the ILP was performed, administered drug, limb toxicity (grade III or IV vs. grade I or II), complications such as wound infection, and seroma needing drainage. The level of ILP was tested because of the more extensive procedure of ILP at the iliac level compared with the femoral level and the usually higher melphalan peak concentration that is obtained in ILP at the iliac level. To study an effect of increasing experience gained with ILP, the time period in which the ILP was performed was evaluated by defining four time periods: 1978 to 1984, 1985 to 1990, 1991 to 1995, and 1996 to 2001.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Tumor Response and Limb Recurrence
Tumor response was not evaluated in one patient in the group >=75 years of age because of severe postoperative complications. She had an incarcerated hernia of small bowel in the iliac fossa with severe bleeding from a lacerated artery. After ileocecal resection and multiple transfusions, an enterocutaneous fistula developed. Subsequently, she developed acute respiratory distress syndrome and hepatic failure and died 6 months after ILP. Therefore, objective responses of 57 ILPs in 52 older patients could be analyzed. In the younger age group, the tumor response was not evaluated in two patients. One patient without a history of cardiovascular disease suddenly died of ventricular fibrillation 2 days after an uncomplicated ILP procedure with melphalan alone. In another patient, local tumor response was not recorded because of progressive metastases at other sites that led to her death 3 months after ILP. The objective tumor response after 158 procedures in 147 younger patients could be analyzed.

Patients >=75 years of age had a complete response rate of 56.1% (n = 32; 95% confidence interval [CI], 43%–69%), compared with 58.2% in the younger group (n = 92; 95% CI, 48%–64%; P = .79). Eighteen of the older patients relapsed in the perfused area (56.3%; 95% CI, 39%–73%) after a median of 9 months (25%–75% interval, 5–18 months). This was not statistically different from the younger group, with a 51.1% relapse rate (n = 47; 95% CI, 41%–61%) after a median of 6 months (25%–75% interval, 4–14 months; P = .61). The 5-year limb recurrence-free survival was 53.4% for patients >=75 years of age who attained a complete response on the ILP and did not differ from that in the younger patients (48.9%; P = .36) (Fig. 1). The 5-year disease-specific survival in the elderly compared with those younger than 75 years of age was also similar (40.6% vs. 37.0%; P = .49) (Fig. 2).



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  		FIG. 1. Relapse-free survival for those with a complete response after isolated limb perfusion (ILP); x-axis, time after ILP (months); y-axis, cumulative survival (%). Numbers of patients at risk are provided at each point in time for both groups.

 


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  		FIG. 2. Disease-specific survival; x-axis, time after isolated limb perfusion (ILP) (months); y-axis, cumulative survival (%). Numbers of patients at risk are provided at each point in time for both groups.

 
Limb Toxicity and Locoregional Complications
Toxicity and complications are listed in Table 4. The encountered limb toxicity in the elderly was comparable to toxicity in the younger patients, with only an insignificantly larger proportion of grade I and II reactions and fewer grade III and IV reactions in the older patients. No grade V reactions of tissue necrosis necessitating amputation were seen. In a univariate analysis, limb toxic reactions after femoral ILP were not significantly different in either age group, with 18.5% grade III or IV reactions among the elderly compared with 28.6% in the younger patients (P = .27). After iliac ILPs, regional toxicity was comparable for both age groups (20.8% vs. 23.7% for grade III and IV reactions, respectively; P = .51). When regional toxicity after ILP was univariately tested irrespective of patient age, the occurrence of more severe toxicity did not seem different after ILP at the iliac or femoral level (20.8% vs. 18.5%; P = .84).


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  		TABLE 4. Toxicity, complications, and hospital stay after ILP in patients in the two age groups
 
The incidence of wound infections and seroma was similar in both groups. A 37-year-old man developed arterial thrombosis, which could be treated conservatively. Postoperative bleeding at the arteriotomy site occurred in two patients, one in each age group, and required reoperation in the older patient.

Systemic Toxicity
In both age groups, an equal percentage of patients (20.7% in the elderly and 20.8% in the younger group) experienced some degree of nausea. Similar minor systemic toxicity was encountered in both age groups regarding white blood cell count and TNF-{alpha}—induced postoperative fever. No other signs of TNF-{alpha} toxicity were encountered in both age groups.

Perioperative Mortality
Perioperative mortality, usually defined as 30-day mortality, was low. No patient in the older age group died within 30 days of ILP, whereas in the younger group, one previously described patient (.6%) died after 2 days because of myocardial infarction. However, the one older patient mentioned previously who died of complications of the procedure was regarded as a perioperative death, because it was clearly procedure related. Among the older patients, the 90-day mortality rate was 1.7%; one patient died after 2 months because of systemic metastases of melanoma. Four additional patients (2.5%) in the younger age group died within 90 days after surgery because of metastatic melanoma.

Hospital Stay
Hospital stay was normally distributed when one outlier was left out of the analysis. This was the patient who was described previously with a complicated hospital stay of 120 days. Patients older than 75 years of age stayed significantly longer in the hospital than younger patients, with a mean stay of 23.0 days (range, 7–65 days; SD, 10.6 days) and 18.8 days (range, 2–69 days; SD, 9.5 days), respectively (P = .007). Results of a multivariate linear regression analysis, performed to determine prognostic factors for length of hospital stay, are listed in Table 5. Age older than 75 years remained an independent risk factor for a significantly longer hospital stay. Also, female sex, wound infection, more severe limb toxicity (grade III or IV), and ILP performed between 1978 and 1984 were risk factors for a longer hospital stay.


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  		TABLE 5. Factors associated with difference in hospital stay after ILP: results from a multivariate linear regression analysis
 
Long-Term Morbidity
No significant differences in long-term morbidity were found between the age groups. Limb malfunction at 2 years after ILP in the younger age groups consisted of ankylosis, fibrosis, and/or muscle atrophy in nine patients (6%). One of these patients also had recurrent ulcers, another had peroneal nerve dysfunction, and one had all three long-term side effects. Three patients in the older group had ankylosis, fibrosis, and/or muscle atrophy (6%). None of the older patients had clinically significant edema 2 years after ILP.

During follow-up, limb amputations were performed after ILP in three patients (2%) younger than 75 years and in four older patients (7.6%; P = .29). In four patients this was because of progressive lesions, and in three, because of extensive relapse after an initial complete response. In none of the patients was the indication for amputation toxicity or morbidity caused by ILP.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The mean life expectancy at age 75 is 8.5 years for men and 11 years for women.9,17 Maintaining or improving the quality of life in this age group is desirable. Therefore, effective palliative measures such as ILP are also important in this phase of life.

Melanoma of the limb locally recurs mostly in the form of in-transit metastases (in 5%–8% of melanoma patients) in the extremity and can present an appalling problem to the patient. Various locoregional treatment options exist, but effective management of regionally recurrent melanoma remains a challenge. The choice depends primarily on the number and size of the lesions and on the general condition of the patient. Treatments vary from (multiple) excisions, laser evaporation, intralesional injection of interferons, and regional chemotherapy (i.e., isolated limb infusion or perfusion).18 Over the years, we have become more and more conservative in our approach to the application of ILP. The indication of its use has been debated, and opinions have varied from ILP being the first choice of treatment for all patients with in-transit metastases to only for those with truly irresectable, often bulky, disease.19 The utility of ILP with melphalan has now been limited to locoregional multiple metastatic and advanced metastatic cases. TNF-based ILP is applied only in the case of two indications, i.e., in bulky metastatic disease and in recurrent disease after previous ILP with melphalan alone.4,5

Recurrent melanoma can be a substantial problem in elderly patients. This study was performed to see whether ILP, when indicated, is sufficiently effective and feasible in these patients. So far, only one report focusing on the application of ILP in patients older than 70 years of age has been published. No conclusions could be drawn from that study because of the small number of patients who underwent therapeutic ILP and the use of various unconventional drugs.20 Our study shows that the complete response rate and limb recurrence-free interval after ILP for advanced locoregional melanoma among patients older and younger than age 75 are similar. The complete response rate of 56% in older patients with advanced melanoma is comparable to data in the literature, where a mean complete remission rate of approximately 54% is reported, regardless of age.1 After a long median follow-up of 6 years, our locoregional relapse rate in patients older than age 75 was higher than that reported in the literature (56.3% vs. 24%–54%) but was not significantly different from that in the younger age group.1 Still, a third of the older patients were rendered locoregionally tumor free for at least 5 years. Thus, ILP in older patients seems to be as effective as in younger patients.

We found no increase in mortality among the older patients with ILP, with one procedure-related death, despite the general finding that mortality increases with age after any surgical procedure.9 Perioperative mortality rates after ILP with melphalan generally range from 0% to 9%, with the majority now being between 0% and 1%.6 Functional status, comorbidity, and emergency situations are the risk factors that account for perioperative mortality and complications, rather than chronological age itself.9,17,21,22 Therefore, careful assessment of the patient’s specific comorbidities is more important than age in determining the preoperative risk.9,17,23 In recent studies from the Dutch ILP centers, it has been clear that no appreciable systemic toxicity occurs with TNF-based ILPs in patients without leakage,7 whereas patients with high leakage (>15%) were reported to have toxicity that could be easily managed.24 Apart from fever in the immediate postoperative phase, we did not see any increase in systemic toxicity after TNF-{alpha} ILP in either age group.

In this study, limb toxicity was similar in older patients compared with younger patients. The proportion of patients with a more severe toxicity reaction (i.e., grade III or IV according to the Wieberdink criteria) was even lower (although not statistically significant) in the older patients (19.0% vs. 27.9%) and was comparable to data in the literature (15%).25 Because the major predictor of long-term morbidity and functional impairment is acute limb toxicity,13,26 we also found little long-term morbidity in patients older than 75 years of age. We generally choose to perform ILP at the femoral level in the elderly unless the disease extends beyond this level, because of the smaller dissection and the potentially increased limb toxicity due to a higher melphalan peak concentration at the iliac level.25,27 However, there was no difference in toxicity between age groups at either the femoral or the iliac level. In this study, we could not demonstrate an increase in toxicity at the iliac compared with the femoral isolation level.

It has been suggested that older patients are more prone to the systemic side effects of the chemotherapy used in ILP,6 but this was not the case in this series. Melphalan leakage at our institution is negligible,7 and this is reflected by our low incidence of any degree of bone marrow depression (7.3%) compared with the literature (up to 59%); there is no significant difference between older and younger patients.6 Systemic toxicity with nausea and vomiting occurred in one fifth of the patients, equally divided between the two age groups. This is probably a side effect of regional tissue damage by the ILP but could also be an adverse effect of anesthesia, because it is known that 10%–50% of patients experience nausea after surgery under general anesthesia.28 Other postoperative complications, such as wound infections and seroma, were evenly distributed between the age groups or, as with deep venous or arterial thrombosis, did not occur in patients older than 75 years of age.

Not unexpectedly, patients older than 75 had a significantly longer length of hospital stay than younger patients. Hospital stay is known to be mostly determined by either medical causes, such as complications or severity of disease, or by social factors, such as waiting for a nursing home.29 In our hospital, the main limiting factor for discharge is mobilization, apart from complications such as wound infections or more severe regional toxicity. Patients should be able to pursue daily activities in a reasonable way when discharged, with the aid of physiotherapy. Older patients tend to recover more slowly and need more time to be fully mobile after ILP, in comparison with younger patients. Also, time was needed to arrange sufficient support during the first weeks at home, because most older patients in our study population were still living independently. In our study, female sex, wound infections, and grade III or IV limb toxicity were independent determining factors for a longer hospital stay. Hospital stay was also significantly longer from 1978 to 1984, reflecting the relative inexperience with the procedure and the generally accepted longer hospital stay in those years.30

In conclusion, patients older than 75 years of age with advanced melanoma of a limb benefit as much from ILP as younger patients, without a higher risk of mortality or morbidity.


   Footnotes
 
Although patients older than 75 years are assumed to have a higher risk of complications from isolated limb perfusion, response rates are similar without increased adverse effects compared with younger patients. Older age is not a contraindication for ILP.

Received for publication May 9, 2002. Accepted for publication August 1, 2002.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Vrouenraets BC, Nieweg OE, Kroon BBR. Thirty-five years of isolated limb perfusion for melanoma: indications and results. Br J Surg 1996; 83: 1319–28.[Medline]
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  15. Wieberdink J, Benckhuijsen C, Braat RP, van Slooten EA, Olthuis GA. Dosimetry in isolation perfusion of the limbs by assessment of perfused tissue volume and grading of toxic tissue reactions. Eur J Cancer Clin Oncol 1982; 18: 905–10.[CrossRef][Medline]
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  25. Klaase JM, Kroon BBR, Van Geel BN, Eggermont AMM, Franklin HR, Hart GA. Patient- and treatment-related factors associated with acute regional toxicity after isolated perfusion for melanoma of the extremities. Am J Surg 1994; 167: 618–20.[CrossRef][Medline]
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