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Annals of Surgical Oncology 8:771-778 (2001)
© 2001 Society of Surgical Oncology

ORIGINAL ARTICLES

Factors Affecting Survival After Complete Response to Isolated Limb Perfusion in Patients With In-Transit Melanoma

Theresa G. Zogakis, MD, David L. Bartlett, MD, Steven K. Libutti, MD, David J. Liewehr, MS, Seth M. Steinberg, PhD, Douglas L. Fraker, MD and H. Richard Alexander, MD

From the Surgery Branch and the Biostatistics and Data Management Section, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.

Correspondence: Address correspondence and reprint requests to: H. Richard Alexander, MD, Surgery Branch/NCI, Building 10, Room 2B07, 10 Center Drive, NIH, Bethesda, MD 20892; Fax: 301-402-1788; E-mail: richard_alexander{at}nih.gov


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: Isolated limb perfusion (ILP) results in complete response (CR) rates of 60% to 90% in patients with regionally advanced melanoma. Survival after a CR may be influenced by various factors, particularly out-of-field disease in iliac lymph nodes (ILN) identified during lower-extremity ILP. We examined clinical and pathological parameters, including ILN status and outcome, for patients with in-transit melanoma who had a CR to ILP.

Methods: From May 1992 to July 1997, 50 patients (16 men and 34 women; median age, 57 years) with stage IIIA or IIIAB melanoma had a CR to a 90-minute hyperthermic iliac ILP with melphalan (10 mg/L limb volume, n = 20) or melphalan and tumor necrosis factor (4–6 mg ± 200 µg interferon; n = 30). Clinical and pathological parameters were analyzed by univariate and Cox proportional hazards models to determine which were associated with survival or in-field recurrence.

Results: The median in-field recurrence–free survival in the cohort of 50 patients after a CR to ILP was 1.4 years, and the actuarial 5-year in-field recurrence–free survival was 30%. By univariate analysis, there was a trend for improved outcome with female sex and stage IIIA (vs. IIIAB) at initial diagnosis was associated with improved survival after a CR to ILP (P = .056 and .012, respectively). Eleven (22%) of 50 patients had positive ILNs identified and resected at ILP. The probability of overall in-field recurrence was 70% after 4 years, and there was no difference between those with or without positive ILNs; median time to in-field recurrence was 13 and 19 months, respectively (P = .62). Similarly, overall survival was not influenced by positive ILN status (median [months]: +ILN, 69 vs. -ILN, 58; P = .68). Of note, Cox models identified that the risk of death was significantly greater in those with a history of prior systemic therapy (hazard ratio: 2.67 [95% confidence interval, 1.17–6.11]; P = .02) and those with an in-transit lesion size >=l.4 cm2 (hazard ratio, 3.12 [95% confidence interval, 1.30–7.5]; P = .011). When these two variables were combined, there was a highly significant association with shortened survival (P = .002 by log-rank test).

Conclusions: These data indicate that for patients undergoing ILP and in whom positive ILNs are found and resected, ILP is justified. In addition, patients who have a CR after ILP and have a history of prior treatment or larger lesions should be considered for adjuvant systemic therapy.

Key Words: Isolated perfusion • Melanoma • Tumor necrosis factor • Hyperthermia • Melphalan


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Isolated limb perfusion (ILP) was first reported for the treatment of extremity melanoma in 1958.1 By physically isolating the vascular supply of the extremity from the systemic circulation, high-dose chemotherapy or biological agents can be delivered to the diseased region by use of a recirculating perfusion device with minimal or no systemic exposure. Since its introduction in clinical practice, ILP has been modified to include hyperthermia, melphalan, or, less often, other chemotherapeutics (dactinomycin, thiotepa, cisplatin), and cytokines (tumor necrosis factor [TNF]-{alpha}, interferon [IFN]-{gamma}).2 Recently, complete response (CR) rates of 76% to 90% have been achieved by use of hyperthermia, TNF-{alpha}, and melphalan,3–5 and this has rekindled interest in the use of ILP for in-transit melanoma.

Little is known, however, about patient characteristics that may affect survival after ILP, particularly in those who have a CR. Survival after eradication of in-transit disease with ILP may be influenced by out-of-field disease such as positive iliac lymph nodes (ILNs) encountered during lower-extremity ILP. It is well known that patients with melanoma of the lower extremity who have positive regional lymph nodes have a worse overall survival than those who do not.6 Furthermore, those patients who have disease extending into ILNs (stage IV) have a worse prognosis than those with disease confined to the inguinal lymph node basin.7,8 This suggests that patients with in-transit melanoma in whom positive ILNs are found at the time of perfusion may not benefit from ILP. In this study, we examined the effects of various clinical and pathological parameters, including ILN status, on survival and in-field recurrence for patients with lower extremity in-transit melanoma who achieved an initial CR to ILP.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
From May 1992 to July 1997, 50 (64%) of 78 patients with stage IIIA or IIIAB malignant melanoma of the lower extremity (M. D. Anderson staging system) had a CR after ILP via an iliac approach. All patients were treated on one of several institutional review board–approved protocols after obtaining informed consent. Demographic data, disease presentation, treatment characteristics, and prior treatment history were retrieved from a prospectively maintained database for all patients. Disease was confined to the lower extremity in all cases. Preoperative physical evaluation was performed. The number of in-transit lesions and the surface area of the largest in-transit lesion were recorded for each patient.

Patients underwent ILP as previously described.2 Briefly, the iliac vessels were exposed with a standard lower-abdominal transplant incision and retroperitoneal dissection. The external iliac artery and vein were dissected distally, and all venous and arterial tributaries were ligated and divided. The external iliac artery and vein were then cannulated, and a tourniquet was wrapped at the most proximal portion of the extremity. A heat exchanger and external warming blanket were used to maintain limb temperature between 38.5°C and 40.0°C. The pump oxygenator was primed with heparinized balanced salt solution and packed red blood cells to maintain a hematocrit of approximately 25%. Continuous intraoperative monitoring was performed to assess for systemic perfusate leakage, and adjustments were made to avoid further leakage when this was discovered. All patients received a melphalan dose of 10 mg/L extremity volume. Twenty-eight patients received .2 mg of IFN-{gamma}, 4 mg of TNF-{alpha}, and melphalan. Two patients received 6 mg of TNF-{alpha} in addition to melphalan. Perfusion of the lower extremity was performed for 90 minutes. The lower extremity was then flushed with 2 L of crystalloid solution and 1 L of 5% albumin. Data were collected intraoperatively on the various perfusion-related parameters, such as flow rate and perfusion pressure, achieved during ILP.

Before perfusion, the operating surgeon assessed ILNs for the presence of metastatic disease. If the surgeon viewed the lymph nodes as positive by inspection or palpation, a resection of the ILNs was performed. All but five patients had ILNs resected and sent to pathology at the time of operation; those five were scored as having negative ILNs on clinical grounds. The number of lymph nodes sent to pathology was recorded, and pathology reports were then evaluated in a retrospective fashion for the number of histologically positive ILNs.

Patients were followed postoperatively at 4 to 6 weeks after ILP, every 3 months for the first year, every 4 months for the second year, and every 6 months thereafter. At each follow-up, each patient underwent physical examination, laboratory tests, and imaging studies (computed tomography of the chest, abdomen, and pelvis). Head magnetic resonance imaging was performed annually, and bone scan was performed when clinically indicated. Photographs were taken of all patients preoperatively and at multiple time points postoperatively to document responses. Some patients with deep lesions that were difficult or impossible to palpate and measure directly were evaluated by sequential extremity computed tomographic or magnetic resonance imaging scans. All patients in this series initially had a CR to ILP; this was defined as the complete disappearance of all lesions and no new areas of disease appearing within the perfusion field. The perfusion field was defined as the region of the limb below a line extending from the inguinal crease medially to the upper one third of the thigh laterally. After ILP, the perfusion field typically had mild chronic erythematous changes that aided in defining the upper extent of treatment. For pigmented lesions in which a tattoo remained after the substance of the lesion regressed, biopsies were performed on representative areas to confirm a complete pathologic response. Nonpigmented lesions were monitored clinically. If recurrence occurred within the perfusion field, it was defined as an in-field recurrence. If it occurred anywhere outside of the perfusion field, it was defined as out of field. Dates of these recurrences were recorded for each patient.

Statistical analyses, consisting initially of individual actuarial analyses, were performed on several patient-, tumor-, and treatment-related factors for the following two outcomes: (1) survival (defined as the time from ILP date to last follow-up date) and (2) in-field recurrence (defined as the time from ILP date to either in-field recurrence date or last follow-up date for patients who have not yet experienced an in-field recurrence).9,10 Although a landmark starting time of when each CR was determined could have been used, we began analysis at the ILP date for simplicity. This was intended primarily to be an exploratory analysis. In view of the number of parameters examined and the techniques used to identify cut-points to form groups for analysis, only unadjusted P values <.01 were interpreted as being statistically significant. Any unadjusted P values such that .01< P <= .05 were interpreted as indicative of a trend and would require independent confirmation to establish the importance of the parameter with respect to either outcome. Unadjusted P values with .05 < P <= .10 suggested potentially weaker trends that may also be worthy of further investigation. After evaluation of the univariate results, Cox proportional hazards model analyses were performed for each outcome, initially incorporating those factors found to have probable significance by univariate analyses.11 Both backward and stepwise model selection processes were performed. Variables remained in the final model if they maintained a P value of <.05.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Fifty of 78 patients were identified from a prospectively maintained database as having a CR after ILP for stage IIIA or IIIAB in-transit melanoma. The female to male ratio was approximately 2:1, and the age at treatment ranged from 29 to 78 years (Table 1). The majority of patients presented with stage IIIA (78%) versus IIIAB disease. The median depth of the primary lesion at initial diagnosis was 2.5 mm, and 62% had a leg (vs. a foot) primary tumor (Table 2). At the time of ILP, all patients presented with more than one in-transit lesion (range of 2 to >50), and the median size of the largest lesion was 1.4 cm2. The median time interval between the diagnosis of the primary melanoma and the development of in-transit disease was 22.8 months (range of 1.2 to 273 months). The median time interval between the diagnosis of in-transit disease and ILP was 12 months (range of 1.0 to 124 months), highlighting the variable nature of progressive disease in this setting.


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  		TABLE 1. Patient demographics
 

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  		TABLE 2. Tumor-related parameters
 
All patients underwent a 90-minute ILP with melphalan (Table 3). Although the range of total melphalan doses administered within the patient cohort was considerable (48 to 181 mg; mean, 113 mg), the total administered melphalan dose was standardized to limb volume. Limb volume was measured by quantifying the displacement of water after immersion of the patient’s leg into a graduated cylinder. All patients then received a melphalan dose of 10 mg/L limb volume. Sixty percent of the patients received 4 or 6 mg of TNF-{alpha}, and 56% of the patients received .2 mg of IFN-{gamma} during ILP. The administration of TNF-{alpha} or IFN-{gamma} and the dose given was determined by the trial under which that patient received treatment. There was no operative mortality, and regional toxicity was transient, consistent with previously published reports of our experience.5,12


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  		TABLE 3. Treatment-related characteristics
 
With a median potential follow-up from ILP of 3.9 years, the median overall survival for all individuals was 5.8 years (Fig. 1). Patients were seen initially at 4 to 6 weeks after ILP and then observed at 3- to 6-month intervals after that. Because of the limitations in determining the time course to best response under these circumstances, the duration to in-field recurrence was calculated from the date of ILP rather than the date of CR. The median overall in-field recurrence–free survival after a CR to ILP was 1.4 years, and 30% remained free of disease in the limb at 5 years (Fig. 2).



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  		FIG. 1.  Overall actuarial survival after complete response to isolated limb perfusion for 50 patients with in-transit melanoma of the lower extremity.

 


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  		FIG. 2.  Overall actuarial in-field recurrence free–survival after a complete response to isolated limb perfusion in 50 patients with in-transit melanoma.

 
Individual actuarial analyses were performed on several clinical and pathological parameters for the two outcomes of survival and the development of in-field recurrence (Table 4). For analysis of continuous variables, two or four strata were created by dividing the data into halves (for number of lesions, tumor thickness, and size of largest lesion) or quartiles (see Table 4), respectively. Sex (P = .056) had a trend toward improved survival, and stage (IIIA vs. IIIAB) at initial diagnosis (P = .012) was significantly associated with improved survival, as previously demonstrated.13 Two thirds of the patients received prior therapy before undergoing ILP, and this group tended to have a worse survival, although it was not significantly different from that of those who had no prior therapy for in-transit disease (P = .094). The 25 patients who had an in-transit lesion size of <1.4/cm2 had a survival advantage over the 25 who had a larger lesion size (P = .04). Those patients who had five or fewer in-transit lesions had a longer in-field recurrence–free survival than those with more than five in-transit metastases (P = .045). Eleven (22%) of 50 patients had pathologically positive ILNs resected at the time of ILP. The actuarial in-field recurrence probability for this group was 76% after 2 years, and there was no difference in survival or in field recurrence time between those with or without positive ILNs (Fig. 3). Of the five patients who did not have lymph nodes resected at the time of ILP, none developed radiographically imageable disease in this region on follow-up.


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  		TABLE 4. Univariate analysis of clinical and pathological factors for survival and in-field recurrence
 


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  		FIG. 3. Overall and in-field recurrence free–survival after a complete response to isolated limb perfusion in 50 patients with (n = 11) or without (n = 39) malignant iliac lymphadenopathy resected at time of treatment.

 
To identify a set of factors jointly associated with survival, the following covariates were initially included in the Cox regression analysis: sex, perfusion pressure (<75 vs. >=75 mm Hg; log-rank P = .088), prior treatment, stage, and lesion size (<1.4 vs. >=1.4 cm2). A backward selection process indicated that both prior treatment (P = .02; hazard ratio = 2.67) and lesion size (P = .011; hazard ratio = 3.12) were important prognostic factors, whereas a stepwise selection process indicated that stage alone was an important factor (P = .017; hazard ratio = 2.82; Table 5 presents both models). In view of the results obtained from the backward selection process, a new variable was created with four strata, one for each combination of the two levels of prior treatment and lesion size. Then an actuarial analysis was performed for survival stratified by both lesion size and prior treatment. The P value for the log-rank test was .005. Because two combinations of factors produced similar results, they were merged into one category, and the resulting analysis, which produced a P value of .002, is displayed in Fig. 4. On the basis of this figure, it is clear that patients with no prior treatment and with lesion size <1.4 cm2 had the highest survival probability, whereas patients with prior treatment and lesion size >=1.4 cm2 had the lowest survival probability.


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  		TABLE 5. Cox proportional hazards analysis for factors affecting overall survival
 


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  		FIG. 4. Log-rank survival analysis after a complete response to isolated limb perfusion in patients with an in-transit lesion >=1.4 cm2, history of prior treatment, or both.

 
For in-field recurrence, IFN (or not), number of lesions (five or fewer vs. more than five), and tumor thickness were the only covariates initially included in the Cox regression analysis. However, the Cox modeling procedure was not able to identify any of these as significantly associated with development of in-field recurrence.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
ILP has gained increased use for the treatment of in-transit malignant melanoma of the extremity, and CR rates of up to 90% have been reported.2,3,14 However, it is not known which patient-, tumor-, or treatment-related characteristics or factors, if any, influence survival after a CR to ILP. Patients with in-transit melanoma metastases are truly a heterogeneous population with respect to the characteristics of their disease. This is reflected in the variable time course of disease progression, the degree of tumor burden in the extremity, and the presence of out-of-field disease in ILNs at the time of ILP. Previous studies looking at prognostic factors and ILP have included patients who had either partial responses or CRs as well as those having various stages of disease.13,15 In contrast, this study was designed to determine factors that may influence survival in a more homogeneous group of patients with stage IIIA or IIIAB malignant melanoma. We analyzed only those undergoing lower extremity iliac ILP, the most commonly used approach, and who achieved a CR to determine what factors may influence outcome when in-transit disease has been successfully eradicated. We evaluated various patient-, tumor-, and treatment-related characteristics for their influence on survival and duration of in-field response in this patient group. Specifically, we sought to determine whether the presence of pathologically involved ILNs identified and resected at the time of ILP would have poor prognostic implications. Knowing characteristics that influence survival or in-field recurrence could help to define a population of patients in whom ILP would be most beneficial.

All 50 patients in this study had an initial CR to ILP and had a 5-year overall survival of 50%. This survival probability is comparable to that of other studies of patients with stage III disease after ILP.13,16–18 Seventy percent of patients developed an in-field recurrence by 5 years after ILP. Both univariate analysis and Cox proportional hazards analyses demonstrated that stage, in-transit lesion size >1.4 cm2, and history of prior treatment negatively influenced overall survival. It has been previously shown that patients with stage IIIA disease have a better prognosis after ILP than those with stage IIIAB disease.13 This indicates that extension of disease into regional lymph nodes imparts a worse prognosis for those patients undergoing ILP. One could extrapolate this finding to imply that extension of disease to ILNs in this patient population may result in an even worse prognosis. This has been shown in studies evaluating the influence of the level of lymph node involvement on prognosis for those patients with melanoma undergoing inguinal or ILN dissection.6–8 Clearly, disease found outside of the perfusion field in ILNs would not be treated by ILP therapy, and the presence of disease in this location may negate any beneficial regional effects of ILP. It is interesting to note that ILN status had no significant influence on overall survival in this study. Thus, patients who had positive ILNs identified and resected at the time of ILP had a similar overall survival and duration of in-field recurrence than those who did not, with both groups having a >50% 5-year survival. This indicates that for patients undergoing ILP in whom positive ILNs are found and resected, ILP is justified.

Similarly, one would consider that the amount of lower-extremity tumor burden might influence survival and in-field recurrence time. Cox regression analysis indicated that in-transit lesion size of >1.4 cm2 resulted in a higher risk of death compared with smaller-sized lesions, after adjusting for prior treatment, but did not significantly influence time to in-field recurrence. The reasons for this are not clear. With respect to survival, larger lesions may have a biology somewhat analogous to that of deep primary tumors and, by virtue of deeper tissue invasion, have a propensity for hematogenous dissemination. The fact that larger lesion size in this group was not associated with a shorter in-field recurrence may have been biased by the fact that only those who had a CR to treatment were analyzed. Patients with bulky or extensive disease may have a lower likelihood of having a CR to ILP even when TNF is included in the regimen. For example, Fraker et al.12 reported a 33% CR rate in 14 assessable patients undergoing palliative ILP with TNF and melphalan for extensive or bulky in-transit disease. Patients with large lesions who have had a CR may have a more favorable tumor histology and, therefore, a lower incidence of recurrence. Conversely, the number of lesions seemed to be associated with time to the development of in-field recurrence, but not survival; patients with more than five lesions had a shorter in-field recurrence–free interval compared with those with five or fewer lesions (P = .045). The reasons for this may relate to the fact that among patients with more numerous lesions, the likelihood of harboring occult or micrometastatic disease in the limb may be greater. The efficacy of ILP in this setting is not completely known, and therefore the presence of micrometastatic disease in the limb may predispose this group to earlier in-field recurrence. This hypothesis is supported by the facts that adjuvant ILP does not seem to completely eradicate micrometastases19 and that after a CR to ILP, patients whose disease recurs tend to have recurrences at new sites within the perfusion field.20 Other studies have evaluated factors associated with outcome after ILP for in-transit melanoma in a slightly different patient population. Klaase et al.15 and di Filippo et al.13 analyzed outcome in patients presenting with one versus more than one extremity lesion and included patients with local recurrence or satellitosis (within 3 cm of the primary site), which represents stage II disease. In these studies, patients with more than one lesion had a shorter in-field recurrence–free interval than those with only one. In our study, all patients presented with two or more lesions and generally had higher-stage (stage IIIA or IIIAB) disease than those in the previous studies. Despite these differences, the number of lesions consistently influenced the duration of in-field response, demonstrating its importance as a prognostic indicator.

Patients with a history of prior treatment or those with lesions >1.4 cm2 had a shortened overall survival without a clear effect on in-field recurrence time. Thus, they were more likely to have distant occult disease at the time of presentation and in the context of clinical trials evaluating the efficacy of ILP or clinical trials evaluating the adjuvant therapy for high-risk patients; consideration of these factors may be very important.

In summary, our analysis of patients with stage IIIA or IIIAB malignant melanoma of the lower extremity has demonstrated that larger lesion size, prior treatment history, and stage of disease are associated with duration of survival. Patients who have a CR after ILP and have a history of prior treatment as well as larger lesions should be considered for adjuvant therapy after ILP. Positive ILNs found and resected at the time of ILP have no significant influence on survival. For patients undergoing ILP and in whom positive ILNs are found, resection and ILP are justified.


   Footnotes
 
Presented at the 54th Annual Meeting of the Society of Surgical Oncology, Washington, DC, from March 15–18, 2001.

Received for publication May 17, 2001. Accepted for publication August 3, 2001.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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  4. Lienard D, Eggermont AMM, Schraffordt-Koops H, et al. Isolated limb perfusion with tumour necrosis factor-alpha and melphalan with or without interferon-gamma for the treatment of in-transit melanoma metastases: a multicentre randomized phase II study. Melanoma Res 1999; 9: 491–502.[Medline]
  5. Fraker DL, Alexander HR, Andrich M, et al. Treatment of patients with melanoma of the extremity using hyperthermic isolated limb perfusion with melphalan, tumor necrosis factor, and interferon-gamma: results of a TNF dose escalation study. J Clin Oncol 1996; 14: 479–89.[Abstract/Free Full Text]
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  8. Karakousis CP, Driscoll DL, Rose B, et al. Groin dissection in malignant melanoma. Ann Surg Oncol 1994; 1: 271–7.[Abstract]
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  11. Cox D. Regression models and lifetables. J R Stat Soc 1972; 34: 187–202.
  12. Fraker DL, Alexander HR, Andrich M, et al. Palliation of regional symptoms of advanced extremity melanoma by isolated limb perfusion with melphalan and high-dose tumor necrosis factor. Cancer J Sci Am 1995; 1: 122–30.[Medline]
  13. di Filippo F, Calabro AM, Giannarelli D, et al. Prognostic variables in recurrent limb melanoma treated with hyperthermic antiblastic perfusion. Cancer 1989; 63: 2551–61.[CrossRef][Medline]
  14. Lienard D, Eggermont AM, Kroon BBR, et al. Isolated limb perfusion in primary and recurrent melanoma: indications and results. Semin Surg Oncol 1998; 14: 202–9.[CrossRef][Medline]
  15. Klaase JM, Kroon BBR, van Geel AN, et al. Prognostic factors for tumor response and limb recurrence-free interval in patients with advanced melanoma of the limbs treated with regional isolated perfusion using melphalan. Surgery 1994; 115: 39–45.[Medline]
  16. Bowers GJ, Copeland EM. Surgical limb perfusion for extremity melanoma. Surg Oncol 1994; 3: 91–102.[CrossRef][Medline]
  17. Bryant PJ, Balderson GA, Mead P, et al. Hyperthermic isolated limb perfusion for malignant melanoma: response and survival. World J Surg 1995; 19: 363–8.[CrossRef][Medline]
  18. Krementz ET, Sutherland CM, Muchmore JH. Isolated hyperthermia chemotherapy perfusion for limb melanoma. Surg Clin North Am 1996; 76: 1313–30.[CrossRef][Medline]
  19. Koops HS, Vaglini M, Suciu S, et al. Prophylactic isolated limb perfusion for localized, high-risk limb melanoma: results of a multicenter randomized Phase III trial. J Clin Oncol 1998; 16: 2906–12.[Abstract/Free Full Text]
  20. Libutti SK, Alexander HR, Bartlett DL, et al. Patterns of local failure in extremity melanoma after a complete response to isolated limb perfusion with melphalan with or without tumor necrosis factor. Proc Am Soc Clin Oncol 1996; 15: 552.



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