Annals of Surgical Oncology Cite Track
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Originally published as Ann Surg Oncol Early Release 10.1245/ASO.2004.04.032 on April 12, 2004

Annals of Surgical Oncology 11:491-499 (2004)
© 2004 Society of Surgical Oncology
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Noorda, E. M.
Right arrow Articles by Kroon, B. B. R.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Noorda, E. M.
Right arrow Articles by Kroon, B. B. R.

ORIGINAL ARTICLES

Isolated Limb Perfusion Prolongs the Limb Recurrence-Free Interval After Several Episodes of Excisional Surgery for Locoregional Recurrent Melanoma

Eva M. Noorda, MD, PhD, Bart Takkenberg, MSc, Bart C. Vrouenraets, MD, PhD, Omgo E. Nieweg, MD, PhD, Bert N. van Geel, MD, PhD, Alexander M. M. Eggermont, MD, PhD, Guus A. M. Hart, MSc and Bin B. R. Kroon, MD, PhD

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


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: The influence of isolated limb perfusion (ILP) on the limb recurrence-free interval (LRFI) and the number of lesions per recurrence was studied for patients with frequently recurring regional in-transit metastases previously managed by excisional surgery.

Methods: All 43 patients who had their first ILP for a third or further limb recurrence were selected from our computer database of 451 patients who underwent therapeutic ILP for recurrent extremity melanoma in our centers. Eighteen patients had resectable and 25 had locally unresectable lesions at the time of ILP. The patients had a total of 269 intervals between treatment of their primary melanoma and last recurrence or last follow-up. Median follow-up was 35 months (interquartile range, 14–64 months).

Results: The median LRFI decreases over time from primary melanoma to the third or further recurrence for which ILP was performed (P < 0.001). The median LRFI is 4.7 times longer (95% confidence interval [CI], 2.8–7.9; P < 0.001) after ILP in comparison with the last interval before ILP. Patients with resectable lesions have a median LRFI that is 5.9 times longer (95% CI, 2.7–13; P < 0.001). In all patients, the number of lesions increases by 22% per recurrence number (95% CI, 10%–35%; P = 0.02). At the same recurrence number, patients before ILP have a 2.6-fold higher (95% CI, 1.6–4.5) mean number of lesions than do patients after ILP (P < 0.001).

Conclusions: ILP lengthens the LRFI and decreases the number of lesions per recurrence significantly in patients with repeatedly recurrent limb melanoma. Therefore, ILP could be a valuable adjunct to excisional surgery for in-transit metastases in these patients whose LRFIs tend to shorten over time.

Key Words: Extremities • Local recurrences • Melanoma • Regional perfusion


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
In some patients with in-transit metastases of extremity melanoma, locoregional recurrences seem to develop with increasing frequency after resection of previous lesions. Distant metastases, however, are often not (yet) present, and these in-transit metastases can impose a major therapeutic dilemma at each new recurrence.1 Many patients who have minimal locoregional disease can be maintained for a long time with local treatments only.2 There are several local treatment options, including excisional surgery, CO2 laser ablation if lesions are numerous and superficially located, and local radiotherapy if these two simple treatments fail; however, none of these impacts the development of further limb recurrences.3–5

Isolated limb perfusion (ILP), however, can treat both macroscopic and microscopic disease by delivering a high dose of therapeutic agent(s) to the whole limb.6 Therefore, prophylactic ILP has the potential to stop or slow down the process of ongoing recurrences by eradicating micrometastases present in the limb. ILP provides a complete response in 54% of patients, with a probably lower complete response rate in those with unresectable rather than resectable lesions.5 In a small prospective randomized trial conducted by the Swedish Melanoma Study Group, 69 patients with recurrent extremity melanoma were randomly treated by excision alone or excision plus ILP. Tumor-free survival was increased after ILP from 10 to 17 months, and the limb recurrence rate decreased from 67% to 45%.7 To determine whether ILP in the population of patients with resectable recurrent in-transit lesions may be indicated, the effect of ILP on further recurrences, the number of lesions per recurrence, and the limb recurrence-free interval (LRFI) in patients with frequently recurring limb melanoma was studied.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Between 1978 and 2001, 451 patients underwent 505 therapeutic ILPs for locoregional recurrent and/or unresectable melanoma of the limbs in our institutions. A computer-assisted database containing all patient, tumor, ILP, and follow-up data allowed selection of 43 patients in whom ILP was performed for a third or later limb recurrence. There were 40 women and 3 men, with a mean age of 62 years (range, 35–83 years). The patients were divided into two groups with unresectable and resectable lesions for the purpose of analysis. Unresectable lesions can be categorized as due to a high tumor load or due to localization or diffuse spread over a large area. A high tumor load is defined either according to Fraker et al. (10 or more lesions or lesions larger than 5 cm)8 or according to Rossi et al. (more than 15 lesions or lesions larger than 3 cm).9

According to either of these sets of criteria, 18 patients had resectable and 25 patients had unresectable melanoma lesions. The lesions forming the indication for ILP were on the upper arm in 3 patients, on the thigh in 2, on the lower leg in 27, on the foot in 3, on the foot extending up to the lower leg in 5, and widely spread over the lower limb in 3. The stage of disease was classified according to the MD Anderson melanoma staging system, adapted for stage II.10 The median number of previous recurrences was 2 (range, 2–10) and the median number of lesions forming the indication for ILP was 4 (range, 2–8). Details about the number and size of the lesions and stage of disease are shown in Table 1. Twenty-five patients underwent ILP for the third recurrence, nine for the fourth, one for the fifth, four for the sixth, two for the seventh, one for the eighth, and one for the eleventh. The indication for ILP was based on unresectability or resectable disease that was believed to pose problems for future locoregional disease control.


View this table:
[in this window]
[in a new window]
  		TABLE 1. Patient and tumor characteristics of patients with resectable or unresectable lesions
 
Our technique of ILP has been described in detail elsewhere.11 In short, isolation of the blood circuit of a limb is achieved by clamping the major artery and vein, by ligating collateral vessels, and by applying a tourniquet around the base of the limb. After cannulation of the vessels, the isolated limb is provided with an artificial circulation by means of an extracorporeal circuit, into which the drugs are administered.

ILP with melphalan is usually carried out with normothermia (37°C to 38°C); ILP with tumor necrosis factor-{alpha} (TNF{alpha}) and melphalan is performed under mild hyperthermia (38°C to 40°C). The circulating time of melphalan is 60 minutes. Nineteen patients were treated with melphalan alone, 19 with melphalan and TNF{alpha}, and 5 with melphalan, TNF{alpha}, and interferon-{gamma} (IFN{gamma}). In these latter patients, 0.2 mg IFN{gamma} was injected subcutaneously for 2 days before surgery. The same dose was given intraoperatively in the isolated circuit. One patient was treated with a sequential ILP, in which ILP with hyperthermia (42°C to 43°C) and no drugs was followed by ILP with melphalan 1 week later under normothermic conditions.12

Regional toxicity after ILP was graded according to Wieberdink,13 and tumor response was defined according to the standard WHO criteria.14 The median follow-up after ILP was 35 months (interquartile range, 14–64 months).

LRFIs were computed from the time of complete remission (CR) after ILP to the next recurrence or the end of follow-up. If partial remission (PR), no change (NC), or progressive disease occurred after ILP, the subsequent interval was scored as 0 months.

Statistical analysis for the LRFI was performed with an accelerated failure time analysis with frailty per patient.15,16 A Weibull survival distribution for the within-patient interval lengths (untransformed) was used in conjunction with a gamma distribution for the frailties. To check the sensitivity of the results, a second analysis was performed based on a proportional hazard analysis of the interval-length data. Correlation between intervals within the same patients was accounted for by the method of Wei et al.17 For analysis of the number of lesions per interval, the method of General Estimating Equations (GEE),18 based on an overdispersed Poisson distribution, was used because of the obvious nonnormality of the number of lesions and the possibility that the numbers of lesions in different intervals for the same patients are correlated. The number of lesions was the dependent variable, and the recurrence number and the status of the interval with respect to perfusion (before or after) were used as independent variables.

Several models were used: an arbitrary or a linear relation between ln (number of lesions) and recurrence number and including or excluding interaction between recurrence number and interval status.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Tumor Response
Results regarding tumor response after ILP are shown in Table 2. Twenty-seven patients had a CR (63%; 95 CI, 48% to 78%), with a median duration of 12 months (interquartile range, 5–46 months). Thirteen of them (48%) experienced a recurrence in the perfused area after a median time of 6 months (interquartile range, 5–13 months) after ILP. Fourteen patients of the total study group (33%) had a persistent CR till the end of follow-up, which had a median duration of 37 months (9.5–62 months). Ten of these patients were still alive without evidence of locoregional disease at the time of analysis.


View this table:
[in this window]
[in a new window]
  		TABLE 2. Response after ILP in resectable and unresectable lesions
 
Limb Recurrence-Free Interval
The median LRFI before and after ILP decreases significantly over time (P < 0.0001). Figure 1 shows the estimated median LRFIs after CR with their 95% confidence intervals. The LRFI after ILP is longer than the LRFI before ILP at the same recurrence number. The latter is also shown in Figure 2, which gives the ratio (after vs. before) of the median LRFIs. The horizontal line is at a ratio of one, i.e., equal medians. Above this line the median LRFI is higher for patients after ILP. Although Figures 1 and 2 Go may create the impression that the relative differences between the "after" and "before" intervals decrease over time, this is not supported statistically (P = 0.27). Assuming a constant ratio, the median LRFI for patients after ILP is estimated to be 4.7 times longer (95% CI, 2.8–7.9; P < 0.0001) than for patients at the same recurrence number treated with excision alone before ILP.



View larger version (20K):
[in this window]
[in a new window]
  		FIG. 1. Effect of ILP on limb recurrence-free interval: median interval length with 95% confidence interval per recurrence number in the entire study population (n = 43). Y-axis indicates median interval (months) and x-axis, the recurrence number.

 


View larger version (16K):
[in this window]
[in a new window]
  		FIG. 2. Effect of ILP on limb recurrence-free interval: ratios of median interval lengths with 95% confidence intervals in entire study population (n = 43). Y-axis indicates interval ratio after ILP/before ILP and x-axis, the recurrence number.

 
For example, if the ILP is performed at the third recurrence, the subsequent median LRFI is 23 months (95% CI, 12–43 months), in comparison with an LRFI of 3 months (95% CI, 2–6 months) for those who have not undergone ILP at the same recurrence number (Fig. 1). The last median LRFI before ILP is 2 months (interquartile range, 1–4 months), and the first LRFI after ILP is 7 months (interquartile range, 2–26 months; P = 0.005).

Number of Lesions
The median number of lesions forming the indication for ILP was four (interquartile range, 2–8) and significantly larger than the number of lesions at the first recurrence after ILP, which was one (interquartile range, 1–3; P = 0.006). Overall, at the same recurrence number, patients before ILP have a 2.6-fold higher (95% CI, 1.6–4.5) mean number of lesions than do patients after ILP (P < 0.001). The number of lesions increases with the recurrence number, and this increase is estimated to be 22% per recurrence (95% CI, 10%–35%; P = 0.02). This is similar before and after ILP, with a 23% increase in number of lesions per recurrence number before and 16% increase after ILP (P = 0.55). In Figure 3, the relation between the mean number of lesions and recurrence number is shown before and after ILP. It shows that the mean number of lesions increases with the recurrences number before as well as after ILP and that the number of lesions for patients after ILP is lower than for patients before ILP. For example, at the fourth recurrence, the mean number of lesions after ILP is 0.6 (68% CI, 0.3–2), in comparison with a mean number of 4 (68% CI, 3.5–4.6) if lesions had only been excised at the third recurrence.



View larger version (16K):
[in this window]
[in a new window]
  		FIG. 3. Effect of ILP on number of lesions: number of lesions with 68% confidence interval per recurrence in the entire study population (n = 43). Y-axis indicates mean number of lesions and x-axis, the recurrence number.

 
Toxicity and Complications
Acute regional toxicity consisted of a grade I or II reaction with mild erythema and/or edema in 30 patients (69%). Twelve patients (28%) had a more severe acute toxicity reaction with blistering, and in one patient an amputation was necessary 9 days after ILP because of extensive tissue necrosis.

Management of Further Recurrences
In two patients a transfemoral amputation of the lower limb was done for intractable recurrences and failure of local radiotherapy with hyperthermia at 1 year and 2 years after ILP, respectively. The limb salvage rate was 93%. The management of recurrences and persisting disease after ILP is indicated in Table 3.


View this table:
[in this window]
[in a new window]
  		TABLE 3. Treatment of limb relapse or persistent lesions after ILP
 
Survival
Overall 5-year survival after ILP was 46% (95% CI, 28%–64%), with a median of 56 months (95% CI, 35–78 months). There was no significant difference in survival between those with unresectable and resectable lesions, with 5-year survival rates of 41% (95% CI, 16–66%) and 54% (95% CI, 31–78%), respectively (P = 0.38).

Patients with Resectable Lesions at the Time of ILP
Tumor response
One patient had more than nine LRFIs. Because this caused estimation problems, we analyzed only the first nine intervals. Eleven of the 18 patients with resectable lesions developed a CR (61%; CI, 36%–86%) after ILP. Four patients had no evaluable tumor response because the lesions were excised at ILP. One other patient had a PR and underwent excision of lesions at the time of maximal response. Two patients had lesions that progressed rapidly after ILP and were treated with local radiotherapy combined with hyperthermia. Five of the 11 patients with CR had a recurrence (46%; 95% CI, 10%–81%) after a median of 5 months (interquartile range, 4–15 months). The mean duration of CR was 25 months (95% CI, 4–81 months).

Limb recurrence-free interval
Figure 4 shows the estimated median LRFIs with their 95% confidence intervals. The median LRFI decreases when the number of times of recurrence increases (P = 0.05). Also, the intervals for patients after ILP in this subgroup are longer than for patients before ILP at the same recurrence number. If, for instance, ILP is performed at the third recurrence, the subsequent median LRFI is 30 months (95% CI, 12–75 months), compared with 5 months (95% CI, 2–15 months) for those who have not undergone ILP at the same recurrence number (Fig. 4). In Figure 5 the ratios of median intervals after versus before ILP are given. Assuming a constant ratio, the median LRFI for patients with resectable lesions after ILP is 5.9 times longer (95% CI, 2.7–13; P < 0.0001) than for patients at the same recurrence number before ILP.



View larger version (18K):
[in this window]
[in a new window]
  		FIG. 4. Effect of ILP on limb recurrence-free interval: median interval lengths with 95% confidence interval per recurrence interval number for the patients with resectable lesions (n = 18). Y-axis indicates median interval (months) and x-axis, the recurrence number.

 


View larger version (15K):
[in this window]
[in a new window]
  		FIG. 5. Effect of ILP on limb recurrence-free interval: ratios of median interval lengths with 95% confidence intervals for the patients with resectable lesions (n = 18). Y-axis indicates interval ratio after ILP/before ILP and x-axis, the recurrence number.

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The recurrent nature of melanoma in-transit metastases after adequate resection imposes a therapeutic dilemma. If these lesions are amenable to local treatments, excision or CO2 laser ablation is simple and effective and has little impact on the patient’s life.3,4 Systemic treatments such as biochemotherapy, high-dose interleukin-2, and dacarbazine- or temozolomide-including regimens are optional if there are (skin) metastases beyond the extremity.19–22 The main indication for ILP has traditionally been in-transit metastases confined to the limb that cannot be removed by local surgery. We speculated whether there might be an indication for ILP in patients with resectable lesions who have a high tendency for locoregional recurrences without evidence of hematological spread. A theoretical advantage of ILP over other local treatment options could be the elimination of any microscopic disease already present in the limb, with consequently a lengthening of the LRFI and reduction of the number of recurrent lesions.

This study showed a significant increase in LRFI after ILP in comparison with excision only. For the entire population, the LRFI was five times longer and for the patients with resectable lesions this was even six times longer at a given recurrence number. For all patients, at the third recurrence, ILP led to a median LRFI of 23 months, compared with 3 months for patients who underwent excision only at that time. This LRFI is longer than the 9–19 months that is known from other reports after ILP with melphalan, with or without TNF{alpha}.7,9,23–26 A single ILP stopped the process of recurring disease in one-third of our patients who were rendered locoregionally tumor-free until the end of follow-up, at a median of 3 years after ILP. These results seem considerably better than results of excision alone for in-transit melanoma, after which 15% to 17% of the patients become long-term free of disease.7,24

Apart from the time between recurrences, the number of lesions per recurrence was also shown to decrease after ILP. These findings strongly suggest that ILP influences the outgrowth of micrometastases in the affected limb. This is supported by the results of a small prospective randomized trial conducted by the Swedish Melanoma Study Group, in which 69 patients with recurrent extremity melanoma were randomly treated by excision or excision plus ILP. The tumor-free survival was increased after ILP from 10 to 17 months, and the limb recurrence rate was decreased from 67% to 45% after a median follow-up of 5 years.7 In a large international randomized trial comparing adjuvant ILP to the excision of primary extremity melanoma with excision alone, a trend for a longer disease-free interval was also seen. A reduction in the incidence of both in-transit metastases (3% vs. 7%) and regional lymph node metastases (13% vs. 17%) in the patients that underwent ILP was observed.6

Another study of the management of extremity recurrences after CR to ILP in 28 patients demonstrated an increased median duration of CR of 15 months after repeated ILP, in comparison with 6 months after excision alone.24

Single ILP with melphalan results in a CR in approximately 54% of the patients.5 Our CR rate of 63% compares favorably with this figure, with a similar rate of recurrence in about half of these patients. Waiting for a third or further recurrence does not seem to diminish the chance of a CR after ILP. This is in contrast to previous studies in which the tumor load on the extremity, which increases over time in these patients, was the strongest negative prognostic factor for tumor response.26–28 However, we confirmed the other finding of these studies, that a high tumor load is a negative predictor of recurrence-free survival, with a larger gain in limb recurrence-free interval after ILP performed at the third recurrence than at a later stage. A higher complete response rate of 72% and 73% has been reported after ILP with TNF{alpha} and melphalan, compared with 58% and 52% after ILP with melphalan alone in these studies.9,23 In the present study, results of these two regimens were not analyzed separately because of the small size of the groups and the fact that the effect on micrometastases is mainly due to the melphalan, as expressed by a similar limb disease-free survival after both regimens.

The main disadvantages of ILP lie in the involved costs, risk of acute regional toxicity, and long-term morbidity. After single ILP with melphalan, regional toxicity is mild in 85% of the patients, with slight edema and erythema that resolves completely within 2 weeks.29 More severe acute skin and soft-tissue reactions with blistering occur in approximately 15% of the patients, but a compartmental syndrome necessitating fasciotomy or amputation occurs in a maximum of 5% of the patients. Clinically observed long-term morbidity after iliac ILP with melphalan consists mostly of restricted function of the ankle and edema. Significant edema is reported in 28% of patients,28 and although an objective restricted function of the ankle has been noted in 25% to 40% of the patients,30,31 only 8% of these patients complained of ankle stiffness.30 In elderly patients, the same efficacy, toxicity, and morbidity have been observed after ILP.22 The risk of the aforementioned downsides of ILP should be weighed against multiple surgical excisions or sessions of CO2 laser ablation, which are likely to be necessary with increasing frequency for a growing number of lesions.

Some argue that systemic treatment would benefit these patients with localized metastatic disease because they are at high risk of distant metastatic disease.2 However, only small groups of patients undergoing systemic treatment for localized inoperable disease have been described. In a phase II randomized trial, biochemotherapy (consisting of chemotherapy combined with IFNa and IL-2) resulted in a 60% response rate and chemotherapy resulted in a 45% response rate in the small proportion of patients with AJCC stage III localized metastatic disease (in-transit or lymph node metastases).19 This was achieved at the cost of systemic toxicity, such as fatigue, anorexia, altered sensorium, and hypotension, in a considerable number of patients, mostly in the combined treatment group.

In a nonrandomized analysis of 631 patients, high-dose IL-2, with the addition of chemotherapy or IFN{alpha} or both, resulted in a 43% overall response rate among patients with cutaneous metastases without lymph node involvement, with a 5-year survival rate of 27%.20 Dacarbazine as a single agent results in a mere 10%–20% overall response rate and also has no proven benefit in terms of survival.21 The value of systemic treatment in localized metastatic melanoma is unclear, and local treatment options should be applied until distant metastases appear.

In conclusion, controlling the locoregional disease process in patients with frequently recurring limb melanoma is of great importance because the prognosis for these patients is reasonable. ILP slows down and sometimes stops this process, with a markedly increased LRFI in comparison with excision alone and a diminished tumor load at the next recurrence. Although a randomized trial would be warranted to provide definitive recommendations, ILP should be considered for patients with a third episode of limb melanoma recurrence (Fig. 6).



View larger version (34K):
[in this window]
[in a new window]
  		FIG. 6. Algorithm for the use of ILP for locoregional recurrences of melanoma.

 


   FOOTNOTES
 
Isolated limb perfusion lengthens the limb recurrence-free and decreases the number of lesions per recurrence significantly in patients with repeatedly recurrent limb melanoma.

Received for publication April 29, 2003. Accepted for publication January 28, 2004.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Lejeune FJ, Lienard D, el Douaihy M, Seyedi JV, Ewalenko P. Results of 206 isolated limb perfusions for malignant melanoma. Eur J Surg Oncol 1989; 15: 510–9.[Medline]
  2. McMasters KM. Isolated limb perfusion in elderly melanoma patients. Ann Surg Oncol 2002; 9: 939–40.[Free Full Text]
  3. Hill S, Thomas JM. Use of the carbon dioxide laser to manage cutaneous metastases from malignant melanoma. Br J Surg 1996; 83: 509–12.[Medline]
  4. Strobbe LJ, Nieweg OE, Kroon BB. Carbon dioxide laser for cutaneous melanoma metastases: indications and limitations. Eur J Surg Oncol 1997; 23: 435–8.[CrossRef][Medline]
  5. 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]
  6. Schraffordt Koops H, 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]
  7. Hafstrom L, Rudenstam CM, Blomquist E, et al. Regional hyperthermic perfusion with melphalan after surgery for recurrent malignant melanoma of the extremities. Swedish Melanoma Study Group. J Clin Oncol 1991; 9: 2091–4.[Abstract]
  8. Fraker DL, Alexander HR, Andrich M, Rosenberg SA. Treatment of patients with melanoma of the extremity using hyperthermic isolated limb perfusion with melphalan, tumor necrosis factor, and interferon gamma: results of a tumor necrosis factor dose-escalation study. J Clin Oncol 1996; 14: 479–89.[Abstract/Free Full Text]
  9. Rossi CR, Foletto M, Pilati P, Mocellin S, Lise M. Isolated limb perfusion in locally advanced cutaneous melanoma. Seminin Oncol 2002; 29: 400–9.
  10. Klaase JM, Kroon B, van Geel AN, et al. Limb recurrence-free interval and survival in patients with recurrent melanoma of the extremities treated with normothermic isolated perfusion. J Am Coll Surg 1994; 178: 564–72.[Medline]
  11. Kroon B. Regional isolation perfusion in melanoma of the limbs; accomplishments, unsolved problems, future. Eur J Surg Oncol 1988; 14: 101–10.[Medline]
  12. Kroon B, Klaase J, van de Merwe SA, van Dongen J, van der Zee J. Results of a double perfusion schedule using high-dose hyperthermia and melphalan sequentially for recurrent melanoma of the limbs: a pilot study. Regional Cancer Treatment 1992: 305–8.
  13. 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]
  14. World Health Organization. WHO Handbook for Reporting Results of Cancer Treatment. Geneva: World Health Organization, 1979.
  15. Kalbfleisch JD, Prentice RL. The Statistical Analysis of Failure Time Data. New York: Wiley, 1980.
  16. Lee EW, Wei LJ, Amato D. Cox-type regression analysis for large number of small groups of correlated failure time observations. In: JPKlein and PKGoel (ed.) Survival analysis, state of the art. Netherlands: Kluwer Academic Publishers; 1992: 237–47.
  17. Wei LJ, Lin DY, Weissfeld L. Regression analysis of multivariate incomplete failure time data by modeling marginal distributions. Journal of the American Statistical Association 1989; 84: 1065–73.[CrossRef]
  18. Liang KY, Zeger SL. Longitudinal data analysis using generalized linear models. Biometrika 1986; 73: 13–22.[Abstract/Free Full Text]
  19. Eton O, Legha SS, Bedikian AY, et al. Sequential biochemotherapy versus chemotherapy for metastatic melanoma: results from a phase III randomized trial. J Clin Oncol 2002; 20: 2045–52.[Abstract/Free Full Text]
  20. Keilholz U, Conradt C, Legha SS, et al. Results of interleukin-2-based treatment in advanced melanoma: a case record-based analysis of 631 patients. J Clin Oncol 1998; 16: 2921–9.[Abstract/Free Full Text]
  21. Hwu WJ. New approaches in the treatment of metastatic melanoma: thalidomide and temozolomide. Oncology (Huntingt) 2000; 14: 25–8.
  22. Noorda EM, Vrouenraets BC, Nieweg OE, et al. Safety and efficacy of isolated limb perfusion in elderly melanoma patients. Ann Surg Oncol 2002; 9: 968–74.[Abstract/Free Full Text]
  23. Fraker D, Alexander H, Ross M, et al. A phase III trial of isolated limb perfusion for extremity melanoma comparing melphalan alone versus melphalan plus tumor necrosis factor (TNF) plus interferon gamma. In: SSO 55th Annual Cancer Symposium 2002;S8.
  24. Feldman AL, Alexander Jr HR, Bartlett DL, Fraker DL, Libutti SK. Management of extremity recurrences after complete responses to isolated limb perfusion in patients with melanoma. Ann Surg Oncol 1999; 6: 562–7.[Abstract]
  25. Lejeune FJ, Deloof T, Ewalenko P, et al. Objective regression of unexcised melanoma in-transit metastases after hyperthermic isolation perfusion of the limbs with melphalan. Recent Results Cancer Res 1983; 86: 268–76.[Medline]
  26. Klaase JM, Kroon BB, 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 with melphalan. Surgery 1994; 115: 39–45.[Medline]
  27. Di Filippo F, Calabro A, Giannarelli D, et al. Prognostic variables in recurrent limb melanoma treated with hyperthermic antiblastic perfusion. Cancer 1989; 63: 2551–61.[CrossRef][Medline]
  28. Vrouenraets BC, Hart GA, Eggermont AM, et al. Relation between limb toxicity and treatment outcomes after isolated limb perfusion for recurrent melanoma. J Am Coll Surg 1999; 188: 522–30.[CrossRef][Medline]
  29. Vrouenraets BC, Eggermont A, Klaase J, et al. Long-term neuropathy after regional isolated perfusion with melphalan for melanoma of the limbs. Eur J Surg Oncol 1994; 20: 681–5.[Medline]
  30. Vrouenraets BC, in’t Veld GJ, Nieweg OE, et al. Long-term functional morbidity after mild hyperthermic isolated limb perfusion with melphalan. Eur J Surg Oncol 1999; 25: 503–8.[CrossRef][Medline]
  31. van Geel AN, van Wijk J, Wieberdink J. Functional morbidity after regional isolated perfusion of the limb for melanoma. Cancer 1989; 63: 1092–6.[CrossRef][Medline]



This article has been cited by other articles:


Home page
 Molecular Cancer TherapeuticsHome page
Y. Yoshimoto, C. K. Augustine, J. S. Yoo, P. A. Zipfel, M. A. Selim, S. K. Pruitt, H. S. Friedman, F. Ali-Osman, and D. S. Tyler
Defining regional infusion treatment strategies for extremity melanoma: comparative analysis of melphalan and temozolomide as regional chemotherapeutic agents
Mol. Cancer Ther., May 1, 2007; 6(5): 1492 - 1500.
[Abstract] [Full Text] [PDF]

Home page
 Ann. Surg. Oncol.Home page
D. Tyler
Editorial: Where are We going with Regional Therapy for Melanoma?
Ann. Surg. Oncol., May 1, 2004; 11(5): 455 - 457.
[Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Noorda, E. M.
Right arrow Articles by Kroon, B. B. R.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Noorda, E. M.
Right arrow Articles by Kroon, B. B. R.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS