Annals of Surgical Oncology Sign the Guestbook
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Originally published as Ann Surg Oncol Early Release 10.1245/ASO.2004.12.042 on August 16, 2004

Annals of Surgical Oncology 11:837-845 (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: What Is the Evidence for Its Use?

Eva M. Noorda, MD, Bart C. Vrouenraets, MD, PhD, Omgo E. Nieweg, MD, PhD, Frits van Coevorden, MD, PhD and Bin B.R. Kroon, MD, PhD

From the Department of Surgery, The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands.

Correspondence: Address correspondence and reprint requests to: Eva M. Noorda, MD, PhD, The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, 1066 CX Amsterdam the Netherlands; Fax: +31-20-5122554; E-mail: em_noorda{at}yahoo.com


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 REFERENCES
 
Background: This study was conducted to assess the best available evidence for the use of isolated limb perfusion.

Methods: Following the principles of Evidence-Based Medicine, we reviewed the best available evidence for isolated limb perfusion (ILP) for melanoma and soft tissue sarcoma (STS) of the limb.

Results: Adjuvant ILP with melphalan (M-ILP) to wide local excision cannot be recommended for patients with primary melanoma with a limited regional benefit and no increase in overall survival (level 1b evidence). Prophylactic M-ILP next to the excision of recurrent melanoma has resulted in a nonsignificant decrease in recurrence rate (33% to 50%), with a significantly longer recurrence-free interval (10 to 17 months), but no survival benefit (level 2b evidence). Therapeutic M-ILP, with or without tumor-necrosis factor alpha and interferon gamma (T(I)M-ILP), seems indicated in unresectable melanoma (level 3 to 4 evidence). In unresectable STS of the limbs, limb salvage can be obtained in 57% to 86% of patients with neoadjuvant T(I)M-ILP (level 3 evidence). A comparison of level 3 to 4 studies on ILP and other neoadjuvant treatment modalities for unresectable STS shows that ILP results in the highest limb salvage rate with the lowest complication rate.

Conclusions: Based on level 3 to 4 evidence, ILP is indicated in unresectable locoregional (recurrent) melanoma and unresectable STS of the limbs. Level 1 and 2b evidence does show an effect of prophylactic ILP on micrometastatic disease in locoregional (recurrent) melanoma of the limb. ILP seems the most effective limb sparing, neoadjuvant treatment modality when compared with other neoadjuvant treatment options for unresectable STS of the limb (level 3 to 4 evidence), although randomized studies are lacking.

Key Words: Melanoma • Soft tissue sarcoma • Regional perfusion • Regional chemotherapy


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 REFERENCES
 
Over time, isolated limb perfusion (ILP) has been used for various indications, with varying results. Evidence from prospective (randomized) studies supporting the current application of ILP is rare. To assess what evidence is available for the use of ILP, we have conducted a systematic analysis of the literature, aiming to include only the best available evidence for the various indications for ILP in extremity melanoma and soft tissue sarcoma (STS). This analysis has been performed following the principles of Evidence-Based Medicine (http://www.cebm.utoronto.ca/practice/ca/).1,2 The question that we have tried to answer is: Based on the best evidence available, what are the indications and results of ILP in patients with melanoma or sarcoma of the extremities?


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
REFERENCES
 
Evidence-Based Medicine is based on four subsequent steps (FRAP) (http://www.cebm.utoronto.ca/practice/ca/):1 (1) Frame the clinical question; (2) retrieve the evidence, through a literature search; (3) appraise the evidence (critically appraised topic = CAT); and (4) patient application: extrapolation of the available best evidence to clinical practice. For this overview, these steps were followed.

First, questions regarding the various clinical applications of ILP were formulated. Clinical questions addressed separately were as follows: What is the value of (1) adjuvant ILP after excision of primary melanoma; (2) prophylactic ILP after excision of recurrent melanoma; (3) ILP in unresectable melanoma; (4) ILP in resectable STS of the extremity; and (5) ILP in unresectable STS of the extremity?

Second, the best available evidence was selected, guided by the following ranking of evidence of interventional studies:1

Level 1a. Systematic review of randomized, controlled trials (RCT) with consistent results
Level 1b. Good quality RCT
Level 2a. Systematic review of observational or case-control studies with consistent results
Level 2b. RCT of less quality or observational or case-control study
Level 2c. Outcomes research (descriptive study)
Level 3. Patient series, observational or case-control study of poor quality
Level 4. The experts’ opinion or generally accepted practice

Ideally, level 1 evidence was included and, if that was not available, evidence from the next level and so forth. If no RCT was available, the analyses with the largest number of patients were discussed, provided that the inclusion criteria, outcome variables, and statistics were reported well. Published and unpublished reports were sought through Pubmed and the Cochrane Controlled Trial Register. For melanoma, the evidence was searched using MesH terms "melanoma" and "perfusion, regional," the result of which was limited to RCT or clinical trials. For STS, the same search was performed using "sarcoma" and the addition of radiotherapy or intraarterial chemotherapy, if applicable. Conference reports and abstracts were retrieved from the Internet, the authors, or conference participants. References from previous review articles were examined.

Third, for each of the aforementioned clinical questions, a CAT of the best available study was performed following the guidelines provided by the Centre for Evidence-Based Medicine in Toronto, Canada.1,2 A CAT is a judgment of the validity of the study and the size and precision of the diagnostic or therapeutic effect, wherein the following questions are answered: Are the results valid? What are the results? Are the results applicable to my patients? This is done by systematically collecting the following data from the analysis: study design, inclusion criteria, size of the study population (per group), treatment arms to which randomized (if applicable), primary endpoints of the study, duration of follow-up, and the results regarding the primary and other relevant endpoints. Possible endpoints were response to ILP, regional and systemic toxicity, morbidity, disease-free survival, and overall survival. For randomized, controlled studies, the absolute risk reduction (ARR) and number needed to treat (NNT) were given with their confidence intervals (CI). A conclusion was based on the results and methodological validity of the study and followed by additional commentary if necessary.

ILP in Melanoma: What is the Value of Adjuvant ILP after Excision of Primary Melanoma Lesions?
Table 1 describes the RCT used to assess the role of adjuvant ILP with melphalan (M-ILP) in extremity melanoma. Three of these trials assessed the value of adjuvant M-ILP in primary melanoma.


View this table:
[in this window]
[in a new window]
  		TABLE 1. Prophylactic ILP for extremity melanoma
 

View this table:
[in this window]
[in a new window]
  		TABLE 2. MD Anderson classification for melanoma
 
The best available evidence comes from the report of a large, multicenter RCT (11 centers in 7 countries) performed between 1984 and 1994.3 This report concerns 852 patients with a so-called "high-risk" primary melanoma (Breslow thickness ≥1.5 mm) on an extremity who were randomized to either wide local excision (WLE) or WLE and a mild hyperthermic (38°C to 40°C) M-ILP. Patients were eligible if they had no locoregional or distant metastases; the tumors were located distal to the middle half of the thigh or upper arm; they were between 15 and 75 years of age; they had not received previous chemo- or radiotherapy; and they had no other (previous) malignancies. The European Organization for Research and Treatment of Cancer (EORTC) performed the randomization. After randomization, 20 patients (10 in each treatment arm) were not included in the analysis because ultimately they were not eligible (n = 15) or were lost to follow-up (n = 5). These patients were not included in the analysis. Data from 412 patients receiving WLE only and 420 WLE + ILP served as the subject of the trial. Elective lymph node dissection (ELND) was performed according to each participating center’s protocol. A panel of pathologists reviewed all resected material. Quality control of the ILP was performed at all participating centers by the surgeons who initiated the trial. The median duration of follow-up was 6.4 years. Primary endpoints were locoregional recurrences as the first site of recurrence and survival.

In-transit metastases occurred in a significantly smaller number of patients with ILP than in those with WLE alone (3.3%, 95% CI, 2.8% to 3.8% vs. 6.6%, 95% CI, 6.1% to 7.1%, P = .05). The ARR of 3.3% (95% CI, 0.3% to 6.0%) was small, however, with a high NNT of 33 (95% CI, 16–333). Incidence of regional node metastases in all patients, regardless whether they had ELND, was not significantly decreased from 16.7% (95% CI, 13.1% to 20.3%) in those who had only WLE to 12.6% (95% CI, 9.4% to 15.7% P = .11) in the ILP group, with an ARR of 4.1% (95% CI, 0.6% to 9%), and a NNT of 24 (95% CI, 11–167). The differences in nodal recurrence rate were also not significant in the subgroups who had had ELND and those who had not. The disease-free survival was significantly increased in the ILP group (P = .02) in the first 2 to 3 years following primary treatment, but no long-term effect was observed. No impact on overall survival was noted.

In conclusion, the limited regional benefit and absence of an increase in overall survival by M-ILP does not outweigh its costs and morbidity. M-ILP, therefore, cannot be recommended as an adjunct to WLE in this group of patients with primary melanoma.

Commentary 1
It is remarkable that a single chemotherapeutic treatment session significantly affects micrometastatic disease, resulting in a relative risk reduction (RRR) of in-transit metastases of 50% (95% CI, 4.4% to 72.9%) and a RRR of lymph node metastases of 25% (95% CI, 4.7% to 84.4%). This reduction in risk of locoregional recurrences was particularly evident in the patients with tumor thickness between 1.5 and 3 mm. Thicker melanoma lesions were more likely to have their first recurrences at distant sites. This difference in dissemination pattern in melanoma lesions thicker and thinner than 4 mm has been reported.4

Commentary 2
The statistical power of this trial is not mentioned. An impression of its power can be gained from the confidence interval of the relative risk (RR) of survival in one treatment arm compared with the other. Overall survival was not significantly different between both treatment arms, with a RR of 1.03 and a 95% CI between 0.78 and 1.37, which means that it could be below or above 1.0. Such a difference would probably not be considered clinically relevant by most clinicians.

Commentary 3
Two other RCT have been performed comparing WLE or WLE and M-ILP for primary high-risk melanoma.5,6 Ghussen et al.6 randomized 107 patients with stage I through III melanoma (Table 2), only 37 of whom had primary melanoma, and followed them for at least 4 years. The applicability of their results to clinical practice is strongly doubted because of the extremely high locoregional recurrence rate of 39% in the control group (compared with 8% in the ILP-group; ARR 31%, 95% CI, 9% to 58%). In general, recurrence rates are about 2% to 3% after adequately resected primary melanoma.7 Secondly, survival in this series was exceptionally high considering that 65% of the patients had locoregional recurrent disease: a 3-year, disease-free survival of approximately 94% in the ILP group and 73% for the controls (P = .02). A small and prematurely closed RCT by Fenn et al.5 included only 30 patients with a mean follow-up of 72 months (range 16 to 113 months). The locoregional recurrence rates of 13% and 43%, in favor of the ILP-group (–2%–61%), were high (P = .14, ARR 30%, 95% CI, 2% to 61%). This trial suggested a survival advantage for patients after ILP, with 5-year survival rates of 88% versus 60%, respectively (P < .03). Because of its small size, however, the value of these findings is limited.

What is the Value of Prophylactic M-ILP after Excision of Recurrent Melanoma Lesions?
The best available evidence comes from a single center, randomized trial, performed by the Swedish Melanoma Study Group8 between 1981 and 1989 (Table 1).

A total of 69 patients with locoregional recurrent melanoma were randomized to WLE alone (36 patients) or WLE with borderline hyperthermic (41°C to 42°C) M-ILP (33 patients). Patients were ineligible if they had distant metastases. Both treatment arms were well balanced for sex, age, tumor thickness, and tumor site on the upper or lower extremity. All patients had a regional lymph node dissection with a mean follow-up of 39 months. Follow-up was performed at each patient’s local hospital. The primary endpoints were further locoregional recurrences and survival.

A lower locoregional recurrence rate was seen in the ILP group: 45% (95% CI, 28% to 62%) of these patients experienced recurrence compared with 67% (95% CI, 52% to 82%) in the group with excision only (P = .13). The ARR was 22% (95% CI, -2% to 44%) with a NNT of 5 (95% CI, 2–59). The median disease-free interval was prolonged to 17 months after ILP compared with 10 months after WLE alone (P = .04). No difference in overall survival was observed, with approximate 5-year survival rates of 39% and 44%, respectively, in favor of the ILP group (P = .28).

In conclusion, a significant increase in tumor-free survival was observed after ILP, with a trend for a lower locoregional recurrence rate. Because no overall survival benefits were observed, however, prophylactic M-ILP with all its costs and associated morbidity cannot be recommended in recurrent melanoma as an adjunct to simple excision of these lesions.

Commentary
This study confirms that ILP influences micrometastatic disease, with a RRR in further locoregional metastases of 32% (95% CI, 5.8% to 58.0%) and a prolonged disease-free interval in patients at high risk of micrometastatic extremity metastases at the time of treatment. This study did not specify whether the patients had early stage recurrent disease (i.e., a first single recurrence) or later stage (i.e., multiple second or further recurrences) as the indication for their ILP. This RCT also shows the remarkable effect of a single application of regional chemotherapy on micrometastatic disease, with a reduction in further locoregional metastases.

To establish the role of ILP as an adjuvant treatment for resectable recurrences of melanoma, larger randomized studies are needed. Because these trials suggest that adjuvant M-ILP has a significant effect on micrometastatic disease, ILP may provide valuable locoregional disease control in selected patients (e.g., those with frequently recurring and multiple lesions) compared with WLE only. For future studies, it might be necessary to select specific patients (e.g., with a third or more recurrence) because these patients have proved their tendency for repeat recurrences.9

What is the Value of Therapeutic ILP for Unresectable Extremity Melanoma?
An overview of the results of ILP in patients with measurable recurrent melanoma lesions is given in Table 3. No RCT have been studying ILP versus other treatments for patients with measurable disease. Although the generally accepted indication for M-ILP is unresectable limb melanoma, no RCT are comparing ILP with other possible treatment options (e.g., radiotherapy, chemotherapy) for this indication. Because most results on tumor response after ILP are from series in which the lesions were deliberately left in situ to monitor the ILP-effect, it is difficult to assess the results of ILP for truly unresectable extremity melanoma.10


View this table:
[in this window]
[in a new window]
  		TABLE 3. Therapeutic ILP for melanoma
 
The best available evidence comes from a subgroup analysis of a multicenter phase III trial carried out in five US centers.11 In a preliminary report, 103 patients with two or more recurrent melanoma lesions on the extremity were included. These patients were randomized to mild hyperthermic M-ILP (n = 51) or ILP with melphalan, tumor necrosis factor alpha (TNF-{alpha}) and interferon-gamma (IFN-{gamma}, TIM-ILP) (n = 52).

In the subgroup of patients with a high tumor load (i.e., >10 lesions or lesions >5 cm), a 19% complete remission (CR) rate after M-ILP was attained versus 58% when TNF-{alpha} and melphalan were used.

In conclusion, this study suggests that high tumor load extremity melanoma lesions are best treated with TIM-ILP, compared with the (remarkably) low CR rate after M-ILP.

Commentary 1
The traditional indication for ILP, namely unresectable limb melanoma, is based on level 3 or 4 evidence. Kapteijn et al12 performed the largest retrospective study that analyzed results of ILP in patients with unresectable melanoma lesions. A total of 49 patients were treated with various ILP schedules, varying from single normothermic to double normothermic and single hyperthermic to a sequential schedule in which high-dose hyperthermia and melphalan were separately and sequentially applied. Criteria for unresectable melanoma lesions were not given. In 28 (57%) of the patients, a CR was attained. Except for the single normothermic ILP, these results are based on ILP types that are no longer performed. Therefore, new studies with M-ILP and T(I)M-ILP seem warranted, preferentially RCT comparing ILP with extensive locoregional treatment (e.g., CO2 laser ablation or excisions).

Commentary 2
These results are preliminary and it is unknown on how many patients with a high tumor load they are based. The results after M-ILP and TIM-ILP for high tumor burden disease are disappointing compared with the results of both ILP types for measurable lesions, as reported in a retrospective, comparative study by Liénard et al.13, with a 73% CR rate after T(I)M-ILP compared with 52% after M-ILP. In addition, a large meta-analysis of retrospective series showed that M-ILP resulted in a CR rate of 54%.10

Commentary 3
Results obtained with multiple surgical excisions or CO2 laser ablation are generally satisfactory if recurring lesions are not too extensive and superficially localized.14,15 Therefore, no evidence exists for the use of ILP in extensive but still resectable lesions. In pursuit of locoregional control with limb salvage for patients with lesions that cannot be managed with excisional surgery, other local treatment options seem subject to limitations. For example, CO2 laser ablation can be applied only to lesions <2 cm in the cutis or superficial subcutis.14,15 Radiotherapy ± hyperthermia can result in a 35% to 62% CR rate, depending on the application of hyperthermia, but has the best effect in tumors <4 cm with the disadvantage that it cannot be applied to large areas with multiple lesions.16 Other intralesional applications of drugs or cytokines result in reasonable response rates up to 50% but mostly for only a short duration.17,18 The local application of dinitrochlorobenzene combined with systemic dacarbazine has resulted in a maximum of 25% CR.19

Commentary 4
The definition of unresectability is subjective and often not clearly defined. Fraker et al.20 have proposed a division based upon tumor burden and on high and low tumor load in which high tumor load is defined by >10 (small) lesions or lesions >5 cm. Rossi et al.21 defined a high tumor load as lesions >3 cm or >15 in number.

ILP in Soft Tissue Sarcoma
Local treatment of advanced extremity STS requires a multimodality approach to obtain maximal local tumor control with preserved limb function. Advanced extremity STS was conventionally treated by amputation of the extremity, until 1982 when Rosenberg et al.22 published the results of a RCT. In this study, patients were randomized to either amputation of the limb or limb-sparing surgery (excision and radiation therapy), which showed no significant difference in overall survival between the treatment arms. This was a landmark finding in the treatment of STS of the extremity, and a tendency for limb-sparing treatment modalities then developed.

The best available evidence was searched on the effectiveness of ILP and other locoregional, limb-sparing treatment modalities for patients with extremity STS. No RCT or other studies were found that provided information on the value of ILP in resectable STS. The value of ILP in unresectable STS only will be discussed, as will three other possible neoadjuvant treatment modalities in these patients, namely radiotherapy, intraarterial chemotherapy, and systemic chemotherapy. The best available evidence was selected and appraised in the same way as for melanoma.

What is the Value of ILP for Patients with Unresectable STS of the Extremity?
No RCT or other comparative study was available that compared ILP with other treatment options (i.e., neoadjuvant or amputation) for locally unresectable STS. Therefore, only (retrospective) case series can be discussed (Table 4).


View this table:
[in this window]
[in a new window]
  		TABLE 4. TNF{alpha}-ILP in patients with unresectable extremity soft tissue sarcoma
 
The best available evidence (i.e., largest series on ILP for unresectable STS of the extremities) is from a retrospective, multicenter study involving eight European centers. This study provides data from 186 patients treated according to the same protocol with melphalan and TNF-{alpha} (TM-ILP) in 1995.23 Patients were selected on the basis of unresectable STS of the limb, based on the following criteria of unresectability: multifocality, fixation to vital structures (nerve/vessels/bone), recurrence in a previously irradiated area, location in or near a joint, large size necessitating an extent of resection that would severely compromise limb function, or a combination of these factors. The patients had a mild hyperthermic (38°C to 40°C) TM-ILP and, in 55 patients, IFN-{gamma} was added (TIM-ILP). If sufficient response allowed resection, the tumor remnant was subsequently removed. Median follow-up was 22 months (range 6 to 58 months). The major endpoints were tumor response (divided into clinical, histologic, and final response) and limb salvage rate.

Clinically, tumor response was complete in 33 patients (18%), partial in 106 (57%), no change was observed in 42 (22%), and tumor progression occurred in 5 patients (3%). In 126 (68%) patients, the tumor remnant could be resected after ILP. Sixty patients did not have post-ILP resection because of an excessive number of tumors, systemic metastases, or refusal to have amputation. The final response was based on a combined judgment of clinical response and pathologic review of the resection specimen (if available) and was complete in 54 patients (29%), partial in 99 (53%), no change was observed in 29 (16%), and tumor progressive in 4 patients (2%). A limb in 34 patients had to be amputated during the course of follow-up, 7 of whom initially had been rendered tumor-free by ILP ± resection. The limb salvage rate was 82%.

In conclusion, limb salvage could be obtained in most patients who would otherwise have had amputation.

Commentary 1
The actual limb salvage rate was 64%, because only 64% attained local tumor control with limb preservation (function).

Commentary 2
Other reports on the use of T(I)M-ILP for STS are also displayed in Table 4. In 1992, TNF-{alpha} was first used in ILP with a 100% response rate in the first four patients with unresectable recurrent STS treated with TNF-{alpha} in combination with melphalan.24 Later, results from different institutions of T(I)M-ILP for unresectable STS of the extremities showed overall response rates varying from 77% to 94%.23,25–28 Various other drugs had been tried in ILP before use of TNF-{alpha} in these patients. An overview of all series containing more than 15 patients and reporting response and limb salvage rates is given in Table 5.


View this table:
[in this window]
[in a new window]
  		TABLE 5. ILP with various drugs for unresectable extremity soft tissue sarcoma
 
Commentary 3
No RCT or prospective studies exist on preoperative radiotherapy in unresectable STS of the extremity. The largest retrospective series is from the Massachusetts General Hospital Cancer Center29 (Table 6). A total of 220 patients had unresectable STS (70 on the extremity) that were rendered resectable by preoperative radiotherapy. No criteria are provided on which unresectability was based. The minimal follow-up was 5 years. No information is given on the completeness of tumor response after radiotherapy. Of patients who had local resection, 10% had a local recurrence. No limb salvage rate is mentioned. This was a biased series because only patients with resectable tumors after neoadjuvant radiotherapy were selected and, thus, no limb salvage rate, a measure for the effectiveness of preoperative radiotherapy, was provided.


View this table:
[in this window]
[in a new window]
  		TABLE 6. Preoperative radiotherapy and intra-arterial chemotherapy for soft tissue sarcoma of the extremities
 
Another study by Tanabe et al.30 from the M.D. Anderson Cancer Center, on preoperative radiotherapy for patients with resectable extremity sarcomas, does provide information about response after preoperative radiotherapy (Table 6). A group of 95 patients, treated with preoperative radiotherapy and subsequent resection, was retrospectively studied after a median follow-up of 66 months (range 16 to 236 months). In 54% of patients, the tumor was <8 cm. A 46% overall tumor response to radiotherapy was seen at histology. After resection of the tumor, recurrences were observed in 14 (15%) of the patients. Of these patients, seven had to have amputation, resulting in a limb salvage rate of 92%.

O’Sullivan et al.31 recently published the results of a preliminary closed RCT comparing pre- and postoperative radiotherapy in resectable extremity STS. The main outcome measure of this trial was the wound complication rate. It did not provide information on the tumor response rate after preoperative radiotherapy, however.

Commentary 4
The largest prospective series on the application of neoadjuvant intraarterial chemotherapy was published by Eilber et al.,32 who combine this treatment modality with radiotherapy in high-risk (intermediate or high grade) extremity STS, with undefined resectability. In the first 107 patients, doxorubicin was delivered intraarterially during 3 days, followed by 10 fractions of 35 Gy of irradiation (Table 6).32 This resulted in a 98% limb salvage rate and a 3% local recurrence rate after a median follow-up of 8 years. A high local toxicity and complication rate of 43%, with pathologic fractures in a third of them, was encountered. This led to a reduction of the radiation dose with 50%. The next 137 patients were treated with the same intraarterial scheme, but with five fractions of 17.5 Gy.33 A limb salvage rate of 97% was attained, but with a 12% local recurrence rate after a median follow-up of 48 months. Compared with the first scheme, a lower complication rate of 26% occurred, however, at the cost of a higher local recurrence rate.33 Subsequent studies showed local recurrence rates varying from 3% to 29%, limb salvage rates of 80% to 98%, and varying complication rates of 3% to 26% (Table 6).34–36

From the aforementioned reports, it is clear that the application of all neoadjuvant treatment modalities is limited by the complications and toxicity they entail. Considering the effectiveness of ILP and the reported complication rates, ILP seems the best option. RCT, however, are warranted that compare preoperative radiotherapy or intraarterial chemotherapy with ILP in patients with unresectable extremity STS to be conclusive.37–44


   FOOTNOTES
 
Prophylactic isolated limb perfusion (ILP) with melphalan results in a significantly longer recurrence-free interval in patients with recurrent limb melanoma. Therapeutic ILP seems indicated in unresectable melanoma and in unresectable soft tissue sarcoma of the limbs. Limb salvage can be obtained in most patients with neoadjuvant ILP.

Received for publication December 22, 2003. Accepted for publication June 13, 2004.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 REFERENCES
 

  1. Sackett DL, Straus SE, Richardson WS, Rosenberg W, Haynes RB. Evidence-based Medicine: How to Practise and Teach EBM. Edinburgh: Churchill Livingston, 2000.
  2. Urschel JD, Goldsmith CH, Tandan VR, Miller JD. Users’ guide to evidence-based surgery: how to use an article evaluating surgical interventions. Can J Surg 2001; 44: 95–100.[Medline]
  3. 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]
  4. Balch CM, Soong SJ, Murad TM, Ingalls AL, Maddox WA. A multifactorial analysis of melanoma. II. Prognostic factors in patients with stage I (localized) melanoma. Surgery 1979; 86: 343–51.[Medline]
  5. Fenn NJ, Horgan K, Johnson RC, Hughes LE, Mansel RE. A randomized controlled trial of prophylactic isolated cytotoxic perfusion for poor-prognosis primary melanoma of the lower limb. Eur J Surg Oncol 1997; 23: 6–9.[CrossRef][Medline]
  6. Ghussen F, Nagel K, Groth W, Muller JM, Stutzer H. A prospective randomized study of regional extremity perfusion in patients with malignant melanoma. Ann Surg 1984; 200: 764–8.[Medline]
  7. Kroon BBR, Nieweg OE. Management of malignant melanoma. Ann Chir Gynaecol 2000; 89: 242–50.[Medline]
  8. 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]
  9. Takkenberg RB, et al. Does isolated limb perfusion prolong the limb recurrence-free interval after several episodes of excisional surgery for limb recurrences of melanoma? Ann Surg Oncol 2003; 10: S18.
  10. 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]
  11. 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. Ann Surg Oncol 2002; S8.
  12. Kapteijn BA, Klaase JM, van Geel AN, Eggermont AMM, Kroon BBR. Results of regional isolated perfusion for locally inoperable melanoma of the limbs. Melanoma Res 1994; 4: 135–8.[CrossRef][Medline]
  13. Liénard D 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]
  14. 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]
  15. Strobbe LJ, Nieweg OE, Kroon BBR. Carbon dioxide laser for cutaneous melanoma metastases: indications and limitations. Eur J Surg Oncol 1997; 23: 435–8.[CrossRef][Medline]
  16. Overgaard J, Gonzalez GD, Hulshof MC, et al. Randomised trial of hyperthermia as adjuvant to radiotherapy for recurrent or metastatic malignant melanoma. European Society for Hyperthermic Oncology. Lancet 1995; 345: 540–3.[CrossRef][Medline]
  17. Storm FK, Sparks FC, Morton DL. Treatment for melanoma of the lower extremity with intralesional injection of bacille Calmette Guerin and hyperthermic perfusion. Surg Gynecol Obstet 1979; 149: 17–21.[Medline]
  18. von Wussow P, Block B, Hartmann F, Deicher H. Intralesional interferon-alpha therapy in advanced malignant melanoma. Cancer 1988; 61: 1071–4.[CrossRef][Medline]
  19. Strobbe LJ, Hart AA, Rumke P, Israels SP, Nieweg OE, Kroon BB. Topical dinitrochlorobenzene combined with systemic dacarbazine in the treatment of recurrent melanoma. Melanoma Res 1997; 7: 507–12.[CrossRef][Medline]
  20. 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]
  21. Rossi CR, Foletto M, Pilati P, Mocellin S, Lise M. Isolated limb perfusion in locally advanced cutaneous melanoma. Semin Oncol 2002; 29: 400–9.[CrossRef][Medline]
  22. Rosenberg SA, Tepper J, Glatstein E, et al. The treatment of soft-tissue sarcomas of the extremities: prospective randomized evaluations of (1) limb-sparing surgery plus radiation therapy compared with amputation and (2) the role of adjuvant chemotherapy. Ann Surg 1982; 196: 305–15.[Medline]
  23. Eggermont AMM, Schraffordt Koops H, Klausner JM, et al. Isolated limb perfusion with tumor necrosis factor and melphalan for limb salvage in 186 patients with locally advanced soft tissue extremity sarcomas. The cumulative multicenter European experience. Ann Surg 1996; 224: 756–64.[CrossRef][Medline]
  24. Liénard D, Ewalenko P, Delmotte JJ, Renard N, Lejeune FJ. High-dose recombinant tumor necrosis factor alpha in combination with interferon gamma and melphalan in isolation perfusion of the limbs for melanoma and sarcoma. J Clin Oncol 1992; 10: 52–60.[Abstract]
  25. Olieman AF, Pras E, van Ginkel RJ, Molenaar WM, Schraffordt Koops H, Hoekstra HJ. Feasibility and efficacy of external beam radiotherapy after hyperthermic isolated limb perfusion with TNF-alpha and melphalan for limb-saving treatment in locally advanced extremity soft-tissue sarcoma. Int J Radiat Oncol Biol Phys 1998; 40: 807–14.[CrossRef][Medline]
  26. van Etten B, van Geel AN, de Wilt JH, Eggermont AMM. Fifty tumor necrosis factor-based isolated limb perfusions for limb salvage in patients older than 75 years with limb-threatening soft tissue sarcomas and other extremity tumors. Ann Surg Oncol 2003; 10: 32–7.[Abstract/Free Full Text]
  27. Lejeune FJ, Pujol N, Liénard D, et al. Limb salvage by neoadjuvant isolated perfusion with TNF alpha and melphalan for non-resectable soft tissue sarcoma of the extremities. Eur J Surg Oncol 2000; 26: 669–78.[CrossRef][Medline]
  28. Gutman M, Inbar M, Lev-Shlush D, et al. High dose tumor necrosis factor-alpha and melphalan administered via isolated limb perfusion for advanced limb soft tissue sarcoma results in a >90% response rate and limb preservation. Cancer 1997; 79: 1129–37.[CrossRef][Medline]
  29. Suit HD, Mankin HJ, Wood WC, et al. Treatment of the patient with stage M0 soft tissue sarcoma. J Clin Oncol 1988; 6: 854–62.[Abstract/Free Full Text]
  30. Tanabe KK, Pollock RE, Ellis LM, Murphy A, Sherman N, Romsdahl MM. Influence of surgical margins on outcome in patients with preoperatively irradiated extremity soft tissue sarcomas. Cancer 1994; 73: 1652–9.[CrossRef][Medline]
  31. O’Sullivan B, Davis AM, Turcotte R, et al. Preoperative versus postoperative radiotherapy in soft-tissue sarcoma of the limbs: a randomised trial. Lancet 2002; 359: 2235–41.[CrossRef][Medline]
  32. Eilber FR, Guiliano AE, Huth J, Mirra J, Morton DL. High-grade soft-tissue sarcomas of the extremity: UCLA experience with limb salvage. Prog Clin Biol Res 1985; 201: 59–74.[Medline]
  33. Huth JF, Eilber FR. Patterns of metastatic spread following resection of extremity soft-tissue sarcomas and strategies for treatment. Seminin Surg Oncol 1988; 4: 20–6.
  34. Levine EA, Trippon M, Das Gupta TK. Preoperative multimodality treatment for soft tissue sarcomas. Cancer 1993; 71: 3685–9.[CrossRef][Medline]
  35. Temple WJ, Temple CL, Arthur K, Schachar NS, Paterson AH, Crabtree TS. Prospective cohort study of neoadjuvant treatment in conservative surgery of soft tissue sarcomas. Ann Surg Oncol 1997; 4: 586–90.[Abstract]
  36. Azzarelli A, Quagliuolo V, Fissi S, et al. Intra-arterial induction chemotherapy for soft tissue sarcomas. Ann Oncol 1992; 3 (Suppl 2): S67–S70.
  37. Klaase JM, Kroon BBR, 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]
  38. Noorda EM, Vrouenraets BC, Nieweg OE, van Coevorden F, van Slooten GW, Kroon BBR. Isolated limb perfusion with TNF-alpha and melphalan for unresectable soft tissue sarcoma of the extremities. Cancer 2003; 98: 1483–90.[CrossRef][Medline]
  39. Krementz ET, Carter RD, Sutherland CM, Hutton I. Chemotherapy of sarcomas of the limbs by regional perfusion. Ann Surg 1977; 185: 555–64.[Medline]
  40. Lehti PM, Moseley HS, Janoff K, Stevens K, Fletcher WS. Improved survival for soft tissue sarcoma of the extremities by regional hyperthermic perfusion, local excision and radiation therapy. Surg Gynecol Obstet 1986; 162: 149–52.[Medline]
  41. Klaase JM, Kroon BBR, Benckhuijsen C, van Geel AN, Albus-Lutter CE, Wieberdink J. Results of regional isolation perfusion with cytostatics in patients with soft tissue tumors of the extremities. Cancer 1989; 64: 616–21.[CrossRef][Medline]
  42. Di Filippo F, Carlini S, Cavalier E, et al. The role of hyperthermic perfusion in the treatment of tumors of the extremities. Adv Exp Med Biol 1990; 267: 223–34.[Medline]
  43. Moseley HS. An evaluation of two methods of limb salvage in extremity soft-tissue sarcomas. Arch Surg 1992; 127: 1169–73.[Abstract/Free Full Text]
  44. Rossi CR, Foletto M, Alessio S, et al. Limb-sparing treatment for soft tissue sarcomas: influence of prognostic factors. J Surg Oncol 1996; 63: 3–8.[CrossRef][Medline]



This article has been cited by other articles:


Home page
 Ann. Surg. Oncol.Home page
H. M. Kroon, M. Moncrieff, P. C. A. Kam, and J. F. Thompson
Outcomes Following Isolated Limb Infusion for Melanoma. A 14-Year Experience
Ann. Surg. Oncol., November 1, 2008; 15(11): 3003 - 3013.
[Abstract] [Full Text] [PDF]

Home page
 Ann. Surg. Oncol.Home page
L. Kretschmer, I. Beckmann, K.-M. Thoms, C. Mitteldorf, H. P. Bertsch, and C. Neumann
Factors Predicting the Risk of In-Transit Recurrence After Sentinel Lymphonodectomy in Patients With Cutaneous Malignant Melanoma
Ann. Surg. Oncol., August 1, 2006; 13(8): 1105 - 1112.
[Abstract] [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