
 Metastatic Disease:  Limb     written and compiled by doctordee  May 2001


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Metastatic Disease -- Local Control -- Treatment Options by Site - Limb

* Limb 
* Isolated Limb Perfusion 
* Radiotherapy and Re-Irradiation
* Hyperthermia [see Hyperthermia Page]



How to Use This Page 

Treatments for local control of the site are listed.  Under each technique, there is a collection of medical journal article references relating to that technique, its success with LMS or sarcomas, if such is available, and further information about its use and complications. Generally, the best way to deal with LMS metastases is by surgical resection, if it is at all possible. 
Should you be interested in a specific technique, abstracts can be highlighted and copied, and then printed out and taken with you to your doctor for further discussion. 
[ ] will indicate editorial comment by the compile. Some sentences are highlighted in bold, again done by the compiler.



For more information, PubMed Search on Treatment of Extremity Sarcomas
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=search&db=PubMed&term=sarcoma%20limb%20treatment

For more information, PubMed Search on Treatment of Extremity Leiomyosarcomas
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=search&db=PubMed&term=leiomyosarcoma%20limb%20treatment



Isolated Limb Perfusion

For general principles of isolated perfusion, see that section under Liver Metastases. 
The best choice of therapy for LMS of the extremities is surgical excision with wide clear margins. This might mean amputation for some sites of primary LMS, but isolated limb perfusion can make limb salvage possible. 
Where surgical excision cannot be done, or where the LMS must be reduced in size to become resectable, isolated limb perfusion has some advantages for treatment. 

 

Search on Pubmed:  Isolated Limb Perfusion and Sarcoma
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=search&db=PubMed&term=sarcoma%20isolated%20limb%20perfusion


 

Isolated Limb Perfusion
Annotated Selected Medical Journal References


(Current Oncology Reports)Volume 3 | Number 4 | 2001 | Melanoma 
Isolated Limb Perfusion for Extremity Soft-Tissue Sarcomas, In-Transit Metastases, and Other Unresectable Tumors: Credits, Debits, and Future Perspectives 
by Alexander M. M. Eggermont, MD, PhD, Timo L. M. ten Hagen, PhD 
"Isolated limb perfusion (ILP) with melphalan is effective against melanoma in-transit metastases but has failed in the treatment of limb-threatening extremity sarcomas. Tumor necrosis factor-a (TNF) has changed this situation completely. Now, ILP with TNF + melphalan is a very successful treatment to prevent amputation. In a multicenter European trial, ILP with TNF + melphalan resulted in a 76% response rate and a 71% limb salvage rate in patients with limb-threatening soft-tissue sarcomas, deemed unresectable by independent review committees ... We have also reported on the success of this regimen against ...drug-resistant bony sarcomas. High-dose TNF destructs tumor vasculature, and, most importantly, it enhances tumor-selective drug uptake (ie, melphalan and doxorubicin) by threefold to sixfold. Similar synergy is observed in well-vascularized liver metastases after isolated hepatic perfusion with TNF and melphalan. New (vasoactive) drugs and mechanisms of action and interaction with chemotherapy are in development. ILP is also a promising treatment modality for adenoviral vector-mediated gene therapy. Many clinical phase I/II evaluations in ILP are now underway."


Eur J Surg Oncol 2000 Nov;26(7):669-78 
Limb salvage by neoadjuvant isolated perfusion with TNFalpha and melphalan for non-resectable soft tissue sarcoma of the extremities. 
Lejeune FJ, Pujol N, Lienard D, Mosimann F, Raffoul W, Genton A, Guillou L, Landry M, Chassot PG, Chiolero R, Bischof-Delaloye A, Leyvraz S, Mirimanoff RO, Bejkos D, Leyvraz PF. 
Multidisciplinary Oncology Centre, and Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland. Ferdy.Lejeune@chuv.hospvd.ch 
"Patients with non-resectable soft tissue sarcomas of the extremities do not live longer if they are treated by amputation or disarticulation. In order to avoid major amputations, we tested isolated limb perfusion (ILP) with tumour necrosis factor alpha (TNF)+melphalan+/-interferon-gamma (IFN) as a pre-operative, neoadjuvant limb salvage treatment" METHODS: "Twenty-two patients... Thirteen cases were recurrent or progressive after previous therapy; five tumours had a diameter >/=20 cm, and four were multiple or regionally metastatic. There were... two leiomyosarcomas..." "Twenty-four ILPs were performed in the 22 patients, and 18 (82%) experienced an objective response: this was complete in four (18%) and partial in 14 (64%)"... " ILP with TNF and chemotherapy is an efficient limb sparing neoadjuvant therapy for a priori non-resectable limb soft tissue sarcomas." [heavily edited summary] Copyright 2000 Harcourt Publishers Ltd. Publication Types: Clinical trial PMID: 11078614 [PubMed - indexed for MEDLINE] 

Ann Surg Oncol 2000 May;7(4):268-75 

Systemic toxicity and cytokine/acute phase protein levels in patients after isolated limb perfusion with tumor necrosis factor-alpha complicated by high leakage. 

Stam TC, Swaak AJ, de Vries MR, ten Hagen TL, Eggermont AM. 
Department of Surgical Oncology, University Hospital Rotterdam-Dr. Daniel den Hoed Cancer Center, The Netherlands. 

" High leakage of TNFalpha to the systemic circulation, caused by a complicated ILP, led to 10-fold to more than 100-fold increased levels of TNFalpha, IL-6, and IL-8 in comparison with patients without leakage. The increase of the acute phase proteins was limited. Even when high leakage occurs, this procedure should not lead to fatal complications. The most prominent clinical toxicity was hypotension (grade III in four patients), which was easily corrected. No pulmonary or renal toxicity was observed in any patient. It is our experience that, even in the rare event of significant leakage during a TNFa-based ILP, postoperative toxicity is usually mild and can be easily managed by the use of fluid and, in some cases, vasopressors." 

Anticancer Res 1998 Sep-Oct;18(5D):3899-905 
TNF alpha in isolated perfusion systems: success in the limb, developments for the liver credits, debits and future perspectives. 
Eggermont AM. University Hospital Rotterdam, Daniel den Hoed Cancer Center, The Netherlands.eggermont@chih.azr.nl 
"The clinical applicability of Tumor Necrosis Factor-a pi (TNF) is under renewed investigation because of its successful use in the isolated limb perfusion in patients with irresectable soft tissue extremity sarcomas. The high response rate of > 80% with a similarly successful limb salvage rate in this patient population has led to the submission of TNF for registration for this indication in Europe.  ... [There is] renewed interest in TNF alpha and in its application in isolated organ perfusions, such as isolated hepatic perfusion. At the Rotterdam Cancer Center a preclinical-clinical interactive development program has been established dedicated to isolated limb, kidney, liver and lung perfusions and the application of new drugs such as TNF and TNF-mutants in these systems. Moreover a program dedicated to reduce the magnitude of surgical procedures by using occlusion balloon catheters is investigating the techniques and pharmacokinetics of procedures such as balloon catheter mediated hypoxic pelvic perfusions (HPP) and isolated hypoxic hepatic perfusions (IHHP). Here we present an overview of these developments." PMID: 9854502 

Surgery 1998 Mar;123(3):335-43 
Safety and efficacy of isolated perfusion of extremities for recurrent tumor in elderly patients. 
Ariyan S, Poo WJ. Yale Melanoma Unit, Yale Cancer Center, New Haven, Conn., USA. 
"... The treatment of bulky recurrent melanotic lesions of extremities with isolated limb perfusion with high dose chemotherapy offers palliation in a number of patients. However, the question is raised whether these major surgical procedures are too risky to warrant performing them in elderly patients. ...: Aggressive treatment in selected patients with regional isolated perfusion of limbs for melanoma can lead to significant palliation of symptoms and salvage of limbs with adequate disease-free control and occasional survival benefit. This series of patients was associated with meaningful disease control and with few serious complications. Perfusions are tolerated well by patients in their 70s and 80s; therefore advanced age is not a contraindication to this procedure in carefully selected patients. PMID:9526527 

Am J Orthop 1997 May;26(5):369-70 
Compartment syndrome after isolated perfusion of the leg: a case report. 
Chan PS, Naranja RJ, Klimkiewicz JJ, Heppenstall RB. 
Department of Orthopaedic Surgery, University of Pennsylvania Medical Center, Philadelphia, USA. 
The authors present a case of a lower leg compartment syndrome that developed after a regional chemotherapy technique was used for recurrent melanoma of the foot in a 74-year-old woman. The diagnosis was based on the results of physical examination, with confirmation by intracompartmental pressures. Prompt consultation of orthopedic surgeons and fasciotomy helped avoid potentially crippling sequelae. [Compartment syndrome occurs when part of an arm or leg is under swelling-type pressure and the muscle in the 'compartment' is crushed.]Publication Types: Review Review of reported cases PMID: 9181198 [PubMed - indexed for MEDLINE] 

Plast Reconstr Surg 1997 Apr;99(4):1023-9 
Regional isolated perfusion of extremities for melanoma: a 20-year experience with drugs other than L-phenylalanine mustard. 
Ariyan S, Poo WJ, Bolognia J. Yale Melanoma Unit, Yale University School of Medicine, New Haven, Conn., USA. 
"Recurrent melanoma of the extremities can lead to bulky symptomatic lesions that become difficult management problems. Treatment of these tumors with isolated limb perfusion with high dose chemotherapy may offer palliation in a number of patients.... In our experience, aggressive treatment in selected patients with regional isolated perfusion of limbs for melanoma has provided meaningful palliation and salvage of the limbs with adequate disease-free control, and occasional survival benefit. This regional treatment modality is associated with meaningful control and with few serious complications.... This series illustrates the safety of controlling limb recurrence with this technique, even with repeat perfusions in the same patient." PMID: 9091898 
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9091898&dopt=Abstract

J Hand Surg [Am] 1997 May;22(3):495-503 
Limb salvage surgery and adjuvant radiotherapy for soft tissue sarcomas of the forearm and hand. 
Bray PW, Bell RS, Bowen CV, Davis A, O'Sullivan B. University Musculoskeletal Oncology Unit, University of Toronto, Mount Sinai Hospital, Ontario, Canada. 
"Twenty-five consecutive patients with soft tissue sarcoma of the forearm and hand were assessed for limb-salvage surgery and were entered into a prospective study evaluating oncologic details and functional outcome. Seventeen patients had received incomplete primary excision elsewhere and presented with local recurrence or residual disease. Three had pulmonary metastases at the time of presentation. Twenty-three patients were candidates for limb-salvage surgery and 20 received adjuvant radiotherapy. ... Eighty-eight percent of those who survived and did not require amputation were able to return to occupational and activities of daily living with no or minimal functional limitation. This study demonstrates that limb-salvage surgery, with adjuvant radiotherapy when necessary, is an effective alternative to amputation in the majority of patients with sarcoma of the forearm and hand. Radiation toxicity is rarely a problem." PMID: 919546
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=919546&dopt=Abstract
 


Arch Surg 1996 Oct;131(10):1103-7; discussion 1108 
Vascular reconstruction for limb salvage in sarcoma of the lower extremity. 
Koperna T, Teleky B, Vogl S, Windhager R, Kainberger F, Schatz KD, Kotz R, Polterauer P. Department of Vascular Surgery, University of Vienna, Austria. 
"Limb-preserving resection of sarcoma of the lower extremity can be performed with satisfactory function of the limb maintained, even if it becomes necessary to resect the femoral vessels. Autologous venous graft for vascular reconstruction is the treatment of choice. In spite of the high incidence of metastases, considerable long-term survival is possible. "  PMID: 8857912 
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8857912&dopt=Abstract 


Ned Tijdschr Geneeskd 1995 Apr 22;139(16):833-7 
[Consensus soft tissue tumors. Dutch Workgroup Soft-Tissue Tumors]. [Article in Dutch] 
Van Geel AN, Van Unnik JA, Keus RB. Dr. Daniel den Hoed Kliniek, afd. Chirurgische Oncologie, Rotterdam. 
"Soft-tissue sarcomas constitute a rare group of malignant tumours with histopathological features of connective, muscular, fatty or peripheral nervous tissue. The prognosis at manifestation depends on only two factors: the spread, both local and remote, and the biological behaviour of the tumour. The latter factor cannot be influenced but the former can: by inexpert manipulation. Consequently, tumours suspected of being soft-tissue sarcomas require multidisciplinary management from the beginning, with the team members familiar with each other's diagnostic and therapeutic skills. Imaging diagnostic methods should precede invasive methods for collection of material for pathological examination. The number of mitotic figures observed at microscopical examination of the tissue is an important prognostic feature. Surgical resection is the treatment of first choice. Radiotherapy is indicated in grade 3 tumours, after recurrence surgery, and when radical resection would involve too much mutilation. Chemotherapy is only given in the context of clinical trials. Surgical treatment of lung metastases may be indicated in selected patients. Regional isolated perfusion with tumour necrosis factor may be an alternative for limb amputation." [NOTE: this is for SARCOMAS in general, not LMS in particular.ed.] Publication Types: Consensus development conference Review PMID: 7731476 

J Infus Chemother 1995 Spring;5(2):73-81 
Administration of high-dose tumor necrosis factor alpha by isolation perfusion of the limbs. Rationale and results. 
Lejeune F, Lienard D, Eggermont A, Schraffordt Koops H, Rosenkaimer F, Gerain J, Klaase J, Kroon B, Vanderveken J, Schmitz P. Centre Pluridisciplinaire d'Oncologie, CHUV, Lausanne, Switzerland. 
"Recombinant tumor necrosis factor alpha (rTNF alpha) has potent antitumor activity in experimental studies on human tumor xenografts. However, in humans, the administration of rTNF alpha is hampered by severe systemic side effects. The maximum tolerated dose ranges from 350 to 500 mg/m2, which is at least 10-fold less than the effective dose in animals. Isolated perfusion of the limbs (ILP) allows the delivery of high-dose rTNF alpha in a closed system with acceptable side effects. A protocol with a triple-drug regimen was based on the reported synergism of rTNF alpha with chemotherapy, with interferon-gamma, and with hyperthermia. ... In unresectable soft tissue sarcomas, this protocol was found to produce a 50% complete response with 87.5% limb salvage, since most tumors became removable. Release of nanograms levels of TNF alpha in the systemic circulation was evident, but control of this leakage and appropriate intensive care resulted in acceptable toxicity. Angiographic, immunohistological, and immunological studies suggest that the efficacy of this protocol is due to a dual targeting: rTNF alpha activates and electively lyses the tumor endothelial cells, while melphalan is mainly cytotoxic to the tumor cells. ILP with rTNF alpha appears to be a useful model for studying the biochemotherapy of cancer in man." PMID: 8521239 [PubMed - indexed for MEDLINE] 


Arch Surg 1995 Jan;130(1):43-7 
Long-term morbidity after regional isolated perfusion with melphalan for melanoma of the limbs. The influence of acute regional toxic reactions. 
Vrouenraets BC, Klaase JM, Kroon BB, van Geel BN, Eggermont AM, Franklin HR. Department of Surgery, The Netherlands Cancer Institute (Antoni van Leeuwenhoek Huis), Amsterdam. 
OBJECTIVE: To determine the influence of acute regional toxic reactions on the incidence and characteristics of long-term morbidity after regional isolated perfusion with melphalan. ...: One hundred sixty patients (44%) showed some degree of objective or subjective morbidity; most (104 [28%]) had lymphedema. Other long-term morbidity consisted of muscle atrophy or fibrosis (42 [11%]), limb malfunction (55 [15%]), neuropathy (13 [4%]), pain (28 [8%]), and recurrent infection (11 [3%]). Miscellaneous complications were seen in 14 patients (4%). Seventy-one patients (19%) had more than one complication. Acute regional toxic reactions had a statistically significant effect on the incidence of long-term morbidity (P < .01). Moderate to severe acute regional toxic reactions were strongly linked to the occurrence of muscle atrophy or fibrosis (P < .001) and limb malfunction (P < .001). Regional lymph node dissection was statistically significantly related to lymphedema (P = .05). CONCLUSION: Improvement of the perfusion technique should be pursued in an effort to reduce acute regional toxic reactions, and thereby long-term morbidity, without compromising the therapeutic effect. PMID: 7802575  
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7802575&dopt=Abstract 
 

Eur J Surg Oncol 1994 Dec;20(6):681-5 
Long-term neuropathy after regional isolated perfusion with melphalan for melanoma of the limbs. 
Vrouenraets BC, Eggermont AM, Klaase JM, Van Geel BN, Van Dongen JA, Kroon BB. 
Department of Surgery, The Netherlands Cancer Institute (Antoni van Leeuwenhoek Huis), Amsterdam. 
.... Long-term neuropathy was encountered ...10/51 patients (20%) after perfusion at the axillary level and in 4/247 patients (2%) after perfusion at the iliac level. ... This complication is probably a result of the isolating Esmarch rubber bandage being applied too tightly during perfusion at a proximal level. At the axillary level, where the brachial plexus lacks the protection from enveloping tissues, nerve damage is especially prone to occur. ... This implies meticulous surgical isolation of the vascular system and accurate monitoring of leakage. PMID: 7995421  
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7995421&dopt=Abstract




Am J Surg 1994 Jun;167(6):618-20 
Patient- and treatment-related factors associated with acute regional toxicity after isolated perfusion for melanoma of the extremities. 
Klaase JM, Kroon BB, van Geel BN, Eggermont AM, Franklin HR, Hart GA. Department of Surgery, The Netherlands Cancer Institute, Amsterdam. 
"... Factors associated with a more severe toxicity reaction proved to be tissue temperatures of 40 degrees C or higher, female gender, a deterioration of the gas values of the venous perfusate during perfusion, and perfusion at a proximal level of isolation. Consideration of these prognostic factors may lead to a further decrease of acute regional toxicity in perfusion." PMID: 8209941


Anticancer Res 1983 Mar-Apr;3(2):87-93 
Isolated extremity perfusion with DTIC. An experimental and clinical study. 
Aigner K, Hild P, Breithaupt H, Hundeiker M, Schwemmle K, Henneking K, Illig L, Merker G, Paul E, Brodkorb J, Jungbluth A. 
"Dacarbazine (DTIC) was used for isolated perfusion of extremities in dogs and man. In the animal experiment perfusions with DTIC at dosages up to 100 mg per kg of extremity weight were well tolerated. The concentration of DTIC in the perfusate ranged from 70 to 400 micrograms/ml without evidence for formation of metabolites. .... Five patients with advanced malignant melanoma or soft tissue sarcoma of the extremities were treated by isolation perfusion with 75 to 133 mg DTIC per kg of extremity at 40 degrees C for 60 minutes. A tumor regression of at least 30% was observed. PMID: 6682645  

 



Limb LMS-Radiotherapy and Re-Irradiation 


Sometimes after irradiation, and subsequent recurrence, re-irradiation can be done.

see also Radiation page and discussion there.

Search Pubmed for Re-irradiation and sarcoma of a limb.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=search&db=PubMed&term=sarcoma%20limb%20treatment%20re-irradiation



Radiother Oncol 1996 Dec;41(3):209-14Related Articles, Books, LinkOut 
Soft tissue sarcoma of the extremity. Limb salvage after failure of combined conservative therapy. 
Catton C, Davis A, Bell R, O'Sullivan B, Fornasier V, Wunder J, McLean M. University Musculoskeletal Oncology Unit, Princess Margaret Hospital, Toronto, Canada. 
PURPOSE: To assess the results of salvage therapy using surgery alone or surgery and re-irradiation for patients with locally recurrent extremity soft tissue sarcoma (STS) following conservative surgery and radiotherapy. MATERIALS AND METHODS: 25 patients with locally recurrent STS after conservative surgery and irradiation were assessed between 1990 and 1995. Two patients with concurrent systemic relapse were treated palliatively. Seven patients were not candidates for conservative re-excision and underwent amputation, 11 patients underwent conservative resection without irradiation. Seven of these patients relapsed, and five went on to receive combined conservative surgery and re-irradiation. A further five patients initially received combined retreatment, for a total of ten patients treated with combined conservative surgery and re-irradiation. Six of these ten patients were treated with brachytherapy alone, one with brachytherapy and external beam therapy, and three with external beam therapy alone. The median retreatment dose was 49.5 Gy (range 35-65 Gy), and the median cumulative soft tissue dose was 100 Gy (range 93-120 Gy). RESULTS: The median follow-up from the most recent treatment is 24 months (range 7-42 months). At the last follow-up 14 patients are alive and disease free; two are alive with local disease and four with systemic disease, and five are dead of disease. Overall local control is 19/23 (91%). The local control for patients treated with conservative excision without irradiation is 4/11 (36%) and for conservative excision with re-irradiation 10/10 (100%). Six (60%) of these patients experienced significant post-irradiation would-healing complications, but three have recovered fully. Functional scores for the entire treated group are significantly lower after treatment, as are those for patients undergoing combined surgery and re-irradiation, but 70% of those treated with conservative surgery and re-irradiation and a good or excellent post-treatment functional score. CONCLUSIONS:Combined conservative surgery and re-irradiation provided superior local control to local re-excision alone and a functional outcome superior to amputation. Combined treatment with re-irradiation should be considered the primary salvage therapy for patients who fail combined therapy and who are suitable for conservative re-excision. Systemic relapse is a significant problem, and optimal therapy should minimize the risk of local relapse after the initial therapy. Eighteen patients (72%) had a history of intralesional excision as their initial intervention, and suggests that inappropriate initial management is a risk factor for relapse after combined conservative therapy. Improvements in therapy must include the appropriate education of the primary care physicians. PMID: 9027935 


 

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