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Local Control: Limb LMS
written and compiled by doctordee
Search LMS site
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 compiler. Some sentences are highlighted in bold, again done by the compiler.
Obtaining Information

For upto date information,
Search Pubmed for Treatment of Extremity Sarcomas
Search Pubmed for Treatment of Extremity LMS

[NOTE: repeated Pubmed searches with limb, extremity, arm, or leg substituted as the keyword, will give you different results.]

You can also search the Conference Abstracts Database at ASCO
Considering Type of Treatment

The gold standard of treatment for LMS tumors is surgery. If it is at all possible, surgical resection with wide clear margins is the treatment of choice for any LMS presence. If surgical resection is not possible, then locally advanced or metastatic spread within a limb can be treated either systemically or locally.

If there is metastatic spread beyond the limb, then a systemic method would probably be best to start with. Some systemic options are chemotherapy, antiangiogenesis treatment, targeted molecular therapy, immunological. Look under the Treatments Techniques section for discussions of some of the systemic options.

If the only tumor presence known is in the limb, however, you have the choice of localized treatment. The advantage of localized treatment is that it spares the rest of the body. This page investigates some localized treatments.

Pubmed searches can be done on any treatment, searching for results for the site or for LMS.
Pubmed searches can be done on any site, searching for treatments.
Pubmed Search Page
Isolated Limb Perfusion

For LMS, unquestionable indications are for Surgical Resection if at all possible. For non-resectable metastases other treatments must be explored [RFA, conventional chemotherapy, and so on.].

Where conventional systemic chemotherapy is chosen, but is ineffective, there are alternative methods of delivering the chemotherapy agent that maximizes tumor exposure. For instance, Chemoembolisation can provide the tumor with high drug concentrations without provoking systemic side effects. These procedures do not prevent the appearance of extra-regional recurrence or metastases.

Isolated limb perfusion is a regional treatment technique that delivers high dose chemotherapy, biologic agents, and hyperthermia via a completely isolated vascular recirculating perfusion circuit as a means of regionally treating tumors. The major artery leading into the limb, and the major vein returning blood from the limb, have their blood supply diverted to a "perfusion circuit" [like a heart lung machine].

The chemotherapy and other agent[s] are injected into the limb circulation, but do NOT get into the rest of the body's circulation. The limb's blood circulation is ISOLATED from the rest of the body. After perfusing the limb for an hour with the high concentration chemotherapy agent, the limb is given a 'washout' and then reconnected normally to the systemic circulation. This allows higher concentration of toxic chemicals to be given to the limb, and spares the rest of the body the exposure to the agent and the side effects.

Side effects of Isolated Limb Perfusion include acute regional toxic reactions, lymphedema, muscle atrophy or fibrosis, limb malfunction, neuropathy, pain, recurrent infection. The majority had more than one side effect. "Acute regional toxic reactions had a statistically significant effect on the incidence of long-term morbidity ... Moderate to severe acute regional toxic reactions were strongly linked to the occurrence of muscle atrophy or fibrosis ... and limb malfunction ... Regional lymph node dissection was statistically significantly related to lymphedema ... 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. " Reference

For general principles of isolated perfusion, see that section under Liver Metastases.
Again, 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 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 Pubmed for Isolated Limb Perfusion and Sarcoma

Isolated Limb Perfusion
Annotated Selected Medical Journal References

1 Surg Oncol Clin N Am. 2003 Apr;12(2):499-521.
Experimental approaches to treatment of soft tissue sarcoma.
Hwang RF, Hunt KK.
Department of Surgical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.

The experimental approaches described in this article represent potential new approaches for targeted therapy. Thus far, none of the preclinical data have demonstrated a cure for sarcomas; however, the antitumor effects of many of these new agents seem to be enhanced when the agents are combined with chemotherapeutic agents. The combination of novel therapeutics with conventional chemotherapy may be the most effective strategy in terms of maximization of tumor killing and minimization of toxicity and the risk of drug resistance. Not only are new drugs being developed for treatment of sarcomas but new ways of delivering drugs are also being investigated. The angiogenic, or metronomic, schedule of drug delivery may be preferable to conventional schedules in achieving optimal tumor inhibition. In addition, isolated limb perfusion is a unique approach to delivery of drugs, such as TNF and melphalan, for sarcomas and melanomas ... The advantages of this method of drug delivery include the ability to administer therapeutic agents in high concentrations to a specific region of the body without systemic toxicity. ...
Fetch PMID: 12916466

2 Cancer. 2003 Oct 1;98(7):1483-90.
Isolated limb perfusion with tumor necrosis factor-alpha and melphalan for patients with unresectable soft tissue sarcoma of the extremities.
Noorda EM, Vrouenraets BC, Nieweg OE, van Coevorden F, van Slooten GW, Kroon BB.
Department of Surgery, The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.

...Since 1992, isolated limb perfusion (ILP) with tumor necrosis factor-alpha (TNFalpha) and melphalan has been used for the treatment of patients with unresectable soft tissue sarcomas of the extremities. The authors retrospectively studied the results of limb salvage surgery using TNFalpha-ILP at their institution.
...: In 1 patient (2%) who died 2 days after undergoing ILP, response and acute limb toxicity could not be assessed. One patient (2%) attained a clinical complete response (2%), 23 patients (47%) attained a clinical partial response, 17 patients (35%) demonstrated no change, and 7 patients (14%) had tumor progression. Thirty-one patients (63%) underwent tumor resection....Final response, based on both clinical and pathologic assessment in which pathology was decisive, was complete in 4 patients (8%) and partial in 27 patients (55%), resulting in a final overall response rate of 63%. Local control with preservation of the limb was attained in 28 patients (57%). Four of 32 patients (13%) who had been rendered tumor free by ILP with or without undergoing resection and radiation therapy, developed a local recurrence. The 5-year disease specific survival rate was 48% for the 49 patients. Acute limb toxicity after ILP was a mild Grade 1-2 reaction in 35 patients (71%) patients, a Grade 3 reaction in 12 patients (25%), and a Grade 4 reaction in 1 patient (2%). Three major ILP-related complications were encountered, including arterial thrombosis in two patients and a fulminant Clostridial infection leading to death in one patient. There were no severe cardiovascular reactions after ILP.
In patients with unresectable soft tissue sarcomas of the limbs who underwent ILP with TNFalpha and melphalan followed by resection of the tumor remnant when possible, a 63% overall tumor response rate and a 57% local control rate with limb preservation was achieved. Copyright 2003 American Cancer Society.DOI 10.1002/cncr.11648
Fetch PMID: 14508836

3 Curr Opin Oncol. 2003 Jul;15(4):300-3.
Hyperthermic isolated limb perfusion in the management of extremity sarcoma.
Hoekstra HJ, van Ginkel RJ.
Division of Surgical Oncology, Department of Surgery, Groningen University Hospital, PO Box 30.001, 9700 RB Groningen, The Netherlands.

High local drug concentrations can be achieved in a limb with minimal systemic toxicity with the technique of hyperthermic isolated limb perfusion (HILP). The currently most successful drugs are still Tumor Necrosis Factor alpha (TNFalpha) and melphalan. With HILP, as an induction chemotherapy treatment of locally advanced primarily irresectable soft tissue sarcomas of a limb, a limb salvage rate of 71% can be achieved, with a minimal treatment related morbidity. For the HILP is no upper age limit. Systemic inflammatory response syndrome is currently seldom seen. The exact working mechanisms of TNFalpha are still unknown. Experimental work is now directed to the development of drugs sensitizing the tumor vasculature to the effects of TNFalpha. In the clinical HILP setting are currently lower doses of TNFalpha in combination with melphalan investigated. Although multidrug resistance (MDR) is a major issue in effectiveness of chemotherapy in human cancer treatment, HILPs with TNFalpha and melphalan did not induce MDR in sarcomas. The future research in HILP with TNFalpha is directed in increasing tumor sensitivity for TNF with lowering the dosage without decreasing tumor response.
Fetch PMID: 12874508 [PubMed - in process]

4 Ann Surg Oncol. 2003 Jun;10(5):562-8.
Pentoxifyllin attenuates the systemic inflammatory response induced during isolated limb perfusion with recombinant human tumor necrosis factor-alpha and melphalan.
Hohenberger P, Latz E, Kettelhack C, Rezaei AH, Schumann R, Schlag PM.
Division of Surgery and Surgical Oncology, Robert Rossle Hospital and Tumor Institute, Max Delbruck Center for Molecular Medicine, Berlin, Germany.

... Isolated limb perfusion (ILP) with recombinant human tumor necrosis factor-alpha (rhTNF-alpha) and melphalan harbors the risk of septic shock-like syndrome. Pentoxifyllin (PTX) produced a beneficial effect on cytokine response and survival in animal experiments of septic shock, and we were interested to explore its effect during TNF-ILP in humans. ...
PTX attenuates systemic cytokine production and influences components of the systemic inflammatory response after TNF-ILP. PTX may play a beneficial role in the management of septic shock-like syndrome, particularly in patients with leakage from the ILP circuit. Clinical Trial
Fetch PMID: 12794024

5 Lancet Oncol. 2003 Jun;4(6):335-42.
Amputation for soft-tissue sarcoma.
Clark MA, Thomas JM.
Department of Surgery, Middlemore Hospital, Auckland, New Zealand.

Soft-tissue sarcomas are a group of rare malignant tumours, many of which arise in the limbs. Most are treated with a combination of wide local excision and radiotherapy, but a small number--including proximal, large, high-grade, or recurrent tumours, or those involving major neurovascular structures--necessitate major amputation including forequarter or hindquarter amputation. These uncommon operations should remain in the surgical armamentarium for carefully selected patients. Those being considered for amputation should be referred to a tertiary sarcoma unit for examination of all other options, such as limb-salvage surgery, tumour downstaging with chemotherapy or radiotherapy (perhaps with subsequent limb-salvage surgery), or novel techniques such as isolated limb perfusion. Only after careful assessment should amputation be carried out. Outcomes after major amputation are highly variable, but such procedures can confer useful palliation to patients with distressing symptoms (pain, bleeding, fungation), long-term disease-free survival with reasonable function in carefully selected patients, and cure in some.
Fetch PMID: 12788405

6 Surg Oncol Clin N Am. 2003 Apr;12(2):469-83.
Isolated limb perfusion in the management of locally advanced extremity soft tissue sarcoma.
Eggermont AM.
Department of Surgical Oncology, Erasmus University Medical Center-Daniel Den Hoed Cancer Center, 301 Groene Hilledijk, 3075 EA, Rotterdam, The Netherlands.

In conclusion, ILP is an interesting and important treatment option in the management of locally advanced extremity soft tissue sarcomas. Large medical centers, dealing with referrals and an important caseload of STS patients, should develop this treatment option and have it readily available to offer patients the best chances for limb salvage. In Europe, the success of TNF-based ILP has lead to the training, accreditation, and activation of TNF-based ILP programs in over 30 cancer centers since the approval of TNF for this indication in 1999. Thus, country by country centers for referral programs are established to deal with those categories of patients that can greatly benefit from the availability and integration of this treatment option in the STS treatment programs.
Fetch PMID: 12916464

7 Ned Tijdschr Geneeskd. 2003 Mar 22;147(12):529-33.
[Regional isolated perfusion: also applicable in elderly patients] [Article in Dutch]
Noorda EM, Vrouenraets BC, Nieweg OE, Kroon BB.
Nederlands Kanker Instituut/Antoni van Leeuwenhoek Ziekenhuis, afd. Chirurgische Oncologie, Plesmanlaan 121, 1066 CX Amsterdam.

In 3 patients over 75 years of age with a malignancy, limb salvage was achieved through the application of isolated limb perfusion with melphalan with or without tumour necrosis factor alpha: an 82-year-old woman with extensive locoregional melanoma metastases on her lower leg, a 78-year-old woman with a large, ulcerating recurrence of melanoma on her lower leg and an 83-year-old woman with recurrent sarcoma of the lower arm. There were no complications and the women recovered well. Isolated limb perfusion can be effectively and safely used in older patients with irresectable tumours of the extremities, offering them limb salvage for the remainder of their lives.
Fetch PMID: 12693077

8 Ann Surg Oncol. 2003 Jan-Feb;10(1):32-7.
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.
van Etten B, van Geel AN, de Wilt JH, Eggermont AM.
Department of Surgical Oncology, University Hospital Rotterdam-Daniel den Hoed Cancer Center, Rotterdam, The Netherlands.

...Isolated limb perfusion (ILP) with tumor necrosis factor (TNF) and melphalan is highly effective in treating limb-threatening soft tissue sarcoma (STS) and other bulky tumors. Because of fear of TNF-associated toxicity, ILP with TNF is not offered to older patients in some cancer centers, although especially in older patients,... In the STS patients, a response rate of 76% and a limb-salvage rate of 76% were achieved; ... Local toxicity was mild. The three postoperative deaths that occurred in the total series of 306 TNF-based ILPs in Rotterdam (<1%) occurred in patients >75 years old after leakage-free perfusions and were not related to TNF but to extremely high-risk profiles in these three patients. : Older patients should not be withheld a TNF-based ILP for limb salvage, because the procedure is safe and highly effective in these patients.
Fetch PMID: 12513957

9 (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."

10 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, et. al.
Multidisciplinary Oncology Centre, and Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland.

"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
Fetch PMID: 11078614

11 Bull Cancer. 2002 Jan;89(1):100-7.
[Update on soft tissue sarcomas][Article in French]
Bui BN, Tabrizi R, Dagada C, Trufflandier N, St ckle E, Coindre JM.
Institut Bergonie, Centre regional de lutte contre le cancer, 229, cours de l'Argonne, 33076 Bordeaux Cedex.

Important refinements have taken place in the diagnosis of soft tissue sarcoma with extensive use of immuno-histochemistry. New entities have been described, while malignant histiocytofibroma, the most diagnosed sarcoma type during the last two decades, has been dismembered. As for prognosis, the new UICC classification is effectively more discriminating in the definition of prognostic groups; but the usefullness of new biological or genetic markers remains to be assessed. Several breakthrough have taken place in the last years in the treatment of soft tissue sarcoma. Isolated limb perfusion with TNF, hyperthermia and melphalan have proven its efficacy, and is now an alternative to preoperative chemotherapy and/or radiotherapy for limb sparing treatment of the primary tumor site or to amputation. For systemic treatments, novel cytostatic drugs have been shown to be active in sarcomas, including ecteinascidine (ET743) and Glivec (STI571). This last drug has been shown to be remarkably active in c-kit+ stromal sarcoma of the gastro-intestinal tract. It can hopefully regarded as an example for targeted therapies, which may come with a better understanding of the molecular mechanisms triggered by the fundamental, specific genetic alterations shown in sarcoma.
Fetch PMID: 11847031

12 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
"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."
Fetch PMID: 9854502

13 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
Fetch PMID: 9181198

14 Cancer. 1997 Mar 15;79(6):1129-37.
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.
Gutman M, Inbar M, Lev-Shlush D, Abu-Abid S, Mozes M, Chaitchik S, Meller I, Klausner JM.
Department of Surgery, Sackler Faculty of Medicine, Tel Aviv University, Israel.

...Recombinant tumor necrosis factor-alpha (rTNF-alpha) is a highly potential antineoplastic agent. However, its systemic administration in humans has resulted in a life-threatening septic shock-like syndrome, and its use has been abandoned. The administration of high dose rTNF-alpha and melphalan via isolated limb perfusion (ILP) eliminated the systemic side effects and was shown to be very effective for metastatic melanoma confined to the limb. The purpose of the current study was to assess the role of rTNF-alpha and melphalan administered via ILP in patients with soft tissue sarcoma. Amputation is unavoidable in 10% of these patients despite aggressive conventional therapy. Limb preservation was the objective in this select group of candidates for amputation or mutilating surgery.
... During a 36-month period, 35 patients with high grade soft tissue sarcoma underwent 41 ILPs with high dose rTNF-alpha (3-4 mg) and melphalan (1-1.5 mg/kg). There were 21 males and 14 females. The mean age was 48 years (range, 14-80 years). Histologic subtypes included malignant fibrous histiocytoma, synovial, liposarcoma, malignant schwannoma, desmoid, clear cell, epithelioid, rhabdomyosarcoma, leiomyosarcoma, and unclassifiable. Twenty-one patients presented with recurrent and 14 with very extensive primary tumors. The tumors were located in the upper extremity in 8 patients and in the lower extremity in 27 patients. Twenty-five patients were candidates for amputation and 10 for extensive mutilating surgery.

ILP was performed via the corresponding vessels proximal to the tumor. Six patients with partial response (PR) insufficient to render them resectable underwent a second ILP. With the exception of 4 of 9 patients with multifocal lesions and 1 who refused surgery, resection of the residual tumor or tumor bed or limb was performed 6-8 weeks after ILP.

...Marked tumor softening occurred within 48 hours, and in tumors protruding through the skin hemorrhagic necrosis was evident within 24 hours. The overall response rate was 91%. Thirteen patients (37%) had a complete response and 19 (54%) had a PR; in 5 of these patients > 90% necrosis of the tumor occurred. In 3 patients (8.5%), only minimal regression was observed (stabilization of disease). The rate of limb sparing was 85% (29 of 34 patients).
...The combination of high dose rTNF-alpha and melphalan given via ILP appears to be effective in patients with advanced soft tissue sarcoma confined to the limb, achieving a high response rate and limb preservation.
Fetch PMID: 9070490

15 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. "
Fetch PMID: 8857912

16 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
Fetch PMID: 7731476

17 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.

...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). ... 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.
Fetch PMID: 7802575

18 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.
Fetch PMID: 7995421

19 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."
Fetch PMID: 8209941

20 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.
Fetch PMID: 6682645

compiled by doctordee
updated November 2003
Radiotherapy and Re-Irradiation

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

Search Pubmed for Extremity Re-Irradiation and Sarcoma
Search Pubmed for Re-Irradiation and Sarcoma
see also the Radiation page on this website, and the discussion there.

Annotated Medical Journal Articles
Re-Irradiation and Extremity LMS

1: Surg Oncol. 1999 Dec;8(4):219-21.
Resectable recurrent extremity sarcomas: is there a role for re-irradiation?
Pollock RE, Feig BW, Pisters PW.
Department of Surgical Oncology, M.D. Anderson Cancer Centre, University of Texas, Houston 77030, USA.
Fetch PMID: 11128837

2: Cancer J Sci Am. 1999 Jan-Feb;5(1):26-33.
Re-resection with brachytherapy for locally recurrent soft tissue sarcoma arising in a previously radiated field.
Pearlstone DB, Janjan NA, Feig BW, Yasko AW, Hunt KK, Pollock RE, Lawyer A, Horton J, Pisters PW.
Department of Surgical Oncology, University of Texas, M.D. Anderson Cancer Center, Houston 77030-4095, USA.

...The use of further radiotherapy among patients with soft tissue sarcoma that recurs in a previously irradiated area is controversial. Presented is a review of our 7-year experience with brachytherapy for recurrent soft tissue sarcoma.
... A retrospective review was performed of 26 patients who underwent perioperative brachytherapy between 1990 and 1997 for recurrent soft tissue sarcoma. In all cases, the sarcoma recurred within a previously irradiated field. ...The prescribed dose rate for the 192Ir wire ranged between 50 and 80 cGy an hour,... The anatomic locations treated included lower extremity (N = 10), upper extremity (N = 7), trunk (N = 7), and head and neck (N = 2).
...Total tumor extirpation, confirmed by negative frozen section margins, was accomplished in all cases. The mean dose of external-beam irradiation received before brachytherapy was 55.6 Gy +/- 1.8 Gy (range, 30.0 to 70.3 Gy). The mean dose of radiation prescribed at the implant procedure was 47.2 Gy +/- 1.6 Gy (range, 11.0 to 50.0 Gy). A tissue transfer flap was placed over the bed of resection in 13 cases.

Complications occurred in five patients including, three with wound breakdown, one with osteonecrosis, and with neuralgia. Operative intervention was required in four of the five patients with complications; ... Recurrence of disease occurred in 13 patients: nine local and four distant metastases. The median follow-up was 16 months (range, 2 to 73 months). The 5-year local recurrence-free, distant recurrence-free, disease-free, and overall survival rates after brachytherapy were 52%, 75%, 33%, and 52%, respectively.

Re-irradiation of recurrent soft tissue sarcoma by brachytherapy in conjunction with resection can be performed with acceptable complication rates. Local control can be achieved for the majority of patients who would otherwise require more radical surgical procedures.
Fetch PMID: 10188058

3: Radiother Oncol. 1996 Dec;41(3):209-14.
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.
...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).

... 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.
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.
Fetch PMID: 9027935

4: Br J Radiol. 1992 Feb;65(770):157-61.
Re-irradiation of soft-tissue sarcoma.
Graham JD, Robinson MH, Harmer CL.
Sarcoma Unit, Royal Marsden Hospital, London, UK.

Re-irradiation for local recurrence of malignancy after radical radiotherapy is of proven benefit at head and neck sites but has seldom been used elsewhere. This paper reports a series of 10 patients re-irradiated with external-beam techniques for local recurrence of soft-tissue sarcoma of the limb and limb girdle following initial limb conserving management with surgery and radiotherapy (dose range 33-60 Gy). Median survival was 14 months following re-treatment. Two cases received treatment with high-energy electrons and the rest with megavoltage photons. Five patients re-treated with radical intent (dose range 40-60 Gy) had a median survival of 36 months and median recurrence-free survival of 16 months. All five patients treated palliatively (dose range 12-50 Gy) have died, although two demonstrated local control until death. Acute reactions were not severe. Radionecrosis was seen in one patient who was re-irradiated twice (total dose 145 Gy) and subsequently required amputation. One other case required amputation for persistent local disease, but in the remaining eight, limb conservation was achieved. Re-irradiation of soft-tissue offers good local control and may avoid amputation.
Fetch PMID: 1371706

5: Int J Radiat Oncol Biol Phys. 1989 Sep;17(3):499-505.
Aggressive management of second primary tumors in survivors of hereditary retinoblastoma.
Smith LM, Donaldson SS, Egbert PR, Link MP, Bagshaw MA.
Department of Radiation Oncology, Stanford University Medical Center, CA 94305.

Survivors of hereditary retinoblastoma are at increased risk for the development of second primary tumors, most commonly osteosarcoma. Recent molecular genetic data demonstrate that a pleiotrophic effect of the retinoblastoma gene may be responsible for the development of these sarcomas. This report describes the incidence of second nonocular malignancies among 53 infants seen at Stanford University Medical Center who have been followed a median of 11.7 years. Of these, 42 initially had bilateral disease and eleven had unilateral disease. Of 53 infants, 50 received irradiation either as part of the initial therapy or as treatment for recurrent disease. The actuarial survival for the entire group is 67% at 30 year follow-up with a median survival of 79% at 11.7 years. Eight patients developed eleven second primary tumors. All occurred in the group having hereditary retinoblastoma. Eight were within the previously irradiated field and three were at distant sites. The second tumors included seven osteosarcomas, one angiosarcoma, one rhabdomyosarcoma, one malignant fibrous histiocytoma, and one unclassifiable round blue cell tumor. The actuarial incidence of the development of a second primary malignancy was 6% at 10 years, 19% at 20 years, and 38% at 30 years. The latent period from treatment of retinoblastoma to the diagnosis of malignancy ranged from 5.2 years to 36.2 years (median 16 years). An aggressive approach with combined modality therapy including radical resection, re-irradiation and/or chemotherapy was used to treat these second primary tumors in five of eight patients. In four of the five, there was no evidence of disease at 22-72 months following treatment. In the three patients who did not receive aggressive combined treatment, there were no survivors. These data confirm the previously reported risk of developing a second primary tumor among survivors with hereditary retinoblastoma. Careful long-term follow-up for this genetically susceptible group is essential for early detection and implementation of curative therapy.
Fetch PMID: 2777644

6: Int J Radiat Oncol Biol Phys. 1988 Jul;15(1):115-21.
Re-irradiation of locally recurrent tumors with fast neutrons.
Saroja KR, Hendrickson FR, Cohen L, Mansell J, Lennox A.
Midwest Institute for Neutron Therapy at Fermilab, Batavia, IL 60510.

Forty-six patients with locally recurrent disease were re-irradiated with fast neutrons at Fermilab. All had received prior radical radiation therapy either with or without surgery. Six were palliative. Forty patients treated with curative intent were analyzed for local response, survival, and complications. The overall response rate was 78% (31/40); 50% (20/40) had a complete local response. Ten of 16 patients (63%) with non-epidermoid carcinomas in the head and neck regions had complete response, whereas only nine of twenty patients (45%) with epidermoid carcinomas were complete responders. In a subset of 12 patients with salivary gland type tumors, 10 had a complete response (83%). Two of these 10 patients are alive beyond 5 years. Observed median survival for the forty patients was 9.3 months, and for complete responders 14.4 months. Observed median survival for partial responders was only 7.5 months. Four of six patients treated for palliation had significant subjective improvement. Significant morbidity, Grade III or greater (EORTC/RTOG scale), was seen in only 10 patients (25%), and this was found to depend directly on the total dose delivered. We conclude that neutron beam therapy can be used as a therapeutic modality for patients with recurrent tumors with an acceptable degree of morbidity.
Fetch PMID: 3391808

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