Isolated limb perfusion with hyperthermia and chemotherapy: predictive factors for regional toxicity

OBJECTIVE:

Isolated limb perfusion combined with melphalan is an accepted treatment for obtaining locoregional control in advanced melanoma of the extremities and other malignant neoplasias restricted to the limb. This study aims to examine the factors associated with toxicity caused by the regional method. We considered the technical aspects of severe complications associated with the procedure in an attempt to diminish the patient morbidity that occurs during the learning curve.

METHODS:

We conducted a retrospective analysis of the records of patients who underwent perfusion at the AC Camargo Hospital in São Paulo, Brazil between January 2000 and January 2009. The Wieberdink scale was applied to classify local toxicity and its relation to clinical and laboratory variables.

RESULTS:

Fifty-eight perfusions were performed in 55 patients. Most patients (86.2%) presented a toxicity level between I and III. Grade V toxicity was seen in five cases (8.6%), four of which occurred in the first 2 years. Creatine phosphokinase, an important predictive factor for toxicity, had an average value of 231.8 for toxicity grades I-III and 1286.2 for toxicity grades IV-V (p = 0.001). There was a relationship between the melphalan dose and toxicity, which was 77 mg (25 to 130 mg) for toxicity grades I-II and 93.5 mg (45 to 120 mg) for toxicity grades IV-V (p = 0.0204).

CONCLUSION:

It is possible to prevent the toxicity associated with melphalan by adjusting the dose according to the patient''s body weight (especially for women and obese patients) and the creatine phosphokinase values in the postoperative period.     

Management of Extremity Recurrences After Complete Responses to Isolated Limb Perfusion in Patients With Melanoma

Background: Despite high rates of complete responses (CRs) to isolated limb perfusion (ILP) for patients with in-transit melanoma (60% to 90%), extremity recurrences are common. We evaluated our experience with managing these recurrences to determine how best to treat these patients.Methods: Between April 1992 and April 1998, 72 patients experienced CRs after hyperthermic ILP using Melphalan, with (n = 46) or without (n = 26) tumor necrosis factor. Of these, 25 patients (35%) experienced initial recurrences in the extremities, and they form the basis of this study.Results: Three patients who underwent repeat ILP for treatment of their recurrences experienced a second CR and recurrence in the extremity (at 9, 15, and 16 months), allowing analysis of 28 cases. For 5 of 20 recurrences managed with excision, 2 of 6 managed with repeat ILP, and 0 of 2 managed with systemic treatment, the patient was free of disease at the last follow-up examination (median follow-up period, 11 months).Conclusions: Isolated extremity recurrences after CRs to ILP occurred in 35% of patients. Initially, these could be managed successfully by excision or repeat ILP for the majority of patients (92%). We recommend excision of small-volume recurrent disease, reserving repeat ILP for patients with increasing numbers of lesions or increasing rapidity of in-field recurrences.     

Isolated Limb Perfusion for Malignant Melanoma: Systematic Review on Effectiveness and Safety

Background.

Isolated limb perfusion (ILP) involves the administration of chemotherapy drugs directly into a limb involved by locoregional metastases. Unresectable locally advanced melanoma of the limbs represents one of the clinical settings in which ILP has demonstrated benefits.

Methods.

A systematic review of the literature on ILP for patients with unresectable locally advanced melanoma of the limbs was conducted. MEDLINE, EMBASE, and Cochrane database searches were conducted to identify studies fulfilling the following inclusion criteria: hyper- or normothermic ILP with melphalan with or without tumor necrosis factor (TNF) or other drugs providing valid data on clinical response, survival, or toxicity. To allocate levels of evidence and grades of recommendation the Scottish Intercollegiate Guidelines Network system was used.

Results.

Twenty-two studies including 2,018 ILPs were selected with a clear predominance of observational studies (90.90%) against experimental studies (9.10%). The median complete response rate to ILP was of 58.20%, with a median overall response rate of 90.35%. ILP with melphalan yielded a median complete response rate of 46.50%, against a 68.90% median complete response rate for melphalan plus TNF ILP. The median 5-year overall-survival rate was 36.50%, with a median overall survival interval of 36.70 months. The Wieberdink IV and V regional toxicity rates were 2.00% and 0.65%, respectively.

Conclusions.

ILP is effective in achieving clinical responses in patients with unresectable locally advanced melanoma of the limbs. The disease-free and overall survival rates provided by ILP are acceptable. ILP is safe, with a low incidence of severe regional and systemic toxicity.     

Isolated limb infusion chemotherapy with or without hemofiltration for recurrent limb melanoma

AIM: To better define the efficacy and the safety of intra-arterial infusion performed with or without hemofiltration for recurrent limb melanoma.METHODS: Patients with the following characteristics were included in the study: recurrent limb melanoma not indicated for surgical resection, measurable disease in the extremity, > 18 years, performances status (Eastern Cooperative Oncology Group ) was 0-1 and life expectancy of at least 6 mo. Twenty nine consecutive patients were enrolled in the study. Patients underwent fluoroscopic placement of angiographic arterial and venous catheters to infuse the drug in the artery [isolated limb infusion (ILI)], and to stop the out flow (venous). Melphalan was rapidly infused into the isolated limb via the arterial catheter after the inflation of venous balloon catheter. Then the circulation of the limb was completely blocked with a pneumatic cuff at the root of the limb. Haemofiltration (HF) was available only in the main center, and was performed with an extracorporeal perfusion system, in order to reduce high systemic toxic peaks of drug.RESULTS: Thirty seven ILI were done in 29 cases (31 ILI-HF and 6 ILI) between 2001 and 2014 at Ancona and Pesaro Hospitals, Italy. Clinical outcomes were monitored 30 d after treatment. Eleven patients (38%) received infusion of melphalan alone, 7 (24%) melphalan associated to mitomicin C and 7 (24%) melphalan associated to cisplatin, the remaining 4 were treated with cisplatin, melphalan and epirubicin or cisplatin and mitomicin C. The overall response rate was 66%, in particular, 3 patients (10%) were complete responders and 16 (56%) were partial responders; whereas 7 patients (24%) had stable disease, and 3 (10%) showed progressive disease. Limb toxicity was assessed adopting Wieberdink scale, with evidence of 90% of low grade (I and II) toxicity.CONCLUSION: ILI-HF and ILI are effective and safe treatments for recurrent non-resectable limb melanoma. They present evidence of favorable clinical benefit and is effective in delaying progression.     

Efficacy and Safety of Busulfan‐Based Conditioning Regimens for Multiple Myeloma

Multiple myeloma is a malignancy of B cells characterized by accumulation of abnormal plasma cells in the bone marrow. In the past 20 years, the use of high‐dose therapies and novel agents has resulted in significant and meaningful improvements in survival. Autologous stem cell transplantation (auto‐SCT) following a high‐dose melphalan‐conditioning regimen represents the standard of care for younger patients as well as older patients with a good performance status. A number of strategies have been proposed to improve the outcome of auto‐SCTs, including the incorporation of new agents such as thalidomide, lenalidomide, and bortezomib into the induction regimen administered before auto‐SCT; the administration of maintenance therapy after auto‐SCT; the incorporation of novel agents into chemotherapeutic regimens after transplantation as consolidation therapy; and the use of reduced‐intensity allogeneic transplantation after an initial autograft. Although these approaches have demonstrated some success in improving responses after auto‐SCT, none of these strategies are curative. An additional strategy to improve outcomes after auto‐SCT is to enhance the immediate pretransplant conditioning regimens by either increasing the dose of melphalan or by incorporating novel agents, such as busulfan. This literature review focuses on the efficacy and safety of busulfan‐based conditioning regimens for auto‐SCT in patients with multiple myeloma.     

Isolated hepatic perfusion with oxaliplatin combined with 100 mg melphalan in patients with metastases confined to the liver: A phase I study

Aim

To improve isolated hepatic perfusion (IHP), we performed a phase I dose-escalation study to determine the optimal oxaliplatin dose in combination with a fixed melphalan dose.

Methods

Between June 2007 and July 2008, 11 patients, comprising of 8 colorectal cancer and 3 uveal melanoma patients and all with isolated liver metastases, were treated with a one hour IHP with escalating doses of oxaliplatin combined with 100 mg melphalan. Samples of blood and perfusate were taken during IHP treatment for pharmacokinetic analysis of both drugs and patients were monitored for toxicity, response and survival.

Results

Dose limiting sinusoidal obstruction syndrome (SOS) occurred at 150 mg oxaliplatin. The areas under the concentration–time curves (AUC) of oxaliplatin at the maximal tolerated dose (MTD) of 100 mg oxaliplatin ranged from 11.9 mg/L h to 16.5 mg/L h. All 4 patients treated at the MTD showed progressive disease 3 months after IHP.

Conclusions

In view of similar and even higher doses of oxaliplatin applied in both systemic treatment and hepatic artery infusion (HAI), applying this dose in IHP is not expected to improve treatment results in patients with isolated hepatic metastases.     

硼替佐米联合化疗治疗10例多发性骨髓瘤

目的:观察硼替佐米联合化疗药物治疗初治、复发难治多发性骨髓瘤(MM)的疗效及安全性。方法:5例初治MM患者在每一疗程的第1、4、8、11天静脉注射硼替佐米0.7～1.3mg/m2,每3周为一疗程;每2个疗程(6周)的第1～4天,口服美法仑9mg/(m2·d)和泼尼松60mg/(m2·d);每例患者至少接受2～10个疗程。5例复发难治患者,在每3周1个疗程,第1、8天分别静脉注射硼替佐米3.5mg,或第1、4、8、11天1.0～1.3mg/m2。每次用硼替佐米前静脉注射地塞米松40mg;每例患者至少接受1～6个疗程。采用Blade标准评价疗效,按照美国国立癌症研究所(NCI)(第3版)判断不良反应。结果:中位随访8个月,5例初治患者中2例完全缓解(CR),1例接近完全缓解(nCR),1例部分缓解(PR),1例轻微反应(MR)。5例复发难治患者中,2例nCR,2例MR,1例无改变(NC)。主要不良反应包括胃肠道症状、不同程度的血小板减少、周围神经症状和乏力等。经对症治疗及调整用药剂量后均能改善。结论:硼替佐米对于初治或复发难治的MM患者,是一种可以耐受的、疗效确切的新的治疗选择。     

Mechanisms of enhancement of the antitumour activity of melphalan by the tumour-blood-flow inhibitor 5,6-dimethylxanthenone-4-acetic acid

 Several studies show that the antitumour activity of melphalan (MEL) and other alkylating agents can be enhanced by the selective inhibition of tumour blood flow, although the mechanism(s) underlying these interactions are unclear. 5,6-Dimethylxanthenone-4-acetic acid (DMXAA), a new anticancer agent currently in phase I clinical trial, inhibits blood flow in murine tumours. DMXAA increased the activity of MEL against the MDAH-MCa-4 mouse mammary tumour maximally when MEL was given about 2 h after DMXAA, without compromising the maximal dose of the alkylating agent that could be given. The plasma pharmacokinetics of MEL were unchanged by DMXAA pretreatment, but the area under the concentration-time curve (AUC) for the tumour increased by 33% as a result of decreasing clearance (consistent with falling tumour blood flow). However, inhibition of tumour blood flow also leads to microenvironmental changes (e.g. acidosis and hypoxia) that might influence sensitivity to MEL. The sensitivity of KHT cells (freshly isolated from tumours) to MEL in vitro was increased by lowering of either pH or oxygen concentration (pO₂), with an overall dose-modifying factor of 15 being recorded for aerobic cells at pH 7.4 versus hypoxic cells at pH 6.5. The cellular uptake of MEL by KHT cells was increased by 74% under hypoxia. Thus, This study was supported by the National Cancer Institute, USA (contract NO1-CM-47019), and the Health Research Council of New Zealand DMXAA appears to augment the antitumour activity of MEL through two different mechanisms, increased exposure (via decreased tumour clearance of MEL) and increased sensitivity resulting from changes to the tumour microenvironment, both of which result from inhibition of tumour blood flow. Received: 13 July 1996 / Acepted: 4 November 1996     

Evidence for increased intracellular transport of m-sarcolysine (alkylating moiety) when combined with two amino acid analogs (PTT-119)

Summary PTT-119 is an antineoplastic agent in which an alkylating moiety, m-sarcolysine, is linked to two amino acid analogs. Previous studies showed a higher in vitro cytotoxicity of PTT-119 when compared to free m-sarcolysine; the mechanisms of this enhanced activity are not completely understood. In this study we incubated peripheral blood cells from 8 chronic lymphocytic leukemia patients with both m-sarcolysine and equimolar concentrations of PTT-119, measuring the intracellular concentration of the alkylating moiety. We observed a significantly higher intracellular concentration of m-sarcolysine in cells incubated with the peptide-bound drug than with the free drug (58.3 ± 39.6 versus 4.4 ± 1.9 ng/10⁶ cells;P = 0.013). This observation could explain the higher cytotoxic activity of PTT-119 and the lack of cross-resistance with melphalan.