Dirk J. Grünhagen

One hundred consecutive isolated limb perfusions with TNF-alpha and melphalan in melanoma patients with multiple in-transit metastases

Objective:The aim of this study is to describe the experience with 100 TNF-based ILP for locally advanced melanoma and to determine prognostic factors for response, time to local progression, and survival. Methods:One hundred TNF-based ILPs were performed between 1991 and 2003 in 87 patients for whom local control by surgery of in-transit melanoma metastases was impossible. In total, 62 iliac, 33 femoral, and 5 axillary ILPs were performed in mild hyperthermic conditions with 2 to 4 mg of TNF and 10 to 13 mg of melphalan per liter of limb volume. Results:Overall response was 95%, with 69% complete response, 26% partial response, and 5% no change. Complete response rate differed significantly for patients with IIIA disease versus IIIAB and IV. Local and systemic toxicity was mild to moderate in almost all cases, with no treatment-related death and one treatment-related amputation. Five-year overall survival was 32%; local progression occurred in 55% after a median of 16 months. In complete response patients, 5-year survival was 42% with local progression in 52% at a median of 22 months. Response rate and survival were significantly influenced by stage of disease; (local progression free) survival was influenced by response rate. Conclusions:TNF-based ILP results in excellent response rates in this patient population with unfavorable characteristics. Response on ILP predicts outcome in patients and reflects aggressiveness of the tumor.

Technology insight: Utility of TNF-alpha-based isolated limb perfusion to avoid amputation of irresectable tumors of the extremities.

Isolated limb perfusion (ILP) with melphalan is effective in the treatment of small multiple melanoma intransit metastases and is utilized widely for this indication. The treatment is much less effective against bulky melanoma metastases and has uniformly failed in the treatment of irresectable extremity soft tissue sarcomas. The addition of tumor-necrosis factor-α (TNF-α) to this treatment approach has changed the situation dramatically. High response rates and limb-salvage rates have been reported in multicenter trials that combined ILP with TNF-α plus melphalan; these trials resulted in the approval of TNF-α for bulky melanoma metastases and soft tissue sarcomas in Europe in 1998. Subsequently, many doctors working in European centers have been trained, and a series of confirmatory reports from single institutions have now been published regarding the efficacy of the procedure. TNF-α has an early and a late effect; it enhances tumor-selective drug uptake during the perfusion, and plays an essential role in the subsequent selective destruction of the tumor vasculature. These effects result in a high response rate in bulky tumors, soft tissue sarcomas, bulky melanomas, and various other tumor types. This induction therapy therefore allows tumor remnants to be resected some 3 months after ILP thus avoiding limb amputation. TNF-α-based ILP is a well-established treatment that aims to avoid amputations regardless of the tumor size and type. It represents an important example of combination therapy that modulates the tumor vasculature and should be offered in high-volume tertiary referral centers.

Isolated Limb Perfusions With Tumor Necrosis Factor and Melphalan for Locally Recurrent Soft Tissue Sarcoma in Previously Irradiated Limbs

BackgroundRecurrent extremity soft tissue sarcoma (STS) in a previously operated and irradiated area can usually be managed only by amputation. Tumor necrosis factor (TNF)-α–based isolated limb perfusion (ILP) is an established alternative to achieve limb salvage but is assumed to require sufficient vasculature. Because radiotherapy is known to destroy vasculature, we wanted to evaluate retrospectively whether the outcome of ILP in patients with radiotherapy for their primary tumor nonetheless showed a benefit from TNF treatment.MethodsWe consulted a prospective database of TNF-based ILPs at the Erasmus MC–Daniel den Hoed Cancer Center in Rotterdam. Out of 342 TNF-based ILPs between 1991 and 2003, 30 ILPs were performed in 26 patients with recurrent STS in the irradiated field after prior surgery and radiotherapy. Eleven patients (42%) had multiple tumors (n = 2–20). All patients were candidates for amputation.ResultsWe observed 6 complete responses (20%), 15 partial responses (50%), no change in 8 patients (27%), and progressive disease in 1 patient (3%). The median duration of response was 16 months (range, 3–56 months) at a median follow-up of 22 months (range, 3–67 months). The local recurrence rate was 45% in patients with multiple tumors and 27% in patients with single tumors. Ten patients (35%) died of systemic metastases. Limb salvage was achieved in 17 patients (65%). Regional toxicity was limited and systemic toxicity minimal.ConclusionsTNF-based ILP can avoid amputations in most patients with recurrent extremity STS in a prior operated and irradiated field.

Efficacy of Repeat Isolated Limb Perfusions With Tumor Necrosis Factor α and Melphalan for Multiple In-Transit Metastases in Patients with Prior Isolated Limb Perfusion Failure

BackgroundIsolated limb perfusion (ILP) is an effective treatment modality for multiple in-transit melanoma metastases confined to the limb. Recurrences after ILP, however, occur in approximately 50% of patients and are a challenge for further treatment. The efficacy of repeat ILPs to prolong local control in this patient category is evaluated in this article.MethodsWe used a prospective database in a tertiary referral center. Out of 100 tumor necrosis factor (TNF)-based ILPs with TNF and melphalan (TM-ILPs) in melanoma patients between March 1991 and July 2003, 25 repeat ILP procedures were performed in 21 patients in whom prior ILP treatment failed. All patients had bulky and/or numerous lesions and were treated with mild hyperthermic TM-ILP by using 2 to 4 mg of TNF and 10 to 13 mg/L of limb volume for the leg and arm, respectively.ResultsThe complete response rate was 76%, a partial response occurred in 20%, and no change was recorded in 4%. There was no difference in the complete response rate or local toxicity between first and repeat perfusions. Local recurrence occurred in 72%; the median time to local progression was 14 months. The 5-year survival rate was 47%, which compares favorably with known survival rates of stage IIIA/AB patients. The median follow-up of the patients was 26 months.ConclusionsPatients who experience treatment failure after previous ILP treatment respond very well to repeat perfusion, and prolonged local control can thus be obtained. The subgroup of patients qualifying for repeat ILP represents a relatively favorable biological behavior of the melanoma.

Isolated Limb Perfusion With Tumor Necrosis Factor and Melphalan Prevents Amputation in Patients With Multiple Sarcomas in Arm or Leg

BackgroundTreatment for extremity soft tissue sarcoma (STS) has shifted in recent years from amputation to local wide excision combined with irradiation. For multiple sarcomas, this limb-sparing approach is often not possible. To avoid amputations, isolated limb perfusion (ILP) with tumor necrosis factor and melphalan is an attractive treatment option for patients with multiple extremity sarcomas.MethodsWe investigated a prospective database at a tertiary referral institute. From July 1991 to July 2003, out of 217 ILPs, 64 ILPs were performed for either multifocal primary sarcomas or multiple sarcoma recurrences in 53 patients. All ILPs were performed under mild hyperthermic conditions by using 1 to 4 mg of tumor necrosis factor and 10 to 13 mg/L of limb volume for leg and arm perfusions, respectively.ResultsThe overall response was 88%, with 42% complete response, 45% partial response, 11% no change, and 2% progressive disease. This response rate is significantly better than our experience in 153 locally advanced single-STS cases (88% vs. 69%). The toxicity of the procedure was mild to moderate in almost all cases; no treatment-related amputation had to be performed. The time to local recurrence was 29 months and differed significantly between multiple primary and multiple recurrent STS. The 5-year survival rate was 39%. Limb salvage was achieved in 45 (82%) of 55 treated limbs.ConclusionsIn a group of patients who are uniformly candidates for amputation, ILP can achieve limb salvage in approximately four out of five patients. Because this treatment option provides excellent local control, it should be considered before an amputation is planned.

Long-term outcome of isolated limb perfusion with tumour necrosis factor-α for patients with melanoma in-transit metastases.

The use of tumour necrosis factor (TNF) α in isolated limb perfusion (ILP) for in‐transit melanoma metastasis is not uniformly accepted. This article reports the long‐term results of adding TNF‐α to standard melphalan‐based ILP (TM‐ILP) for treatment of melanoma in‐transit metastases.

Favorable overall survival in stage III melanoma patients after adjuvant dendritic cell vaccination

Melanoma patients with regional metastatic disease are at high risk for recurrence and metastatic disease, despite radical lymph node dissection (RLND). We investigated the immunologic response and clinical outcome to adjuvant dendritic cell (DC) vaccination in melanoma patients with regional metastatic disease who underwent RLND with curative intent. In this retrospective study, 78 melanoma patients with regional lymph node metastasis who underwent RLND received autologous DCs loaded with gp100 and tyrosinase and were analyzed for functional tumor-specific T cell responses in skin-test infiltrating lymphocytes. The study shows that adjuvant DC vaccination in melanoma patients with regional lymph node metastasis is safe and induced functional tumor-specific T cell responses in 71% of the patients. The presence of functional tumor-specific T cells was correlated with a better 2-year overall survival (OS) rate. OS was significantly higher after adjuvant DC vaccination compared to 209 matched controls who underwent RLND without adjuvant DC vaccination, 63.6 mo vs. 31.0 mo (p = 0.018; hazard ratio 0.59; 95%CI 0.42–0.84). Five-year survival rate increased from 38% to 53% (p < 0.01). In summary, in melanoma patients with regional metastatic disease, who are at high risk for recurrence and metastatic disease after RLND, adjuvant DC vaccination is well tolerated. It induced functional tumor-specific immune responses in the majority of patients and these were related to clinical outcome. OS was significantly higher compared to matched controls. A randomized clinical trial is needed to prospectively validate the efficacy of DC vaccination in the adjuvant setting.

Isolated Limb Perfusion with TNF-α and Melphalan in Locally Advanced Soft Tissue Sarcomas of the Extremities

Limb-sparing surgery has become all the more important in soft tissue sarcoma (STS) of the extremities since we learned that amputation does not improve survival of these patients. In bulky tumours, however, preoperative strategies to reduce tumour size are then required. Isolated limb perfusion (ILP) with tumour necrosis factor (TNF) has been developed as a biochemotherapeutic therapy to act both on the tumour-associated vasculature and on the tumour itself. It has shown to be a very potent treatment modality, as in early reports response rates were around 80%. Limb salvage could then be achieved in a quite similar percentage. Many confirmatory studies have been performed since, with consistent results even in patients with multiple tumours, after extensive radiotherapy or with metastatic disease, all at the cost of very limited toxicity. This chapter gives an overview of the ILP studies performed in patients with soft tissue limb sarcoma, discusses the mechanism of TNF-mediated vasculotoxic effects on tumour vasculature, and places TNF-based ILP in the multimodality treatment of these patients with extensive STS of the extremities.

GITR engagement in combination with CTLA-4 blockade completely abrogates immunosuppression mediated by human liver tumor-derived regulatory T cells ex vivo

In liver cancer tumor-infiltrating regulatory T cells (Ti-Treg) are potent suppressors of tumor-specific T-cell responses and express high levels of the Treg-associated molecules cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and glucocorticoid-induced tumor necrosis factor receptor (GITR). In this study, we have evaluated the capacity of GITR-ligation, CTLA-4-blockade and a combination of both treatments to alleviate immunosuppression mediated by Ti-Treg. Using ex vivo isolated cells from individuals with hepatocellular carcinoma (HCC) or liver metastases from colorectal cancer (LM-CRC) we show that treatment with a soluble form of the natural ligand of GITR (GITRL), or with blocking antibodies to CTLA-4, reduces the suppression mediated by human liver tumor-infiltrating CD4+Foxp3+ Treg, thereby restoring proliferation and cytokine production by effector T cells. Importantly, combined treatment with low doses of both molecules exhibited stronger recovery of T cell function compared with either treatment alone. Our data suggest that in patients with primary and secondary liver cancer both GITR-ligation and anti-CTLA-4 mAb can improve the antitumor immunity by abrogating Ti-Treg mediated suppression.

Isolated limb perfusion using tumour necrosis factor α and melphalan in patients with advanced aggressive fibromatosis

Aggressive fibromatoses (desmoid tumours) may be locally aggressive, but do not metastasize. Although a conservative approach is advocated for most patients, pain and functional impairment are indications for active treatment. Tumour necrosis factor (TNF) α and melphalan‐based isolated limb perfusion (TM‐ILP) is a limb‐saving treatment modality for soft tissue tumours. This study reports the results of TM‐ILP treatment in patients with aggressive fibromatosis.