Isolated limb perfusion with actinomycin D and TNF-alpha results in improved tumour response in soft-tissue sarcoma-bearing rats but is accompanied by severe local toxicity

Previously we demonstrated that addition of Tumour Necrosis Factor-α to melphalan or doxorubicin in a so-called isolated limb perfusion results in synergistic antitumour responses of sarcomas in both animal models and patients. Yet, 20 to 30% of the treated tumours do not respond. Therefore agents that synergise with tumour necrosis factor alpha must be investigated. Actinomycin D is used in combination with melphalan in isolated limb perfusion in the treatment of patients with melanoma in-transit metastases and is well known to augment tumour cell sensitivity towards tumour necrosis factor alpha in vitro. Both agents are very toxic, which limits their systemic use. Their applicability may therefore be tested in the isolated limb perfusion setting, by which the tumours can be exposed to high concentrations in the absence of systemic exposure. To study the beneficial effect of the combination in vivo, BN-175 soft tissue sarcoma-bearing rats were perfused with various concentrations of actinomycin D and tumour necrosis factor alpha. When used alone the drugs had only little effect on the tumour. Only when actinomycin D and tumour necrosis factor alpha were combined a tumour response was achieved. However, these responses were accompanied by severe, dose limiting, local toxicity such as destruction of the muscle tissue and massive oedema. Our results show that isolated limb perfusion with actinomycin D in combination with tumour necrosis factor alpha leads to a synergistic anti-tumour response but also to idiosyncratic locoregional toxicity to the normal tissues. Actinomycin D, in combination with tumour necrosis factor alpha, should not be explored in the clinical setting because of this. The standard approach in the clinic remains isolated limb perfusion with tumour necrosis factor alpha in combination with melphalan

Tumour necrosis factor alpha increases melphalan concentration in tumour tissue after isolated limb perfusion

Several possible mechanisms for the synergistic anti-tumour effects between tumour necrosis factor alpha (TNF-α) and melphalan after isolated limb perfusion (ILP) have been presented. We found a significant sixfold increase in melphalan tumour tissue concentration after ILP when TNF-α was added to the perfusate, which provides a straightforward explanation for the observed synergism between melphalan and TNF-α in ILP. © 2000 Cancer Research Campaig

Low radiographic muscle density is associated with lower overall and disease-free survival in early-stage colorectal cancer patients

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Isolated Limb Perfusion with Melphalan and TNF-α in the Treatment of Extremity Sarcoma

Isolated limb perfusion (ILP) with chemotherapy alone has uniformly failed in the treatment of irresectable extremity soft tissue sarcomas. The addition of tumor necrosis factor-alpha (TNF-α) to this treatment approach contributed to a major step forward in the treatment of locally advanced extremity soft tissue sarcoma (STS). High response rates and limb salvage rates have been reported in multicenter trials, which combined ILP with TNF-α plus melphalan, which resulted in the approval of TNF-α for this indication in Europe in 1998. Subsequently a series of confirmatory single institution reports on the efficacy of the procedure have now been published. 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 high-grade soft tissue sarcomas. This induction therapy thus allows for resection of tumor remnants some 3 months after ILP and thus avoidance of limb amputation. TNF-α-based ILP is a well-established treatment to avoid amputations. It represents an important example of tumor vasculatory-modulating combination therapy and should be offered in large volume tertiary referral centers

TNF- α augments intratumoural concentrations of doxorubicin in TNF- α -based isolated limb perfusion in rat sarcoma models and enhances anti-tumour effects

We have shown previously that isolated limb perfusion (ILP) in sarcoma-bearing rats results in high response rates when melphalan is used in combination with tumour necrosis factor alpha (TNF-α). This is in line with observations in patients. Here we show that ILP with doxorubicin in combination with TNF-α has comparable effects in two different rat sarcoma tumour models. The addition of TNF-α exhibits a synergistic anti-tumour effect, resulting in regression of the tumour in 54% and 100% of the cases for the BN175-fibrosarcoma and the ROS-1 osteosarcoma respectively. The combination is shown to be mandatory for optimal tumour response. The effect of high dose TNF-α on the activity of cytotoxic agents in ILP is still unclear. We investigated possible modes by which TNF-α could modulate the activity of doxorubicin. In both tumour models increased accumulation of doxorubicin in tumour tissue was found: 3.1-fold in the BN175 and 1.8-fold in the ROS-1 sarcoma after ILP with doxorubicin combined with TNF-α in comparison with an ILP with doxorubicin alone. This increase in local drug concentration may explain the synergistic anti-tumour responses after ILP with the combination. In vitro TNF-α fails to augment drug uptake in tumour cells or to increase cytotoxicity of the drug. These findings make it unlikely that TNF-α directly modulates the activity of doxorubicin in vivo. As TNF-α by itself has no or only minimal effect on tumour growth, an increase in local concentrations of chemotherapeutic drugs might well be the main mechanism for the synergistic anti-tumour effects. © 2000 Cancer Research Campaig

Predictors of undergoing multivisceral resection, margin status and survival in Dutch patients with locally advanced colorectal cancer

Background: The aim of this nationwide observational study was to evaluate factors associated with multivisceral resection (MVR), margin status and overall survival in locally advanced colorectal cancer (CRC). Material and methods: Patients with (y)pT4, cM0 CRC between 2006 and 2017 were selected from the Netherlands Cancer Registry. Cox-proportional hazards modelling was used for survival analysis, stratified for T4a and T4b. Annual hospital volume cut-off was 75 for colon and 40 for rectal resections. Results: A total of 11.930 patients were included and 2410 patients (20.2%) underwent MVR. Factors associated with MVR for colon and rectal cancer besides cT4 category were more recent diagnosis (OR 3.61, CI 95% 3.06–4.25 (colon) and OR 2.72, CI 95% 1.82–4.08 (rectum)) and high hospital volume (OR 1.20, CI 95% 1.05–1.38 (colon) and OR 2.17, CI 95% 1.55–3.04 (rectum)). Patients ≥70 year were less likely to undergo MVR for colon cancer (OR 0.80, 95% CI 0.70–0.90). Risk factors for incomplete resection were cT4 (OR 3.08, CI 95% 2.35–4.04 (colon) and OR 1.82, CI 95% 1.13–2.94 (rectum)) and poor/undifferentiated tumors (OR 1.41, CI 95% 1.14–1.72 (colon) and OR 1.69, CI 95% 1.05–2.74 (rectum)). More recent diagnosis was independently associated with less incomplete resections in colon cancer (OR 0.58, CI 95% 0.40–0.76). Independent predictors of survival were age, resection margin, nodal status and adjuvant chemotherapy, but not MVR. Conclusion: Treatment of locally advanced CRC with MVR at population level was influenced by year of diagnosis and hospital volume. Margin status in colon cancer improved substantially over time.</p

Predictors of undergoing multivisceral resection, margin status and survival in Dutch patients with locally advanced colorectal cancer

Background: The aim of this nationwide observational study was to evaluate factors associated with multivisceral resection (MVR), margin status and overall survival in locally advanced colorectal cancer (CRC). Material and methods: Patients with (y)pT4, cM0 CRC between 2006 and 2017 were selected from the Netherlands Cancer Registry. Cox-proportional hazards modelling was used for survival analysis, stratified for T4a and T4b. Annual hospital volume cut-off was 75 for colon and 40 for rectal resections. Results: A total of 11.930 patients were included and 2410 patients (20.2%) underwent MVR. Factors associated with MVR for colon and rectal cancer besides cT4 category were more recent diagnosis (OR 3.61, CI 95% 3.06–4.25 (colon) and OR 2.72, CI 95% 1.82–4.08 (rectum)) and high hospital volume (OR 1.20, CI 95% 1.05–1.38 (colon) and OR 2.17, CI 95% 1.55–3.04 (rectum)). Patients ≥70 year were less likely to undergo MVR for colon cancer (OR 0.80, 95% CI 0.70–0.90). Risk factors for incomplete resection were cT4 (OR 3.08, CI 95% 2.35–4.04 (colon) and OR 1.82, CI 95% 1.13–2.94 (rectum)) and poor/undifferentiated tumors (OR 1.41, CI 95% 1.14–1.72 (colon) and OR 1.69, CI 95% 1.05–2.74 (rectum)). More recent diagnosis was independently associated with less incomplete resections in colon cancer (OR 0.58, CI 95% 0.40–0.76). Independent predictors of survival were age, resection margin, nodal status and adjuvant chemotherapy, but not MVR. Conclusion: Treatment of locally advanced CRC with MVR at population level was influenced by year of diagnosis and hospital volume. Margin status in colon cancer improved substantially over time.</p

Pre-to-post diagnosis weight trajectories in colorectal cancer patients with non-metastatic disease

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Cutaneous Melanoma and Sentinel Lymph Node Biopsy

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Risk of regional recurrence in triple-negative breast cancer patients: a Dutch cohort study

Triple-negative breast cancer is associated with early recurrence and low survival rates. Several trials investigate the safety of a more conservative approach of axillary treatment in clinically T1-2N0 breast cancer. Triple-negative breast cancer comprises only 15 % of newly diagnosed breast cancers, which might result in insufficient power for representative results for this subgroup. We aimed to provide a nationwide overview on the occurrence of (regional) recurrences in triple-negative breast cancer patients with a clinically T1-2N0 status. For this cohort study, 2548 women diagnosed between 2005 and 2008 with clinically T1-2N0 triple-negative breast cancer were selected from the Netherlands Cancer Registry. Follow-up data until 2014 were analyzed using Kaplan–Meier. Sentinel lymph node biopsy was performed in 2486 patients, and (completion) axillary lymph node dissection in 562 patients. Final pathologic nodal status was pN0 in 78.5 %, pN1mi in 4.5 %, pN1 in 12.3 %, pN2–3 in 3.6 %, and pNx in 1.1 %. During a follow-up of 5 years, regional recurrence occurred in 2.9 %, local recurrence in 4.2 % and distant recurrence in 12.2 %. Five-year disease-free survival was 78.7 %, distant disease-free survival 80.5 %, and 5-year overall survival 82.3 %. Triple-negative clinically T1-2N0 breast cancer patients rarely develop a regional recurrence. Their disease-free survival is more threatened by distant recurrence, affecting their overall survival. Consequently, it seems justified to include triple-negative breast cancer patients in randomized controlled trials investigating the safety of minimizing axillary staging and treatment