Strategies to decrease inequalities in cancer therapeutics, care and prevention: Proceedings on a conference organized by the Pontifical Academy of Sciences and the European Academy of Cancer Sciences, Vatican City, February 23-24, 2023.

Analyses of inequalities related to prevention and cancer therapeutics/care show disparities between countries with different economic standing, and within countries with high Gross Domestic Product. The development of basic technological and biological research provides clinical and prevention opportunities that make their implementation into healthcare systems more complex, mainly due to the growth of Personalized/Precision Cancer Medicine (PCM). Initiatives like the USA-Cancer Moonshot and the EU-Mission on Cancer and Europe's Beating Cancer Plan are initiated to boost cancer prevention and therapeutics/care innovation and to mitigate present inequalities. The conference organized by the Pontifical Academy of Sciences in collaboration with the European Academy of Cancer Sciences discussed the inequality problem, dependent on the economic status of a country, the increasing demands for infrastructure supportive of innovative research and its implementation in healthcare and prevention programs. Establishing translational research defined as a coherent cancer research continuum is still a challenge. Research has to cover the entire continuum from basic to outcomes research for clinical and prevention modalities. Comprehensive Cancer Centres (CCCs) are of critical importance for integrating research innovations to preclinical and clinical research, as for ensuring state-of-the-art patient care within healthcare systems. International collaborative networks between CCCs are necessary to reach the critical mass of infrastructures and patients for PCM research, and for introducing prevention modalities and new treatments effectively. Outcomes and health economics research are required to assess the cost-effectiveness of new interventions, currently a missing element in the research portfolio. Data sharing and critical mass are essential for innovative research to develop PCM. Despite advances in cancer research, cancer incidence and prevalence is growing. Making cancer research infrastructures accessible for all patients, considering the increasing inequalities, requires science policy actions incentivizing research aimed at prevention and cancer therapeutics/care with an increased focus on patients' needs and cost-effective healthcare.

European Groundshot-addressing Europe's cancer research challenges: a Lancet Oncology Commission.

Cancer research is a crucial pillar for countries to deliver more affordable, higher quality, and more equitable cancer care. Patients treated in research-active hospitals have better outcomes than patients who are not treated in these settings. However, cancer in Europe is at a crossroads. Cancer was already a leading cause of premature death before the COVID-19 pandemic, and the disastrous effects of the pandemic on early diagnosis and treatment will probably set back cancer outcomes in Europe by almost a decade. Recognising the pivotal importance of research not just to mitigate the pandemic today, but to build better European cancer services and systems for patients tomorrow, the Lancet Oncology European Groundshot Commission on cancer research brings together a wide range of experts, together with detailed new data on cancer research activity across Europe during the past 12 years. We have deployed this knowledge to help inform Europe's Beating Cancer Plan and the EU Cancer Mission, and to set out an evidence-driven, patient-centred cancer research roadmap for Europe. The high-resolution cancer research data we have generated show current activities, captured through different metrics, including by region, disease burden, research domain, and effect on outcomes. We have also included granular data on research collaboration, gender of researchers, and research funding. The inclusion of granular data has facilitated the identification of areas that are perhaps overemphasised in current cancer research in Europe, while also highlighting domains that are underserved. Our detailed data emphasise the need for more information-driven and data-driven cancer research strategies and planning going forward. A particular focus must be on central and eastern Europe, because our findings emphasise the widening gap in cancer research activity, and capacity and outcomes, compared with the rest of Europe. Citizens and patients, no matter where they are, must benefit from advances in cancer research. This Commission also highlights that the narrow focus on discovery science and biopharmaceutical research in Europe needs to be widened to include such areas as prevention and early diagnosis; treatment modalities such as radiotherapy and surgery; and a larger concentration on developing a research and innovation strategy for the 20 million Europeans living beyond a cancer diagnosis. Our data highlight the important role of comprehensive cancer centres in driving the European cancer research agenda. Crucial to a functioning cancer research strategy and its translation into patient benefit is the need for a greater emphasis on health policy and systems research, including implementation science, so that the innovative technological outputs from cancer research have a clear pathway to delivery. This European cancer research Commission has identified 12 key recommendations within a call to action to reimagine cancer research and its implementation in Europe. We hope this call to action will help to achieve our ambitious 70:35 target: 70% average 10-year survival for all European cancer patients by 2035.

The Porto European Cancer Research Summit 2021.

Key stakeholders from the cancer research continuum met in May 2021 at the European Cancer Research Summit in Porto to discuss priorities and specific action points required for the successful implementation of the European Cancer Mission and Europe's Beating Cancer Plan (EBCP). Speakers presented a unified view about the need to establish high-quality, networked infrastructures to decrease cancer incidence, increase the cure rate, improve patient's survival and quality of life, and deal with research and care inequalities across the European Union (EU). These infrastructures, featuring Comprehensive Cancer Centres (CCCs) as key components, will integrate care, prevention and research across the entire cancer continuum to support the development of personalized/precision cancer medicine in Europe. The three pillars of the recommended European infrastructures - namely translational research, clinical/prevention trials and outcomes research - were pondered at length. Speakers addressing the future needs of translational research focused on the prospects of multiomics assisted preclinical research, progress in Molecular and Digital Pathology, immunotherapy, liquid biopsy and science data. The clinical/prevention trial session presented the requirements for next-generation, multicentric trials entailing unified strategies for patient stratification, imaging, and biospecimen acquisition and storage. The third session highlighted the need for establishing outcomes research infrastructures to cover primary prevention, early detection, clinical effectiveness of innovations, health-related quality-of-life assessment, survivorship research and health economics. An important outcome of the Summit was the presentation of the Porto Declaration, which called for a collective and committed action throughout Europe to develop the cancer research infrastructures indispensable for fostering innovation and decreasing inequalities within and between member states. Moreover, the Summit guidelines will assist decision making in the context of a unique EU-wide cancer initiative that, if expertly implemented, will decrease the cancer death toll and improve the quality of life of those confronted with cancer, and this is carried out at an affordable cost.

Perioperative chemotherapy and regional hyperthermia for high-risk adult-type soft tissue sarcomas.

A group of patients with adult-type soft tissue sarcoma is at high risk of local recurrence and distant metastases. Age, tumour site, histological subtype, tumour size and grade have been identified as the most important independent adverse prognostic factors. Macroscopically complete tumour resection is considered as the mainstay of treatment with the addition of preoperative or postoperative radiotherapy for extremity or trunk localisation. Retroperitoneal localisation requires compartmental resection and is associated with a worse prognosis. Here, radiotherapy is of no proven value. Perioperative chemotherapy is considered to treat micrometastatic disease not detectable at the time of diagnosis. The neoadjuvant application gives the risk of distant metastasis the greatest importance as therapy is carried out at the earliest possible time, whereas adjuvant chemotherapy is delayed by surgery and the necessary wound healing. With reported response rates up to 30%, both the operability may be improved and the risk of intraoperative tumour cell dissemination may be reduced, resulting also in reduced local relapse rates. However, the potential risk of early tumour progression may counteract this benefit. Optimised strategies with multimodality approaches including chemotherapy, regional hyperthermia (RHT) and immunotherapeutic agents have been shown to improve survival in high-risk patients. Here, we focus on the data from available randomised studies investigating the use of perioperative chemotherapy in patients with high-risk adult-type soft tissue sarcoma, including the use of RHT for local enhancement of chemotherapy effect and immune induction.

Towards a cancer mission in Horizon Europe: recommendations.

A comprehensive translational cancer research approach focused on personalized and precision medicine, and covering the entire cancer research-care-prevention continuum has the potential to achieve in 2030 a 10-year cancer-specific survival for 75% of patients diagnosed in European Union (EU) member states with a well-developed healthcare system. Concerted actions across this continuum that spans from basic and preclinical research through clinical and prevention research to outcomes research, along with the establishment of interconnected high-quality infrastructures for translational research, clinical and prevention trials and outcomes research, will ensure that science-driven and social innovations benefit patients and individuals at risk across the EU. European infrastructures involving comprehensive cancer centres (CCCs) and CCC-like entities will provide researchers with access to the required critical mass of patients, biological materials and technological resources and can bridge research with healthcare systems. Here, we prioritize research areas to ensure a balanced research portfolio and provide recommendations for achieving key targets. Meeting these targets will require harmonization of EU and national priorities and policies, improved research coordination at the national, regional and EU level and increasingly efficient and flexible funding mechanisms. Long-term support by the EU and commitment of Member States to specialized schemes are also needed for the establishment and sustainability of trans-border infrastructures and networks. In addition to effectively engaging policymakers, all relevant stakeholders within the entire continuum should consensually inform policy through evidence-based advice.

Cancer Core Europe: A translational research infrastructure for a European mission on cancer.

Cancer Core Europe is a European legal alliance consisting of seven leading cancer centres - most of them Comprehensive Cancer Centres (CCCs) - with a single portal system to engage in various research projects with partners. Cancer Core Europe was established to create a sustainable, high-level, shared research infrastructure platform hosting research collaborations and task forces (data sharing, clinical trials, genomics, immunotherapy, imaging, education and training, and legal and ethical issues), with a controlled expansion agenda. Translational cancer research covers the cancer research continuum from basic to preclinical to early clinical, late clinical, and outcomes research. Basic-preclinical research serves as the 'engine' for early clinical research by bridging the early translational research gap and is the primary and current focus of the consortium as exemplified by the launching of the Basket of Baskets trial, Europe's largest precision cancer medicine trial. Inspired by the creation of Cancer Core Europe, the prevention community established Cancer Prevention Europe, a consortium of ten cancer prevention centres aimed at supporting the complete prevention research continuum. Presently, Cancer Core Europe and Cancer Prevention Europe are integrating therapeutics and prevention strategies to address in partnership the widening cancer problem. By providing innovative approaches for cancer research, links to healthcare systems, development of quality-assured multidisciplinary cancer care, and assessment of long-term outcomes, the virtual infrastructure will serve as a hub to connect and interact with other centres across Europe and beyond. Together, Cancer Core Europe and Cancer Prevention Europe are prepared to function as a central engine to tackle, in collaboration with various partners, a potential 'mission on cancer' addressing the cancer burden.

European Academy of Cancer Sciences - position paper.

The European Academy of Cancer Sciences (EACS) is an independent advisory body of well-recognised medical specialists and researchers striving to create a compelling interactive continuum of cancer research, from innovative basic research to implementation of state-of-the-art evidence-based cancer care and prevention. Achieving the above will entail bridging high-quality basic and preclinical cancer research to research on prevention, early detection and therapeutics as well as improving coordination of translational research efforts across Europe. The latter is expected to be expedited through quality assuring translational cancer research in Comprehensive Cancer Centres - entities that link research with the healthcare system - and networks of cancer research centres. Achieving a critical mass of expertise, resources and patients is crucial. Improving late translational research, which involves clinical studies to assess effectiveness, and added value for the health care is also a high priority. Both high-quality Big Data collections and the intelligent use of these data will promote innovation in cancer research and support outcomes research to assess clinical utility, quality of cancer care and long-term follow-up of treated patients. The EACS supports the mission-oriented approach recently proposed by the European Commission in Horizon Europe to deal with major challenges and would like to persuade the EU and its member states to formally launch a mission in cancer to boost and streamline the cancer research continuum in Europe. Building a coherent translational cancer research continuum with a focus on patients and individuals at risk will require, however, foresight as well as the extensive and continuous provision of evidence-based advice to inform policy.

Development and evaluation of an isolated limb infusion model for investigation of drug delivery kinetics to solid tumors by thermosensitive liposomes and hyperthermia.

The combined administration of thermosensitive liposomes (TSLs) and hyperthermia (HT) has been increasingly shown to be a powerful tool for the treatment of solid tumors. At present, it is hypothesized that the circulation of TSLs through the vasculature of a heated tumor results in the rapid release of the entrapped drug, followed by its uptake and distribution within the tumor microenvironment. However, simple questions on the transport kinetics of TSLs through the heated tumor and how much drug is retained upon passage of TSLs through the tumor microcirculation have not been investigated in an experimental setting to-date. The present work describes a novel methodology for investigating these parameters by isolated limb infusion (ILI), developed in a rat model of sarcoma. This approach was used to assess the efficacy of Doxorubicin (Dox) delivery by TSL in a heated (42°C) tumor following a single passage of TSL through the tumor vasculature. Analysis of the effluent post-ILI, whole-tumor histological sections, and tissue homogenates revealed that upon a single passage, Dox delivery by TSL at 42°C did not exceed delivery under conventional (i.e. free Dox) or physiological (i.e. TSL at 37°C, or normothermia; NT) conditions. In fact, mathematical modeling demonstrated that at least thirteen passages are required to obtain the intratumoral Dox levels typically achieved using TSL (i.e. ~5%ID/g). Overall, this work investigates TSL-based determinants for achieving efficacious drug delivery using a model of ILI in tumor-bearing rats and the results bear important implications for TSL disposition in vivo.

Comparing the therapeutic potential of thermosensitive liposomes and hyperthermia in two distinct subtypes of breast cancer.

Local drug delivery of Doxorubicin (Dox) with thermosensitive liposomes (TSL) and hyperthermia (HT) has shown preclinically to achieve high local drug concentrations with good therapeutic efficacy. Currently, this is clinically studied for treatment of chest wall recurrence of breast cancer, however with various outcomes. This study examines the potency of neoadjuvant TSL HT combination therapy in two orthotopic mouse models of human breast cancer, MDA-MB-231 and T-47D, which morphologically correlate to mesenchymal and epithelial phenotypes, respectively. Both cell lines showed improved in vitro chemosensitivity and Dox uptake at HT. Dox-loaded TSL (TSLDox) was stable in vitro in FBS, BALB/c-nu plasma and human plasma, although release of the drug at HT was incomplete for the latter two. Combination treatment with TSLDox and HT in vivo was significantly more effective against MDA-MB-231 tumors, whereas T-47D tumors showed no significant therapeutic response. Ex vivo investigation revealed a higher mean vessel density and poorly differentiated extracellular matrix (ECM) in MDA-MB-231 tumors relative to T-47D tumors. Although in vitro results of the TSLDox and HT treatment were favorable for both cell types, the therapeutic efficacy in vivo was remarkably different. The well-differentiated and slowly-growing T-47D tumors may provide a microenvironment that limits drug delivery to the target cell and therefore renders the therapy ineffective. Mesenchymal and invasive MDA-MB-231 tumors display higher vascularization and less mature ECM, significantly enhancing tumor response to TSLDox and HT treatment. These results yield insight into the efficacy of TSL treatment within different tumor microenvironments, and further advance our understanding of factors that contribute to heterogeneous therapeutic outcomes in clinical trials.

Investigation of Particle Accumulation, Chemosensitivity and Thermosensitivity for Effective Solid Tumor Therapy Using Thermosensitive Liposomes and Hyperthermia.

Doxorubicin (Dox) loaded thermosensitive liposomes (TSLs) have shown promising results for hyperthermia-induced local drug delivery to solid tumors. Typically, the tumor is heated to hyperthermic temperatures (41-42 °C), which induced intravascular drug release from TSLs within the tumor tissue leading to high local drug concentrations (1-step delivery protocol). Next to providing a trigger for drug release, hyperthermia (HT) has been shown to be cytotoxic to tumor tissue, to enhance chemosensitivity and to increase particle extravasation from the vasculature into the tumor interstitial space. The latter can be exploited for a 2-step delivery protocol, where HT is applied prior to i.v. TSL injection to enhance tumor uptake, and after 4 hours waiting time for a second time to induce drug release. In this study, we compare the 1- and 2-step delivery protocols and investigate which factors are of importance for a therapeutic response. In murine B16 melanoma and BFS-1 sarcoma cell lines, HT induced an enhanced Dox uptake in 2D and 3D models, resulting in enhanced chemosensitivity. In vivo, therapeutic efficacy studies were performed for both tumor models, showing a therapeutic response for only the 1-step delivery protocol. SPECT/CT imaging allowed quantification of the liposomal accumulation in both tumor models at physiological temperatures and after a HT treatment. A simple two compartment model was used to derive respective rates for liposomal uptake, washout and retention, showing that the B16 model has a twofold higher liposomal uptake compared to the BFS-1 tumor. HT increases uptake and retention of liposomes in both tumors models by the same factor of 1.66 maintaining the absolute differences between the two models. Histology showed that HT induced apoptosis, blood vessel integrity and interstitial structures are important factors for TSL accumulation in the investigated tumor types. However, modeling data indicated that the intraliposomal Dox fraction did not reach therapeutic relevant concentrations in the tumor tissue in a 2-step delivery protocol due to the leaking of the drug from its liposomal carrier providing an explanation for the observed lack of efficacy.

Cancer Core Europe: a consortium to address the cancer care-cancer research continuum challenge.

European cancer research for a transformative initiative by creating a consortium of six leading excellent comprehensive cancer centres that will work together to address the cancer care-cancer research continuum. Prerequisites for joint translational and clinical research programs are very demanding. These require the creation of a virtual single 'e-hospital' and a powerful translational platform, inter-compatible clinical molecular profiling laboratories with a robust underlying computational biology pipeline, standardised functional and molecular imaging, commonly agreed Standard Operating Procedures (SOPs) for liquid and tissue biopsy procurement, storage and processing, for molecular diagnostics, 'omics', functional genetics, immune-monitoring and other assessments. Importantly also it requires a culture of data collection and data storage that provides complete longitudinal data sets to allow for: effective data sharing and common database building, and to achieve a level of completeness of data that is required for conducting outcome research, taking into account our current understanding of cancers as communities of evolving clones. Cutting edge basic research and technology development serve as an important driving force for innovative translational and clinical studies. Given the excellent track records of the six participants in these areas, Cancer Core Europe will be able to support the full spectrum of research required to address the cancer research- cancer care continuum. Cancer Core Europe also constitutes a unique environment to train the next generation of talents in innovative translational and clinical oncology.

Regulation of CD4(+)NKG2D(+) Th1 cells in patients with metastatic melanoma treated with sorafenib: role of IL-15Rα and NKG2D triggering.

Beyond cancer-cell intrinsic factors, the immune status of the host has a prognostic impact on patients with cancer and influences the effects of conventional chemotherapies. Metastatic melanoma is intrinsically immunogenic, thereby facilitating the search for immune biomarkers of clinical responses to cytotoxic agents. Here, we show that a multi-tyrosine kinase inhibitor, sorafenib, upregulates interleukin (IL)-15Rα in vitro and in vivo in patients with melanoma, and in conjunction with natural killer (NK) group 2D (NKG2D) ligands, contributes to the Th1 polarization and accumulation of peripheral CD4(+)NKG2D(+) T cells. Hence, the increase of blood CD4(+)NKG2D(+) T cells after two cycles of sorafenib (combined with temozolomide) was associated with prolonged survival in a prospective phase I/II trial enrolling 63 patients with metastatic melanoma who did not receive vemurafenib nor immune checkpoint-blocking antibodies. In contrast, in metastatic melanoma patients treated with classical treatment modalities, this CD4(+)NKG2D(+) subset failed to correlate with prognosis. These findings indicate that sorafenib may be used as an "adjuvant" molecule capable of inducing or restoring IL-15Rα/IL-15 in tumors expressing MHC class I-related chain A/B (MICA/B) and on circulating monocytes of responding patients, hereby contributing to the bioactivity of NKG2D(+) Th1 cells.

A novel two-step mild hyperthermia for advanced liposomal chemotherapy.

Liposomal chemotherapy brings the advantage of minimizing systemic toxicity towards healthy organs and tissues, while has the drawbacks of limited nanoparticle accumulation and low drug bioavailability at targeted tumors. The aim of our study is to apply a clinically available mild hyperthermia (HT) treatment with thermosensitive liposomes (TSL) to tackle both issues. A two-step HT approach was combined with systemic administration of doxorubicin (Dox) TSL, in a first step to maximize nanoparticle accumulation in tumors and second step to actively trigger Dox release. The therapeutic activity of the two-step approach was compared to a one-step HT triggering intravascular Dox release from circulating TSL. Whereas the intravascular drug release approach requires fast releasing Dox-TSL (Dox-fTSL), the TSL formulation used in the two-step approach is fine-tuned to prolong Dox retention at physiological temperature in circulation, while releasing their drug content at mild HT at a slower rate (Dox-sTSL). Cytotoxicity assays show that a first-step HT at 41°C for 1h causes no drug resistance on murine BFS-1 sarcoma, human BLM melanoma cell lines and Human Umbilical Vein Endothelial Cells (HUVEC) towards subsequent exposure to Dox. However, HT sensitizes HUVEC towards Dox at higher concentrations (10-100µM). After 2h of intratumoral Dox-TSL accumulation, HT at 42°C for 1h was applied to trigger Dox release from Dox-sTSL. Quantification of intratumoral Dox accumulation revealed that the two-step HT approach increased TSL accumulation and Dox bioavailability reaching levels comparable to the intravascular release approach. The two-step HT in combination with Dox-sTSL delayed tumor growth for 12days compared to PBS group, however, was less effective compared to intravascular Dox release from Dox-fTSL using one-step HT. The two-step approach focuses on interstitial drug release upon mild HT, instead of intravascular drug release. This novel two-step approach represents an attractive alternative for the treatment of large and deep seated tumors, which are difficult to heat precisely and require loco-regional HT of the tumor area and accumulated Dox-sTSL therein to obtain a precise intratumoral drug delivery.

Mild hyperthermia triggered doxorubicin release from optimized stealth thermosensitive liposomes improves intratumoral drug delivery and efficacy.

Liposome mediated anticancer drug delivery has the advantage of reducing cytotoxicity in healthy tissues. However, undesired slow drug release impedes the therapeutic efficacy of clinically applied PEG-liposomal doxorubicin (Dox). The aim of this study is to combine stealth thermosensitive liposomes (TSL) and local mild hyperthermia (HT) to increase bioavailable Dox levels in tumors. Dox was encapsulated in stealth TSL (~80nm) with optimized PEG concentration in the membrane, and compared with lysolipid-based Dox-LTSL for in vitro stability, release kinetics, and in vivo tumor growth control. In vitro cytotoxicity of Dox-TSL against murine BFS-1 sarcoma and, human BLM melanoma cell lines and Human Umbilical Vein Endothelial Cells (HUVEC) under normothermia (37°C) and HT (42°C) was compared with non-encapsulated Dox. In vitro Dox uptake in nuclei was imaged in BLM and HUVEC. In vivo intravascular Dox release from TSL in BFS-1 tumors under local mild HT in dorsal skin flap window chamber models was captured by intravital confocal microscopy. Intravascular Dox-TSL release kinetics, penetration depth and interstitial Dox density were subjected to quantitative image analysis. Systemic Dox-TSL administration in combination with local mild HT on subcutaneous tumor growth control was compared to Dox-LTSL plus local mild HT. Dox-TSL was stable at 37°C, while released over 95% Dox within 1min in 90% serum at 42°C. Dox-TSL demonstrated efficient in vivo intratumoral Dox release under local mild HT, followed by significant Dox uptake by tumor and tumor vascular endothelial cells. Dox-TSL plus mild HT showed improved tumor growth control over Dox-LTSL plus mild HT. Survival after a single treatment of Dox-TSL plus mild HT was 67%, while survival after Dox-LTSL plus mild HT was 22%. This combination of Dox-TSL and local mild HT offers promising clinical opportunities to improve liposomal Dox delivery to solid tumors.

Improved intratumoral nanoparticle extravasation and penetration by mild hyperthermia.

Accumulation of nanoparticles in solid tumors depends on their extravasation. However, vascular permeability is very heterogeneous within a tumor and among different tumor types, hampering efficient delivery. Local hyperthermia at a tumor can improve nanoparticle delivery by increasing tumor vasculature permeability, perfusion and interstitial fluid flow. The aim of this study is to investigate hyperthermia conditions required to improve tumor vasculature permeability, subsequent liposome extravasation and interstitial penetration in 4 tumor models. Tumors are implanted in dorsal skin flap window chambers and observed for liposome (~85 nm) accumulation by intravital confocal microscopy. Local hyperthermia at 41°C for 30 min initiates liposome extravasation through permeable tumor vasculature in all 4 tumor models. A further increase in nanoparticle extravasation occurs while continuing heating to 1h, which is a clinically relevant duration. After hyperthermia, the tumor vasculature remains permeable for 8h. We visualize gaps in the endothelial lining of up to 10 µm induced by HT. Liposomes extravasate through these gaps and penetrate into the interstitial space to at least 27.5 µm in radius from the vessel walls. Whole body optical imaging confirms HT induced extravasation while liposome extravasation was absent at normothermia. In conclusion, a thermal dose of 41°C for 1h is effective to induce long-lasting permeable tumor vasculature for liposome extravasation and interstitial penetration. These findings hold promise for improved intratumoral drug delivery upon application of local mild hyperthermia prior to administration of nanoparticle-based drug delivery systems.

Is restaging with chest and abdominal CT scan after neoadjuvant chemoradiotherapy for locally advanced rectal cancer necessary?

BACKGROUND: There is no evidence regarding restaging of patients with locally advanced rectal cancer after a long course of neoadjuvant radiotherapy with or without chemotherapy. This study evaluated the value of restaging with chest and abdominal computed tomographic (CT) scan after radiotherapy. METHODS: Between January 2000 and December 2010, all newly diagnosed patients in our tertiary referral hospital, who underwent a long course of radiotherapy for locally advanced rectal cancer, were analyzed. Patients were only included if they had chest and abdominal imaging before and after radiotherapy treatment. RESULTS: A total of 153 patients who met the inclusion criteria and were treated with curative intent were included. A change in treatment strategy due to new findings on the CT scan after radiotherapy was observed in 18 (12%) of 153 patients. Twelve patients (8%) were spared rectal surgery due to progressive metastatic disease. CONCLUSIONS: Restaging with a chest and abdominal CT scan after radiotherapy for locally advanced rectal cancer is advisable because additional findings may alter the treatment strategy.

Hyperthermic pelvic perfusion with tumor necrosis factor-α for locally advanced cancers: encouraging results of a phase II study.

PURPOSE: To assess the efficacy of isolated pelvic perfusion (IPP) with tumor necrosis factor (TNF)-α and melphalan in patients with locally advanced cancers in the pelvic and groin area requiring mutilating surgery. METHODS: A total of 27 patients were enrolled (carcinoma, n = 17; sarcoma/melanoma, n = 4; and endocrine tumor, n = 6). They were candidates for exarticulation (n = 3) or exenteration (n = 11) or were judged unresectable (n = 13). In installing IPP, tourniquets were positioned around both thighs, and an inflated pressure suit was placed at a subthoracic position. Tumor necrosis factor-α (300 µg) was injected in the perfusate, followed 5 minutes later by melphalan at 1.5 mg/kg. After 30 minutes, the remaining drugs were washed out. Leakage was assessed with technetium Tc 99m radiolabeled human serum albumin, and a pharmacokinetic study was performed. Efficacy was based on the complete response rate observed on magnetic resonance imaging. RESULTS: Pelvic/systemic ratios of melphalan/TNF/technetium Tc 99m were 14.2/7/3.6. Responses on magnetic resonance imaging were as follows: 30% complete, 30% partial, 19% no change, and 15% progression. Two patients were not evaluable because they did not receive the treatment. Pre-IPP/post-IPP median percentage of necrosis on magnetic resonance imaging was 10%/70%. Median follow-up was 43 months. Median overall survival was 17 months. Twelve-month survival rate, disease-free survival, and local and metastatic recurrence rates were 67%, 30%, 57%, and 26%, respectively. CONCLUSIONS: Isolated pelvic perfusion with TNF-α compares favorably with historical data, as it was observed in limb perfusion and could provide a chance to translate its successful combination with chemotherapy into treatment of locally advanced pelvic cancers.

Delivering affordable cancer care in high-income countries.

The burden of cancer is growing, and the disease is becoming a major economic expenditure for all developed countries. In 2008, the worldwide cost of cancer due to premature death and disability (not including direct medical costs) was estimated to be US$895 billion. This is not simply due to an increase in absolute numbers, but also the rate of increase of expenditure on cancer. What are the drivers and solutions to the so-called cancer-cost curve in developed countries? How are we going to afford to deliver high quality and equitable care? Here, expert opinion from health-care professionals, policy makers, and cancer survivors has been gathered to address the barriers and solutions to delivering affordable cancer care. Although many of the drivers and themes are specific to a particular field-eg, the huge development costs for cancer medicines-there is strong concordance running through each contribution. Several drivers of cost, such as over-use, rapid expansion, and shortening life cycles of cancer technologies (such as medicines and imaging modalities), and the lack of suitable clinical research and integrated health economic studies, have converged with more defensive medical practice, a less informed regulatory system, a lack of evidence-based sociopolitical debate, and a declining degree of fairness for all patients with cancer. Urgent solutions range from re-engineering of the macroeconomic basis of cancer costs (eg, value-based approaches to bend the cost curve and allow cost-saving technologies), greater education of policy makers, and an informed and transparent regulatory system. A radical shift in cancer policy is also required. Political toleration of unfairness in access to affordable cancer treatment is unacceptable. The cancer profession and industry should take responsibility and not accept a substandard evidence base and an ethos of very small benefit at whatever cost; rather, we need delivery of fair prices and real value from new technologies.

Long-term results of tumor necrosis factor alpha- and melphalan-based isolated limb perfusion in locally advanced extremity soft tissue sarcomas.

PURPOSE: Because there is no survival benefit of amputation for extremity soft tissue sarcomas (STSs), limb-sparing surgery has become the gold standard. Tumor size reduction by induction therapy to render nonresectable tumors resectable or facilitate function-preserving surgery can be achieved by tumor necrosis factor α (TNF) -based and melphalan-based isolated limb perfusion (TM-ILP). This study reports the long-term results of 231 TM-ILPs for locally advanced extremity STS. PATIENTS AND METHODS: We analyzed 231 TM-ILPs in 208 consecutive patients (1991 to 2005), who were all candidates for functional or anatomic amputation for locally advanced extremity STS. All patients had a potential follow-up of up to 5 years. TM-ILP was performed under mild hyperthermic conditions with 1 to 4 mg of TNF and 10 to 13 mg/L of limb-volume melphalan. Almost all patients (85%) had intermediate- or high-grade tumors. RESULTS: The overall response rate (ORR) was 71% (complete response, 18%; partial response, 53%). Multifocal sarcomas had a significantly better ORR of 83% (P = .008). The local recurrence rate was 30% (n = 70); local recurrence rates were highest for multifocal tumors (54%; P = .001) and after previous radiotherapy (54%; P < .001). Five-year overall survival rate was 42%. Survival was poorest in patients with large tumors (P = .01) and with leiomyosarcomas (P < .001). Limb salvage rate was 81%. CONCLUSION: We demonstrated that TM-ILP results in a limb salvage rate of 81% in patients with locally advanced extremity STS who would otherwise have undergone amputation. Whenever an amputation is deemed necessary to obtain local control of an extremity STS, TM-ILP should be considered.