Think global, act local!

Though the foundation of interventional oncology lies in the treatment of hepatocellular carcinoma, needle-guided tumor ablation and trans-arterial therapies are steadily gaining ground as first line treatment of unresectable colorectal and non-colorectal liver metastases (figure), intrahepatic cholangiocarcinoma, small-size renal cell carcinomas, primary and secondary lung tumors, early stage prostate cancer, lymph node metastases and painful bone metastases. Dozens of ongoing studies investigate the potential value of thermal and non-thermal ablation to treat locally advanced pancreatic cancer, perihilar cholangiocarcinoma, head and neck malignancies and nowadays even pediatric retinoblastoma and primary brain tumors and the advances do not seem to be levelling off yet. Palliative pain management, draining obstructed or leaking bile ducts or urinary tracts, abscess drainage, trans-arterial coiling or stenting of actively bleeding arteries, for example following surgery, particle or glue embolisation of hemorrhagic tumors, future liver remnant augmentation using portal vein and nowadays hepatic vein embolisation, placement of filters to prevent pulmonary embolism and stents for stenosed caval veins exemplify the reason why interventional radiology has become one of the key players in the multidisciplinary care of oncology patients. Looking into an interventional oncologists’ mirror, the field still suffers from several teething problems, which can be summarized by an insufficient baseline vali- dation of its therapies. The rapidly changing field and the multiplicity of innovations have caused a lack of substantiation and harmonization regarding universal treatment protocols. Spinning off from vascular interventional radiology, where the authentication to recanalize blocked arteries and stop acute life threatening hemorrhages often is self-evident, referring physicians are not automatically convinced of added value for their oncology patients just by demonstrating our ability to eradicate malignancies. As a step towards adulthood, a large group of interventional oncologists from all over the world recently teamed-up with the French organization DATECAN (Definition for the Assessment of Time-to-event Endpoints in CANcer trials) to reach consensus regarding new research guidelines on how to collect, analyze and report results in interventional oncology research(1). The following sections on locoregional therapies for colorectal liver metastases, cholangiocarcinoma and pancreatic cancer further demonstrate that the community is more than ever dedicated to advance oncology research and multidisciplinary collaborations, as this is indisputably required to eventually culminate in higher cure rates, more long-term durable responses and eventually improved length and quality of life. Colorectal liver metastases Colorectal cancer is the third most common malignancy worldwide and the second most common cause of cancer-related deaths in developed countries. Although approximately half of all patients develop liver metastases in course of their disease, only 15–20% is considered eligible for curative intent surgical resection. For patients with an impaired general health status, history of extensive abdominal surgery, the presence of lesions with an unfavorable anatomical location or an insufficient future liver remnant to perform partial hepatectomy, thermal ablation nowadays is accepted as standard of care to eliminate small unresectable CRLM(2,3). With a remarkable difference in eight-year overall survival, 8.9% for the chemotherapy alone group vs. 35.9% for the radiofrequency plus chemotherapy group, the long-term results of the EORTC-CLOCC trial demonstrate that aggressive local treatment can considerably prolong survival and, in a subset of patients, even provide cure(4). Several short-term challenges for interventional oncology have become apparent. Should ablation replace surgery to become the standard of care for small-size colorectal liver metastases (≤ 3cm)(5)? Should we prefer thermal ablation over stereotactic radiotherapy for intermediate-size (3-5cm) unresectable tumors? What is the added value of locoregional therapies for multi-organ metastatic colorectal cancer and what is the exact role of trans-arterial radioembolisation for liver-dominant disease? The ongoing randomized controlled COLLISION trial (clinicaltrials.gov NCT03088 150; Dutch Colorectal Cancer Group), a two-arm, multicenter, phase III, single-blind prospective randomized controlled trial for patients with liver-only resectable CRLM up to 3cm to prove or disprove non-inferiority of thermal ablation compared to the current gold-standard: partial hep-atectomy(6). When compared to partial hep-atectomy, the interim results, presented at CIRSE 2021, unmistakably show a lower number and lower grade of complications (p = 0.001), a considerably shorter length of hospital stay (p=0.03) and a superior and near perfect local control, defined as the rate of metastases eventually completely eradicated allowing repeat treat- ments, with thermal ablation. Oncological outcomes such as overall survival (OS), dis- ease-free survival (DFS) and local tumor progression free survival (LTPFS) were not-significantly different. With a conditional probability to eventually prove non-inferiority (equality or superiority) of 88.3%, ablation may well, in the near future, replace surgery as the standard of care for small colorectal liver metastases (≤ 3 cm) given a lower toxicity profile, reduced costs and improved local control rates. The ongoing COLLISION-XL trial (clinical-trials.gov NCT04081168) compares stereat-actic ablative radiotherapy (SABR) with multi-antenna microwave ablation for unresectable intermediate-size (3.1-5cm) colorectal liver metastases and the future European COLLISION-RELAPSE project will hopefully shed light on the question whether to treat patients with recurring new colorectal liver metastases (within 12 months following the initial treatment) with upfront repeat local treatment or with neo-adjuvant systemic therapy first(7,8). Though the final results of the COLDFIRE-2 trial (clinicaltrials.gov NCT02082782), proved the ability of irreversible electroporation to eradicate peribiliary and perivascular metastases, presumed unresectable and unsuitable for thermal ablation (≤ 5 cm) in > 70 % of patients treated, sometimes with > 5 year disease-free survival, the complexity and operator-dependence of using pulsed electrical fields demands a direct comparison between SABR and IRE for this indication (COLD- FIRE-3)(9). The ORCHESTRA trial (clinical-trials.gov NCT01792934), which is about to close patient accrual, will provide us with the answer whether cytoreductive debulking of multi-organ metastatic colorectal cancer is beneficial over chemotherapy alone(10). The work of Salem and colleagues has recently climaxed with the first large-size prospective randomized controlled trial on chemotherapy plus Yttrium-90 selective internal radiotherapy (SIRT) as second-line treatment (EPOCH trial) to have reached its primary endpoint with an improved progression-free survival over 2nd-line chemotherapy alone(11). Pioneering efforts by Guiu and colleagues, have resulted in the wide-scale acceptance of liver venous deprivation (LVD), where not only the ipsilateral portal vein but also the hepatic vein is embolised with plugs and glue, to further enhance and accelerate future liver remnant growth prior to major hepatectomy(12). The international DRAGON-1 trial project has concluded its first phase and, confirming Guiu’s early results, have led to the initiation of the randomized controlled DRAGON-2 trial(13). Perihilar cholangiocarcinoma Patients with locally advanced perihilar cholangiocarcinoma are known to have a poor prognosis. Due to biliary obstruction, recurrent cholangitis and stent dysfunction are frequently observed. Though the role of interventional radiology in percutaneous transhepatic cholangiography-guided drainage (PTCD) is evident, the role of interventionists to percutaneously or trans-ductally ablate unresecatble disease has opened a new treatment paradigm. The unpublished but presented results of the ALPACA pilot study demonstrate that percutaneous CT-guided IRE for patients with locally advanced or recu rent PHC was feasible and associated with a promising 19 months median overall survival(14). However, even without mortality, the fact that fifty percent of patients experienced serious adverse events does imply that more research is necessary before this treatment method can be adopted in the international guidelines. Pancreatic adenocarcinoma Pancreatic adenocarcinoma is one of the most aggressive forms of cancer and pr jected to arise as the second leading cause of cancer-related deaths in Europe by 2030. Considering the poor survival, a lot of research from the last decade focused on combining systemic chemotherapy with local ablative therapies, such as radiofrequency ablation (RFA), microwave ablation (MWA), cryoablation, irreversible electroporation (IRE), stereotactic body radiation therapy (SBRT), iodine-125 seed implantation, high-intensity focused ultrasound (HIFU), and photodynamic therapy (PDT). The ablative techniques all share the mutual goal to achieve local tumor control, as this likely impacts quality-of-life and survival. The PANFIRE-1 and PANFIRE-2 trials have shown a potential survival benefit of 3- 6 months over chemotherapy alone, albeit at the cost of a fairly high-risk of serious adverse events(15-17). The ongoing PELICAN trial, which compares radiofrequency ablation plus chemotherapy to chemotherapy alone, the ongoing CROSS- FIRE trial (clinicaltrials.gov NCT02791503), comparing chemotherapy plus SABR to chemotherapy plus IRE and the DIRECT project (clinicaltrials.gov NCT03899649), comparing chemotherapy ± IRE will hope-fully provide further evidence for the rationale to add local ablation to systemic regimens(18). Interventional oncology meets immuno-oncology (IO2) Immune checkpoint-targeted monoclonal antibodies directed at Programmed Death Receptor 1 (PD-1), Programmed Death Lig-and 1 (PD-L1) and Cytotoxic T-Lymphocyte Associated Protein 4 (CTLA-4) are currently revolutionizing the prognosis of many cancers. The clarification why still the majority of patients and cancer types do not show a durable response is complex, multifactorial and not well understood, but a lack of antigen presentation and the absence of a certain lever to produce a potent systemic response seem to be largely subsidiary. Though ablative techniques are diverse in mechanism of cell death, they share one key-feature: creating in situ availability of destructed tumor material. Previous preclinical work has demonstrated that an ablated tumor can induce a systemic immune response which targets viable disease at distant sites. To eventually produce durable responses in human cancer patients, the addition of systemic and/or local forms of immunotherapy seems indispensable(19). Given the fact that currently >100 registered trials are currently combining a form of local ablative treatment with systemic immunotherapy and an even higher number are looking into the systemic (abscopal) effect of several forms of intratumoral immunotherapy to use the tumor as its own vaccine, immuno-oncology and interventional oncology seem bound to join forces. The success of this alleged synergy depends on the collective efforts of preclinical and clinical researchers to address fundamental questions regarding the global effect of acting local.