Author:

Lorenzo Monfardini

Abstract

Interventional oncology therapies use image-guided, minimally invasive procedures to target cancer deep inside the body. Here the Author proposes in the first line testimonials provided by some key players in this field to give their point of view about the most thrilling, challenging and difficult moments they had at that time, the main purpose being their witness to be inspiring for younger generations. Then information on the progressive development of this new discipline is provided showing how Interventional Oncology is an emerging pillar of cancer care.

If for hepatocellular carcinoma the role of percutaneous ablation has been recognized since more than two decades, for other malignancies interventional techniques struggled to take place in the oncology care scenario. Since 2016 however, ESMO guidelines for colon adenocarcinoma were proposed the so called “loco regional toolbox” as a useful instrument for the decision-making process in patients with oligo metastatic disease. For the first time Surgery and Radiotherapeutics techniques were at the same level with Percutaneous Ablation. Even if other guidelines and several consensus papers for other neoplastic conditions have recently included interventional techniques, there is still much to be done in the future.

Introduction

Interventional Oncology is a subspecialty of Interventional Radiology focused on treating patients with cancer using minimally invasive, image-guided procedures employing X-ray, ultrasound, computed tomography (CT) or magnetic resonance imaging (MRI) to help guide miniaturized instruments (e.g. biopsy needles, ablation electrodes, intravascular catheters) to allow targeted and precise treatment of solid tumours. The Interventional Oncology Road Map for the future has been clearly pointed out with a precise time deadline: “the defining characteristic of interventional oncology in 2023 will be a well-developed clinical and research infrastructure that enables greater integration of interventional oncology procedures into standard practice.” (2- Elsayed M 2023). Such an ambitious challenge is possible thanks to the growing level of technology but mostly to the commitment of scientist and researchers. But if it’s true that “to build up a future you have to know the past”, an overlook on the early growing era of interventional oncology should be of great value for the interested researchers and physicians. The main purpose of the present article is to make available the point of view of committed scientists at the time they were working on novel technologies not yet validated. The troubles faced, the failures, the solution strategies and the accomplishments are recalled and described by some of the main actors with the intent to help and motivate the next step toward the future. Then the information on this initial development mainly describing liver and kidney cancer loco regional treatments, will be followed by some spots about the progressive development of other treatment modalities for different oncological conditions

How it all started

The Author witnessed some the initial developments of Interventional Oncology and recalls the main changes he remembers since the first years of fellowship. He distinctly remembers that in late 90’s ablation was not yet an established technique. He attended since 1995 as a student at National Cancer Institute of Milan the Interventional Radiology Department: liver transplantation was at the very beginning and alcoholisation was considered the gold standard for hepatocellular carcinoma (HCC.) The most significant turning point occurred after a couple of years during his fellowship in the late 90’s: a cluster of milestone papers were published on “Radiology”, the most prestigious Journal in the field. The one with the heaviest impact on clinical practice written by Tito Livraghi with the co- Authorship among others of Luigi Solbiati, Nahum Goldberg and Scott Gazelle stated “liver ablation was better than ethanol injection (alcoholisation) in the treatment of small hepatocellular carcinoma” and “Radiofrequency Ablation (RF) is the treatment of choice for most patients with HCC” (4- Livraghi T 1999). After this achievement the most prestigious International study group for hepatocellular carcinoma, BCLC (Barcelona Clinic Liver Cancer) group recognized liver ablation as first choice treatment for very early and early HCC, even over surgery, and ablation continued deeply to evolve even for the treatment of hepatic metastases (5- Reig M 2022).

Fig. 1: from the left side respectively Scott Gazelle, Nahum Goldberg, Luigi Solbiati and Tito Livraghi

The main precursors and founders of Interventional Oncology can be considered Luigi Solbiati, Tito Livraghi, Nahum Goldberg and Scott Gazelle (Fig 1) . The first preliminary experience was carried out by Luigi Solbiati in a case of Parathyroid adenoma, while Tito Livraghi, in collaboration with Luigi Solbiati from 1983 to 1993 begun to treat with percutaneous ethanol injection patients with hepatocellular carcinomas. Nahum Goldberg with Scott Gazelle developed a new RF machine with cool-tip electrodes that allowed to achieve larger volumes of coagulative necrosis .

After many years, in 2024 the Author had the opportunity to contact Luigi Solbiati to have his valuable opinion and guidance on a two papers related to fusion imaging and ablation. To revisit the initial history of Interventional Oncology he took the chance at a second time of posing to him some of the most compelling questions on the story of his work with Tito Livraghi, Nahum Goldberg and Scott Gazelle back in the 90’s If in hindsight it’s obvious our key players were on the right path, to recall how was the team work, the trouble faced and the way they followed can better explain the steps leading to their big achievement. But also they can be in the position now, in view of their past experience, to have a critical vision of the present and offer a perspective on the future of Interventional Oncology.

Some questions to one of the Pioniers

Taking the opportunity of directly contacting one of the forerunners some questions on the past have been posed by the Author to Luigi Solbiati, who provided written responses as here reported.

1. The first question the Autor had in mind was about radiofrequency: “Why was such a complex energy source chosen instead of the simpler ethanol injection?”

Luigi Solbiati reminded me that from the original first treatment of a large inoperable parathyroid adenoma through percutaneous US-guided injection of absolute ethanol, successfully performed by his group in 1982, the very first percutaneous “treatment without removal” of solid tumor ever performed worldwide, from 1983 to 1993 Percutaneous Ethanol Injection (PEI) was the only local treatment of hepatocellular carcinomas (HCCs), initially carried out by Livraghi and his group. The decision to inject alcohol was based on its effects on tissues: immediate dehydration of cytoplasmic proteins with consequent coagulation necrosis, followed by fibrosis and necrosis of endothelial cells, and platelet aggregation with thrombosis of small vessels followed by tissue ischemia. Additionally, the capsule, present in most HCCs, allows ethanol, slowly injected, to remain inside the nodule, avoiding diffusion into perilesional tissues and the softer consistency of HCCS compared to the surrounding hard cirrhotic liver allows ethanol to easily and uniformly diffuse inside the neoplastic tissue. The substantial comparability of survival between PEI and resection for very early HCCs was clearly demonstrated. In the meantime, in the first 90’s the efficacy of PEI for HCC was demonstrated, associated with other advantages, like repeatability and lower mortality and major complication rates. However, the most significant limitations of PEI were the high local tumor progression rate for HCCs larger than 2-2.5 cm, the inability to treat HCC satellites because ethanol had to remain inside the lesions to be effective (ablative margins not achievable) and to treat hepatic metastases, lesions usually hypovascular and non-capsulated.

At the beginning of the 90’s, the very first modalities for local, image-guided treatment of liver neoplasms, interstitial laser photocoagulation (ILP) and radiofrequency (RF) were developed and tested. ILP was rapidly abandoned due to the small volumes of necrosis achievable with single fibers and consequently the need to use multiple fibers that made ablations very time consuming and poorly effective, while since the very beginning RF seemed able to provide better results. The initial studies in animals and in human patients were performed and published by John McGahan in Sacramento (USA) and Sandro Rossi in Piacenza, but the volumes of necrosis achievable were still small. In 1994 Solbiati and Livraghi met at the RSNA (Radiological Society of North America) in Chicago. Nahum Goldberg and Scott Gazelle from the Massachusetts General Hospital in Boston who had successfully performed accurate studies on animals using a new RF machine with cool-tip electrodes that allowed to achieve larger volumes of coagulative necrosis compared to the first systems. They could not treat human patients in USA yet, due to the lack of approval from the Food and Drug Administration and, based on their results, we accepted to test this new system in Italy and the very first ablations with cool-tip RF for HCCs and colorectal metastases were performed at Busto Arsizio and Vimercate in 1995 and 1996, respectively.

2. The following issue was: “What made you think this could be potentially more effective than ethanol or laser? Why dedicate time to this “unconventional idea”?”

The answer was that for the treatment of HCC, RFA showed better local efficacy and required fewer treatment sessions compared to PEI. Particularly, in HCCs in the range of 3 cm in size, RFA obtained complete ablation in nearly the totality of cases, plus an additional 0.5-1.0 cm thick safety margin, thus significantly reducing the number of LTPs on the follow-up. Consequently, PEI and ILP were almost completely abandoned. In addition, RFA made feasible also the treatment of hepatic metastases, mostly from colorectal carcinoma, that was not possible with PEI and particularly difficult with ILP. When, in 2008-2009, needle-like microwave applicators (“antennas”) became clinically available, High-power Microwave Ablation (MWA) became an important “competitor” of RFA for percutaneous treatment of liver malignancies, with some advantages over RFA, mostly the capability of achieving larger ablation volumes in shorter operative times, and significantly less heat sink effect (with better outcomes in the treatment of perivascular tumors), but also some disadvantages, like the higher complication rate and the higher risks in the ablation of peribiliary tumors. Nowadays, the field of local treatment of hepatic malignancies is becoming more and more complex, due to the introduction of new techniques (e.g. the stereotactic RFA) and new therapies associated to RFA and MWA (irreversible electroporation, transarterial chemoembolization, immunotherapy, histotripsy, etc ..).

3. A further question was on the colleagues that somehow shared this important effort: “Who were they and how much the “group” was an added value?”

At the beginning of his experience with PEI Luigi Solbiati had the great luck to work with a famous cytopathologist, Prof. Ravetto, who greatly helped to develop the technique of ultrasound-guided percutaneous procedures (biopsy, ethanol injection). Being PEI a relatively safe procedure, any significant opposition in my Hospital was evident, while strong discussions with surgeons took place during Meetings and Congresses, because for some years they did not accept this local treatment as alternative to surgery. When Solbiati’s experience with RFA started, they had to form a group including hepatologists, gastroenterologists, oncologists and surgeons and this group had a fundamental importance for the selection of patients candidate to ablation, pre-treatment evaluation, assistance in the immediate follow-up and management of possible complications, but the most important achievement was the creation of a small group of interventional radiologists ( Tiziana Ierace at first), anesthesiologists, technicians and nurses who assisted him for many years.

4. Then: “What do You think could have been the hardest difficulties and troubles from a technical and practical point of view during this kind of full-commitment work?”

Particularly following the start of the RFA program, there were major difficulties and troubles in Professor Solbiati’s Hospital. Being a General Hospital of a relatively small town, there were problems to create a section of the Department of Radiology dedicated only to interventional procedures, to obtain the availability of beds for patients’ hospitalization and of anesthesiologists particularly dedicated to interventional procedures, to balance costs of devices and reimbursements from the National Health Service, etc. Outside Hospital, for some years the major difficulties and troubles were to create and progressively increase the level of credibility of scientific institutions and single colleagues about the extremely favourable outcomes of percutaneous ablation of hepatic neoplasms. Only in 2000 the very first guidelines on the treatment of HCC that included RFA were produced, while for colorectal metastases the first guidelines with Prof Solbiati’s important contribution were published only in 2015.

5. The next question was: “To what extent could Professor Solbiati foresee the impact he would have on Interventional Oncology at that time?”

He thinks that it was not easy to predict the level of development and diffusion of ablative procedures at the beginning of this experience (that is actually the beginning of this therapy worldwide!). The dream to make “Interventional Oncology” the fourth pillar of Oncology went on for many years, but finally it was successful.

6. Still: “What event or realisation of these years would he describe as the greatest achievement?”

There were many great technical “realizations” during the last 40 years and it is not easy to select “the greatest achievement”. In the field of image guidance, is possible to indicate fusion imaging as the most important achievement, in the field of assessment of outcomes the software for precise definition of ablative margins is extremely valuable, and in the field of modalities of treatment I would indicate combination treatments as the most relevant.

7. And looking at the past perspective on the future development of Interventional Oncology: “Is it anything different that Professor Solbiati would have done during those years.”

Here his reply: “I should honestly say that I would not have done anything different from what I actually did. Particularly, for years I took great care to the teaching of ablative procedures to hundreds of Italian and foreign physicians. Having been able to gather more than 400 interventional radiologists and clinicians in approximately 30 years in a Hospital of a relatively small town is something I am really very proud of”

8. While concerning the acceptance of this new treatment approach by the other clinical oncologists the question was: “Were there any challenges in collaborating with medical oncologists or surgeons?”

Professor Solbiati replies that in his personal experience he spent a long time before being able to persuade oncologists that in some situations of hepatic metastases ablation should precede chemotherapy and not follow it, if needed. When he moved to Humanitas Clinical and Research Hospital, the existence of a multidisciplinary group facilitated the relationship with oncologists, even though based on the discussion of single cases rather than on protocols of treatment. As regards to surgeons, the first years of ablation activity were very difficult because they did not accept to suggest ablation even in cases for which this was the ideal treatment. Later and progressively, relationship with surgeons improved, also thanks to the development (with my scientific contribution) of international protocols, like the BCLC for HCC, that included ablation among the different therapies. In the field of metastases, the debate with surgeons is still going on, even if in selected cases they recognize the role of ablation.

9. Finally: “What about inspiring young apprentices wishing to follow Professor Solbiati’s career?”

He feels that the work of interventional radiologists/oncologists is completely different from that of diagnostic radiologists who have usually (unfortunately) more relations with images and machines than with patients. If a young fellow is really interested to develop human relationships with patients during the phase of treatment but mostly after the treatment, during the follow-up, the interventional activity is the one he/she should perform.

Interventional Oncology is a lot more than liver ablation

The results reached by Luigi Solbiati in liver ablation are remarkable. Yet there are organs in which there is still a long way to go: the most critical is renal ablation. Despite the largest scientific evidence (1 Chlorogiannis DD 2024) about the same clinical efficacy compared to the lower invasiveness, guidelines for small renal cancers suggest it upfront only in very selected frail elderly patients. The first evidences for his role even in metastatic renal cancers are available (6 Scheipner L 2024), but more often outside comprehensive cancer centres ablation is only suggested not by urologist but when anaesthesiologist disclose a risk far too high for surgery.

At present ablation is used in several other neoplastic conditions such as lung for oligo metastatic patients generally in patients with previous surgery or radiation therapy as parenchyma sparing technique. Also for palliative treatment of soft tissue or bone lesions in case of pain, ablation with cold energy “crioablation” provides relief in case of radiation therapy failure.

A further technique very effective in controlling cancer growth is vascular occlusion. Embolisation is defined as the vessel occlusion by means of dedicated devices released in the bloodstream by means of small catheters entering by specific vascular access entry-point. Devices available for cancer vessels occlusions are usually small particles capable to penetrate deeper into micro vascular cancer network inducing necrosis. Even if such a technology is available since more than 4 decades, his most recent development for liver cancer allow such a particle to bind both chemotherapeutic drugs or radioactive substances (respectively chemo and radio embolization). Their injection in the tumour feeding vessel induce necrosis of liver lesions.

Not to be missed is also the contribution provided since the mid -80s-90s by Interventional Oncologists to Surgeons, Radiotherapists and Medical Oncologists for the interdisciplinary management of cancer patients.

Their ability to reach deep organs with a minimal discomfort to the patients for diagnostic biopsies has been invaluable. The option to use imaging guidance and fine needles to reach deeper organs allows to obtain reliable cytological/histological diagnoses.

Conclusions

There is a clear path for research and clinical application in the field of Interventional Oncology. The curiosity and interest sparked by mentors in this fascinating discipline will undoubtedly inspire young physicians, fellows and medical students leading to valuable contributions to its future development.

References

1. Chlorogiannis DD, Kratiras Z, Efthymiou E, Moulavasilis N, Kelekis N, Chrisofos M, Stravodimos K, Filippiadis DK. Percutaneous Microwave Ablation Versus Robot-Assisted Partial Nephrectomy for Stage I Renal Cell Carcinoma: A Propensity-Matched Cohort Study Focusing Upon Long-Term Follow-Up of Oncologic Outcomes. Cardiovasc Intervent Radiol. 2024 May;47(5):573-582. doi: 10.1007/s00270-024-03695-z. Epub 2024 Apr 1. PMID: 38561521.

2. Elsayed M, Solomon SB. Interventional Oncology: 2043 and Beyond. Radiology. 2023 Jul;308(1):e230139. doi: 10.1148/radiol.230139. PMID: 37432086.

3. Gillams A, Goldberg N, Ahmed M, Bale R, Breen D, Callstrom M, Chen MH, Choi BI, de Baere T, Dupuy D, Gangi A, Gervais D, Helmberger T, Jung EM, Lee F, Lencioni R, Liang P, Livraghi T, Lu D, Meloni F, Pereira P, Piscaglia F, Rhim H, Salem R, Sofocleous C, Solomon SB, Soulen M, Tanaka M, Vogl T, Wood B, Solbiati L. Thermal ablation of colorectal liver metastases: a position paper by an international panel of ablation experts, The Interventional Oncology Sans Frontières meeting 2013. Eur Radiol. 2015 Dec;25(12):3438-54. doi: 10.1007/s00330-015-3779-z. Epub 2015 May 22. PMID: 25994193; PMCID: PMC4636513

4. Livraghi T, Goldberg SN, Lazzaroni S, Meloni F, Solbiati L, Gazelle GS. Small hepatocellular carcinoma: treatment with radio-frequency ablation versus ethanol injection. Radiology. 1999 Mar;210(3):655-61. doi: 10.1148/radiology.210.3.r99fe40655. PMID: 10207464.

5. Reig M, Forner A, Rimola J, Ferrer-Fàbrega J, Burrel M, Garcia-Criado Á, Kelley RK, Galle PR, Mazzaferro V, Salem R, Sangro B, Singal AG, Vogel A, Fuster J, Ayuso C, Bruix J. BCLC strategy for prognosis prediction and treatment recommendation: The 2022 update. J Hepatol. 2022 Mar;76(3):681-693. doi: 10.1016/j.jhep.2021.11.018. Epub 2021 Nov 19. PMID: 34801630; PMCID: PMC8866082.

6. Scheipner L, Incesu RB, Morra S, Baudo A, Jannello LMI, Siech C, de Angelis M, Assad A, Tian Z, Saad F, Shariat SF, Briganti A, Chun FKH, Tilki D, Longo N, Carmignani L, De Cobelli O, Pichler M, Ahyai S, Karakiewicz PI. Primary tumor ablation in metastatic renal cell carcinoma. Urol Oncol. 2024 Nov 12:S1078-1439(24)00699-9. doi: 10.1016/j.urolonc.2024.10.019. Epub ahead of print. PMID: 39537442.

Bibliography

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