The Past and Future of Nonsurgical Cancer Treatments and Interventional Oncology in the 21st Century

Cancer surgery remains a standard treatment capable of curing early-stage disease. However, medicine's present and future goal is to provide treatment without compromising the patient's bodily integrity and self-image, or with only minimal intervention.

Nonsurgical cancer treatments aim to prevent cancer cell proliferation without surgery or through minimally invasive procedures. They can include radiotherapy, chemotherapy, immunotherapy, and various minimally invasive approaches.

Examples of nonsurgical cancer treatment include:

• Radiotherapy: Radiation is delivered to cancerous tissue to prevent cancer cell proliferation and stop growth.
• Chemotherapy: Cell-killing (cytotoxic) drugs are administered to prevent cancer cell proliferation and stop growth.
• Immunotherapy: This aims to direct the body's own defenses to destroy cancer cells.
• Minimally invasive (interventional) oncology is a medical field involving minimal use of invasive techniques in cancer treatment. These methods aim to reduce the use of surgical instruments during interventions and shorten recovery. They can include laparoscopy, robotic surgery, endoscopic surgery, and interventional radiology techniques such as freezing (cryoablation) or heating (radiofrequency ablation).
  • Laparoscopic surgery: Surgical instruments are passed through small openings. Compared with open surgery, laparoscopy causes less tissue injury and shortens recovery.
  • Robotic surgery: Robotic technology controls surgical instruments during an operation. Compared with open surgery, it causes less tissue injury and shortens recovery.
  • Endoscopic surgery: An endoscope, an optical device providing magnification and illumination, is used to control surgical instruments. Compared with open surgery, it causes less tissue injury and shortens recovery.
  • Interventional radiology procedures: These aim to destroy a tumor by heating it, freezing it, or blocking its blood supply. They seek to prevent cancer cell proliferation and generally require no surgery. Minimally invasive procedures usually do not require general anesthesia and are performed under local anesthesia. Oncology applications can include:
    • Radiofrequency ablation (RFA): This aims to destroy cancerous tissue by heating it.
    • Embolization: Arteries supplying the tumor are blocked to deprive cancer cells of nutrients. Embolization prevents cancer cell proliferation and stops growth.
    • Chemoembolization: Drugs that prevent cancer cell proliferation are administered while the cancer cells' nutrient supply is blocked.
    • Cryoablation: This acts by freezing cancerous tissue.
    • Microwave ablation: A microwave energy source treats a tumor or another tissue abnormality. It rapidly heats and thereby destroys the tumor or abnormal tissue.

In the rest of this article, we will use the shorter term "interventional oncology" instead of "minimally invasive oncological procedures."

Introduction to Interventional Oncology

Like surgery, chemotherapy, and radiotherapy, interventional oncology has proven effectiveness in the local treatment of many malignant tumors.

Immuno-oncology (immunotherapies) arose from the possibility of controlling tumors through the immune system and molecules, bringing major changes to oncology. In the 21st century, it is therefore impossible to think about interventional oncology without considering immunology . This means greater attention must be paid to the previously neglected immunomodulatory effects of interventional oncology, and its potential synergy with immuno-oncology must be investigated. Combining the approaches is expected to help overcome problems such as limited regional effects and high adverse-effect rates. However, this requires breaking down disciplinary boundaries and strengthening interdisciplinary research. If successful, the future of interventional oncology is exciting.

The Role of Interventional Oncology in Cancer Treatment

Until now, the main goal of cancer treatment has been to reduce tumors to an absolute minimum, potentially requiring components such as surgery, chemotherapy, and radiotherapy. Interventional oncology has emerged from diagnostic and interventional radiology in recent years.

Its techniques resemble the basic concepts of "classical" treatments delivered in a minimally invasive manner. Defining criteria include focal or regional application and effects, together with fewer adverse effects and better patient tolerance.

In many clinical situations, interventional oncology outcomes resemble those of surgery and chemotherapy. Indeed, for early and locally advanced hepatocellular carcinoma (HCC, the most common liver cancer) and oligometastatic lung cancer (with few metastases), or early kidney cancer, interventional oncology techniques are superior to previous standard treatments.

Interventional oncology can therefore be viewed as the fourth pillar of treatment in various cancers and often as a problem-solver in multimodal treatment concepts.

Although the success of interventional oncology treatments is increasing, the risk of tumor recurrence remains a problem. Cancer cells can remain in the body even after all visible tumors are treated, emphasizing the need for multiple treatments.

Ongoing research is also producing a deeper understanding of tumor biology and the often highly complex immune processes that stimulate or suppress cancer cell growth.

This rise of immuno-oncology, including interventional oncology, will change oncology and current and future treatment concepts. The "classical" model of treating a defined disease with a standard protocol is evolving toward precision medicine , which tailors every component of healthcare to the individual patient.

Advances in Medical Oncology

In the past century, oncology meant pursuing a disease with curative intent. Biomedical research meanwhile provided deeper insights into cancer's molecular mechanisms. More recently, numerous tools have been developed to identify cancer-control mechanisms and use or modify them for potentially therapeutic purposes.

The ambitious vision is to enter an era in which cancer is detected and treated through liquid biopsies before becoming visible as a tumor on imaging. Our ambitious effort to treat and cure cancer also includes identifying biomarkers that predict the disease course regardless of stage; detecting and understanding cancer-driving mutations ; targeting them; and ultimately improving immune control of cancer cells.

After—and alongside—"classical" chemotherapy and treatments suppressing cellular metabolism, immuno-oncology is considered the leading edge of medical oncology.

The hallmarks of cancer, first proposed by Hanahan and Weinberg in 2000, have been revised over time into the current 14 key features leading to carcinogenesis (cancer development) :

1. Having their own growth factors
2. Evading growth suppressors
3. Evading the immune system
4. Sustained ability to divide
5. Tumor-promoting inflammation
6. Migration to other tissues and organs (invasion or metastasis)
7. Angiogenesis (new blood vessel formation)
8. Mutations (errors) in genetic structure
9. Evading cell death mechanisms
10. Altering energy metabolism
11. Phenotypic plasticity and disrupted differentiation
12. Nonmutational epigenetic reprogramming
13. Polymorphic microbiome
14. Senescent cells

Many of these are likely to be connected to immune processes and cancer's ability to alter the immune system. This widespread hope—and sometimes pitfall—in biological therapies is supported by enormous research efforts.

The Immuno-Oncology Revolution

A recent "Nature Reviews" analysis found a 92% increase in immune drug development alone between 2017 and 2019, with almost 5200 active trials worldwide.

Key Immunotherapy Terms

Monoclonal antibodies (mAbs)

• Treatment with laboratory-engineered monoclonal antibodies (mAbs) directed at a particular target, such as a protein on a cancer cell's surface, to enhance immune responses, kill cancer cells, or stop their growth.

Immune system modulation

• Treatment with conjugated mAbs used to carry a drug or radioactivity to a specific cell.
• Treatment with bispecific mAbs comprising two antibody components that bind two proteins simultaneously.
• Certain mAbs (checkpoint inhibitors) block checkpoint proteins, such as PD-1 and PD-L1, that make tumor cells "invisible" to the immune system, releasing immune activity again.

Tumor-agnostic treatments (independent of the organ of origin)

• Treatment with mAbs targeting mutations caused by cancer cells rather than targeting tumor cells according to their organ of origin, meaning that a cancer containing those mutations will also be targeted.

• Cytokines, such as interferons and interleukins, stimulate the immune system without specifically targeting cancer cells and are often given with chemotherapy or radiotherapy.

Adoptive T-cell therapy

• Treatment involving isolation of cancer-specific T cells and laboratory expansion to increase T-cell numbers within the body.
• Treatment with tumor-infiltrating lymphocytes (TILs) modified in the laboratory to support cancer cell destruction within the body.
• Treatment with genetically engineered chimeric antigen receptor (CAR) T cells producing an artificial T-cell receptor that combines antigen binding and T-cell activation.

Cancer vaccines

• Preventive vaccines to prevent cancer cell development.
• Therapeutic vaccines stimulating the immune system to attack tumor cells.

Oncolytic virus vaccines

• Oncolytic virus therapy uses genetically modified viruses to target and kill cancer cells, with a secondary release of antigens that stimulates an immune response.

As numerous trials have shown, many of these treatments produce limited responses, sometimes only in vitro (in the laboratory). Increasingly complex personalized regimens are therefore expected to emerge by combining approaches tailored to a particular patient ("personalized treatment").

These regimens will rely on selective genetic and immunological analysis to identify suitable patients and treatment components. Further progress requires larger biopsy specimens (cell and tissue samples). General use of liquid biopsies will also develop in oncology—for example, collecting non-solid samples from bodily fluids such as blood and analyzing circulating tumor cells, DNA and RNA components, or other biomarkers.

Experience with treatments such as checkpoint inhibitor immunotherapies also shows that the tumor microenvironment is crucial for effective therapy. Patients suitable for newer treatments such as immunotherapy or targeted drugs can be identified through DNA, RNA, and germline DNA sequencing. Image-guided biopsy of the target tissue or tissues will therefore become even more critical.

All this may sound too good to be true, suggesting that understanding biological mechanisms could solve almost every problem and complication—much as nuclear physics was viewed 100 years ago. Increasing understanding of cancer biology is accompanied by growing knowledge of complex biological mechanisms and their interactions, but also reveals even more complex mechanisms and potential adverse effects.

Only limited data are currently available on the capabilities and risks of evolving molecular therapies. Although only a small subgroup of patients accesses and benefits from these expensive immune treatments, finding the right treatments—or combinations—for the right patient at the right time remains our greatest priority. Big data analysis and artificial intelligence may help identify suitable targets, optimize selection of immune tools, and predict effective outcomes.

The Future of Medical Oncology

Above all, oncology's great ambition in the 21st century remains curing cancer patients. This goal becomes more attainable as immuno-oncology and related sciences continually decipher, understand, and modify the molecular biological mechanisms of carcinogenesis.

Approximately 20 million cancers are diagnosed worldwide each year, and fewer than half still cannot be completely treated. Nevertheless, immunotherapies selected for a tumor's genetics and other systemic and/or local immunomodulatory treatments can contribute substantially to controlling cancer. In terms of the best possible quality of life, "healing" could mean tumor cells remaining in the body but controlled harmlessly: cancer becomes a "chronic" disease without substantial harm to its host.

A Brief History of Interventional Oncology—Past and Present (the First 30–40 Years)

Continued development of underlying techniques and clinical applications has made interventional oncology highly effective in treating primary tumors and metastases in organs such as the liver, lungs, kidneys, and bones. It is characterized by absent or minimal systemic adverse effects and by the ability to combine it with "classical" surgery, medical oncology, and radiation oncology.

Applying the basic principles of established treatments such as surgery, chemotherapy, and radiotherapy, interventional oncology techniques already represent a form of individualized treatment and act mainly locally or regionally.

By access route and treatment delivery, techniques are grouped as transvascular and percutaneous (Table 2).

When Yamada and colleagues introduced transarterial chemoembolization (TACE) in 1977 as the first interventional oncology technique for unresectable HCC (hepatocellular carcinoma, liver cancer), it was regarded worldwide as state-of-the-art treatment. Various improvements and modifications of the original lipiodol-based technique have since been developed. Current advances favor more selective and superselective application, with better understanding of intratumoral and peritumoral flow dynamics translating into more refined embolization techniques.

Current meta-analyses of TACE, still far from standardized, report approximately 15-30% 5-year survival in early and locally advanced HCC, with a trend toward better outcomes using DEB-TACE in recent years.

Transarterial perfusion techniques such as hepatic artery infusion (HAI) with 5-fluorodeoxyuridine (FUDR), 5-fluorouracil (5FU), and oxaliplatin have also attracted considerable interest for liver metastases, with clear evidence in metastatic colorectal cancer (mCRC). In unresectable liver metastases, HAI plus systemic chemotherapy provides 70-85% 5-year median survival rates, compared with 40-50% for systemic chemotherapy alone.

A special "version" of HAI, percutaneous chemosaturation, is an innovative interventional oncology approach for unresectable primary liver tumors or metastases from other organs. It keeps most of the drug in the liver while delivering high-dose melphalan directly to it. Still performed occasionally in selected centers, the technique is currently preferred for advanced ovarian cancer, myeloma, and melanoma; efficacy in other cancers remains unclear. The future will show whether it gains a major clinical impact.

Transarterial radioembolization (TARE) with yttrium-90, a "brachytherapy variant" of TACE, has generated debate in recent years. Contrary to expectations, large new multicenter randomized trials comparing TARE as first-line treatment for HCC and mCRC, TARE plus systemic therapy, and systemic therapy alone mainly showed equivalence. Nevertheless, numerous studies have demonstrated the versatility of yttrium-90 in primary and metastatic liver tumors.

The newer Holmium-166 compound may offer practical radiation-related advantages over yttrium-90, but clinical efficacy has not yet been established.

Among percutaneous thermal ablation techniques, radiofrequency ablation was first performed in 1988. Technical advances such as cooled systems, microwave ablation, and pulsed energy delivery have made thermal ablation a robust technique with well-established indications and thoroughly documented outcomes.

Other ablative methods, including cryoablation, irreversible electroporation, and high-intensity focused ultrasound, remain under investigation. Dating to the 1990s, cryoablation is now used mainly for renal cell cancer and bone tumors. Despite benefits such as less pain during ablation and MRI compatibility, it has no proven superiority over the other techniques.

Nanoknife (irreversible electroporation) and HIFU (high-intensity focused ultrasound) initially raised high expectations. However, currently available data suggest that neither is particularly well suited to clinical needs.

Supporting Technologies

Enormous advances in information technology—artificial intelligence (AI), big data, intelligent algorithms, robotics, machine learning, and deep learning—affect everyday life and will substantially change medical practice. In oncology, analytically linking medical databases with individual patient data, such as genomic information from blood or tumor samples, will support diagnostic and treatment decisions.

Disease assessment and treatment methods will increasingly be supported by artificial intelligence.

Advanced imaging technologies—including ultrasound/MRI fusion imaging and potentially dielectric or optical imaging—and robot-assisted imaging and procedures incorporating AI, augmented reality, and virtual reality will enable highly precise interventional oncology with minimal radiation exposure for patients and operators.

Looking into the Crystal Ball of the 21st Century

If we had imagined the 21st century during the 20th, ultrasound, CT, MRI, and catheter-based procedures probably would not have occurred to anyone.

The Fourier transform was described in 1805, X-rays were detected in 1895, and almost 80 years later the first computed tomography was introduced—impossible, of course, without the Fourier transform. In 1925, Wolfgang Pauli proposed electron spin; developing the first MRI scanner took another 50 years. Werner Forssmann performed the first right-heart catheterization (cardiac angiography) in 1924. It was then forgotten and reinvented, and in 1977 Andreas Gruentzig developed the technique as the first balloon angioplasty. The foundations of today's transformative immune checkpoint inhibitor immunotherapies were laid in 1990 with James Allison's discovery of CTLA-4 ...

Over the coming decades, we should expect the wheel of knowledge to turn even faster and assume that the foundations of many dramatic future developments are already in place.

All cancer treatments have undoubtedly advanced enormously in recent years and will progress further in the 21st century. Yet the coming decades will bring particular challenges in caring for patients, mainly because of global demographic and economic developments. In many highly developed Eastern and Western countries, aging populations will include medically well-cared-for people likely to develop several cancers over their lifetimes and at older ages.

Treatment concepts will therefore need to account for older patients with multiple comorbidities and reimbursement within different healthcare systems. In poorer, less developed countries, often with rapidly growing populations, the main challenge will be providing sufficient healthcare. As with infectious diseases, cancer rates may be lower than in wealthier countries, but diagnosis may occur at more advanced stages.

Medical knowledge will continually change and develop. Existing treatments and practices will disappear and be replaced, as in the past. With numbers increasing in every respect, it is not difficult to predict greater medical complexity because of:

• More and older patients needing individualized treatment because of comorbidities
• Economic pressures on healthcare, as seen during the Covid-19 pandemic
• Growing requirements for patient comfort in outpatient care and short hospital stays
• More drugs, especially immune-based treatments
• More medical data processed by intelligent algorithms, generating new evidence and probably unexpected connections
• Cybertechnologies for self-optimization and automated diagnosis using implantable devices ("nanomachines") that allow earlier disease detection and other applications

Many current recommendations in national and international cancer guidelines (ESMO, ECCO, EASL, ASCO-NCCN) also show treatment philosophy shifting toward personalized approaches. Complete tumor clearance nevertheless remains the goal. Turning a devastating diagnosis into a chronic disease controlled through long-term treatment, maintaining high quality of life and a low tumor burden, may be sufficient and appropriate treatment goals. In settings with limited resources and economic capacity, these concepts may be reasonable, acceptable, and affordable.

Cancer as a Moving Target

We are also dealing with a moving target in several respects. Most, if not all, tumors can change their genomic, microbiological, and macrobiological behavior over time. The patient hosting the tumor also changes in age, comorbidities, resistance to particular treatment, and psychological acceptance.

Precision medicine addresses many of these issues. However, genome-tailored precision medicine—gene editing, tumor-specific cancer vaccines, and CAR T-cell therapy—currently suits only a small fraction of patients, remains very expensive, and often has serious adverse effects limiting tolerance.

Better immune control of tumors will likely influence how future treatments are delivered. But unless immuno-oncology completely eliminates tumors first in the laboratory and then in real patients, there will remain strong demand for surgery, radiation therapy, chemotherapy, and interventional oncology as oncology's minimally invasive arm.

Challenges Facing Interventional Oncology

Because of immunotherapies, targeted drugs, hormonal therapies, their combinations, and ultimately precision medicine, interventional oncology is not currently the main focus of most oncology professionals. For example, it is not even mentioned among the eight cancer treatments listed on the US National Cancer Institute website: surgery, radiation therapy, chemotherapy, immunotherapy, targeted therapy, hormone therapy, stem cell transplantation, and precision medicine. Charitably, we might assume it falls under "targeted and precision medicine."

Predicting interventional oncology's future more than a few years ahead may be like gazing into a crystal ball.

Nevertheless, trends and lessons from the past can indicate where it may go and which barriers must be overcome

In recent years, interventional radiology has built extensive evidence for the effectiveness of various techniques. In summary, tumors within the size limits suitable for interventional oncology can be treated across many cancer types and organs with effects comparable to surgery or radiotherapy.

Beyond the synergistic effects already discussed, interventional oncology's imaging, guidance, and treatment capabilities can add versatile value to all oncological and immuno-oncological treatments. This ranges from technically straightforward, highly precise tissue sampling for tumor characterization based on complex image analysis to maximally precise percutaneous or transvascular treatments. Precise local drug/molecule delivery may overcome systemic administration limits by improving regional distribution and concentration with less systemic toxicity.

For image-guided treatments, interventional oncology will benefit substantially from AI-driven advances in imaging and image-based data processing.

Greater medical and biological knowledge will generate new treatments, while technical advances will produce new procedures, creating new needs and opportunities for interventional oncology. Whether these will continue to sit within different medical specialties remains uncertain, as interdisciplinary work is still regarded as a major achievement today.

As future medical specialists, engineers, and administrators move beyond traditional categories and specialty boundaries, new healthcare structures may emerge that combine disease-system expertise and skills.

Conclusion

Immune-based treatments will probably dominate oncology in the 21st century. Yet advanced immuno-oncological and genetic treatments, such as gene editing and living-cell vaccines, have so far achieved impressive success only in certain cancers, at high cost and with potentially serious adverse effects.

Interventional oncology methods have clearly proven effective across tumor types for regional control with few adverse effects, but their known immunomodulatory effects are generally too weak to produce substantial systemic therapeutic effects.

Combining interventional oncology and immuno-oncology may overcome these limitations through synergy. This requires leaving disciplinary silos behind and focusing on finding the best treatment for the patient.

An important step is strengthening interventional oncology's interdisciplinary presence to promote mutual knowledge exchange among competing specialties and combine research efforts as comprehensively as possible. With its broad range of excellent tools and concepts, the field may have a bright future, and the 2nd era of interventional oncology may begin.