Role of Radiotherapy in Treating Hepatocellular Carcinoma

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Hepatocellular carcinoma, also HCC, represents the most frequent primary liver cancer and is often associated with a poor prognosis and few therapy options, especially in the late stages. HCC is a growing global health problem largely due to chronic hepatitis infections and other liver diseases, and therefore the need for appropriate treatment methods cannot be overemphasized. In all the treatment approaches, radiotherapy has come through as a powerful modality in the treatment of patients with HCC, especially those who cannot undergo surgical or other localized therapies. This article explores the role of radiotherapy in managing HCC, its advantages and shortcomings, and perspectives on its development.

Understanding Radiotherapy in HCC Treatment

Radiation therapy, formerly employed in some cancers such as those of the breast, lung, and prostate, has been increasingly used in liver cancers, inclusive of HCC. The liver is known though to have a low tolerance to radiation, and therefore the use of radiotherapy has in the past been restricted, but with recent developments in both technology and techniques, the role of radiotherapy has begun to increase. Over the past few years, new approaches to radiotherapy have emerged in the form of stereotactic body radiation therapy (SBRT), intensity-modulated radiation therapy (IMRT), and other precision-based techniques of hepatic irradiation in an attempt to give high doses to tumors while sparing much of the normal surrounding liver tissue.

Stereotactic Body Radiation Therapy (SBRT)

SBRT is a very conformal radiotherapy technique where a high dose of radiation is given to the tumor in a small number of fractions. It is most helpful for small-sized HCC patients who will not benefit from surgery or other localized therapies. A total of 101 patients with small-sized HCC followed up after SBRT using an abdominal compression technique had a better prognosis with a median follow-up of more than 23 months. The 1-year, 3-year, and 5-year local control rates were high and proved that SBRT could control the tumor with a reasonable profile of complications. In particular, this paper found that the modified fractionation regimen with a total dose of 6-10 fractions was sufficient to achieve quite favorable results in terms of the control of the disease with relatively few side effects.

These are helical intensity-modulated radiation therapy and image-guided radiation therapy, which boost the efficiency of SBRT. These technologies help minimize the radiation delivered to the surrounding area, thus minimizing damage to the liver and other close structures. They also require that much precision in the case of liver cancers, especially because preserving liver function is of importance to the wellbeing of the patient and his tolerance to the treatments.

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Image-Guided Intensity-Modulated Radiotherapy (IG-IMRT)

IG-IMRT is yet again another addition to the list of improvements within the realm of radiotherapy for HCC. This technique entails the employment of innovative imaging equipment to direct the delivery of radiation and hence more accurately target tumors that are otherwise hard to address. In a phase 3 comparative analysis of IG-IMRT with non-IG-IMRT in HCC patients with lymph node metastasis, the evaluation of IG-IMRT exhibited better short-term survival and local tumor control. In turn, the mean biological effective dose achieved through IG-IMRT was significantly higher than in non-IG-IMRT, which promoted consequently improved rates of overall survival and the rate of one-year survival. Also, IG-IMRT resulted in less severe late hepatotoxic effects, which underscores the idea of the benefits of this method for patients with advanced disease.

Neoadjuvant Radiotherapy and Hepatectomy

In patients with resectable HCC combined with PVTT, external beam radiation therapy before the hepatectomy has been reported to improve the survival rate. A multicenter controlled trial has examined the results of neoadjuvant three-dimensional conformal RT followed by surgery with surgery only. The present work proved that neoadjuvant RT significantly decreased the probability of HCC-related mortality and failure regarding survival rates increasing due to the operation only.

The use of neoadjuvant RT as part of the approach has certain benefits: Since neoadjuvant RT makes the tumor smaller and helps prevent the spreading of the cancer before surgery, it contributes to successful resection and lowers the chances of recurrence. Interleukin-6 (IL-6) was also identified as a biomarker that could be used to predict the response to RT according to the results of the study. The patients who completed the therapy and had low IL-6 levels got better results; thus, it can be stated that the individualization of the RT using biomarker evaluation could improve the outcomes.

Combination Therapies with Radiotherapy

It has therefore become common to use radiotherapy in combination with other forms of treatment, including TACE and immunotherapy. There is one more localized treatment of HCC called thermal ablation, and its effectiveness is lower if the tumor is bigger than 3 cm in size. Nevertheless, one can state that the use of ablation in conjunction with transarterial embolic therapy is more effective. This combination takes advantage of the fact that radiotherapy assists ablation therapy in the effective management of large cancers.

Furthermore, approaches combining radiation with immunotherapy, especially immune checkpoint inhibitors such as patients with PD-1/PD-L1 blockade, are being investigated. This combination is planned to mobilize the body’s immune system to improve outcomes of radiotherapy in terms of its antitumor activity. Although this is one of the relatively young fields, some of the preliminary outcomes indicate that this cooperation could provide synergistic effects, especially in the treatment of advanced or inoperable HCC.

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Challenges and Considerations

However, the radiation-induced plication of radiotherapy in the treatment of HCC has its shortcomings. Nevertheless. Hepatic radiation tolerance is still a critical issue, especially for patients with other liver pathologies or poor liver reserve. There is always the possibility of developing Radiation-Induced Liver Disease, or RILD, that requires strict planning and accurate dosing to avoid much damage. Besides, HCC treatment is challenging because of the tumor heterogeneity, where the patients may develop multiple tumor nodules, and the degree of liver involvement may differ.

I was able to identify that another problem is related to the application of radiotherapy to previously established regimens. In patients with HCC, curative-intent treatments involve surgery, systemic therapy, and locoregional therapy. There is still much debate about when radiotherapy should commence and what other therapies it should be combined with, all of which is a difficult decision to make and involves the integration of multidisciplinary teams including oncologists, radiologists, and surgeons.

Future Directions in Radiotherapy for HCC

The need for technology enhancement and the application of individualized approaches are all that could define the further therapy of HCC by radiotherapy. A broad discussion of the main ideas of radiomics and its application in imaging analysis and facilitation of the development of artificial intelligence in the identification of patterns that inform treatment outcomes. Some of them might point to biomarkers that correlate with a better response to radiotherapy, allowing personalized treatment plans that would combine the best of this therapy with minimal side effects.

Furthermore, the discovery of new technologies in radiotherapy, for instance, proton beam therapy (PTB) and carbon ion therapy (CIT), will provide better precision and outcome in comparison to conventional treatments. These therapies give radiation in a manner that affects healthy tissues still more gently than current modalities and hence are well suited to tackle HCC patients with tough or bulky tumors.

It is also necessary to carry on further studies of combined therapy. A combination of radiotherapy with other new stellar therapies, like, for example, targeted therapy and novel immunotherapies may open up new therapeutic possibilities for HCC patients. Only clinical trials aiming at investigating the safety, efficacy, and way of using these above-mentioned combinations will prove it.

Conclusion

Radiotherapy has undoubtedly been proven to be an essential instrument for the treatment of HCC. The development of technology in radiation oncology allows the use of radiotherapy as a feasible and reasonable treatment strategy for HCC, irrespective of the stage of the disease in the patient. Of course, there are obstacles in the management of HCC, but if radiotherapy works to increase survival rates and make the quality of these patients’ lives significantly better, it would be a great thing. As researchers continue to drive the limits of the modality, radiotherapy is expected to occupy a more pivotal position in the comprehensive management of hepatocellular carcinoma.

References

  1. Chen, Y.X., Zhuang, Y., Yang, P., Fan, J., Zhou, J., Hu, Y., Zhu, W.C., Sun, J. and Zeng, Z.C., 2020. Helical IMRT-based stereotactic body radiation therapy using an abdominal compression technique and modified fractionation regimen for small hepatocellular carcinoma. Technology in Cancer Research & Treatment, 19, p.1533033820937002.
  2. Jang, W.I., Bae, S.H., Kim, M.S., Han, C.J., Park, S.C., Kim, S.B., Cho, E.H., Choi, C.W., Kim, K.S., Hwang, S. and Kim, J.H., 2020. A phase 2 multicenter study of stereotactic body radiotherapy for hepatocellular carcinoma: Safety and efficacy. Cancer, 126(2), pp.363-372.
  3. Zhang, H., Chen, Y., Hu, Y., Yang, P., Wang, B., Zhang, J., Sun, J. and Zeng, Z., 2019. Image-guided intensity-modulated radiotherapy improves short-term survival for abdominal lymph node metastases from hepatocellular carcinoma. Annals of Palliative Medicine, 8(5), pp.71727-71727.
  4. Wei, X., Jiang, Y., Zhang, X., Feng, S., Zhou, B., Ye, X., Xing, H., Xu, Y., Shi, J., Guo, W. and Zhou, D., 2019. Neoadjuvant three-dimensional conformal radiotherapy for resectable hepatocellular carcinoma with portal vein tumor thrombus: a randomized, open-label, multicenter controlled study. Journal of Clinical Oncology, 37(24), pp.2141-2151.
  5. Stein, J.E., Lipson, E.J., Cottrell, T.R., Forde, P.M., Anders, R.A., Cimino-Mathews, A., Thompson, E.D., Allaf, M.E., Yarchoan, M., Feliciano, J. and Wang, H., 2020. Pan-tumor pathologic scoring of response to PD-(L) 1 blockade. Clinical Cancer Research, 26(3), pp.545-551.
  6. Lewis, A.R., Padula, C.A., McKinney, J.M. and Toskich, B.B., 2019, October. Ablation plus transarterial embolic therapy for hepatocellular carcinoma larger than 3 cm: science, evidence, and future directions. In Seminars in Interventional Radiology (Vol. 36, No. 04, pp. 303-309). Thieme Medical Publishers.

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