Dawson Outlines Evolving Role of Radiotherapy in Liver Cancers

Laura Dawson, MD

Laura Dawson, MD

Although the adoption of radiotherapy in the treatment of liver tumors has been slow, its role continues to evolve as more data becomes available.

Radiation therapies such as stereotactic body radiation therapy (SBRT) currently have a role in the treatment of patients with hepatocellular carcinoma (HCC), liver metastases, and biliary cancers, but there is still a need for further high-level evidence, explains Laura Dawson, MD.

Additionally, ongoing trials are now investigating the potential promise for using radiotherapy in combination with immunotherapy to help improve the efficacy of immunotherapies in patients with HCC.

In an interview withTargeted Oncologyduring the3rd AnnualSchool of Gastrointestinal Oncology^™Meeting, Dawson, professor, Department of Radiation Oncology, University of Toronto, and staff radiation oncologist, Princess Margaret Hospital/University Health Network, discussed the current and future role of SBRT in the treatment of liver tumors.

TARGETED ONCOLOGY:Can you provide an overview of your talk on the role of SBRT in liver tumors?

Dawson:Radiotherapy is an excellent treatment for most cancers and has a very strong role in most cancers. It has been a little bit slower to be adopted in hepatobiliary cancers, for several reasons.

The liver has a low tolerance to radiation, and before we were able to target tumors very precisely, there would be a high risk of toxicity. The role of radiotherapy in the treatment of primary liver cancers, biliary cancers, and liver metastases is still evolving and there is still a need for high-level evidence.

I talked about the evidence there is for using radiotherapy in those 3 settings: HCC, cholangiocarcinoma, and liver metastases.

Liver metastases are interesting because survival for colorectal metastases to the liver have improved so much, partially from systemic therapy improvements and targeted agents, but probably also due to more patients having surgery for liver-only metastases. Radiotherapy is a local therapy for those patients who may not be suitable for surgery that could improve their time to progression, survival, and even lead to cure for some patients, but it has yet to be shown in a phase III study.

This is partially why I'm talking about the use of radiation, because it can ablate tumors, and it can ablate colorectal metastases, so I think it has a very strong potential to help patients. In the era of immunotherapy, radiation may have other benefits. It may increase the antigen presentations that may help the patient's immune system fight the cancer. It may help improve the efficacy of immunotherapy in patients who are suitable for that.

HCC is the most common primary liver cancer and I think the role of radiotherapy is far stronger there. There are very few randomized studies [currently available, but] there are many randomized studies going on. HCC is very challenging, because most patients have cirrhosis and poor liver function and most are not suitable for transplant or surgery, which are the optimal therapies. Patients often present with locally advanced disease, sometimes evading the large vessels, the portal vein, or the hepatic vein. That is a particular adverse prognostic factor and all our therapies aren't as effective if the tumor is evaded into the vein. Radiotherapy is an excellent treatment in that situation. It can ablate tumors in the vein, we don't have to worry about surgical barriers. It can hopefully help prevent an impairment of liver function due to the tumor as well. When cancer spreads to the vein, it can increase the pressure in the liver and lead to a decline in liver function, so it's a little bit of a circle. There is strong motivation to improve our treatments in that particular setting.

There is one comparative study that was just published that looked at sorafenib (Nexavar), which is the standard of care in those patients, compared to transarterial chemoembolization (TACE) and [external beam] radiotherapy in patients with HCC with vascular invasion. That was led by Sang Min Yoon, MD, PhD, of Asan Medical Center in Korea. It was a small study, and it was powered to show a difference in progression-free survival (PFS), and it met its primary endpoint. In fact, it even showed an improvement in survival for these challenging patients. That was despite crossover, so patients who had recurred after sorafenib were then offered TACE and radiotherapy and did better than expected. That was the only randomized trial that is completed as planned. I think it's a very strong signal for the benefit of radiation. In North America, there is another trial, RTOG 1112, for similar patients, and also patients with a low burden of extra hepatic disease comparing sorafenib to SBRT and sorafenib (NCT01730937). That study is ongoing with mostly North American participation and some international participation. I am the primary investigator of that study and I really hope we can accrue as planned, and that will hopefully show the benefit of radiation on top of sorafenib for that patient population. 

The other type of cancer where radiation has a role is in biliary cancers. These cancers are particularly challenging because patients are at risk of cholangitis and biliary obstruction, and the multidisciplinary team is very important. It's important for all cancers, but particularly important for cholangiocarcinomas, as patients may need stents, they may have cholangitis, and need to be treated appropriately. In that particular population, SBRT or hypofractionation is associated with more toxicity. A different way of delivering radiation that appears effective is with 15 fractions of conformal radiotherapy. That is my preference for those tumors right now for cholangiocarcinoma, and we just have to be a little more careful because of the potential for biliary obstruction if using hypofractionation for those tumors.

There are a lot of promising single-institution data, multi-center data, and very few comparative data for radiation for all types of liver cancer primary and secondary, but the good news is, there are many randomized trials ongoing, so hopefully in the future we will have high levels of evidence for the role of radiotherapy in treating these patients.

TARGETED ONCOLOGY:Are there any types of liver tumors that might not be good for radiotherapy?

Dawson:External beam radiotherapy (EBRT) can treat focal cancers, and part of the philosophy of treating liver cancers with radiation is sparing enough functional liver. We cannot treat the whole liver to ablative doses safely. Unfortunately, many cancers may present with diffuse disease. If there is entire infiltration of the liver, multi-focal lesions throughout the entire liver, sometimes it's technically not possible to give an ablative dose to treat those tumors. For colorectal cancer metastases, they tend to be quite radiation-resistant, so there is strong motivation to give high doses. In some tumors, that may be in close proximity to the stomach, we need to use strategies to move those organs at risk away and deliver high doses, but sometimes that's not possible.

For small colorectal metastases, although radiation is a fantastic treatment, if other local therapies can be used, assuming surgery is not an option, I would prefer that. Ablative therapy is not [a good choice] for diffuse disease, regardless of the cause. Palliative radiotherapy could be used to treat diffuse disease. That is something that many people don't realize. After all the standard-of-care systemic therapies, locoregional therapies have been done. If someone has pain from either primary or metastatic liver cancer, in the very end-stage, a single dose of radiation can help with pain. There is a randomized study going on in Canada looking for that benefit. There is a role, it's just a very different role than stereotactic radiotherapy or ablative dose radiotherapy where we hope to control the tumor and lead to improvements in long-term PFS and survival. Those would be the main situations where I would not recommend radiotherapy. In many cancers, it is still important to have standard-of-care therapy. In metastatic colorectal cancer, standard-of-care first-line chemotherapy is very important, so I would advocate for chemotherapy first.

In cholangiocarcinoma, we usually start with chemotherapy for unresectable lesions and then follow with radiotherapy. For HCC, in my clinic, if there are more than 5 lesions, I don't recommend radiotherapy. I would recommend a regional therapy or a systemic therapy that can target the occult lesions in the liver as well.

Something else to consider is liver function, such as patients who have very poor functioning livers, cirrhosis, which we describe in different ways. One is the Child-Pugh score. Those with Child-Pugh scores greater than 7, we'd have to be very careful in using radiotherapy for those patients because they have a higher risk of having a decline in liver function, so I wouldn't recommend that as a routine for oncologists across all cities. In fact, I recommend those patients be treated on studies or supportive measures and not using ablative radiotherapy. Child-Pugh A and B7 can be treated with SBRT, although the risk is a little higher in patients with slightly impaired function. B7 compared with A5, we still can benefit, and the risks are acceptable. We need to look at goals of care and keep treatments simple if patients need palliation.

TARGETED ONCOLOGY:How do you envision the role of radiotherapy evolving?

Dawson:I think it's increasing, especially for primary liver cancer. There are more and more data every week. Because radiation is not accepted in the guidelines in many countries for treatment of HCC, as that evidence evolves, I expect that it would become an accepted standard, and not only as a backup, but hopefully upfront, even for potentially curable patients with HCC. Many thought leaders in many countries don't have it in the recommendations for early stage treatment, but patients who have early stage HCC and who are not suitable for transplant surgery, local therapies like radiofrequency ablation or microwave, I would strongly advocate that radiation can lead to long-term control and cure of some of those patients. Hopefully that will change in years to come as we have more evidence and we share how to deliver radiation safely. I think there will be a very big difference in guidelines and as the evidence improves, hopefully then there will be more use of radiotherapy for liver cancers.

TARGETED ONCOLOGY:What is the key takehome message from your talk?

Dawson:To recognize that radiotherapy, and SBRT is one type of radiotherapy, has a large role to play in the treatment of primary metastatic liver cancers. Sometimes people don't realize that radiation can ablate tumors, so the few indications where I would suggest radiation therapy be considered would be metastases that are isolated to the liver, for example, colorectal metastases, but not resectable, or not well suited for other local therapies, so at the portal confluence adjacent to those vessels. Those patients have a potential for cure with isolated liver metastases, so I would very strongly advocate for the use of radiotherapy if there are few metastases in that region making them unresectable after first-line chemotherapy.

For early stage HCC, in potentially curable patients, but who are not well suited for standard local therapies, if regional therapies are delivered first, so chemoembolization, then I would recommend strong follow-up in a multidisciplinary manner so that patients don't have rapid progression of their cancer before they are referred for radiotherapy. The other 2 settings are HCC with vascular invasion, again, not suitable for other treatments, such as sorafenib, TACE, any treatment other than best supportive care. It's worth it to hear about radiation oncology that sometimes can lead to long-term control. I think our understanding of HCC and our treatments are so different today than 10 years ago. It's worth considering radiation as part of the treatment.

Finally, the role of palliative radiation for patients who have pain or discomfort. Regardless of the type of liver cancer consider simple radiotherapy to help palliate symptoms. It's a very effective tool, and despite very few randomized studies, I think there is enough evidence of how to deliver it safely in some of those settings, so hopefully it can be considered.

TARGETED ONCOLOGY:Is there anything else you would like to highlight from your talk?

Dawson:There is huge potential for radiotherapy to be combined with immunotherapies. We hope that by doing that we can improve the efficacy of immunotherapy. There are earlier phase I and II trials going on with radiotherapy and immunotherapies for HCC. That's very exciting. In the next year or 2, we will be seeing results of those studies, which would open up the potential for radiotherapy to be used with such therapies as they become more standard for our patients with HCC.