In 2013, Oxaliplatin (trade name Loxadine) was approved in China for locally advanced and metastatic hepatocellular carcinoma that is not amenable to surgical resection or local treatment. This was the first approved oxaliplatin systemic chemotherapy regimen for hepatocellular carcinoma in the world.
Behind this milestone breakthrough, many people did not know that liver cancer was once an area that chemotherapy drugs could not conquer.
Hepatocellular carcinoma was once a “tough nut to crack” with chemotherapy
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As a systemic therapy, chemotherapy has an irreplaceable place in the treatment of many cancers. In particular, for patients with inoperable advanced metastatic cancer, chemotherapy is a major tool to relieve symptoms and prolong survival.
In contrast, liver cancer has been a tough nut to crack with chemotherapy drugs. Although the newly introduced 5-fluorouracil, and later adriamycin, cisplatin, and mitomycin, were tried as early as the 1950s for advanced liver cancer, they have not been shown to extend patient survival.
Why is liver cancer so “oil and salt” in the face of chemotherapy?
- First, many patients with liver cancer have hepatitis and cirrhosis, and with liver dysfunction, the dose of chemotherapy drugs should not be too strong or too frequent, which will inevitably affect the effectiveness of treatment.
- Second, hepatocellular carcinoma cells are multidrug resistant and have some natural resistance to these drugs.
- Lastly, these traditional chemotherapeutic drugs are inherently more toxic, which may offset or even mask the benefit.
For a long time, research on systemic chemotherapy for liver cancer was at a standstill.
While sorafenib, the first targeted agent for liver cancer, was introduced in 2007, it still has drawbacks such as narrow applicability (needing to fit a specific genotype), high price, and possible drug resistance. After drug resistance, people still need to find new chemotherapy drugs to keep them alive.
It wasn’t until 2010 that oxaliplatin, a highly effective and less toxic chemotherapy drug, broke the mold.
How does oxaliplatin destroy cancer cells?
Platinums are a large family of drugs that have made their mark in the battle of chemotherapy drugs against solid tumors.
The first generation is cisplatin, which is “highly effective and highly toxic”; the second generation is represented by carboplatin, which is less toxic overall but has stronger side effects of bone marrow suppression than cisplatin.
Oxaliplatin, a third-generation platinum drug, is less toxic to the gastrointestinal tract and bloodstream than the previous two generations, and has almost no hepatic or renal toxicity. The common neurotoxic side effects are also reversible and fade away with discontinuation of the drug.
The mechanism by which it kills cancer cells is also simple: it mainly blocks the DNA replication and transcription of cancer cells, stopping them from growing and reproducing endlessly.
Oxaliplatin is already well known as a commonly used chemotherapy drug. Since 2000, it has been used in the treatment of colorectal, gastric, and ovarian cancers, often in combination with 5-fluorouracil/calcium folinate.
The experts in the field of liver cancer are not going to let go of such a “versatile” chemotherapy drug.
China’s first “challenge” with oxaliplatin for hepatocellular carcinoma was successful
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In 2007, the team of Academician Sun Yan and Professor Qin Shukui initiated an international multicenter randomized controlled phase III clinical study (code-named “EACH”), and interim results were presented at the 2010 American Society of Clinical Oncology annual meeting.
This trial involved 371 patients with locally advanced or metastatic, inoperable or locally treated liver cancer from multiple Asian countries and regions, with the majority of patients from China, accounting for 75% of the patients.
Interim results showed that compared with the adriamycin (also known as doxorubicin) single-agent regimen, the oxaliplatin-based FOLFOX4 chemotherapy regimen extended median overall survival from 4.9 months to 6.4 months, with a 20% lower risk of death and a 38% lower risk of recurrence and metastasis in patients with advanced liver cancer.
That is, half of the patients with advanced liver cancer had their survival extended to more than six months with an oxaliplatin-containing chemotherapy regimen.
Knowing that advanced liver cancer itself has a poor prognosis, the average survival in Europe and the United States is 6 to 9 months if given supportive therapy alone, while in Asian countries it is only 3 to 4 months! For Asian patients, this is quite a breakthrough.
The study then went through 4 years of follow-up before it was all over in 2014. It found that oxaliplatin-based chemotherapy regimens extended the median overall survival of Chinese liver cancer patients from 4.3 months to 5.9 months!
While there was more prominent hematologic toxicity in the oxaliplatin chemotherapy arm, it was all manageable. This result is promising.
It was because of oxaliplatin’s unique performance in the trial that in 2013 we approved oxaliplatin for the treatment of hepatocellular carcinoma that is not amenable to surgical resection or local treatment.
Oxaliplatin and hepatic artery infusion chemotherapy successfully hold hands
Since oxaliplatin can be used for systemic chemotherapy for hepatocellular carcinoma, can it be “transposed” to local chemotherapy, that is, hepatic artery infusion chemotherapy?
According to previous studies, hepatic artery infusion chemotherapy has a high response rate and long survival, but the results are inconsistent and vary from person to person, with survival times ranging from 6 months to 15.9 months.
So researchers began to consider having FOLFOX4 chemotherapy regimens and hepatic artery infusion chemotherapy working together.
In 2017, the results of the study code-named “FOXAI” were published in Gut, which included 55 patients with advanced liver cancer, 93.9% of whom had hepatitis B virus-induced cirrhosis.
The results showed that patients had a median progression-free survival time of 6.1 months to tumor progression of 7.1 months. The six-month survival rate reached 71.4% and the one-year survival rate reached 55.1%.
That is, half of the patients with liver cancer with these treatment options were able to effectively control disease progression for more than six months and survive for more than one year!
Based on the good performance of FOLFOX4 for hepatic artery infusion chemotherapy in trials, investigators generally agree that this therapy can provide significant benefit to patients with advanced liver cancer and is expected to become the standard of care for advanced liver cancer.
Summary
Oxaliplatin, a highly effective, low-toxic, and affordable chemotherapy drug, has been used flexibly in the treatment of liver cancer, breaking the “no chemotherapy for liver cancer” treatment bottleneck and bringing hope to patients with liver cancer.
The oxaliplatin-based FOLFOX4 regimen has shown good results in patients with advanced hepatocellular carcinoma, especially in combination with hepatic artery infusion chemotherapy.
The next step still requires medical experts and patients to work together and continue to explore. We are also looking forward to a better performance of oxaliplatin, which will bring more benefits to patients with liver cancer.