A dynamic duo of chemotherapy and radiology benefits patients with liver complications due to CRC
The incidence of colorectal cancer (CRC) has been declining by 2% a year for over 10 years due to advances in social behavior and science-such as smoking cessation and early detection, respectively. Despite this, it remains the fourth most prevalent cancer in the world. A staggering 50,000 deaths are attributed to the disease in the United States alone each year.1,2 Despite early detection techniques, approximately one quarter of people diagnosed with colorectal cancer will learn they have liver metastases at the initial diagnosis, with a further 25-35% developing these during the course of their disease.3,4
Ultimately, liver failure is the leading cause of mortality in patients with metastatic colorectal cancer (mCRC), with liver metastases and overuse of chemotherapy being the most significant contributors to that result.5,6,7,8 Addressing liver metastasis is one of the most challenging aspects of treating mCRC . The outlook for patients with surgically unresectable mCRC is very poor, with a five-year survival rate of less than 5%. Outside of traditional systemic and biological approaches, the use of non-systemic liver directed therapies to assist these patients have been limited.
A serious challenge to treatment is that many patients do not know they have cancer in their liver until it is at an advanced stage, when surgery is no longer possible. The standard treatments for these patients are systemic chemotherapy and biologically targeted agents. These therapeutic options have dramatically prolonged survival of patients with mCRC, but rarely lead to long-term remission. Liver-directed therapy with Selective Internal Radiation Therapy (SIRT)-specifically Y-90 resin microspheres-has been shown to safely shrink tumors, slow progression and prolong life for patients with mCRC.9, 11,12,13
Recently, the SIRFLOX study examined whether the combination of Y-90 Resin microspheres with chemotherapy is more effective at slowing disease progression than chemotherapy alone in patients recently diagnosed with mCRC (first-line treatment). The prospective, open-label, international, multi-center, randomized controlled trial (RCT) was conducted at more than 100 worldwide sites, including 20 in the United States. The study enrolled 530 patients, making it the largest study of liver-directed therapy in oncology.
While the primary endpoint of the study, progression free survival at any site in the body, showed similar outcomes with both study arms, the clinically significant finding was observed in the secondary study on controlling liver tumors (PFS in the liver). It showed the median liver PFS was significantly longer in the patients treated with both SIRT and chemotherapy versus those treated with chemotherapy alone. Specifically, the study revealed and average of 12.6 months of PFS in the liver in the chemotherapy arm, compared to 20.5 months of PFS in the liver in the SIRT and chemotherapy arm.
Additional secondary endpoints included tumor response rate, tumor recurrence rate, safety and tolerability and the surgical rate enabled by tumor downsizing from the two treatment arms. 14% of patients had tumors surgically removed in both arms, and 6% experienced complete responses in the SIRT and chemo arm-three times the rate experienced in the chemotherapy-only arm.
SIRT in Oncology
Research into the use of yttrium-90 (Y-90) resin microspheres as a treatment for liver cancer began in the 1960s, and the early pioneers included an impressive list of international research scientists, radiologists and oncologists. In the late 1980s, hepatobiliary surgeon Bruce Gray developed Y-90 bound microspheres that could be carried in the bloodstream directly into, but not through, the capillary bed of liver tumors. The evolution and refinement of this technology has resulted in today’s SIRT in the form of Y-90 resin microspheres.
A multitude of retrospective studies, small prospective studies and RCT’s published in oncology journals have supported the use and effectiveness of SIRT.9,10,11,12 Until recently, medical oncologists primarily referred patients who were no longer responding to chemotherapy to interventional radiologists who then performed the SIRT procedure. By that point, these were typically very sick patients with very poor long-term prognoses. This approach was due to uncertainty about sequencing with systemic chemotherapy.
Level 1 evidence and the results from the SIRFLOX study were announced at the 2015 American Society of Clinical Oncology (ASCO) Annual Meeting. With that grew a tangible amount of interest from medical oncologists. Almost a year after the original wave of interest, the results were published in the prestigious Journal of Clinical Oncology (JCO). The publication provided more data and context, demonstrating the importance of significant Liver PFS in patient outcomes. Additional data, published for the first time in this manuscript, provided the insight that, while SIRT helped chemotherapy significantly delay the growth of cancer in the liver, cancer growth outside the liver was not accelerated when SIRT was added to a patient’s chemotherapy treatment regimen.
SIRT in the Interventional Radiology Space
Prior to the SIRFLOX study, the early adopters of SIRT in the interventional radiology space were seen by their oncology peers as over-reaching in their decision to treat liver metastases from a systemic disease with a liver-directed therapy like SIRT. As the peer-reviewed data continued to grow, interventional radiologists began to play a more active role in various multidisciplinary tumor boards and oncologists (medical, surgical, radiation) started to experience the positive patient outcomes for themselves. Since then, the procedure has grown from being perceived as “boutique” in the medical device community to being welcomed not only the ASCO stage, but also by influential associations across multiple disciplines.
Liver-directed cancer therapies, such as transcatheter arterial chemoembolization (TACE), drug-eluting beads and radiofrequency ablation (RFA), have also recently gained mainstream use in the treatment of primary liver cancer. This occurred due to the lack of effective or tolerable systemic therapy options available for this disease state.
The Business of SIRT
When it comes to patient care for cancers in the liver, a multidisciplinary approach is critical to determine the combination of therapies and sequencing needed in order to maximize the individual patient’s outcomes. It’s in this manner that a personalized medicine approach can be taken, and many patients’ cancers can be managed as a chronic disease instead of as a short-term terminal disease. In many instances, multidisciplinary teams consisting of various specialties, including medical oncology, surgical oncology, radiation oncology, gastroenterology and nutrition, pathology, interventional radiology and genetics, meet weekly to discuss each patient’s treatment plan. At smaller institutions, collaboration between the available disciplines is also the standard approach.
As each case is presented, prognostic indicators are discussed, guidelines such as those from the National Comprehensive Cancer Network (NCCN) are reviewed, clinical trial options are considered and decisions are made collaboratively to ensure the best possible treatment and outcome for the patient. This system of collaboration opens up the communications channels between the different specialties, enhancing physician relationships and improving patient outcomes. Limiting patients to systemic chemotherapy choices alone may reduce multidisciplinary care and treatment options shown to prolong patients’ lives.9,13
In the U.S., both the SIRT procedure and the Y-90 microspheres are reimbursed by Medicare-and often by the majority of private insurance companies. Additionally, offering SIRT as an integral part of an active interventional oncology program enables treatment centers to receive a growing stream of referred cancer patients. When treated by a multidisciplinary team, these patients will receive an appropriate sequence of accepted, emerging medical treatments to prolong patient survival and provide an annuity of ongoing procedures for the hospital.
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- GLOBOCAN 2012 Estimated cancer mortality, incidence and prevalence worldwide, Available at http://globocan.iarc.fr/Default.aspx.
- Robert J. Porte and Pierre-Alain Clavien, “Etiology, and Natural History of Liver Tumors,” Malignant Liver Tumors: Current and Emerging Therapies, second edition, edited by Pierre A. Clavien (Jones and Bartlett Publishers, 2004), pp. 27-38
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- Kennedy A et al. Int J Radiation Oncology Biol and Phys 2006; 65: 412–425.
- Seidensticker R, Denecke T, Kraus P, et al. Matched-pair comparison of radioembolization plus best supportive care versus best supportive care alone for chemotherapy refractory liver-dominant colorectal metastases. Cardiovasc Intervent Radiol. 2011 July 29.
- van Hazel GA, Heinemann V, Sharma NK et al on behalf of the SIRFLOX Study Group. SIRFLOX: Randomized Phase III Trial Comparing First-Line mFOLFOX6 (Plus or Minus Bevacizumab) Versus mFOLFOX6 (Plus or Minus Bevacizumab) Plus Selective Internal Radiation Therapy in Patients With Metastatic Colorectal Cancer. J Clin Oncol 2016 February 22; ePub doi: 10.1200/JCO.2015.66.1181.
- van Hazel et al. J Surg Oncol 2004;88:78–85.
- Hendlisz et al. J Clin Oncol 2010;28:3687–94.
- Bester et al, 2012. J Vasc Interv Radiol 2012; 23:96–105.