Liver tumors: 3-D MRI scans better predict survival after chemo

03/25/2014

In a series of studies involving 140 American men and women with liver tumors, researchers at Johns Hopkins have used specialized 3-D MRI scans to precisely measure living and dying tumor tissue to quickly show whether highly toxic chemotherapy – delivered directly through a tumor’s blood supply – is working.

The investigators say their findings, to be presented March 22-27 in San Diego at the annual meeting of the Society of Interventional Radiology, are the first “proof of principle” that this technology can show tumors in three dimensions and accurately measure tumor viability and death. Early data was also presented at the Radiological Society of North America annual meeting, December 1-6 in Chicago.

They also say their results – in patients with either primary liver cancers or metastatic tumors from cancers originating elsewhere in the body -- are evidence that using this technology before and after treatment is a faster and better tool for predicting patient survival after chemotherapy targeted directly at tumors, called chemoembolization.

Unlike standard methods to assess tumor response after chemoembolization, which are based on two-dimensional images and tumor size, the Johns Hopkins-developed 3-D technology also distinguishes between dead and live tissue, giving an accurate assessment of tumor cell death.

The new technology builds on standard 2-D methods and uses computer analytics to evaluate the amount of so-called contrast dye absorbed by tumor tissue. The dye is injected into patients before their MRI scan to enhance image production. Researchers say live tissue will absorb more dye than dead tissue, affecting image brightness, which can also be measured for size and intensity.

“Our high-precision, 3-D images of tumors provide better information to patients about whether chemoembolization has started to kill their tumors so that physicians can make more well-informed treatment recommendations,” says Johns Hopkins interventional radiologist Jean-Francois Geschwind, M.D., the senior investigator on the studies.

Geschwind, a professor in the Russell H. Morgan Department of Radiology at the Johns Hopkins University School of Medicine and its Kimmel Cancer Center, says that knowing the true extent of a tumor’s response to chemoembolization is particularly important for patients with moderate to advanced stages of the disease, whose liver tumors might initially be too large or too numerous to surgically remove.

In the first study, researchers compared the standard imaging method and the newly developed technology in 17 Baltimore men and women with advanced liver cancer. All were treated with surgery or liver transplantation after chemoembolization. The research team used existing MR analysis techniques, as well as the new 3-D method to compare the radiologists’ analyses with pathologic review of tumor samples after therapy and surgical removal. The error margin of the new 3-D image analysis, they say, was low (at up to 10 percent) when predicting the amount of dead tumor tissue found by pathologists whereas the standard, 2-D method deviated by as much as 40 percent from actual values.

In a series of additional studies, Geschwind and his team used the standard and new imaging techniques to analyze the MRI scans of more than 300 liver tumors in some 123 other men and women, also from the Baltimore region. All patients were treated at The Johns Hopkins Hospital between 2003 and 2012, and each received pre- and post-chemoembolization MRI scans to assess the effects of therapy on the tumors.

Using the new 3-D method method, Geschwind’s team found that patients who responded well to therapy lived 19 months longer (an average of 42 months) than patients who did not respond well (average 23 month survival). Standard methods showed slightly less difference in survival (average 18 months longer) between patients who responded to therapy and those who did not respond.

Geschwind says the 3-D technology’s improved accuracy removes a lot of the guesswork that now goes into evaluating treatment outcomes. The new assessment takes seconds to perform, he adds, so radiologists can provide faster, almost instantaneous treatment advice.

Geschwind and his team plan further software refinements to the new approach before training more physicians to use it. He also has plans to study how it can affect treatment decisions, and whether these therapy choices help people live longer.

The software used in the MRI scans was developed at Johns Hopkins and at Philips Research North America, in Briarcliff Manor, N.Y. Philips, whose parent company is based in the Netherlands, manufactures some of the MRI devices used in the study.

Liver cancer kills nearly 20,000 Americans each year, and is much more prevalent outside the United States, where it is among the top-three causes of cancer death in the world. Experts cite the rising numbers of hepatitis C infections, which cause chronic liver inflammation and are a leading risk factor for liver cancer.

Funding support for this study was provided by the French Society of Radiology and Philips Research North America. Additional funding support was provided by the National Cancer Institute, and the National Center for Research Resources, both members of the National Institutes of Health (R01 CA160771, P30 CA006973, and UL1 RR 025005), and the Rolf W. Günther Foundation for Radiology and Radiological Sciences.

In addition to Geschwind, Johns Hopkins scientists involved in the study were Julius Chapiro, M.D., Rafael Duran, M.D., Laura Wood, M.D., Ph.D., Vania Tacher, M.D., Toby Charles Cornish, M.D., Ph.D., Nikhil Bhagat, M.D., Constantine Frangakis, Ph.D., Hooman Yarmohammadi, M.D., Michael Chao, M.Sc., Rongxin Chen, M.D., Ph.D., Zhijun Wang, M.D., Ph.D., and Vivek Charu, M.D., Ph.D. Additional research assistance was provided by MingDe Lin, Ph.D., a Philips biomedical engineer based at Johns Hopkins who has been collaborating with Geschwind for the past seven years on the new technology.

Abstracts described in this news release include:

SIR abstracts:

1830145 Quantitative 3-D Volumetric Assessment of Tumor Response after Intra-arterial Therapy of Colorectal Cancer Metastases to the Liver - a new surrogate marker for survival;
Scientific Session TACE IV, Wednesday 3/26 - 1:39 PM - 1:48 PM, Room 16 A

1859360 Uveal Melanoma Metastatic to the Liver: the Role of Quantitative and Functional MR Imaging in the Assessment of Early Tumor Response after TACE;
Scientific Session TACE I, Sunday 3/23 - 2:42 PM - Room 16 A

1831150 Radio-pathological correlation of 3-D-quantitative contrast-enhanced and functional MRI in HCC patients after TACE- do we see what we treat?
Scientific Session TACE II, Monday 3/24 - 9:03-9:12 AM - Room 16 A

RSNA abstract:

SSSC16-07 Volumetric Tumor assessment Predicts Survival in Patients Treated with Transarterial Chemoembolization for Hepatocellular Carcinoma

For additional information, go to:
http://www.sirmeeting.org/
http://www.hopkinsmedicine.org/vascular/staff/physicians/geschwind.html
http://www.hopkinsmedicine.org/vascular/procedures/chemoembolization/

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Largest Comparative Study of Radioembolisation Shows SIR-Spheres Microspheres Significantly Improves Survival for Cancer Patients with Inoperable Liver Tumours

PRESS RELEASE

March 23, 2012, 10:00 a.m. EDT

ORLANDO, March 23, 2012 /PRNewswire via COMTEX/ -- New Australian Data Provides Further Evidence of Survival Benefit for Radioembolisation

Findings from the largest comparative multi-centre study performed to date using radioembolisation report a significantly prolonged survival benefit following SIR-Spheres microspheres in patients with treatment-refractory liver tumours from colorectal and other cancers. The results of the study were presented today at the 65th Annual Cancer Symposium of the Society of Surgical Oncology, by Associate Professor Lourens Bester, Director of Radiology at St Vincent's Hospital, Sydney.[1]

Radioembolisation, which is also called Selective Internal Radiation Therapy or SIRT, is a novel approach to treating liver tumours using microspheres labelled with radioactive yttrium-90 (90Y). The microspheres are implanted by interventional radiologists to selectively target the tumours with radiation while sparing the remaining healthy liver tissue.

Prof. Bester and his colleagues evaluated 463 patients with chemotherapy refractory liver-dominant tumours and found that "radioembolisation is associated with a significantly improved and clinically meaningful survival benefit. Whilst confounding factors may play a role, offering this treatment may confer the best prognosis for these patients," he said.

Among the 251 patients with colorectal liver metastases, median survival in the 220 patients treated with SIR-Spheres microspheres was 11.6 months, compared to only 6.6 months for the 31 patients who received standard or best supportive care (p=0.021). In 212 patients with liver tumours from other cancers, including cholangiocarcinoma (41), neuroendocrine (40), hepatocellular carcinoma (27), pancreatic (13) breast (11), gastric (9) and other cancers (71), median survival was 9.5 months in the 180 patients treated with SIR-Spheres microspheres versus 2.6 months in 32 patients who received standard or best supportive care (p=0.013).

"The significant improvement in overall survival in this study confirm the benefits demonstrated in two previous but smaller comparative studies that were performed in patients with treatment-refractory colorectal liver metastases, notably the multi-centre phase III randomised controlled trial conducted by Hendlisz and colleagues in Belgium, and the matched-pair analysis by Seidensticker and colleagues from Magdeburg, Germany, that reported median survivals of 10.0 and 8.3 months, respectively," Prof. Bester added.[2,3]

Two large international randomised controlled trials are currently underway to evaluate the effectiveness of adding radioembolisation using SIR-Spheres microspheres to first-line chemotherapy in order to assess whether this treatment should be used as an early intervention in the treatment of patients with colorectal cancer liver metastases. In addition, three large randomised controlled trials are evaluating radioembolisation using SIR-Spheres microspheres in hepatocellular carcinoma.

About the study

The aim of the study conducted at St Vincent's Hospital was to compare the outcomes of patients with liver tumours treated using radioembolisation with patients receiving standard or best supportive care alone in the setting of treatment-refractory disease.

All patients had chemotherapy refractory liver-dominant tumours with radiologically confirmed progression, and were no longer qualified for other treatment modalities such as resection, ablation or chemoembolisation.

The study excluded any patient with extensive extrahepatic metastases, symptoms that confined them to bed for more than 50% of the waking hours (ECOG performance status >2), excessive liver tumour burden (>75% of liver replaced by tumour) and/or compromised residual liver function.

Of the 463 patients who underwent initial evaluation for radioembolisation, 63 patients were considered unsuitable, due either to (a) hepatic arterial anatomy that could not be corrected and which could otherwise have led to complications, (b) extensive hepatopulmonary shunting between the liver and lungs, which raised the potential for excess radiation exposure to the lungs (>30 Gy), or (c) reasons relating to patient consent, such as a preference for another treatment option.

"The patients who were unsuitable for radioembolisation were referred back to their treating physician for conservative treatment or continued supportive care," explained Prof Bester. "This group was unlikely to represent patients with more advanced disease and was consequently used as a standard-care comparison cohort."

About Colorectal Cancer

In 2008, 153,000 people in the United States of America and 333,000 in the European Union were diagnosed with colorectal cancer.[4] Around half of these patients will develop metastases that have spread from the original site of the disease, predominately to the liver. Up to 90% of these patients ultimately die from liver failure due to the spread of the disease.

References:

Saxena A, Chua TC, Meteling B et al. Radioembolization with yttrium-90 microspheres is associated with a significantly improved survival compared to conservative therapy after treatment of unresectable hepatic tumors: A large single center experience of 537 patients. 65th Annual Cancer Symposium of the Society of Surgical Oncology, Asia-Pacific Journal of Clinical Oncology 2012; 7 (Supplement s4): Abstract 212.

Hendlisz A, Van den Eynde M, Peeters M et al. Phase III trial comparing protracted intravenous fluorouracil infusion alone or with yttrium-90 resin microspheres radioembolization for liver-limited metastatic colorectal cancer refractory to standard chemotherapy. Journal of Clinical Oncology 2010; 28: 3687-3694.

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. Cardiovascular and Interventional Radiology 2011; ePub doi: 10.1007/s00270-011-0234-7.

International Agency for Research on Cancer. GLOBOCAN 2008: Colorectal Cancer Incidence and Mortality Worldwide in 2008. http://globocan.iarc.fr/factsheets/cancers/colorectal.asp accessed 12/8/2011.

SOURCE St Vincent's Hospital Sydney Limited

Source

Multi-centre Phase II Trial Reports Safety and Clinical Benefits of Radioactive Microspheres in Patients with Colorectal Cancer Liver Metastases who have Failed Chemotherapy

Aug. 19, 2010, 9:36 a.m. EDT

ROME, August 19, 2010 /PRNewswire via COMTEX/ -- Radioactive yttrium-90 labelled resin microspheres (SIR-Spheres; Sirtex Medical, Sydney, Australia) appear to be a safe and effective treatment for patients with colorectal cancer liver metastases who have failed available chemotherapy options, according to the final results of a prospective clinical multi-centre phase II trial conducted by the Italian Society of Locoregional Therapies in Oncology (SITILO) and published in the British Journal of Cancer.[1]

The results of the 52-patient study revealed that the liver tumours completely disappeared in one patient (2%), and 11 (22%) patients had a partial response involving at least a 30% reduction in tumour size, which met the pre-determined criteria for significance (P = 0.05). A further 12 (24%) patients had stable disease. The liver tumours shrank sufficiently in two patients (4%) to enable potentially curative surgery to be performed. The median overall survival was 12.6 months for all patients in the trial, with significantly longer survival in the 24 (48%) patients that responded to SIR-Spheres or who had stable disease compared to non-responders (median 16 months versus 8 months; P = 0.0006), and 40% of the responders remaining alive at two years compared to none of the non-responders. Mild-to-moderate side effects consisting mostly of fever and pain were reported in 16% of patients in the first 48 hours and 22% in days 3 to 30.

"These results reveal that radioembolisation using SIR-Spheres is a promising therapy for patients with colorectal cancer liver metastases who have failed chemotherapy," said Prof. Maurizio Cosimelli, Professor of Surgery at the Regina Elena National Cancer Institute in Rome, and co-ordinator of the study. "The prolonged 12.6-month median survival and encouraging tumour response reported in the SITILO study compares favourably with the clinical trial results of second- or third-line chemotherapy, even though three-quarters of our patients had previously received at least four different combinations of chemotherapy drugs and therefore had a poor prognosis with no other treatment options available."

"At a minimum, patients with liver-only or liver-dominant colorectal cancer who are failing chemotherapy and who remain fit should be considered for radioembolisation using SIR-Spheres," said Prof. Cosimelli. "However, SITILO will be conducting a multi-centre randomised trial using SIR-Spheres in combination with chemotherapy at an earlier line of treatment since we believe that this may further improve the prognosis for patients with colorectal liver metastases. Above all, it will be possible to clarify the potential of SIRT together with chemotherapy to increase the rate of surgical resections in patients that were previously unresectable."

Patients in the SITILO study had to have liver metastases from colorectal cancer that could not be removed by surgery and which had progressed despite modern chemotherapy regimens containing oxaliplatin and irinotecan. The presence of metastases outside the liver did not exclude the patients from treatment as long as these were limited in number, size and in the same organ. All patients were heavily pre-treated, having received at least 3 previous chemotherapy regimens: 24% had received 3 different lines or courses of chemotherapy, 50% had received 4 lines and 26% had received 5 lines.

The SITILO study used a single-arm design since this group of patients had no other treatment options available. Patients were reviewed by a multidisciplinary team of cancer specialists prior to recruitment into the study. The median survival of metastatic colorectal cancer treated in clinical studies using modern chemotherapy regimens such as cetuximab plus irinotecan at second-line and panitumumab at third-line treatment has been reported to be 8.6 to 10.7 months[2-5] and 6.3 to 9.3 months[6-9] respectively.

Each year, more than 145,000 Americans and 307,000 Europeans are diagnosed with colorectal cancer. Around half of these patients will develop metastases that have spread from the original site of the disease, predominately to the liver. Up to 90% of these patients ultimately die from liver failure due to the spread of the disease. Selective Internal Radiation Therapy (SIRT) using 90Y microsphere therapy is a novel approach to treating liver metastases. The microspheres are implanted by interventional radiologists to selectively target the tumors with radiation while sparing the much-needed healthy liver tissue.

The SITILO study was conducted by a multidisciplinary team of interventional radiologists, nuclear medicine physicians, medical oncologists, surgeons and other specialists at the Regina Elena National Cancer Institute in Rome, the University of Bologna, the University of Udine and the Cancer Institute of Naples in Italy. SIR-Spheres was developed by, and is manufactured by, Sirtex Medical, and is the only FDA-approved microsphere therapy for colorectal cancer liver metastases.

SITILO is the only Italian multidisciplinary oncology society. Different specialties work together within SITILO to design prospective clinical trials on loco-regional therapies in the field of liver metastases and primary carcinoma, melanoma, soft tissue sarcoma, and other cancers. Each protocol includes a biological component aimed at identifying predictive factors in serum and tissue.

The SITILO trial was conducted at the following hospitals:

- Regina Elena Cancer Institute, Rome, Italy
- University of Bologna, Bologna, Italy
- University of Udine, Udine, Italy
- Fondazione Pascale Cancer Institute, Naples, Italy

References

1. Cosimelli M, Golfieri R, Cagol PP et al. Multi-centre phase II clinical trial of yttrium-90 resin microspheres alone in unresectable, chemotherapy refractory colorectal liver metastases. British Journal of Cancer 2010; 103: 324-331.

2. Sobrero AF et al. EPIC: Phase III trial of cetuximab plus irinotecan after fluoropyrimidine and oxaliplatin failure in patients with metastatic colorectal cancer. Journal of Clinical Oncology 2008; 26: 2311-2319.

3. de Cerqueira Mathias et al. Front cetuximab plus irinotecan in patients (pts) with metastatic colorectal cancer (mCRC) progressing on or after prior irinotecan therapy: final results of the LABEL study. ECCO meeting, European Journal of Cancer Supplements 2007; 5: Abs. P3055.

4. Wilke H et al. Cetuximab plus irinotecan in heavily pretreated metastatic colorectal cancer progressing on irinotecan: MABEL study. Journal of Clinical Oncology 2008; 26: 5335-5343.

5. Cunningham D et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. New England Journal of Medicine 2004; 351: 337-345.

6. Hecht JR et al. Panitumumab monotherapy in patients with previously treated metastatic colorectal cancer. Cancer 2007; 110: 980-988.

7. Van Cutsem E et al. Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. Journal of Clinical Oncology 2007; 25: 1658-1664.

8. Van Cutsem E et al. An open-label, single-arm study assessing safety and efficacy of panitumumab in patients with metastatic colorectal cancer refractory to standard chemotherapy. Annals of Oncology 2008; 19: 92-98.

9. Yoshino T et al. Phase II study of panitumumab (Pmab) monotherapy in Japanese patients (pts) with metastatic colorectal cancer (mCRC) after the failure of fluoropyrimidine, irinotecan (CPT-11), and oxaliplatin (OHP) chemotherapy. ASCO GI Symposium 2008; Abs. 366.

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