Cancer Survivors With Low Volume Metastases May Benefit From Radiotherapy

“Precisely targeted radiation therapy can eradicate all evidence of disease in selected patients with cancer that has spread to only a few sites, suggests the first published report from an ongoing clinical trial. … Six of the 29 [21%] initial patients had lasting tumor control, with no detectable evidence of disease 15 months after treatment. Many patients had a complete response in at least one tumor. Thirty-one of the 56 treated tumors (55%) completely disappeared. Two tumors (4%) had a partial response, defined as reduction in tumor volume of more than 30 percent. Only three of the 56 tumors progressed (5%), growing in size by 20 percent or more during the treatment phase … Crucial to this approach is careful patient selection, distinguishing between patients who have a treatable number of tumors and those who have widespread metastasis, including multiple tumors too small to detect. Currently, there are no known genetic “signatures” to differentiate between widespread cancer versus oligometastasis, the authors point out.”

Image-Guided Radiation Therapy Used To Treat "Oligometastasis"

Image-Guided Radiation Therapy (IGRT) Used To Treat "Oligometastasis"

“Precisely targeted radiation therapy can eradicate all evidence of disease in selected patients with cancer that has spread to only a few sites, suggests the first published report from an ongoing clinical trial.

In the August 15, 2008, issue of Clinical Cancer Research, (published online August 12) researchers from the University of Chicago Medical Center report that targeted radiation therapy had completely controlled all signs of cancer in 21 percent of patients who had five or fewer sites of metastatic disease.

‘This was proof of principle in patients who had failed the standard therapies and had few, if any, remaining options,’ said the study’s senior author, Ralph Weichselbaum, MD, professor and chairman of radiation and cellular oncology at the University of Chicago Medical Center. “We had encouraging results, including several long-term survivors, in patients with stage-IV cancers that had spread to distant sites.’

In 1994, Weichselbaum and colleague Samuel Hellman proposed that there was an intermediate state between cancer that had not spread at all and cancer that had spread extensively. They named this phenomenon “oligometastases,” meaning cancer that had spread to a few distant sites.

In some cases, surgeons have successfully treated such limited cancer spread, producing long-term survival by removing the primary cancer and one or two distant tumors, off-shoots of the original cancer–usually in the lung or liver. However, some patients are not fit for surgery or have cancer that is inoperable.

Recent improvements in tumor detection and precise image-guided radiation therapy, however, have made simultaneous treatment of multiple tumor sites with radiation feasible. So in 2004, Weichselbaum organized a clinical trial to test the ability of local radiation therapy to control a limited number of related tumors which colleague Joseph Salama, MD, assistant professor of radiation oncology at the University of Chicago has directed since 2005.

Patients with stage-IV cancer with one to five distant metastases and no tumors bigger than 10 centimeters (about four inches) in diameter were eligible to participate in the study either before or after chemotherapy treatment.

Each patient received three doses, separated by at least two days, of precisely targeted radiation therapy focused on each metastatic tumor. Treatment was usually completed within one week. The first patients in the study received lower doses. As few side effects were seen, radiation doses were gradually increased in subsequent groups of patients.

‘Previous studies determined the maximal radiotherapy doses for single organs,’ said Salama, lead author of the study, ‘but this technique has not been tested for simultaneous use on multiple organs. So we designed a dose-escalation trial to determine the optimal dose, starting with fairly low levels and increasing the dose in later groups of patients.’

From November 2004 through February 2008, 29 patients, with a total of 56 cancerous lesions, enrolled in the trial. Of the 29 patients, 24 had progressed after at least one round of systemic chemotherapy. For the other five, there was no promising choice of therapy.

Six of the 29 initial patients had lasting tumor control, with no detectable evidence of disease 15 months after treatment.

Many patients had a complete response in at least one tumor. Thirty-one of the 56 treated tumors (55%) completely disappeared. Two tumors (4%) had a partial response, defined as reduction in tumor volume of more than 30 percent. Only three of the 56 tumors progressed (5%), growing in size by 20 percent or more during the treatment phase.

Tumor control improved as the radiation dose increased. Thirty-nine percent of the 31 tumors treated with 24 gray of radiation met the criteria for tumor control–a complete or partial response. That increased to 79 percent for the 19 tumors treated with 30 gray, and to 83 percent for the six tumors treated with 36 gray.

‘This suggests that the initial doses were too low,’ said Salama. ‘We have seen improved response rates with higher radiation doses without an increase in side effects yet.’

Typical treatment doses for a patient with breast cancer, for example, are in the range of 50 to 60 gray, spread over 20-30 sessions. The trend however, is toward delivering higher doses in fewer sessions.

Patients tolerated the treatment, the authors write, with ‘limited difficulty.’ All had some fatigue but few had serious side effects. The most severe included one patient being treated for abdominal tumors who developed vomiting that required hospitalization. One lung cancer patient developed a severe cough. One patient had gastrointenstinal [sic] bleeding three months after treatment that required blood transfusion and laser treatment.

Crucial to this approach is careful patient selection, distinguishing between patients who have a treatable number of tumors and those who have widespread metastasis, including multiple tumors too small to detect. Currently, there are no known genetic “signatures” to differentiate between widespread cancer versus oligometastasis, the authors point out. This is one area of active research. Only five of the 29 patients treated so far, however, had tumor progression in more than five sites.

The technique could also be applied after chemotherapy, the authors suggest, in cases where the drugs had eliminated most the smaller cancer, leaving only a few larger tumors behind.

The trial is still underway. ‘We now have about 50 patients,’ said Weichselbaum, ‘and several of them remain disease-free, one of them three years after treatment.’

The Ludwig Center for Metastasis Research and the University of Chicago Cancer Research Center funded this study. Additional authors include Steven Chmura, Neil Mehta, Kamil Yenice, Walter Stadler, Everett Vokes, Daniel Haraf and Samuel Hellman, of the University of Chicago Medical Center.”

Quoted Source: Targeted Radiation Therapy Can Control Limited Cancer Spread, Press Release, The University of Chicago Medical Center, August 15, 2008 (summarizing the findings of An initial report of a radiation dose-escalation trial in patients with one to five sites of metastatic disease; Salama JK et. al., Clin Cancer Res. 2008 Aug 15;14(16):5255-9. (” … RESULTS: Twenty-nine patients with 56 metastatic lesions were enrolled from November 2004 to March 2007, with a median follow-up of 14.9 months. Two patients experienced acute (radiation pneumonitis and nausea) and one experienced chronic (gastrointestinal hemorrhage) grade >/=3 toxicity. Fifty-nine percent of patients responded to protocol therapy. Twenty-one percent of patients have not progressed following protocol treatment. Fifty-seven percent of treated lesions have not progressed at last follow-up. Progression was amenable to further local therapy in 48% of patients. CONCLUSIONS: Patients with low-volume metastatic cancer can be identified, safely treated, and may benefit from radiotherapy.”))

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A Celebration of Libby’s Life

Elizabeth Kay Remick

Elizabeth Kay Remick

Elizabeth Kay Remick passed away peacefully at 11:33 A.M. on Monday, July 28, at home with family by her side. Our family was blessed with Libby’s presence for 26 years. She battled ovarian cancer for 18 months with courage and an indomitable spirit.

A celebration of Libby’s life will be held on August 17th at 2:00 P.M. E.D.T. at the Highlands at Newberry Estates, in Dallas, Pennsylvania. We invite everyone who shared her life to gather, remember, and honor Libby … a precious wife, daughter, sister, cousin, niece, and friend. For those inspired, there will be an opportunity to share memories and experiences of being touched by such a wonderful person.

To honor Libby’s fight against ovarian cancer, a charitable organization will be established to expand upon the critical mission of the Libby’s H*O*P*E* weblog, which is to increase ovarian cancer awareness and provide educational support to ovarian cancer survivors and their families. In life, Libby always showed care and concern for those around her, but her spiritual legacy will shepherd the future charitable organization to uplift and empower countless ovarian cancer survivors on a wide-reaching global scale.

In lieu of flowers and cards, Libby’s family suggests that a small donation be made to the Ovarian Cancer Research Fund (OCRF). The OCRF is the largest private funding agency in support of ovarian cancer research. To date, OCRF has awarded $23 million in grants for the formulation of early diagnostic treatment programs and research towards the ultimate conquest of ovarian cancer.

Please CLICK HERE if you would like to make a donation to OCRF in Libby’s name and celebrate her life with a short written comment that will appear under her OCRF Wall of Hope tribute (written by Libby’s husband).

Combination Targeted Therapy With Sorafenib & Bevacizumab Shows Antitumor Activity

The results from a recent Phase I solid tumor clinical trial indicate that combination targeted therapy with sorafenib and bevacizumab produces anti-tumor activity (and enhanced toxicity) with respect to 43% of the ovarian cancer patients enrolled in that trial. Sorafenib (Nexavar®) inhibits the Raf kinase and vascular endothelial growth factor (VEGF) receptor. Bevacizumab (Avastin®) is a monoclonal antibody targeted against VEGF.

Dr. Elise Kohn, Principal Trial Investigator, NCI Center for Cancer Research

Dr. Elise Kohn, Principal Trial Investigator, NCI Center for Cancer Research

The results from a recent Phase I solid tumor clinical trial indicate that combination targeted therapy with sorafenib and bevacizumab produces antitumor activity (and enhanced toxicity) with respect to 43% of the ovarian cancer patients enrolled in that trial. Sorafenib (Nexavar®) inhibits the Raf kinase and vascular endothelial growth factor (VEGF) receptor. Bevacizumab (Avastin®) is a monoclonal antibody targeted against VEGF. The trial is sponsored by the National Cancer Institute (NCI) and Elise Kohn is the principal trial investigator.

The patients enrolled in the trial had advanced solid tumors, with Eastern Cooperative Oncology Group performance status of 0 to 1. A phase I dose-escalation trial of sorafenib and bevacizumab was initiated at below-recommended single-agent doses because of possible overlapping toxicity: sorafenib 200 mg orally twice daily and bevacizumab intravenously at 5 mg/kg (dose level (DL1)) or 10 mg/kg (dose level (DL2)) every 2 weeks. Additional patients were enrolled at the maximum-tolerated dose (MTD).

Thirty-nine patients were treated under the trial protocol. DL1 was the MTD and was administered to 27 patients. Dose-limiting toxicity in DL2 was grade 3 proteinuria and thrombocytopenia. Adverse events included hypertension, hand-foot syndrome, diarrhea, transaminitis, and fatigue. Partial responses (PRs) were seen in six (43%) of 13 patients with ovarian cancer (response duration range, 4 to 22+ months) and one of three patients with renal cell cancer (response duration, 14 months). PR or disease stabilization ≥ 4 months (median, 6 months; range, 4 to 22+ months) was seen in 22 (59%) of 37 assessable patients. The majority (74%) required sorafenib dose reduction to 200 mg/orally at a median of four cycles (range, one to 12 cycles).

The trial investigators concluded that combination therapy with sorafenib and bevacizumab has promising clinical activity, especially in patients with ovarian cancer. The trial investigators also noted that the rapidity and frequency of sorafenib dose reductions indicates that sorafenib at 200 mg twice daily with bevacizumab 5 mg/kg every 2 weeks may not be tolerable long term, and alternate sorafenib dosing schedules should be explored.

Source: Combination targeted therapy with sorafenib and bevacizumab results in enhanced toxicity and antitumor activity; Azad NS et. al., J Clin Oncol. 2008 Aug 1;26(22):3709-14.

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