Surgeons have successfully treated some patients with limited cancer spread (a phenomenon dubbed oligometastasis) by removing the primary and one or two distant tumours - usually in the lung or liver. Other patients with such disease, however, are not fit for surgery or have cancer that's inoperable.
With this in mind - and spurred by recent improvements in tumour detection and image-guided radiation therapy - Ralph Weichselbaum, professor and chairman of radiation and cellular oncology at the University of Chicago, set up a clinical trial to test the ability of hypofractionated radiation therapy to control a limited number of related tumours.
From November 2004 to March 2007, 29 patients with 56 metastatic lesions were enrolled in the trial. All participants had stage-IV cancers, between one and five distant metastases, and tumours of 10 cm or less in diameter. Twenty-four of the patients had progressed after at least one round of systemic chemotherapy, while no suitable therapy was available for the other five.
Each patient received three doses, separated by at least two days, of precisely targeted radiation focused on each metastatic tumour. Patients received CT scans of the chest, abdomen and pelvis, plus 18F-fluorodeoxyglucose PET, one month after treatment and then every three months, with a median follow-up of 14.9 months.
Many of the patients had a complete response in at least one tumour. Six of the 29 had lasting tumour control, with no detectable evidence of disease 15 months after treatment. Of the 56 treated tumours, 31 completely disappeared, while two had a partial response (reduction in tumour volume of more than 30%). Only three of the tumours progressed, growing in size by 20% or more during the treatment phase.
"This was proof-of-principle in patients who had failed the standard therapies and had few, if any, remaining options," explained Weichselbaum. "We had encouraging results, including several long-term survivors, in patients with stage-IV cancers that had spread to distant sites."
Dose dependent
The first subjects in the study received lower radiation doses. The dose was then gradually increased in subsequent patient groups. "Previous studies determined the maximal radiotherapy doses for single organs, but this technique has not been tested for simultaneous use on multiple organs," explained Joseph Salama, current director of the study. "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."
The researchers noted that tumour control improved as radiation dose increased. Of 31 tumours treated with 24 Gy of radiation, 39% met the criteria for tumour control - a complete or partial response. That figure increased to 79% for the 19 tumours treated with 30 Gy and to 83% for six tumours treated with 36 Gy.
"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."
According to the study authors, patients tolerated the treatment with "limited difficulty". All experienced fatigue but few had serious side-effects. The most severe side-effects included one patient with abdominal tumours developing vomiting that required hospitalization. One lung cancer patient developed a severe cough and one patient had gastrointestinal bleeding three months after treatment.
The authors point out that careful patient selection - distinguishing between those who have a treatable number of tumours and those with widespread metastases - is critical for this approach. They note that there are currently no known genetic "signatures" to differentiate widespread cancer from oligometastasis, although this is an area of active research. Only five of the 29 patients treated so far, however, had tumour progression in more than five sites.
The trial is still underway, with about 50 patients now enrolled. "Several of them remain disease-free, one of them three years after treatment," said Weichselbaum.