Dose-escalated hypofractionated radiotherapy yielded a maximum tolerated dose for patients with locally advanced non-small-cell lung cancer (NSCLC) and shed light on dangerous toxicity at higher doses, according to a new study. The toxicity was dominated by late radiation toxicity to the central and perihilar structures including the proximal bronchial tree and surrounding vasculature.
“In most of the randomized concurrent chemotherapy trials, patients were treated to doses of 60 to 66 Gy but nevertheless still experienced local failure rates of approximately 30%,” wrote authors led by Donald M. Cannon, MD, of the Mountain States Tumor Institute in Twin Falls, Idaho. “Given these suboptimal results, strategies of treatment intensification to improve outcomes continue to be explored.”
The new phase I study, published online ahead of print on October 21 in the Journal of Clinical Oncology, enrolled 79 patients with NSCLC at a single institution. After five patients were treated on a pilot study at a dose of 57 Gy of hypofractionated radiotherapy, the study’s dose escalation protocol (without any concurrent chemotherapy) proceeded. Forty-seven of the patients ended up receiving only the 57 Gy base dose; 11 patients received 63.25 Gy, 3 received 69.25 Gy, 12 received 75 Gy, 4 received 80.5 Gy, and 2 received 85.5 Gy. The median dose was 57 Gy in 25 fractions.
After a median follow-up period of 17 months, the median overall survival rate was 16 months; 29% of the cohort survived to 3 years. There was no difference seen in rates of local control between those treated at 69.25 Gy and higher and those treated at the lower 57 and 63.25 Gy doses (P = .81).
The maximum tolerated dose was established at 63.25 Gy. There were no cases of grade 3 or higher radiation pneumonitis, and 12 patients (16%) had grade 2 pneumonitis. There were also no instances of grade 3 or worse acute or late esophageal toxicities, though 48% of the cohort experienced grade 2 esophagitis.
Six grade 4 or 5 toxicities were deemed likely to be related to radiotherapy. One patient treated at 63.25 Gy died from progressive hypoxemia with bilateral lung infiltrates without disease progression 1 month after therapy. Three patients treated at 75 Gy and above died from massive hemoptysis 8 or more months after the therapy. Univariate analysis showed that higher delivered dose was significantly associated with development of any grade 4 to 5 toxicity, with a hazard ratio of 1.13 (95% CI, 1.04-1.23; P = .0036).
While the study suggests this therapy up to 63.25 is well tolerated, the authors noted that “our results are a reminder that the spectrum of toxicities from dose-intensified thoracic radiotherapy can be broad.” The results have implications for design of trials aiming to improve rates of local control. “In addition to controlling for pneumonitis risk, radiation dose-escalation studies in lung cancer should require strict limits to doses received by the proximal bronchial tree,” they concluded.
E-cigarettes and electronic nicotine delivery systems should be better..E-cigarettes and electronic nicotine delivery systems (ENDS) have not been scientifically validated and may be more dangerous than they are often considered, according to the International Union Against Tuberculosis and Lung Disease. The Union issued a newposition statementin November on e-cigarettes and ENDS, calling for stricter regulation of these products, which are rapidly growing in popularity.
“Right now, significant numbers of people around the globe are using these products,” said Jose Luis Castro, the interim executive director of the organization, in a press release. “They just don’t know what they are ingesting, what that might mean for their health in the long term or what their use of e-cigarettes and ENDS means for the people around them. It is an echo of the traditional cigarette industry in the 20th century, which created the current global epidemic of tobacco-related harm and mortality. To avoid repeating the same mistakes, we need to act now to regulate e-cigarettes and protect consumers around the world.”Importantly, the Union asserts that the safety of these devices has not been scientifically demonstrated. In general, it is claimed that they release only water vapor, but “adverse health effects for third parties exposed cannot be excluded because the use of electronic cigarettes leads to emission of fine and ultrafine inhalable liquid particles, nicotine, and cancer-causing substances into indoor air,” according to the position statement. Anassessment by the German Cancer Research Centerfound that the aerosol of some liquids in the devices contains substances including formaldehyde, acetaldehyde, acrolein, diethylene glycol, chromium, and lead.And aside from potential third-party health effects, the efficacy of the devices themselves has yet to be conclusively proven. They are intended as smoking cessation aids, but research on their efficacy as such has been somewhat inconclusive. Some people do indeed cut back or quit smoking using e-cigarettes.
Among the only randomized trials on their efficacy was conducted in New Zealand. The study randomized 657 smokers who wanted to quit to either nicotine e-cigarettes, nicotine patches, or placebo e-cigarettes. After 6 months, verified abstinence from smoking was found in 7.3% of nicotine e-cigarette patients, 5.8% of patch patients, and 4.1% of placebo patients; they concluded that there was thus insufficient statistical power to determine any differences, and that more research is “urgently needed” to establish benefits of the devices.
The Union also points out that regulation of e-cigarettes and ENDS varies widely around the world, and they advocate regulating them as medicines. Some countries, including Brazil, Norway, and Singapore, have simply banned the devices.
“E-cigarette and ENDS manufacturers and vendors have been vocal about the supposed benefits of their products and quick to shout down calls for regulation or questions about their contents,” Castro said. “Based on our review of the available evidence, we strongly support the regulation of the manufacture, marketing, and sale of electronic cigarettes or electronic nicotine delivery systems; and our preferred option is to regulate these products as medicines.”
Lung cancer is the number one cancer killer in the U.S., causing more deaths than the next three most common cancers – colon, breast and prostate – combined. Worldwide, lung cancer accounts for 1.3 million deaths annually. An estimated $10.3 billion per year is spent in the U.S. on lung cancer treatment alone, yet those diagnosed with the disease have just a 15 percent survival rate.1
Physicians at The University of Texas MD Anderson Proton Therapy Center are leaders in the research and treatment of lung cancer and pioneers in developing proton therapy for lung cancer patients. With its advanced image guidance and ability to precisely target tumors in the lungs, the powerful radiation of protons can be delivered with optimal accuracy – sparing critical nearby structures, such as the esophagus, heart and spinal cord. Because the tumor can be treated with a higher dose of radiation, benefits may include better local control of the disease, higher survival rates and improved quality of life.
“MD Anderson is at the forefront of the most advanced lung cancer treatments available. It is part of our mission to raise awareness of proton therapy as a potential option for people fighting for their lives,” says James D. Cox, M.D., former head of Radiation Oncology at MD Anderson. “When the Proton Therapy Center was established in 2006, for example, it was the first to treat lung cancer with protons and chemotherapy.”
Proton Therapy at MD Anderson
Roughly 15 to 20 percent of lung cancer patients have tumors that can be treated with surgery combined with other therapies such as radiation. Another 30 to 50 percent of patients have locally advanced tumors that require a combined treatment regimen that includes chemo or targeted therapy in addition to radiation therapy. However, it is challenging to deliver an adequate dose of radiation to a cancerous tumor while sparing nearby normal tissues.
Proton therapy’s advantage for many lung cancer patients is based on this feature. Further, by minimizing the exposure of normal tissues, proton treatment may also reduce some of the side effects of traditional radiation and help patients maintain good quality of life.
Proton therapy is currently available at only 11 centers in North America (13 centers are in development). MD Anderson has one of the largest and most technically advanced centers in the world. The 96,000-square foot Proton Therapy Center – the first proton center in the world within a comprehensive cancer center – offers a range of proton treatment options. These include pencil beam proton therapy, a highly precise form of proton radiation also known as scanning beam, and intensity-modulated proton therapy (IMPT) – the most advanced form of proton radiation. For patients with recurrent lung cancer, who have already received full doses of traditional radiation, pencil beam and intensity-modulated therapies may further limit or eliminate radiation to sensitive areas.
The Proton Therapy Center treats as many as 900 patients annually. Nearly 5,000 patients have been treated to date, accounting for 15 percent of the total number of patients who have received proton treatment nationally. Approximately 1,000 of these patients have been treated for lung cancer. The best lung cancer candidates for proton radiation are those whose cancer is localized in the chest and can’t be removed surgically, notes Cox.
“We’re just beginning to see the potential benefits of proton therapy and as we move forward it looks more and more like an excellent treatment modality,” says Anne S. Tsao, M.D., associate professor in Thoracic/Head and Neck Medical Oncology. “As we learn more and gather evidence of these benefits, proton therapy will likely be extended to a broader patient population.”
“We’re just beginning to see the potential benefits of proton therapy and as we move forward it looks more and more like an excellent treatment modality,” says Anne S. Tsao, M.D., associate professor in Thoracic/Head and Neck Medical Oncology. “As we learn more and gather evidence of these benefits, proton therapy will likely be extended to a broader patient population.”
Research
Cox explains the outcomes of proton therapy with concurrent chemotherapy, how lung cancer patients typically tolerate treatment and what the future holds for lung cancer patients being treated with proton therapy at MD Anderson.
The Proton Therapy Center is advancing the science of proton therapy by providing answers to critical knowledge gaps, confirming the effectiveness of proton therapy and evaluating its use in combination with chemotherapy, targeted molecular therapies and conventional radiation therapy.
Every patient treated at the Proton Therapy Center is offered the opportunity to participate in one of more than 25 clinical protocols, which allow for the capture, analysis and reporting on treatment results related to tissue toxicity, dose optimization, and quality of life.
Lung cancer patients, for example, may take part in a phase II randomized clinical trial comparing high-dose traditional intensity-modulated radiation therapy (IMRT) with high-dose proton therapy. MD Anderson researchers are also investigating such areas as long-term outcomes for patients with locally advanced lung cancer treated with proton therapy and survival rates among proton lung patients versus those treated with traditional radiation and chemotherapy.
Since 2005, MD Anderson has published more than 175 studies focused on proton therapy for lung cancer. Recent findings include:
Concurrent chemoradiation therapy, the standard of care for locally advanced non-small-cell lung cancer (NSCLC), can cause esophagitis and pneumonia, and X-ray-based radiation often cannot be given at doses high enough to destroy tumor cells without toxicity to nearby normal tissues. In a study published in thejournal Cancer, researchers showed that higher doses of proton radiation can be delivered to lung tumors with lower risk of these life-threatening conditions.
Comparing toxicity and tumor coverage delivered to stage 1 NSCLC patients via traditional stereotactic body radiation therapy, passively scattered proton therapy and intensity-modulated proton therapy, researchers found that: the proton radiation approaches were better in terms of target volume coverage; significantly reduced the mean total lung dose; and reduced mean maximal dose to other nearby critical structures, including the aorta, heart, pulmonary vessels and spinal cord. The study was published in theInternational Journal of Radiation Oncology, Biology, Physics.
Proton Therapy Center researchers have completed phase I of a study, published in the International Journal of Radiation Oncology, Biology, Physics, examining the effect of shorter courses of proton beam therapy in patients that have locally advanced NSCLC but that cannot receive chemotherapy with radiation. Using higher doses of proton beam therapy, treatment was typically completed in approximately three weeks.
“Advances are rapidly occurring in the field of proton therapy for lung cancer. Consider the ability to precisely target a tumor that moves with every breath or radiating a recurrent cancer that previously we wouldn’t have because of the toxic effects of earlier treatments,” says Daniel Gomez, M.D., assistant professor in Radiation Oncology. “Evidence-based innovations in proton therapy are making it possible to treat complicated tumors that traditional forms of radiation can’t target as effectively. As more patients are treated, the technology will continue to improve.”
Este Artículo es con fines informativos, se reflejan sus fuentes.
