CHICAGO—Radiotherapy plus chemo-therapy is the mainstay of treatment for locally advanced non-small cell lung cancer (NSCLC), but these poor-prognosis patients have a high rate of -locoregional failure and distant metastases. Standard therapy leads to a cure rate of only 10% to 30%, with high morbidity and high toxicity. “Since the introduction of radiotherapy and chemotherapy we have seen significant changes in clinical practice, but the absolute increase in survival in these patients has been small,” said Michael Baumann, MD, of the University Hospital Carl Gustav Carus and Technical University of Dresden, Germany, at a Special Session on “Per-sonali-zed Medicine in Locally Advanced NSCLC” here at the ASCO Annual Meeting.
“Some patients in clinical trials show gains with new treatments. This demonstrates this disease has biological heterogeneity, and calls for personalized medicine.”
Locally advanced NSCLC therapy should be curative with personalized medicine, commented ASCO 2009-2010 President Douglas Blayney, MD. “There is a bigger gap in what we know and what we would like to know. There are no biomarkers as yet to identify treatment benefit or -toxicity.”
Lung cancers clearly have a defect in the ability to control genomes and repair double-stranded DNA breaks. This mechanism is mediated by p53, the most common mutation protein found in lung cancer, but there are no current therapies that target p53.
What’s known is that patients with cell sensitivity to double-stranded DNA breaks have poorer outcomes. They may have genetic lesions induced by cigarette smoking, Dr. Blayney said. “If we could convert p53 to wild type, that might improve the efficacy of chemo-radiotherapy in a molecularly targeted way; p53 protein restoration or conversion to wild type is the Holy Grail to work towards in targeted treatment of -locally advanced disease.”
Potential biomarkers may help identify features of tumors to select better therapy. Development of a therapeutic index might be able to determine whether normal tissue is better able to handle a particular radiation insult than tumor tissue is.
Plasma proteomics may identify toxicity markers to allow the use of the lowest radiation doses and thereby lower the risk of toxicity. And more advanced studies will generate useful prediction markers on which drug and radiation combinations may interact synergistically to improve outcomes, Dr. Blayney said.
4-D & Adaptive RT
External-beam radiotherapy, often combined with chemotherapy, is the treatment of choice for locally advanced inoperable lung cancer. Locoregional control and disease-free survival, however, are limited with the current clinically applied treatment strategies.
An important factor is the inability to deliver sufficiently high dose levels. The main limiting factor is a lack of geometrical accuracy, which impedes further escalation of the radiation dose.
“We have a real opportunity to improve results with biological modification of radiotherapy through technical modifications,” said Michael Brada, MD, Professor of Clinical Oncology at the Institute of Cancer Research and Royal Marsden NHS Trust in London.
Conformal radiotherapy can identify tumor margins and the spread of microtumors. “We can treat patients with multiple radiation beams to provide high-dose treatment and minimize damage to surrounding tissue based on efficacy biomarkers.”
Recent developments in imaging, treatment planning, and treatment delivery have the potential to increase the efficacy of lung cancer radiation therapy. Imaging techniques that correlate with a patient’s respiratory patterns can now produce four-dimensional (4-D) scans that represent the patient’s anatomy through computed tomography and the patient’s biology through positron emission -tomography (PET). PET scans provide information on heterogeneous lung tumor characteristics, noted Dr. Brada.
“4-D radiotherapy provides real-time tracking of both amplitude and frequency of an individual patient’s breathing pattern. The technology is now available to have real-time positioning of lung tumors, with the benefit of sparing normal lung tissue. This can reduce the mean radiation dose to the lung by 10 to 20 percent, which translates into a real benefit.”
In addition, repetitive imaging during treatment can quantify patient-specific parameters and allow for progressive variations in radiotherapy—i.e., adaptive radiotherapy, which has the potential to considerably improve the accuracy of radiation, reducing the exposure to the lungs, facilitating safe dose escalation, and improving local control as well as overall survival.
Dr. Brada said he routinely uses adaptive radiotherapy for patients with locally advanced lung cancer. In general, lung tumors change positions slightly during a six-week course of radiotherapy and shift during consolidation. “We adjust the volume of radiotherapy halfway into treatment. This translates into a real benefit by reducing the radiation dose to the lung by 5 Gy,” he said.
“We have the technological ability to individualize radiotherapy doses.”
Four-dimensional and adaptive radiotherapy devices can easily be added to conventional radiotherapy approaches in the treatment of lung cancer. “This requires some expertise, but is not beyond the scope of conventional radiotherapy departments,” he said. “We routinely use adaptive breathing control in our lung cancer patients, with more than 90% compliance.”
Individualized radiotherapy is the equivalent of using pharmacodynamics in medical oncology to find the best tolerable dose, said Dr. Blayney. “A personalized radiation dose is an eye-opener and a nice technical advance.” So far, clinical outcomes are based on a small number of trials, and clinical trials are needed with survival endpoints before this becomes widely accepted, he said.
Molecular Targeted Agents
In addition to optimizing radiotherapy, another current strategy to improve the treatment of Stage III disease has been the introduction of molecular targeted agents. There are 60 ongoing Phase I/II trials combining radiotherapy with molecular targeted agents, noted Jean-Charles Soria, MD, of Gustave Roussy Institute of Cancer in Paris.
One of the most promising is a novel tyrosine kinase inhibitor that shows impressive clinical activity with an excellent safety profile for advanced NSCLC patients who have a specific oncogene fusion. When the ALK gene fuses with another gene, it promotes lung cancer cell growth by encoding the production of a tumor-specific protein called anaplastic lymphoma kinase, or ALK—an enzyme that is critical for the growth and development of cancer cells.
About 5% of NSCLC patients have ALK gene fusions, said Dr. Soria, and patients with ALK-positive NSCLC do not appear to respond to epidermal growth -factor receptor (EGFR) tyrosine kinase -inhibitors.
In one of the four plenary papers at the ASCO Annual Meeting, crizotinib (PF-02341066), an experimental drug that works by inhibiting the ALK enzyme, was found to have impressive clinical activity in an expanded Phase I study of 82 ALK-positive NSCLC patients, as reported by Yung-Jue Bang, MD, of Seoul National University College of Medicine.
At eight weeks, 87% of the patients who received crizotinib responded to treatment, and more than half (57%) had tumor shrinkage. These results are an example of rapid clinical development from target identification to clinical validation and support a personalized approach to NSCLC treatment, said Dr. Bang.
Commented Dr. Soria: “We are moving away from pathology-based therapy in NSCLC and toward molecular characteristics and target-oriented therapy. This ALK inhibitor elicits superb responses after only eight weeks of therapy and shows that identifying molecular targets is a way to move forward.”
Dr. Soria’s research includes an ongoing Phase II trial of the mTOR inhibitor RAD001 combined with radiotherapy that is designed to use molecular characteristics to select patients who may be more sensitive to this approach. Dr. Brada added that future studies may include a combination of poly [ADP-ribose] polymerase 1 (PARP1) inhibitors with radiotherapy.
“Studies of molecular targeted therapies combined with radiotherapy provide an opportunity to use modern radiotherapy technology to target specific tissue,” he said.
Clinical information is already a powerful predictor in locally advanced disease, said Dr. Soria. Patients with T4 disease are more prone to relapse; those with N3 disease are more prone to metastatic spread. “What we need is a prognostic indicator to clarify Stage III local relapse versus metastatic relapse.”
While questions still remain about the molecular reality of advanced NSCLC, Dr. Soria said, “If I had Stage III disease, I would have a molecular portrait to help predict my radiotherapy sensitivity.”