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Radon’s Role in Lung Cancer
As we head in to National Lung Cancer Awareness Month, we are all aware of the role cigarettes and tobacco play in the cause of lung cancer. We also are aware that not ALL lung cancers are caused by smoking, and that 10% of men and 20% of women who are diagnosed in the U.S. with lung cancer are never-smokers.
So what other factors cause lung cancer in these patients? There are links between lung cancer and cooking oil fumes in homes without adequate ventilation in other parts of the world; links with air pollution both indoors and out; links with heavy metal exposures and concerns about diesel exhaust fumes. In the U.S. the second-most common cause of lung cancer behind tobacco exists as a silent presence inside a person’s own home.
Radon is a colorless, odorless gas. It is a naturally-occurring gas that forms as a breakdown product of the small quantities of uranium that exist in rock. As rocks break down over time, the gas is released upward. Radon gas in turn quickly breaks down into radioactive particles, which, when inhaled, can cause damage to the lung tissues leading to increased risk of lung cancer. In a ventilated outdoor area, radon is dispersed into the air into concentrations that are harmless. Radon can build up though in pockets in the earth, such as mines or contained caves, where there is little relative air movement. It can also build up in homes, where basements are a particular area of concentration.
When Will Patients with Squamous Cell Lung Cancer Get a Break?
When one reviews the excitement that has been generated over the last several years in regards to the advancement of therapy for NSCLC, it becomes painfully apparent that patients with adenocarcinoma have reaped the greatest benefits, and patients with squamous cell lung cancer have been more or less left out in the cold.
The addition of Avastin to doublet chemotherapy prolongs life for patients with non-squamous cell lung cancer, while patients with squamous cell lung cancers have an increased risk of life-threatening bleeding from the lungs. Although Tarceva can prolong survival for patients with advanced NSCLC of all histolologies that has grown after chemotherapy, patients with the greatest chance of benefit in the first-line or salvage setting (those with activating EGFR mutations) almost exclusively have adenocarcinoma. Alimta, a “traditional” chemotherapy drug with a much lower toxicity profile than most chemotherapy agents, was shown to be active in non-squamous cell lung cancers, and to have virtually no activity in squamous NSCLC. This caused Alimta to lose its indication for NSCLC of squamous cell histology.
Recently, a new mutation has been identified for NSCLC, the EML4-ALK translocation. This translocation, much like the EGFR activating mutations, drives cancer cell function in a dependent fashion, and inhibition with a novel c-met and ALK inhibitor is showing promise in early clinical data. Again, this mutation occurs in patients with non-squamous cell lung cancers, more commonly in lifetime never smokers.
So where is the drug for squamous cell lung cancer? Although squamous cell NSCLC is decreasing in frequency as adenocarcinoma of the lung becomes more common, squamous cell tumors are far from rare.
Can BCL-2 inhibitors make progress in SCLC?
The development of targeted therapy drugs has improved survival for patients with NSCLC, and the “pipeline” of agents in development awaiting further testing in clinical trials seems to be increasing by the day. The improvements in survival in particular subpopulations of patients with NSCLC inspires both patients and physicians who treat lung cancer to hope that similar gains may be made, perhaps incrementally, for patients in all subpopulations of NSCLC.
In contrast, progress in small cell lung cancer (SCLC) has been disappointingly slow. Although there was hope initially about improved survival with the combination of cisplatin and irinotecan over the “old standard” of cisplatin with etoposide based upon a trial in Japan, two randomized trials in a more heterogeneous North American population, one trial community-based and another conducted by SWOG, failed to show any survival advantage. The greatest gains we have thus seen recently for patients with SCLC come from radiation, with twice daily radiation improving survival for patients with limited-stage disease (for those patients who may be able to tolerate the increased toxicities) and prophylactic cranial irradiation (PCI) improving survival for patients with extensive stage disease.
This frustrating lack of improvement from a chemotherapy front does not come from lack of effort. Much like for NSCLC, a large number of targeted therapy drugs have been tested in SCLC, but with no major breakthroughs.
But lung cancer doctors are by definition optimists, and we are always hopeful that breakthroughs that make real differences in the lives of our patients may be just around the corner. One of the active areas of research involves BCL-2 inhibitors. BCL-2 is a protein involved in cell survival, and is overexpressed in many cancers, including SCLC. Overexpression of BCL-2 helps to protect a cancer cell from dying, and increased levels of BCL-2 expression help make a cancer cell more resistant to chemotherapy.
EGFR Mutations in African American Patients: What Little We Know
In the last several years we have seen an explosion in the knowledge and understanding of the molecular basis of cancer behavior. The identification of EGFR mutations, and their utilization in predicting response and survival in patients with untreated advanced lung cancer, provides lung cancer oncologists with the optimism that we may truly be able to offer effective “personalized therapy” for patients with lung cancer in the near future.
The majority of knowledge regarding EGFR mutations comes from studies of patients of East Asian ethnicity or of Caucasian backgrounds from either the US or Europe. It is evident and widely discussed from the data from these populations that lung cancer patients of East Asian ethnicity have a higher rate of EGFR mutation than Caucasian patients do.
What about patients however of other backgrounds? Do African American, Latino, or Native American patients have the same rates of EGFR mutations as Caucasians or East Asians, or are they different? How great is the disparity of mutation rate between never-smokers and those patients with a smoking history in these populations?
Avastin Alone or with Alimta Following First-Line Chemotherapy: A Tale of 3 Trials
For many years, chemotherapy for advanced or metastatic NSCLC had been limited to the use of “doublet” (two-drug) therapy using different combination regimens that were overall found to have very similar outcomes, but with different toxicity (side effect) profiles. Attempts to add a third chemotherapy agent for a triplet regimen, and numerous attempts to add different targeted-therapy agents, had dismal success. Not only did most of the combinations fail to improve on the survival outcomes, they increased the number of side effects compared with doublet chemotherapy alone.
Avastin was the first targeted therapy agent to improve upon these outcomes. In a landmark phase III trial conducted by the Eastern Cooperative Oncology Group (ECOG 4599), 878 patients with advanced NSCLC received either standard-of-care carboplatin with paclitaxel, or the same doublet chemotherapy with Avastin. Due to risks of fatal bleeding in patients with squamous cell NSCLC seen in an earlier study, this trial was restricted to patients with non-squamous NSCLC. Patients received 6 cycles of chemotherapy with or without Avastin, and those on the Avastin arm then received maintenance Avastin until disease progression or intolerable toxicity.
Median survival with the doublet regimen was consistent with survival outcomes from previous studies (10.3 months), while survival for patients on the Avastin arm was significantly superior by 2 months (12.3 months). Progression-free survival (PFS, the time it takes for a cancer to start growing on chemotherapy) was also improved with the triplet, with PFS of 6.2 months compared with 4.5 months with the doublet regimen alone.
Treatment of Locally-Advanced NSCLC in the Elderly: As Individualized as Medicine Gets
“Locally-advanced NSCLC” is a term generally applied to lung cancers with tumors that have either grown into major structures (such as vertebrae or spine bones, the central airways, or involve the main blood vessels supplying the lung or central chest) or those cancers that have spread to lymph nodes in the central chest (the mediastinum). In the case of many of these cancers, removing them with surgery is not possible, but treatment with the combination of chemotherapy and radiation given at the same time may be used with the goal of curing the cancer.
While administering chemotherapy and radiation at the same time (termed “concurrent therapy”) is more effective at killing cancer cells than when the treatments are given separately, this approach also causes increased side effects for the patient. Side effects may include nausea, vomiting, neutropenia (decreased levels of white blood cells which can lead to increased risk of infection) with or without infections, anemia, fatigue, and pain with swallowing (from radiation “sunburn” to the esophagus). In order for a patient to tolerate this rather stout combination, they need to be fairly healthy and active, and to have a strong physical reserve (measured with a term “performance status”).
Most studies of the combination of chemotherapy and radiation, although not excluding older patients, have enrolled younger patients. Typically, the average age of patients enrolled on trials like these is 64 or 65. This allows for decent conclusions to be drawn for patients of this age group and younger, but how do these studies apply to the elderly; patients 75, 80, older?
Cetuximab (Erbitux) for Advanced NSCLC: Promising Results, But is it Ready for Prime Time?
There has been quite a lot of discussion recently about the EGFR tyrosine kinase inhibitors (TKIs), erlotinib (Tarceva) and gefitinib (Iressa). Recently however the final results of the FLEX trial were published in The Lancet, bringing attention back to one of the antibodies against EGFR, cetuximab (Erbitux). Dr. West had previously written about the early presentation of results from this trial in a post after the ASCO meeting last year.
As a background, cetuximab is a monoclonal antibody that is given through the vein weekly. It has been shown to prolong life in combination with chemotherapy for patients with head and neck cancers, as well as for patients with colon cancers. The FLEX (First-Line ErbituX in lung cancer) study was a large randomized trial evaluating whether the combination of cetuximab with chemotherapy would prolong life for patients with NSCLC.
This study enrolled patients with NSCLC whose tumors showed staining by immunohistochemistry (IHC) for EGFR, even if it was only one tumor cell. Patients must have incurable NSCLC and could not have previously received chemotherapy. Of 1688 patients with tumors tested, 1442 demonstrated at least one cell positive for EGFR. 1125 patients were ultimately randomized to receive either six cycles of chemotherapy with cisplatin and vinorelbine (Navelbine) or the same chemotherapy with weekly Erbitux. Patients in the Erbitux arm who didn’t show progression after six cycles then continued to receive it weekly until progressive disease or until they experienced toxicity requiring stopping the drug.
Never-smoking Women with Lung Cancer: More Common or More Recognized?
When I joined GRACE earlier this month, a question was posed by a reader regarding whether there is an increasing frequency of the diagnosis of lung cancer in women who have never smoked. This is a very interesting question that those of us who specialize in lung cancer frequently wonder about.
We know that the vast majority of lung cancers in both men and women are caused by tobacco. Overall however, approximately 10% of lung cancers occur in never-smokers of both genders. In women more like 20% of lung cancers occur without a history of tobacco use. Other known risk factors for developing lung cancer, particularly in lifetime nonsmokers, include exposure to secondhand tobacco smoke (the most common reason, either through exposures in the home through a spouse or from parents when a child is growing up) or radon exposure. Asbestos is an agent that more frequently causes mesothelioma, but also increases lung cancer risk. In Asian countries, links have been drawn between certain cooking oils in poorly-ventilated homes and lung cancers. Heavy metal exposures such as nickel and cadmium have been tied to lung cancers, generally for people involved in the mining and heavy metal industries. Associations with diesel exhaust and other environmental air pollutants have been posed, as well.
The trouble with most studies looking at the “other” causes of lung cancer is that in most cases the results of the epidemiologic studies are clouded by the fact that many people evaluated have also had a smoking history. This makes the act of piecing together which compounds cause lung cancer on their own versus which are made worse by tobacco, or are completely unrelated, very difficult.
Statistics regarding cancer incidence and cancer deaths in the United States are published every year. We have finally seen a decrease in the incidence and death rates in men with lung cancer over the last several years. This has reflected the overall decrease in tobacco use. Women as we know have been slower to give up tobacco, but usage rates are also declining. Thus over the last several years, although we have not yet seen a decline in the incidence or death rates in lung cancer among women, we are at least seeing a plateau, or leveling of the curves.
Unfortunately what we do not have is comparable statistical information regarding how many of these patients, and what proportions, are never smokers. We know that the majority of lung cancers are now diagnosed in former tobacco users (thanks to the increasing quit rate), but we do not have a measure from year to year of the never smokers.
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