Late-stage lung cancer is often over-treated with radiation

Almost half of patients with advanced lung cancer receive more than the recommended number of radiation treatments to reduce their pain, according to a new study published in the Journal of the National Cancer Institute.

Radiation therapy that is palliative, or not intended to cure, can reduce the pain from lung tumors and improve quality of life. But unnecessary treatments add to costs and require needless trips to the hospital – and can lead to radiation toxicity and difficulty in swallowing.

Guidelines developed from clinical trials recommend no more than 15 radiation treatments be given for pain in stage 4 lung cancer. The guidelines recommend that patients not receive chemotherapy at the same time, to reduce the risk of toxicity.

The new analysis looked at 47,000 patients who received palliative radiation for stage 4 lung cancer in the U.S. between 2004 and 2012 and found that about one in five had received chemotherapy at the same time. Nearly a third of patients received more than 25 radiation treatments — 10 above the recommended maximum.

This study uncovered that there’s a lot of treatment of late-stage lung cancer with palliative radiation that goes beyond what is recommended by several national guidelines and multiple clinical trials,” said the study’s lead author, Dr. Matthew Koshy, a radiation oncologist at the University of Illinois Hospital & Health Sciences System.

More education is needed for radiation oncologists, to prevent over-treatment — which has not been proven to further improve symptoms or quality of life, and can have some significant side effects,” Koshy said.

The researchers also looked for any particular type of patient more likely to be overtreated.

Having private insurance was the number-one predictor of being overtreated,” Koshy said. Privately insured patients were 40 percent more likely than others to receive more than the recommended 15 treatments. Patients treated in community cancer centers – clinics without ties to an academic institution – were also more likely to be over-treated.

Koshy said physicians might tend to overtreat privately insured patients because services are billed per-treatment, creating a financial incentive. However, he said, “it could also be because these patients may be perceived to have better potential for a more positive outcome.”

Koshy et al. Prevalence and predictors of inappropriate delivery of palliative thoracic radiotherapy for metastatic lung cancer. J Natl Cancer Inst. 2015; 107 (12): djv278 doi: 10.1093/jnci/djv278 [Abstract]

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Survey sheds light on common clinical practice for incompletely resected lung cancer

A landmark survey of more than 700 specialists provides crucial real-world insight into the treatments most oncologists choose for lung cancer patients whose tumour has been incompletely resected, an expert from the European Society for Medical Oncology (ESMO) says.

Jean Yves Douillard, from the ICO Institut de Cancerologie de l’Ouest René Gauducheau, France, Chair of the ESMO Educational Committee, was commenting on a paper published in the journal Lung Cancer. In the study, researchers led by Raffaele Califano of The Christie NHS Foundation Trust, Manchester, UK, surveyed 768 oncologists from 41 European countries about the treatments they offered patients who had “R1 resected” non-small-cell lung cancer.

R1 resection is a term used by oncologists to indicate that it is possible to find microscopic evidence of cancer cells remaining after a cancer has been surgically removed.

We know that incomplete resection, or R1 resection, is associated with a higher risk of relapse but there are currently no strong evidence-based recommendations on how to treat these patients after surgery,” Douillard says.

This study is important since it provides a good overview on how the problem is handled in clinical practice all over Europe by practitioners who treat lung cancer.”

Overall, 83% of experts surveyed were medical oncologists –specialists trained to treat cancer using chemotherapy, targeted therapies, immunotherapy and other medications.

Of the respondents, 91.4% prescribed chemotherapy, mostly cisplatin/vinorelbine or cisplatin/gemcitabine. The survey showed that the majority of doctors (85%) discussed with the patient the fact that there was limited clinical evidence to guide treatment options. Almost 50% of participants prescribed radiotherapy, with radiation oncologists most likely to offer this treatment approach.

Treating physicians clearly believe in what they do, and try to provide the best for their patients,” says Douillard. “According to the survey, however, practice is heterogeneous and varies according to the specialty of the treating physician—whether they are radiation oncologists or medical oncologists. This is why treatment decisions are best made by multidisciplinary teams.”

The evidence gathered in this survey is supported by the recommendations of the 2nd ESMO Consensus Conference on Lung Cancer held in 2013, Douillard notes. That group of worldwide recognised experts recommended adjuvant chemotherapy and adjuvant radiation in R1 resected patients.

The authors of the latest paper call for prospective trials to be undertaken to provide stronger evidence to guide post-surgery treatment in this situation. Douillard agrees that such trials would be informative.

However, trials of adjuvant treatment in R1 resected lung cancer would be very difficult to design and perform, as this is fortunately an infrequent occurrence. R1 resection would also need to be clearly defined in such studies, as it actually represents a quite heterogeneous group.”

Based on evidence from clinical trials in resected patients in whom all tumour cells have been completely removed, there is a rationale for using both chemotherapy and radiotherapy in R1-resected non-small-cell lung cancer,” Douillard says.

As the authors of this survey state, definitive proof would come from a randomised clinical trial, although such studies would be difficult to perform.”

Additional Information:

Califano et al., (2014). Use of adjuvant chemotherapy (CT) and radiotherapy (RT) in incompletely resected (R1) early stage Non-Small Cell Lung Cancer (NSCLC): A European survey conducted by the European Society for Medical Oncology (ESMO) Young Oncologists Committee. Lung Cancer85(1):74–80 [Abstract][pdf]

Pattern in lung cancer pathology may predict cancer recurrence after surgery

Findings could help identify patients most likely to benefit from lung-sparing surgery

A new study by thoracic surgeons and pathologists at Memorial Sloan-Kettering Cancer Center shows that a specific pattern found in the tumor pathology of some lung cancer patients is a strong predictor of recurrence. Knowing that this feature exists in a tumor’s pathology could be an important factor doctors use to guide cancer treatment decisions.

According to the study’s authors, the findings offer the first scientific evidence that may not only help surgeons identify which patients are more likely to benefit from less radical lung-sparing surgery, but which patients will benefit from more extensive surgery, potentially reducing the risk of lung cancer recurrence by 75 percent. The study will be published in the August 20 issue of the Journal of the National Cancer Institute.

Researchers retrospectively evaluated the clinical characteristics and pathology information of 734 patients who had surgery for early-stage adenocarcinoma — the most common subtype of non-small cell lung cancer — and found that tumors in 40 percent of those patients exhibited an abnormal cell pattern strongly associated with cancer recurrence after surgery. No study to date has investigated the prognostic utility of this classification, called micropapillary (MIP) morphology, for patients with small, early-stage lung adenocarcinomas. Currently there are no evidence-based criteria for choosing the most effective surgical approach for this group.

The findings suggest that limited resection may not be appropriate for patients with the MIP pattern, as they were found to have a 34 percent risk of the cancer returning within five years after lung-sparing surgery, or limited resection, in which the tumor is removed by minimally invasive means and lung function is preserved. In contrast, patients with the MIP pattern who underwent lobectomy — the standard approach in which up to a third of the lung is removed along with the tumor — had only a 12 percent incidence of recurrence over a five-year period.

The study observations may play a key role in deciding whether to perform lung-sparing surgery or lobectomy for patients with small lung adenocarcinomas. It currently takes an expert lung pathologist to identify the MIP pattern during an operation. If the surgeon performs lung-sparing surgery in the presence of the MIP pattern, the chance of recurrence is high within the spared lobe of the lung. A lobectomy can reduce this chance of recurrence by 75 percent. If the MIP pattern is not found, the surgeon can confidently perform lung-sparing surgery.

Only a handful of cancer centers in the country have the expertise needed to identify the MIP pattern during surgery. Patients whose tumors are later found to have the MIP pattern after lung-sparing surgery may require another excision or a full lobectomy to reduce their risk of recurrence. Researchers at Memorial Sloan-Kettering are working to develop new technology that can be used to precisely identify which tumors have the MIP pattern before or during surgery. This will not only help doctors recommend the most effective surgical approach for each patient, but will result in fewer patients requiring additional treatment.

Nearly 250,000 patients are diagnosed with non-small cell lung cancer each year in the United States. The detection of small, early-stage lung adenocarcinomas is expected to increase as a result of advances in imaging technology, the widespread use of CT screening, and professional guidelines recommending screening long-time smokers for lung cancer. The findings of the new study will have immediate implications for the management of these patients.

Nitadori et al., (2013). Impact of micropapillary histologic subtype in selecting limited resection vs lobectomy for lung adenocarcinoma of 2cm or smaller. J. Natl. Cancer Inst., EPub Ahead of Print [Abstract]

Effect of obesity on patients with advanced non-small cell lung cancer

Obesity increases health risks for many things. Researchers wanted to know the impact of obesity on outcomes of patients with advanced non-small cell lung cancer. In the September issue of the International Association for the Study of Lung Cancer’s journal, the Journal of Thoracic Oncology (JTO), researchers conclude that obese patients had superior outcomes early on in the study, but then experienced increased hazards.

During the period from 1993 to 2004, the Eastern Cooperative Oncology Group enrolled 2684 patients to three phase III trials of first-line systemic chemotherapy for advanced NSCLC. At a median follow-up of 64.9 months, 2585 of the patients were declared eligible and included in this research. The patients had their body mass index (BMI) calculated. Consistent with the general population, 4.6 percent of patients were underweight, 44.1 percent were normal weight, 34.3 percent of patients were classified as overweight, and 16.9 percent were obese.

The median overall survival estimated among underweight patients was 7.0 months, among normal weight patients was 8.6 months, among overweight patients was 9.3 months and among obese patients was 11.0 months.

In multivariable models, obese patients had significantly different overall survival when compared with normal-weight and overweight patients; however, their risk of death from any cause increased dramatically once they had been on study longer than 16 months.

Researchers says, “this indicates that the protective effect of obesity in lung cancer patients is for a limited time, after which the ultimate impact of obesity on survival from all causes supersedes.”

Dahlberg et al., (2013). Body Mass Index and Its Association with Clinical Outcomes for Advanced Non-Small-Cell Lung Cancer Patients Enrolled on Eastern Cooperative Oncology Group Clinical Trials. J.Thoracic Oncol., EPub Ahead of Print [Abstract]

 

Emerging cancer drugs may drive bone tumors

Cancer drugs should kill tumors, not encourage their spread. But new evidence suggests that an otherwise promising class of drugs may actually increase the risk of tumors spreading to bone, according to researchers at Washington University School of Medicine in St. Louis.

The drugs, IAP antagonists, block survival signals that many cancer cells rely on to stay alive. Working in mice, the investigators found that targeting the same protein that makes tumors vulnerable to death also overactivates cells called osteoclasts, which are responsible for tearing down bone. The research appears in the February issue of Cancer Discovery.

“These investigational drugs are getting broad attention right now because they seem to be very effective against primary tumors,” says senior author Deborah V. Novack, MD, PhD, associate professor of medicine. “There is also excitement because until now, these drugs have not appeared to have major side effects.”

In light of the study, Novack urges oncologists to think about protecting bone in patients taking IAP antagonists, including patients with cancers that don’t typically spread to bone. Numerous IAP antagonists are in early clinical trials against breast, lung, pancreatic, ovarian, prostate, liver, skin and blood cancers.

“For many of these cancers, doctors are not watching bone,” Novack says. “Osteoporosis is not the biggest concern when treating cancer, but if they’re not doing bone scans, they may miss a cancer spreading to bone.”

To maintain healthy bone, osteoclasts work in tandem with cells that build new bone. But IAP antagonists overactivate osteoclasts, destroying bone that is not replaced. In mice, the researchers showed that the drug led to osteoporosis, creating an environment that encouraged tumor growth in degrading bone, even while simultaneously killing breast cancer cells elsewhere.

After showing that the problem with IAP antagonists is specific to bone, Novack and her colleagues tested long-established drugs called bisphosphonates that inhibit osteoclasts and are used to treat osteoporosis.

“We found that bisphosphonate treatment protected bone from the negative effects of these drugs,” Novack says. “While bisphosphonates are common for breast cancer patients, they’re not, for example, commonly given to lung cancer patients. But since IAP antagonists are now in lung cancer trials, we’re saying doctors may want to consider bisphosphonate treatment for lung cancer or other cancer patients receiving these drugs. Or at least closely monitor the bone status.”

IAP antagonists are now only available to patients enrolled in phase 1 or 2 clinical trials. While these kinds of trials examine the short-term safety and effectiveness of new drugs, the researchers say they may not catch bone metastasis.

“These trials do not necessarily look for long-term effects of the drugs,” says Chang Yang, MD, PhD, staff scientist and the paper’s first author. “If the cancer is going to metastasize to bone, it may take six months to two years to see that outcome. This may not be seen during the clinical trial.”

Numerous drug companies are developing IAP antagonists intended for many kinds of cancer, but only Genentech agreed to provide Novack and her colleagues with its drug, called BV6, to evaluate in the study. Because the investigators could not obtain other proprietary IAP antagonists, they also made two other similar drug compounds and found them to have the same detrimental effects on the bone.

And to further ensure that over-stimulated osteoclasts are the only culprit in the bone metastasis associated with these new drugs, they performed studies in mice that lack the ability to dial up the production of osteoclasts. Even when given IAP antagonists, these mice were protected from osteoporosis and osteoclast activation.

Together, Novack says the studies have demonstrated that these results are unlikely to be a quirk of a particular compound.

“The osteoporosis and spread of tumors we see in bone are unintended side effects of IAP antagonists, but they’re not off-target effects,” she says. “They’re based on the mechanism of action for the entire class of drugs.”

Yang et al., (2013). Anticancer IAP inhibition increases bone metastasis via unexpected osteoclast activation. Cancer Discovery3: 125-127 [Abstract]