Fight against lung cancer: Priorities and challenges ahead

Shobha Shukla - CNS
Lung cancer, the most common cancer worldwide, is a major public health problem. In 2012, there were an estimated 1.8 million new lung cancer cases (13% of all cancers diagnosed), and 1.59 million deaths (19.4% of the total cancer deaths). As of now, there is a 27% 5 years survival rate for patients of lung cancer. According to the latest cancer registry data released by the Indian Council of Medical Research, 0.114 million new lung cancer cases (83,000 in males and 31,000 in females) are estimated during 2016 in India.

During the last Asia Pacific Lung Cancer Conference (APLCC 2016) held in Chiangmai, Thailand in May 2016, medical oncologists, from across the globe, shared the latest cutting edge advancements made in the field of early diagnosis and novel treatment regimens that have raised the hope of making lung cancer a chronic, if not a curable, illness.

As Dr Lam Kai Seng, clinical oncologist from Kuala Lumpur, summed up succinctly—“First we must try to find ways to reduce incidence of lung cancer. So there has to be awareness about what are the pre disposing factors that contribute to lung cancer. Next comes early detection that provides best chances of a cure. Lastly, patients, diagnosed with the disease, should have access to the most advanced treatments available”.

So the top priorities should focus on all aspects of managing the disease—prevention, diagnosis, treatment and care, along with ensuring that the existing options are affordable and accessible.

Tobacco use and air pollution are two major causes of lung cancer. Dr Prakit Vathesatogkit, Executive Secretary of Action on Smoking and Health Foundation of Thailand, shared some scary statistics— “In ASEAN region, out of the total 467,194 smoking related deaths every year, an estimated 107,454 are due to lung cancer. So despite major advances in the field of diagnosis and treatment, tobacco related lung cancer rate might shoot up because of the combined effect of tobacco industry’s aggressive marketing, and weak political will on tobacco control.”

However Dr Purvish Parikh, Director of Precision Oncology at the Asian Institute of Oncology, Somaiya Hospital, Mumbai, warned that, “It is incorrect to devise lung cancer control strategies just around the premise of tobacco control, as not all lung cancer cases are tobacco related. The other causes could be exposure to hazardous substances like fertilisers, pesticides, pollution that can damage the DNA, lack of exercise, and increased fat content in the diet.”

Early Diagnosis
The earlier lung cancer is detected, better is the survival rate. Agreed Dr Busyamas Chewaskulyong, medical oncologist from Thailand, that, “Early diagnosis of lung cancer is very important, as patients can go for curative surgery. But only 20% of my patients present themselves in early stages of the disease”.

For early detection, annual screening with low dose computed tomography (LDCT) is currently the standard technique. The National Lung Screening Trial (NLST), launched in 2002, found that screening with LDCT resulted in a 15%—20% lower lung cancer-specific mortality and 6·7% lower all-cause mortality relative to chest radiography (X-ray) over a median of 6.5 years of follow-up.

However, even though cure rates can be higher by adoption of LDCT scans there are many concerns – such as the high false-positives (96%), over diagnosis, accumulation of radiation exposure, and high cost of screening.

Another challenge is generalization of lung cancer screening with LDCT in TB endemic countries, like India.

“TB mimics lung cancer. Symptoms of cough, chest pains, weakness, weight loss, fever and night sweats are common in both active pulmonary TB and symptomatic lung cancer. The radiographic findings of TB, such as mass-like lesion, solitary/multiple pulmonary nodule(s), mediastinal lymph node  enlargement, or pleural effusion, also mimic those for lung cancer. Furthermore, pre-existing TB increases risk of lung cancer and lung cancer may promote TB infection. No clear evidence of lung cancer screening benefit has been established in high-risk populations in a TB endemic area”, said Dr Natthaya Triphuridet, Pulmonologist at Chulabhorn Hospital, Thailand.

Agreed Dr Akhil Jain, Medical Oncologist from India, that, “As India has large number of TB cases, physicians empirically start with ATT, and only when it fails do they advise biopsy. General physicians must not ignore  early symptoms of the disease and should be well informed to advise investigations for lung cancer early on.”

With more improvements, screening is likely to be of greater importance in the near future.

Novel treatment regimens
Until the mid-2000’s, treatment options were mostly limited to surgery, chemotherapy and radiation. But now there are major advancements in lung cancer treatment. “For early stage patients there is VATS (Video Assisted Thoracoscopic Surgery) which is effective, cheaper, and has better outcomes in terms of morbidity and mortality,” said Dr Paul Bunn, a medical oncologist at University of Colorado.

Another advancement is Stereotactic Body Radiation Therapy (SBRT), which holds the promise of not only curing early-stage operable non-small cell lung cancer (NSCLC), but does so with minimal toxicity and offers the patient more comfort and convenience.

“What is important to ensure is that the cancer is under 5cm in diameter, and is in a location away from the heart or major blood vessels and airways, which could be damaged with this very high dose technique,” said Professor David Ball, Chair of Lung Service, Peter MacCallum Cancer Centre, Australia.

Prasert Lertsanguangsinchai, a radiation oncologist from Thailand said that to treat small cell lung cancer (SCLC) there are new external beam radiation therapy (EBRT) techniques like (i) 3-dimensional conformal radiation therapy (3D-CRT) that precisely map the location of the tumour(s) and aim the radiation beams from several directions; (ii) Intensity modulated radiation therapy (IMRT), in which intensity of the beams can be adjusted to limit the dose reaching nearby normal organs; and (iii) a variation of IMRT called volumetric modulated arc therapy (VMAT) that delivers radiation quickly as it rotates once around the body.

More information about mutations and genetic changes that take place in lung cancer, has helped in molecular profiling of patients, and in discovery of more targeted treatment options as well. These personalized treatments recognize that, as the genetic mutations in each tumour are different, the treatments for each mutation will be different. Two of these promising treatments are targeted therapy and immunotherapy.

Targeted therapy
Targeted therapy uses drugs that act like guided missiles to attack specific targets—mutant or abnormal proteins— that are present only in cancer tumour cells, but not in normal cells. Chemotherapy drugs, on the other hand attack healthy cells also, along with cancer cells. There are multiple types of targeted therapies available, including monoclonal antibodies, tyrosine kinase inhibitors (TKIs), and inhibitors of growth factor receptors. Patients have a 60-80% chance of responding to an oral targeted therapy compared to a 20-30% chance with chemotherapy. The duration of response is also 2-3 times longer with these treatments. The two gene changes/mutations in lung cancer that have targeted therapies approved by the Food and Drug Administration (FDA) are epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK).

Immunotherapy treatment helps the body’s immune system to target and attack the cancer cells. Immunotherapies that are being tested to treat lung cancer, include (i) monoclonal antibodies (ii) checkpoint inhibitors, (iii) adoptive T-cell transfer, and (iv) vaccines.

Bunn elaborated that, “The first form of immunotherapy approved for lung cancer involves monoclonal antibodies that are directed to proteins called checkpoint inhibitors. Checkpoints are proteins that cancer cells make to protect them from being killed by the lymphocytes present in our immune system. The monoclonal antibodies, given intravenously, block proteins that protect the cancer cells and enable the lymphocytes to kill them. The response of immunotherapy with monoclonal antibodies lasts much longer and has far less toxicity.”

But, unfortunately, immunotherapy does not work on all patients of lung cancer because all patients do not have checkpoint inhibitors. So scientists are trying to find biomarkers to define which patients may respond to immunotherapy. Some of the best cancer treatments in future will combine targeted therapies and immunotherapies. As Dr Michael Boyer, Professor of Medicine at the Sydney Cancer Centre said—“The challenge is to ensure that the right patient gets the right treatment at the right time.”

A major challenge in the use of the novel treatments is their high cost, more so in the South Asia region, where most countries are low and middle income countries. While there can be a better prognosis in patients through access to the novel medicines, Dr Virote Sriuranpong, Associate Professor, Department of Medicine Chulalongkorn University, Bangkok, lamented that though the new oral TKI drugs Gefitinib and Afatinib, give good response in lung cancers with EGFR mutations (that are quite prevalent in Asian countries), being very expensive, they are unaffordable for most patients. There is need to not only get good access to medicines, but also find suitable ways to reach them to the right patients.

Costs will have to be brought down to be able to effectively use the latest technology for diagnosis and treatment of lung cancer. Dr Gilberto Lopez, medical oncologist from Latin America suggested some proven strategies that governments and pharmaceutical companies can use to make latest lung cancer medication more affordable and accessible. Price control and Compulsory licensing can be used by  governments. While price controls, at times, have forced consumers to buy the product in the black market at still higher prices, compulsory licensing has been used effectively by countries like Thailand and India to drastically reduce drug prices, including those for cancer.

Price discrimination or market based differential pricing allows manufacturers to charge different prices for the same product from different consumers, based on consumers’ ability to pay. “Thus differential pricing by pharmaceutical companies can help expand the use of new and expensive medications in low- and middle-income countries”, said Lopez. Development of generic medicines for lung cancer, and of biosimilars for the more expensive monoclonal antibodies (like Rituximab and Cetuximab) are another way to decrease medication costs.

The future:
Dr Nagahiro Saijo, Chief Executive Officer of Japan Society of Medical Oncology, insists that, “Establishment of nationwide/ global genomic screening systems for identification of driver genes will be crucial to development of new drugs to improve lung cancer treatment outcomes in future. Japan’s ‘Lung Cancer Genomic Screening project for individualized medicine’ is one such effort. Based on innovative technology for gene analysis, the ‘one-size fits all’ medicine should be converted to precision medicine.”

Bunn strongly advocates for reversing the pessimism that has enveloped lung cancer historically— “Outcomes for patients of lung cancer are much better in 2016 than they were in 2000. So, a lung cancer ‘cure’ is not a hype. There is hope that in the future, with improved understanding of lung cancer, and the combination of drugs to use, cure rates for lung cancer will go up.

Shobha Shukla, Citizen News Service - CNS
14 June 2016