Cancer has emerged as an alarming cause of morbidity and mortality in India. According to The National Centre for Disease Informatics and Research of the Indian Council of Medical Research (ICMR) at Bengaluru, India, 1.65 million cases of cancer were estimated to be diagnosed in 2019. This burden is likely to become double in the next 20 years. Also, we are a country of a humongous, demographically complex population with diverse cultures and lifestyles. While the North and the Northeastern states may register the highest number of gallbladder cancer, Southern states and cities like Chennai and Bengaluru are suffering from high incidences of stomach cancers. Industry experts discuss about the research avenues being explored to provide cancer treatment to such a multiplex populace By Tarannum Rana
2020 looks ahead at an exciting time in Indian oncology
2020 looks ahead at an exciting time in Indian oncology. The list of targeted therapies that are available on the biosimilars list made in India keeps expanding. Meanwhile, access to expensive therapies from the west including immunotherapy is becoming more streamlined with purchase and adoption both rising in the private sector despite the associated costs. Homegrown technology is shining though, with the advent of CAR-T cell trials at Tata Memorial Center and Biocon, the launch of the Apollo Proton Centre, and the expansion of artificial intelligence (AI) based clinical decision analysis support for patients by the National Cancer Grid and Navya.
Proton therapy is a specialised type of radiation therapy with minimal side effects compared to traditional radiation. It can precisely target the radiation beam at the tumour and stop the beams from penetrating the normal tissue behind the tumor. This is particularly valuable for tumors in difficult to access and neurologically sensitive regions of the body, such as tumors of the skull base, spinal cord, eye, oral cavity, prostate etc. Apollo Proton Center in Chennai is the first of its kind in India, bringing this technology within reach of the pediatric and adult cancer patients who benefit from this specialized care. The cancer center has also launched an online initiative apollocanceropinion.com to enable patients to know whether proton therapy is the right choice for their tumors or not.
CAR-T cells are a specialised form of immunotherapy that hold promise for recurrent or relapsed blood cancers, which often affect young and healthy people. Currently this therapy is expensive and only available in the US, China or Israel. Both Tata Memorial Center (TMC) and the Biocon are developing CAR-T cells in house and hope to begin clinical trials in late 2020. This will provide much needed access to our patients to another novel frontier in cancer care.
AI is making a big splash in healthcare abroad with news of large tech companies analysing health data to predict better outcomes or maximise care plans. Tata Memorial Center, the National Cancer Grid have popularised a domestic initiative (www.navya.care) to use AI technologies to speed up response time and achieve a comprehensive response to patients at scale.
Patients who are otherwise unable to get the time of experts at large academic cancer centres like TMC, AIIMS, Adyar Cancer Center etc., can use this NCG service which is AI-enabled to get rapid reviews from experts on their cases within 24 hours. The impact of this service was presented at European Society of Medical Oncology (ESMO) in late 2019 to show that patients on average saved two days of work absences, 1000 km of travel and almost RS 70,000 in costs by avoiding expensive trips to the large cancer hospitals for purposes of a second opinion alone.
There is a need to develop proper clinical research environment
There is significant geographical variation in the incidence of cancer in India. Specific cancer research programmes to focus on biology of population present in various Indian states with PBCRs will help determine risk factors responsible and suggest strategies for prevention.
Although a notable progress in this field has been made in the recent years, there is a need to develop proper clinical research environment. This includes exposing graduate and postgraduate medical students, community physicians and medical college teachers about translation clinical research, and developing adequate infrastructure. Indian pharmaceutical industry has made phenomenal growth in the field of generic molecules; they need to invest in the development of new molecules and India centric cancer research.
India has a large pool of individuals with genetic diversity (4000 anthropologically distinct groups and 22 languages). This provides an opportunity to study environmental influences on drug metabolism (such as smoking, alcohol and use of herbal medicine), variation in drug targets (for example, higher incidence of activating mutations of epidermal growth factor receptor in lung cancer in patients from Asia), and genetic polymorphism in drug-related genes. Indian population is unique in terms of genetics, culture, languages and food habits. Well-planned genome-wide association studies may yield insights into disease aetiology and potential responses to therapy. In the era of precision medicine, it will be important to define risks or susceptibility of certain population or ethnic subgroups for high incidence of cancer seen in these areas and also from treatment point of view if these subgroups need dose modification or special precaution during the treatment. Translational studies involving imaging, pathology, gene expression profiling, sequencing, bioinformatics and detection of circulating tumour cells can be done in few centres, and then data generated can be evaluated for its translation at other centres.
Key priority areas for research
One of the important tasks would be to develop consensus on key priorities for cancer research in Indian context based on common cancers in males and females in a particular region. There is a need to focus research on prevention of some cancers with high incidence in certain areas, for example, gallbladder cancer in Gangetic belt, penile cancer in rural population, oesophageal cancer in NE region, colon cancer in Goa, stomach cancer in southern and northeast India. Whether these regional differences in epidemiology are due to a difference in genomics and biology or due to differences in the prevalence of cancer risk factors or both are not yet known and would be an important area of research. These cancers are rare in West and therefore, not a focus for large research programmes. Similarly, directing research for upcoming problems like lifestyle and obesity-related cancers would be timely.
Since most patients have advanced disease and poor performance status at presentation, research efforts to develop cost-effective protocols for palliative care would be meaningful. Developing protocols to less toxic regimens (e.g. metronomic therapy with minimal visits to a busy cancer centre) and minimising need for imaging (e.g. computed tomography scan) in the follow up would be simple, yet important solutions. An active collaboration between investigators, funding agencies, industry and regulatory bodies would be important to understand needs of each other.
The environment of research in India is still warming up and has a huge potential in the space
Notable progress has been observed in the way cancer is diagnosed and treated today. We have seen a shift towards genetic-based testing and molecular diagnostics. New diagnostics methods based on genomic and proteomic profiling of the molecular changes associated with the disease are being developed that are important for therapeutic decision making. At CORE, we provide Patient Support Programme and clinical trials, on patients to bring down the cost of diagnosis and treatment along with prominent epidemic studies. In addition to this, Government initiatives, under public-private partnership (PPP) model, are exploring options to provide quality diagnostic services for screening of the disease.
Thankfully, there are many hospitals and laboratories that offer targeted next generation sequencing. But still there is a dire need to focus on research for prevention of some cancers with high incidence in certain areas. With rapid advancement and availability of new technology, many more new assays are now being offered including the NGS-based assays for better and focused tumour profiling, liquid biopsy for very early diagnosis of cancers, and Minimal Residual Disease (MRD) in leukaemia. These advanced assays have helped researchers, clinicians and patients to understand molecular basis of cancer and plan more specific and successful target-based therapies.
The environment of research in India is still warming up and has a huge potential in the space. It can include biomedical research, epidemiological studies, health services research, as well as behavioural, social, and economic studies of factors that impact health. Indian population is unique in terms of genetic diversity, culture and food habits and this provides an opportunity for a well-planned approach towards improving the way to treat and manage cancer as well as understand what raises or lowers a person’s risk of developing cancer. Recently, Government of India’s department of biotechnology joined hands with UK based cancer research firm to launch a research challenge for affordable approaches to cancer. The initiative is focused to fund research projects to address the challenges in affordability, diagnosis and treatment of cancer, by bringing together research strengths of India and the UK. We would need a planned and coordinated approach at various levels including collaboration with research groups to bring in the necessary transformation in cancer diagnosis and treatment.
New therapies that will gradually shifting focus from chemotherapy have arrived
In earlier times, cancer was associated with early mortality due to lack of dedicated treatment approaches. Chemotherapy, radiation therapy, supportive drugs, palliative/allied therapies are the mainstay in management of cancers. However, with newer technologies being developed, the hope of improving the overall survival rates and quality of life of individuals with cancer appears within reach. Welcome to the era of molecular medicine- where diseases are not treated by their symptoms but by targeting the underlying mechanisms creating havoc in the body.
Looking back at the start of the millennium, India broke the worldwide stranglehold of high cost Anti-retro viral therapy drugs by supply of generic Anti-retro viral drugs (ARV) at low cost to the HIV-AIDS epidemic stricken African nations. Since then, India has been a major supplier of ARVs across the world. Today, India is at the brink of another such revolution, this time in terms of cancer drug therapy. The prime factor for the growth of the Indian healthcare market is technological advances. We now have better diagnostic modalities that facilitate early screening, diagnosis, and prompt treatment planning of various cancers. New therapies that are gradually shifting focus from chemotherapy to specific cancer targeted therapy, immunotherapy, and hormone therapies drive the Indian oncology drug market. Over the past five years, 70 new oncology treatments have been launched and are being used to treat over 20 different tumor types. Many more such drugs are in the pipeline at various stages of clinical trials.
Along with newer drugs being developed, recent advances also aim to harness the power of immune cells of the body and train them to specifically attack cancerous cells. Immune effectors are capable of identifying and destroying cancerous cells that are inaccessible to conventional treatment modalities. Specificity and generation of long-term immune surveillance against cancer cells is the chief goal of immunotherapy. Several types of immune system cells such as: T cells, Dendritic cells (DC), Natural Killer cells (NK) etc., are candidates being researched in cancer immunotherapy.
Studies have shown that host immune system cells also mediate killing of cancer cells through activation of other types of cells and cytokines. This had led to research on development of combination strategies that can capitalise on the synergistic effects of various immune cells. One such example would be combination of immunotherapy and chemotherapy, radiation or monoclonal antibody therapy.
Despite ongoing research on cancer therapy, we are just at the tip of the iceberg. The need of the hour is development of techniques that would exclusively target cancer cells and spare normal cells and tissues. This is imperative to minimise the side effects of current therapies and achieve tangible results from therapy. Future areas for development in vaccines using immune cells for cancer therapy should include applicability to individual tumor types, optimisation of cell biology including migratory and co-stimulatory properties, and the manipulation of the host and tumour microenvironments to alleviate immunosuppressive mechanisms.
Targetted therapies: A new hope for patients
To deal with cancer, constant evolution is taking place in the medical field. The cutting edge technology and new treatment is a ray of hope for patients with cancer and can help them lead a normal life. Some of the recent developments in cancer treatment are:
- The role of neoadjuvant chemotherapy and neoadjuvant radiation: Earlier, in chemotherapy, it used to be the drug, given through IV, that would kill cancer cells. But, it affects the normal cells as well. One experiences side effects like weakness, loose motions and hair loss. Nowadays however, targeted therapies which those cells will only act on the cancerous cells and not on the normal cells have been invented.
- Immunotherapy: In this, readymade antibodies are given to the patients to kill the cancerous cells. Hence, newer therapies like the targeted therapy and immunotherapy can be opted for.
- Speaking about surgeries, when it comes to prostate cancer, robotics can do the trick as this will reduce the hospital stay of the patient and there is no need to cut the skin for long lengths like for example, 10 cm to 15 cm. Instead, of that, it will be keyhole surgery.
- When it comes to radiation, back then, when there was a lesion in the brain, the skull was opened. But now, if there is a lesion in the brain, Stereotactic radiosurgery (SRS) or cyberknife, can be used as a non-invasive alternative for the treatment of both cancerous and non-cancerous tumors in the body including one’s brain, spine, prostate, pancreas, and kidney.
- In the near future, genetic sequencing of the tumour will carry a lot of importance. Here, the expert will be able to know about the problem in each and every gene as cancer is nothing but genetic mutation. The particular gene is targeted and treated properly. Thus, a focused treatment can be opted for.
- In the olden days, ovarian cancer patients were given chemotherapy. Now, hyperthermic intraperitoneal chemotherapy (HIPEC) is given to them immediately once the tumour is removed. Also, during the same surgery, a highly concentrated, heated dose of chemotherapy is delivered directly to one’s abdomen, while targeting the area where one needs the treatment most.
Furthermore, after treating the patient, follow-up sand rehabilitation is needed to stop any cancer recurrence. In the follow-ups, investigation can be done in the form of tumor markers, sonography, and CT scan. If the patient’s tumor biology is bad then cancer may recur early.
Hypo-fractionation form of radiation is a safer alternative to conventional schemes
There are three main modalities to treat cancer patients i.e. surgery, chemotherapy and radiation therapy. Radiation therapy has evolved over a period of time in last century from very basic techniques to treat cancer patient till the latest machines capable of delivering much focused Radiation with sub-millimetre accuracy. It has resulted in increased cure rate by delivering high radiation doses to tumor at the same time decreased side effects and morbidities.
Evolution in the field of radiation therapy is mainly in two directions i.e. technology and radiobiology. Technological evolution starts from very basic conventional irradiation using simple treatment fields toward highly conformal radiotherapy technique such as Intensity Modulated Radiotherapy (IMRT), Volumetric Modulated Arc therapy (Vmat) and Stereotactic Radiotherapy (SRT), which aim to improve the outcome by escalating the radiation dose to target and minimising the toxicity to normal tissue and critical organs.
With the help of recent technological advances in imaging and treatment, we can treat the moving targets like Lung, Liver etc, tumors in real time using motion management gadgets and technique like 4D-CBCT, respiratory gating to mitigate effect of tumor motion due to respiration.
Radiation therapy is very much a technology-driven modality. Technological advances have mainly been the result of integration of imaging information in every phase of treatment i.e. simulating the actual treatment before it is actually being delivered and imaging while the patient is being treated for more accuracy.
Radiobiological evolution starts from conventional fractionation i.e. small dose per session of radiation over a period of one and a half to two months to now a day, hypo-fractionation i.e. larger dose of radiation over a much shorter period of time. It is a safe and well tolerated alternative to longer conventional schemes.
This is a big advantage for patients in term of convenience. Indeed, high-precision extremely hypo- fractionated radiotherapy has been called virtual surgery, since in many situations, it can have a radical curative effect locally that is similar to surgery. It is called Stereotactic Radio Surgery (SRS).
The past decade has seen an increase use of particle therapy particularly ‘Protons’. It has an advantage that it reduces the low and intermediate dose to surrounding normal tissues due to it, certain physical property (Bragg peak). In conclusion, radiation therapy has undergone tremendous progress over last century with technological developments that have revolutionised it clinical use.
Cancer treatment is no more a blanket therapy but a patient tailored management
Currently, we are in era of precision medicine and things have progressed from biopsy to bioinformatics. About 1.16 million Indians are being diagnosed with cancer every year and approximately 2.26 millions are living with it.
Over last two decades genetic and molecular research has revealed that cancer is a heterogeneous disorder with different mechanism of origin and survival in different individual. This implies that cancer treatment is no more a blanket therapy but a patient tailored management. Such treatment decisions are based on individual patient’s characteristics based on the type of tumour, genetic alterations and molecular events responsible for the origin and survival or the disease. Cancer diagnostics plays a large role in defining such patient characteristics.
Clinical research in cancer diagnostics and its utility in therapeutic decision making have been successfully implied in many cancer types. Breast cancer is no more a single disease entity and every patient is managed according to the burden and type of genetic alterations. This has not only resulted in better survivals but has also proved to be helpful in avoiding unnecessary treatment and hence therapy related toxicities. That is why it is termed as patient tailored management i.e. therapy that is tailored as per patient’s characteristics and requirement to achieve best clinical results.
Here, two of the most important molecular techniques are briefly explained:
Liquid Biopsy: It’s a technique that has changed the outlook in diagnosis and characterising malignancies. This involves isolation of the tumour DNA and exosomes from blood so that further determination of tumour nature and gene alterations can be done. Previously liquid biopsy was solely used as prognostic tool, but currently it is being used to diagnose the cancer as well as to modify the treatment depending on mutation detection. Liquid biopsy is also used to detect the cause of resistance to treatment i.e. secondary mutations and minimal residual disease. Efforts are being done to use this technique in screening of cancers. At present liquid biopsy is not recommended as a routine clinical test but it is a promising tool in modern oncology management.
Next Gene sequencing {NGS}: It refers to a deep and thorough DNA sequencing of tumour tissue obtained from biopsy. Almost all of tumour DNA characteristics like deletion, insertions, rearrangements, driver mutations and chemosensitivity. The complete utility of NGS in managing oncology patients is yet to be defined. It is an upcoming investigation which needs to be studied and defined for the best of care of patients. At present, NGS is used in cases where first line of treatment has failed, where cancer has recurred, where cancer is high grade or where all treatment options are exhausted. It can analyse large numbers of tissue simultaneously and find genetic variants and different genetic aberration.
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