Personalized Therapy in Lung Cancer- A Success Story

Lung cancer is the most common cause of death due to cancer in India and is often detected in an advanced and metastatic stage. The overall prognosis of lung cancer is poor with average survival historically being a few months. However, over the past 5 years, there has been a paradigm shift in the management of lung cancer resulting in an increase in survival and improvement in the quality of life.

The major advances include 

  • Recognition that the type of cancer determines the best treatment.
  • Discovery of molecular pathways active in lung cancer and discovery of drugs that specifically target them.
  • Role of newer and more conformal radiotherapy techniques.
  • Advances in supportive management and palliative care.

Histology determines treatment

Lung cancer is divided into small cell and non-small cell lung cancer {NSCLC}. Previously, all patients with NSCLC were treated with the same chemotherapy schedule. However, recent landmark trials have shown that histology should determine the regimen. The treatment of adenocarcinomas is pemetrexed and for squamous cell carcinomas is gemcitabine or paclitaxel. Hence, it has become essential to do a biopsy and immunohistochemistry to determine the subtype of NSCLC and for performing molecular studies.

Molecular targeted therapy

The biggest breakthrough in the management of lung cancer has come about with the discovery of EGFR mutations and tyrosine kinase inhibitors. EGFR is a transmembrane receptor which is overexpressed in mainly adenocarcinomas. When there are mutations in the EGFR, they can be targeted by specific tyrosine kinase inhibitors like Gefitinib and Erlotinib. These oral drugs are significantly better than traditional chemotherapy {as shown by the separation of the curves in fig.1.} and moreover, do not have the feared side effects associated with chemotherapy. They are easy to administer and are effective within a week of starting therapy. The average life expectancy has increased to around 2 years with a   significant improvement in the quality of life.

grp

Fig.1. Gefiinib is significantly better than chemotherapy in lung cancer patients with EGFR mutations.

Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009 Sep 3;361(10):947-57.

EGFR mutation testing is now a standard part of workup for adenocarcinomas. The frequency of these mutations is around 30% in Indian patients. Mutations are more common in women and nonsmokers. The facility for testing is available in most major centers in India, including our hospital.

The newest agent in lung cancer is a drug called crizotinib which specifically targets a molecular translocation called the ALK-EML. Though relatively rare at around 2-3%, this agent is a breakthrough due to its superiority over chemotherapy and ease of administration.

There are other targeted drugs like bevacizumab, cetuximab and nanoparticle paclitxel which are emerging as useful therapies for lung cancer.

Conformal radiotherapy

Conformal, precise and high intensity radiotherapy can now be delivered to specific lung tissue, sparing the surrounding normal areas and leading to better tolerability and efficacy. The newer techniques are useful in early as well as advanced cancers.

Stereoetactic radiosurgery is the latest technique for small lung cancers especially in elderly patients and in patients unfit for surgery.

 Supportive care

There are supportive medications including colony stimulating factors, erythropoietin agonists and bone-sparing agents that have significantly improved the quality of life for patients. Newer drugs like denosumab are superior in reducing the incidence of fractures and other skeletal related events.

Maintenance chemotherapy

Recent trials have shown that continuing chemotherapy like Pemetrexed after initial treatment can increase the survival. This is associated with acceptable side effects and is well tolerated by most patients.

Facilities available in India

Our hospital, Apollo Cancer Institute, has the necessary infrastructure and expertise in handling patients in accordance with the latest international guidelines. The molecular tests, the latest drugs and advanced radiotherapy machines are available here and we can offer Indian patients the same standard of care as the west, at a fraction of the cost.

Conclusions

The treatment of lung cancer has been revolutionized by the discovery of rational, evidence-based and scientific personalized therapy which takes into account the histological and molecular characteristics of the tumor and is detailed for individual patient profiles.

Shifting Paradigms in Surgical oncology - Future of Robotic surgery

Dr. Chinnababu Sunkavalli
M.B.B.S, M.S, M.Ch.,
Surgical Oncology, Minimally invasive & Robotic Surgery

Robotic surgery has revolutionized the treatment from a surgery which involved lot of blood, need for transfusion, immense pain, longer hospital stay to the point where a patient can now be assured of going home next day after a surgery with much less pain. Certainly the experience of the surgeon and the people involved in the procedure is much more important than the technology in itself. 

cim2In Robotic surgery, the doctor sits at a computer console, either in or outside the operating room, using the surgical robot to accomplish what once took a team of people to perform. The use of a computer console to perform operations from a distance opens up the idea of telesurgery, which would involve a doctor performing delicate surgery miles away from the patient. If it were possible to use the computer console to move the robotic arms in real-time, then it would be possible for a doctor in Trivandrum to operate on a patient in Hyderabad.

Successful in the past, hence hope for the future

Thanks to the rapid and continuing development of robotic technology, this will enable us to perform all kinds of benign and malignant endoscopic surgeries and thoracoscopic/ laparoscopic surgeries. New technology like Software integration for precise anatomy, 3D Animation and Artificial intelligence would compensate for the absence of tactile feedback. Robotic surgery has several advantages over conventional surgery, including enhanced precision and reduced trauma to the patient. It is about time for Indian Hospitals to embrace Robotic Assisted Surgeries as we have at Apollo.  

Hereditary Breast Cancer and Prophylactic Surgery. Is it the dawn of Epidemic of Prophylactic surgery?

Dr. Chinnababu Sunkavalli
M.B.B.S, M.S, M.Ch.,
Surgical Oncology, Minimally invasive & Robotic Surgery

Hollywood star Angelina Jolie, who underwent double mastectomy last year says she is yet to get another surgery. "There's still another surgery to have, which I haven't yet. I'll get advice from all these wonderful people who I've been talking to, to get through that next stage," Jolie said.

cimg1Angelina Jolie was unfortunate to have inherited one faulty version of the BRCA1 gene, harboring the kinds of changes that she reported would give her an 87% chance of developing breast cancer in her lifetime – as well as a 50% chance for ovarian cancer. Her mother had died relatively young, at 56, from ovarian cancer. Angelina Jolie's decision to tell the world about her preventive double mastectomy may have raised some awareness — but has also generated plenty of confusion.

 Sensationalizing a celebrity’s health issue may not be of benefit to community. It could increase the awareness but at the same time there is threat of causing undue fear. More research is needed to understand impact of this on public.

 Who would benefit from surgery? 

Women with BRCA mutations associated with a high risk of breast cancer, confirmed by testing, and with a strong family history of breast cancer, a previous breast cancer, and who show signs of certain pre-cancerous conditions are among those who could benefit from the surgery,

Can a normal healthy person undergo such genetic tests to know the fact whether they may get cancer later in life and do a surgery? 

No, in general. We need to understand that only 5% of breast cancers are hereditary. There are certain guidelines for carrying out Genetic testing for cancer. Genetic tests are done to find out mutation (change) of gene which predisposes for high probability of a particular cancer.

 Who should consider genetic testing for BRCA1 and BRCA2 mutations? 

The person being tested has a personal or family history that suggests an inherited cancer risk condition.

  • Breast cancer diagnosed before age 50 years
  • Cancer in both breasts
  • Both breast and ovarian cancers
  • Multiple breast cancers
  • Two or more primary types ofBRCA1- or BRCA2-related cancers in a single family member
  • Cases ofmale breast cancer
  • Ashkenazi Jewishethnicity

So only those who fall into this high risk category can get genetic testing done

Head and Neck Cancers – The ‘Life-style’ Cancers

Dr. Umanath K. Nayak
MBBS ; M.S. (General Surgery).
Fellow in Head and Neck Oncology and skull based surgery, Head &
Neck and Robotic Thyroid Surgeon.

Cancers which occur in the region of the head and neck (excluding the brain) are together termed as Head and Neck Cancers. Over 80% of these cancers arise from the inner epithelial lining of the upper aero-digestive tract (the upper part of the food and air passages). They include oral cancers (cancers of the mouth and tongue), throat cancers (cancers of the larynx and pharynx) and sinus cancers. These cancers are generally related to habits and life-style, specifically, the use of tobacco and alcohol and thus may be termed as ‘life-style’ cancers.

 Causes

cim3Over two thirds of head and neck cancers are related to the use of tobacco. Both epidemiologic and experimental studies have clearly shown that chronic exposure to tobacco in any form induces changes in the cells that lead to the development of cancer.  While smokers have a higher risk of lung and throat cancer, those who chew tobacco run an increased risk of cancer of the mouth, throat and food passages. The brunt of the tobacco is borne by the throat and lungs in smokers and the oral cavity in tobacco chewers. The tobacco chewer’s oral cancer is universally referred to as the ‘Indian oral cancer’ in view of its typical location in the furrow between the cheek and the lower gum - the location where the tobacco or pan masala is usually kept.

 Warning signs of head and neck cancer

  1. Ulcer or growth in the tongue or mouth
  2. Persistant change in voice or difficulty in swallowing
  3. Abnormal lump or swelling in the head and neck region
  4. Blood in sputum or saliva
  5. A mole or wart which increases in size or starts itching or bleeding

Treatment

Head and Neck cancers are highly curable with proper treatment. The main modalities of treatment are Surgery, Radiation therapy and Chemotherapy in isolation or in combination depending on the site and stage of the cancer.

Surgery is the main modality of treatment for oral cancers and some advanced cancers of the larynx and pharynx as well as cancers of the thyroid and salivary glands. Advances in surgical techniques for oral cancer and refinements in reconstructive methods have made major surgery for these cancers safe, effective as well as cosmetically and functionally acceptable.  

 Radiation therapy is mainly used for early and intermediate stage aero-digestive tract cancers (other than oral cancers) as well as advanced cancers which are not surgically operable. Technological advances in the delivery and planning of radiation therapy with techniques such as IMRT, IGRT etc. have made radiation treatment for head and neck cancer precise with minimal side-effects and high cure rates.

Chemotherapy in primarily used in lymphomas and in combination with radiotherapy in advanced aero-digestive cancers of the head and neck. It is also sometimes used before surgery to reduce the size of the tumor and make it more manageable during surgery.

 Prevention and life-style changes

Changes in life-style and avoidance of tobacco and drinking habits can prevent most head and neck cancers. Screening of high risk population by regular oral and throat examination can detect early cancers where treatment strategies are most effective.

Many commercial preparations (Nicotine skin patches, nicotine impregnated chewing gum, etc) are available in the market to help smokers to get rid of smoking.  

The Government has only recently woken up to the reality of the health hazards of the various tobacco products.  While restrictions on smoking in public places and a ban on advertising of all tobacco products have been in existence since 2003, it has done precious little to stop the menace of tobacco chewing. Subsequent to this law, a modest reduction in the sale of cigarettes and other smoking products was negated by a significant increase in the sale and consumption of chewed tobacco.   A pictorial warning depicting oral cancer on all tobacco products (including chewed) was made mandatory from June 2010.  Time will tell whether this results in any significant reduction in the incidence of head and neck cancers in the country.

Radiosurgery by X-knife & Cyberknife

Dr. P. Vijay Anand Reddy
MBBS; M.D.(RT), D.N.B, Medical Onc, (ESMO),FUICC (UK),FNDM (USA),FUICC (AUS)
Primary Specialty – Radiation Oncology Subspecialty – Medical Oncology /
Clinical Oncology

Paradigm Shift in Radiation Treatment Schedule Radiation Therapy involves the use of ionizing radiation (commonly X rays) for the treatment of malignant and some benign tumors. Since the discovery of X rays in late 19th century, the technology of radiation delivery, understanding of tumor biology and radiobiology has grown by leaps and bounds.

cim5Traditionally, the standard radiation therapy protocol involves, daily dose of 1.8-2Gy, one fraction a day, five fractions per week and five to seven weeks of treatment depending upon the tumor type, site and stage etc. With the availability of sensitive imaging modalities like PET/CT, MRI (for target and critical structure delineation), high precision techniques like Stereotactic Radiotherapy for treatment delivery, in room CT Scanners and Gating techniques (for accurate reproducibility and verification), Stereotactic Radiotherapy with X-knife & Cyberknife is being increasingly utilized in oncology practice, to reduce the overall treatment time, with equivalent or better tumor control rates and more importantly no normal tissue damage.

The Novalis Tx Radiotherapy system with inbuilt X-knife technology is a versatile combination of advanced technologies, which can accurately deliver radiation doses anywhere in the body in just few minutes. The tumors where the Hypofractionation is now increasingly used and showed a reasonable difference in the control rates and/or toxicities are

Benign Brain tumors: Acoutic Neuroma / Schwanoma / Pituitory adenoma etc

Asteio Venous Malformation (AVM), • Brain Metastases, Bone Metastases., Lung Cancer Breast Cancer Prostate Cancer

Though, the above short term hypofractionation protocols have shown equivalent results in terms of control rates and toxicities, but proper patient selection, availability of expertise and experience is imperative. The indiscriminate use of the above technology may cause severe radiation induced sequelae and should be avoided at all costs. Stereotactic (Short Course) Radiotherapy, in future has a potential to become the standard protocol in radiation oncology practice in the properly selected patient cohort

Be Breast Aware

Dr. Kausik Bhattacharya
MBBS ; MD RADIATION ONCOLOGY
Head and Neck Cancer, Organ Preservation, Rehablitation of Cancer Patients,
Brain Tumor Management, Sterotactic Radiotherapy and Radiosurgery

Breast cancer is one of the leading causes of cancer death amongst women in the world. In India, the incidence of breast cancer is rapidly rising especially in urban populations and its affecting younger women. 

The key to success in treating breast cancer lies in early diagnosis it is important that both women as well as their family physicians be ‘Breast- Aware’. This starts with the understanding that any lump in the breast must be investigated to rule out malignancy. Routine Breast Self Examination and mammography must be advised to all women above the age 40. In case of a family history of breast cancers screening should be started earlier. 

cim4Tru-cut biopsy or FNAC can determine if a breast lump is benign or malignant. Unplanned excision biopsy should be avoided. Early stage breast cancer is ideally treated with Breast-Conservation Surgery (Lumpectomy and Axillary Clearance). Sentinel node biopsy of axillary nodes is a standard of care in many parts of the world in early breast cancer. Locally advanced breast cancers are surgically treated with Modified-Radical Mastectomy. 

Radiotherapy should be planned for Patients undergoing conservative breast surgery and patients with locally advanced breast cancers, who have undergone mastectomy. The duration of radiation is minimized from 5 weeks to 3 weeks without any loss of efficacy. In early breast cancer patients, properly conducted Breast conservative therapy offers the same cure rate as mastectomy. 

Systemic therapy in the form of chemotherapy or hormonal therapy which prevents local relapse as well as distant metastasis in patients who have either positive axillary nodes or a tumor size more than 2cm. Newer drugs like Herceptin and Lapatinib have given a new ray of hope to a select group of patients even when they have metastases. 

The first-line of defense against this disease is the family physician and gynecologist who play a crucial role in correctly diagnosing, co-coordinating with the specialty oncology team and subsequently be a part of the follow-up program.

Multiple Myeloma – A Case Study

Dr. S.V.S.S. Prasad
MBBS ; MD (Pediatrics), DM (Medical Oncology)
Bone Marrow Transplantation First in India to be quali􀏔ied in both Pediatrics and Oncology

A 56 year old lady presents with history of fever of 1 month’s duration and breathlessness of 2 days duration to our Secunderabad Centre. Chest X-ray showed bilateral pulmonary opacities – pneumonia was suspected. CBC showed severe anemia (Hb3g%), elevated TLC of 46000/cu.mm and a platelet count of 80,000/cu.mm. Peripheral smear examination showed atypical lymphocytes and a suspicion of lymphoproliferative disorder. She was shifted to our main centre at Jubilee Hills for further management.

A working diagnosis of ARDS/infectious pneumonia with leukemoid reaction and toxic myelopoiesis was made, patient placed in ICU and BiPAP support provided for oxygenation. Here too, CBC showed similar blood counts and peripheral smear showed normocytic normochromic anemia with leucoerythroblastic reaction and 3% plasmacytoid atypical lymphocytes. Our Hematology lab suggested the possibility of Multiple Myeloma.

Continuing the BiPAP support, a bone marrow examination was done sending the samples to Hematology and Molecular Biology departments. In the next few hours a report of hypercellular marrow with 90% immature plasma cells was released confirming the diagnosis of Multiple Myeloma.

Biochemistry samples were sent for serum protein electrophoresis  and serum free light analysis – kappa/lambda, asked for a radiological skeletal survey, counseled the patient and her family and instituted Bortezomib/Thalidomide/Dexamethasone (VTD regimen) therapy while continuing the BiPAP, antibiotics and others including measures for prevention of Tumour Lysis Syndrome – all within 24 hours of the patient’s arrival.

Patient started improving dramatically, was off BiPAP in the next 12 hours, and even off nasal oxygen in the next 24 hours. She was shifted out of the ICU and by 7 of institution of the VTD regimen the CXR became normal indicating that the opacities seen initially were myelomatous infiltrates. Patient was discharged on Day 9, continuing further treatment as out-patient.

Serum protein electrophoresis showed a discrete Monoclonal spike of 7.28 g/dL, serum free light analysis showed kappa chain elevation (kappa = 565mg/L and lambda 8.31mg/L). Myeloma panel from Molecular Biology showed positive for deletion of 13q.14.3 (D13S25), and negative for deletion 17p13 (p53), FGFR31/IGH translocation t(4;14) (p16;q32) and CCND1/IGH translocation t(11;14) (q13;q32). The skeletal survey was normal.

Patient is planned for 4 cycles of the VTD regimen after which she would be taken up for High Dose Chemotherapy (HDCT) and Autologous Bone Marrow Transplantation (ABMT) in the BMT unit.

This interesting case of Myelomatous infiltration of the lung showcases what all can be achieved with rapidity withappropriate ‘state-of-the art’ facilities under one roof and team work.  The Emergency, ICU, Hematology, Biochemistry, Molecular Biology and the Medical Oncology –Hematology departments are the proud members of the team here.