Are we ready to accept the benefits of Targeted Therapy of lung Carcinoma in India?

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1 Original article: Are we ready to accept the benefits of Targeted Therapy of lung Carcinoma in India? 1Ghosh Dastidar Aloke, 2 Basu Anjana, 3 Gupta Phalguni, 4 Sadhukhan Susmita, 5 Halder Anirban, 6 Das Tapas 1, 4, 5 Department of Radiotherapy, IPGME&R, Kolkata 2 Department of Anaesthesiology, RG Kar Medical College, Kolkata. 3,6 NRS Medical College, Kolkata Corresponding author: Dr Aloke Ghosh Dastidar, Associate Professor, Department of Radiotherapy, IPGME&R, Kolkata, India alokeghoshdastidar@yahoo.com Abstract: Incidence of Lung Cancer in tertiary level cancer centre of West Bengal, India for the last decade is increasing and in last three years, varies from 8.1 to 8.3 %, mostly Non Small Cell Lung Cancer (NSCLC) with preponderance in male. Majority is diagnosed by CT Guided Fine Needle aspiration Cytology. Most of our patients received Taxane and Carboplatin based combination Chemotherapy. If these patients are diagnosed by biopsy including Immunohistochemical study, epidermal growth factor receptor (EGFR) & Vascular epithelial growth factor receptors (VEGFR) study, then survival may be increased by Targeted Therapy like Gefitinib, Erlotinib and newer agents like Afatinib, crizotinib who are resistant or failed to sustain response with erlotinib/gefitinib. Key words: Lung cancer, NSCLC, Targeted therapy Introduction: male population. Yearly incidence of primary lung In the last decade there has been tremendous carcinoma -Non small cell Lung carcinoma and development in the subject of molecular biology small cell Lung carcinoma (NSCLC+SCLC)] in and targeted therapy in Medical Oncology. With Indians 12.7% (estimated 1.61 million new cases, the more intricate knowledge on growth factor and the most common cause of death from cancer, receptors we can design the protocol of with 1.38 million deaths 18.2% of the total). [1] How personalized medicine and are able to predict the much of total lung carcinoma sufferers are able to disease outcome more accurately. Lung cancer is get benefit from modern medicine is the object of now interpreted with novel imaging techniques this study. This study was conducted at an apex with histopathology, Immunohistochemical study, referral Government Hospital of Kolkata, India. EGFR & VEGFR study, gene expression study, Methodology : quantitative PCR etc.being worlds second largest The records of cancer patients attending populated country, India, Lung cancer sufferers are Radiotherapy Department in consecutive three the second biggest cancer killer amongst Indian calendar years were analysed. This is a 162

2 retrospective non-randomized open ended non comparative analytical study to ensure how much of the total patients were fit to enable targeted therapy. From January 2010 to December 2012 records from Institutional Cancer Registry were revisited. Cytopathology, Histopathology, Imaging evidences at the time of presentation or before starting anticancer medications were recorded. The patterns of primary modality of treatment and subsequent follow-up and disease specific survival curve were evaluated. Socio-economic status & nutritional status of the patient at presentation were recorded. From these data we can understand the natural history of Lung cancer in India. Result: Total number of newly diagnosed malignant disease registered in the calendar year 2010, 2011, 2012 were 2809, 2878 & 2816 respectively. The number of lung cancer patients determined either by cytology (FNA) or by histopathology (biopsy) were 230, 236 & 250 respectively. More than 90% cases were non-small cell lung carcinoma (NSCLC). All patients had x-ray chest at presentation but CT Scan Thorax at presentation were 83%, 71.6% & 48.2% (mean 67.6%) respectively. This means about 32.4% of our patients had to start treatment without evidence of CT Scan Thorax image analysis. To evaluate stage of disease at presentation CT Thorax and USG whole abdomen is considered minimal noninvasive procedure. It is observed on 2010 CT Scan Thorax was done only in 48.0% of patients but that as a basic diagnostic tool has increased to 83% on 2012 reason being better understanding by the general physician about the importance of CT Thorax as basic investigation. CT Thorax& USG Whole Abdomen at presentation was seen 10.6%, 21.2% & 40% in three consecutive years respectively. Indicating that metastatic work up was inadequate in most of the cases. (Table 1) Lung cancer and Brain metastasis is a common problem. We estimated 8, 4 and 3 cases, in the year 2010, 2011, 2012 respectively, at the time of registration presented with Brain metastasis. Although the numbers were small, not all patients had been screened for CT Brain at the time of diagnosis. From table2, we see that 49.68% patient could completed 6 cycles of first line chemotherapy, indicating that half of our patient did not even completed the basic chemotherapy course. 32 patients out of 2816 did have chemotherapy & radiotherapy both (year 2010), in the year 2011 & 2012 that figure increased to 55/2899(23.3%) & 68/2878(27.2%) respectively indicating more & more patients of lung cancer are recruited for chemoradiation. As per record 52.6% (121), 27.35% (65) & 23.2% (63) had undergone incomplete treatment. Median duration of survival was 10 months, 11 months & 14 months respectively. Discussion: Treatment of lung cancer depends on various factors like the stage of disease, histopathology, patterns of EGFR mutation etc. Multidetector computed tomography (MD-CT) and computed tomography guided lung biopsy has revolutionized the early detection process with high therapeutic ratio and less false positivity. [2] The advances in cytopathology in last two decades were made possible by improvement in medical imaging, more accurate evaluation of lung lesion & with CT guidance, the diagnostic precision and allay risk of [3, 4, 5] complications are possible. In developed nations, CT scan is widely available, cost effective and allows radiologically target smaller and deep seated lesions with a better yield compared with trans-bronchial biopsy. [6] But in our 163 2

3 study about one third of patients still could not afford CT scan Thorax facility.60% of patients are coming from suburban or rural areas are mostly from low socioeconomic status and unable to partake CT scan thorax when advised from referral hospital to this tertiary care hospital. Only CT guided FNA with a strip of CT image and not the whole thorax CT scan films are provided at the cost,the patients can afford and the oncologist is compelled to start therapy with the information available from the cytopathologist-- definite subtypes and clear cut diagnosis is lacking in many a times. In our study 90.4% of the patients of lung cancer were found to have only cytology based diagnosis and treatment. The role of surgery to eliminate small primary NSCLC and removal of residual lesion after adjuvant therapy is unchallenged. In USA alone 221,130 newpatients is suffering from lung carcinoma in the year Even with adjuvant (postoperative) chemotherapy & radiation, more than 40% of patient will develop recurrence locally & systemically & ultimately succumb to their disease. [7] 6 cycles platinum based first line chemotherapy was possible in 33.4%, 47.6% & 49.1% respectively in 2010 to 2012 period. This means majority of our patients (more than 50%) are not ready to accept the benefit of cytotoxic anticancer medication owing to socio-economic constraints. Immunotherapy as an adjuvant to surgery, chemotherapy &/or Radiotherapy is used to augment the efficacy of current treatment strategies. Immunotherapy is very effective against minimal disease burden & small deposits of tumour cells that are accessible by the circulating immune cells. [7] Due to financial constraints majority of the patient population could not afford bevacizumab, erlotinib or gefitinib. In our study none of the patients of lung cancer did have maintenance phase therapy with any of the above targeted agents in last three years ASCO guidelines for the management of advanced NSCLC (table 2) depicted that EGFR & IHC study is a basic minimum investigation to be conducted before starting of first line cytotoxic chemotherapy (CCT) against stage IV NSCLC case. [8] In our study, we found 78 % of the patients were either stage III or above (Advanced Lung Carcinoma). In developed world four main combinations of chemotherapy were used in the past for the management of lung cancer, namely cisplatin/gemcitabine, cisplatin/docetaxel, cisplatin/paclitaxel & cisplatin/vinorelbine. In 2008, cisplatin/pemetrexed become a new option in this setting on the basis of phase III result & presently declared as the most used combination for stage IV [9, 10] non-squamous NSCLC patient. From table 3, we found cisplatin/paclitaxel based chemotherapy was given to 15.44% of the patient & carboplatin/paclitaxel based chemotherapy was given to 38.05% of the patient. Only 1.11% patient was treated with cisplatin/docetaxel combination. From record it revealed none of the patient was treated with cisplatin/vinorelbine combination as first line treatment although this is an established option. [11] Knowing it fully well that overall survival for cisplatin plus pemetrexed over cisplatin plus gemcitabine is superior for patients of advanced lung adenocarcinoma (12.6 vs months, respectively). [12,13] In India pemetrexed based combination chemotherapy is more expensive and in our study only 7.32% was given that combination.since carboplatin is better tolerated than cisplatin, so carboplatin/pemetrexed combination is more commonly used than the former combination (10.2 %). Together we found 1643

4 17.54% of the total lung cancer patient since 2010 had been treated with pemetrexed containing regimen. Carboplatin/ paclitaxel combinationis mostly used (239/628=38 %) since these combination is better tolerated, less expensive & broad spectrum in efficiency. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) have proven efficacy in advanced non-small cell lung carcinoma (NSCLC). [14] EGFR protein expression was determined by immunohistochemistry (IHC), performed with overnight incubation using a clone31g7 mouse monoclonal EGFR-antibody at 1:300 dilution, the tumour was considered positive when more than 10% of tumour cells showed membrane staining of any intensity. [15, 16,17,18] This test is a complex procedure and the NABL accredited few laboratories are only expert and thus very expensive. To perform the test fine needle aspiration is not helpful, tissue block is needed. 9.56% of our patient is eligible for the procedure even if money is not the issue. Three landmark trials, IDEAL (Iressa Dose Evaluation in Advanced Lung Carcinoma) and INTACT (Iressa NSCLC Trial Assessing Combination Treatment) and ISEL (Iressa Survival Evaluation in Lung Carcinoma) studies, report evolved inconclusive decision regarding benefit of Gefitinib in lung cancer. [19,20,21] Whereas IDEAL studies concluded with the fact that Gefitinib demonstrated a remarkable 10-20% response rate in patients who failed previous chemotherapy, the INTACT trial and ISEL trial evaluated Gefitinib in combination with chemotherapy as first line treatment or as second line or third line treatment after resistance to chemotherapy developed were disappointing. [22] Newer agents which are effective against EGFR TKI resistance has developed such as, Afatinib, crizotinib which are targeting ENL4-ALK fusion protein. [23,] These are the new protein effective for patients who failed to sustain response with erlotinib/gefitinib. Conclusion: Lots of new agents for target specific lung carcinoma treatment have been developed in the last decade but the flavour of these newer agents are yet to reach the poorest of the poor victims of lung cancer patients of India. Most of the patients are starting treatment with chemotherapy with the cytological evidence only and histopathology and EGFR mutation study report is unavailable in majority of lung cancer patients. Patients attending government hospitals for treatment are true representative class of our society who are deprived from getting advantage of modern medicines that have evolved to terminal disease process of lung cancer. Although overall survival of the lung cancer is 26.1 % & 16.0 % in stage III & IV disease in US; we found only 8.0 % of patients in our study indicating biopsy proven disease diagnosis & EGFR mutation study is very much needed. [24, 25] The real challenge of the coming era is to encompass more and more of such poor patients under the ambit of modern anti-cancer approach, the pivotal role of which is played by targeted therapy. Financial & competing interests Disclosure: The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents reviewed or pending, or, royalties. 1654

5 No writing assistance was utilised in the production of this manuscript. Table1: Demography of lung cancer patients attended referral tertiary cancer centre of Kolkata Parameters Total no of newly diagnosed cancer patient registered Male: Female 1868: : :1002 Lung Ca 230(8.17%) 236(8.4%) 250(8.6%) Non-small cell lung ca 217(94.3%) 229(97.03%) 237(94.8%) Small cell lung ca 13(5.65%) 7(2.97%) 13(5.2%) HP proved lung cancer cases 18(7.82%) 19(8.05%) 32(12.8%) FNAC proved lung ca case 212(92.2%) 217(91.9%) 218(87.2%) Whole body CT scan before Nil Nil 1 starting of t/t Only CT thorax before 110(48%) 169(71.6%) 207(83%) starting of treatment CT thorax & abdomen 14(6.3%) 17(7.2%) 28(11.3%) CT thorax & USG W/A 24(10.6%) 50(21.2%) 100(40%) Lung ca with brain mets at 8(3.47%). 4(1.69%) 3(1.2%) presentation Six cycle of CCT completed 77(33.4%) 116(49.1%) 119(47.6%) CT +RT given 32(13.9%) 55(23.3%) 68(27.2%) Median duration of survival 10 months 11 months 14 months (6-20 m) (3-28 m) (1-16 m) Table 2: Chemotherapy of lung cancer patients used in Chemotherapy Started 628 Percentage (total patients) Incomplete CCT(1-3Cycles) Incomplete CCT(4-5Cycles) Total 6 Cycles Completed

6 Table 3: Chemotherapy regimen used for lung cancer patients (year ) Chemotherapy combinations No. of patients percentage Cisplatin/Gemcitabin Cisplatin / Docetaxel Cisplatin/ paclitaxel Carboplatin / paclitaxel Cisplatin/ Vinorelbin Cisplatin / Pemitrexed Carboplatin / Pemetrexed Cisplatin / etoposide Cyclophos/Doxo/Etoposide Etoposide/ Ifos/Cisplat eto/ifos/cisplat cyclo/doxo/eto cis/eto carbo/pemetrexed cis/premetrexed cis/vinorelbin carbo/pacli cis/pacli cis/doce cis/gem Fig 1 : bar chart showing relative frequency of use of different regimens in Lung cancer. Eto=etoposide, ifos= ifosfamide, cisplat=cisplatinum, cyclo= cyclophosphamide, doxo = doxorubicin, Carbo= carboplatin, pacli=paclitaxel, doce=docetaxel

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