Table of Contents

Original ArticlesCorrelations between MHLC Scores and Indicators of Immune Response in Egyptian Women with Breast Cancer .............. .............. 07Eman M. EL-Baiomy, Mohamed L. Salem, Azza El-Amir, Noha A. Sabry, Kenneth A. Wallston, Nehal EL-Mashad

Open label, non-randomized, interventional study to evaluate response rate after induction therapy with docetaxel and cisplatin in locally advanced squamous cell carcinoma of oral cavity ........................................................................................... 12S. H. Manzoor Zaidi, Ahmad Ijaz Masood, Syed Ijaz Hussain Shah, Irfan Hashemy

The Association Between Clinicopathological Features and Molecular Markers in Bahraini Women with Breast Cancer .................. 19Aysha AlZaman, Eman Ali, Bayan Mohamad, Moinul Islam, Entisar AlZaman, Yahya AlZaman

Immunohistochemical Staining for Ras-Related Protein 25 (RAB25) Associates with Luminal B Breast Cancer Subtype .................. 26Amina Belhadj, Lynda Addou-Klouche, Issam Bouakline, Miloud Medjamia, Hamid Jelloul Benammar, Tewfik Sahraoui

Bibliometric and Comparative Analysis of Castration Resistant and Refractory, Hormone Resistant and Refractory Prostate Cancer Publications .......................................................................................................... 34Selahattin Çalışkan, Alkan Çubuk, Abdullah Ilktac

ALK gene rearrangement status in non-squamous non-small cell lung carcinoma in the Middle Eastern population ..................... 38Samah El Naderi, Rosy Abou-Jaoude, Marc Rassy, Hussein Nasreddine, Elie El Rassy, Claude Ghorra

Micronucleus Test for Diagnosing Uncertain Cases (BI-RADS 3) in Breast Cancer Screening: A Review and Preliminary Results ... 45Roberto Menicagli, Ortensio Marotta, Roberta Serra

Preoperative Leukocytosis as a Prognostic Marker in Endometrioid-Type Endometrial Cancer: A Single-Center Experience from Saudi Arabia .................................................................................................................................................................. 51Hany Salem, Ahmed Abu-Zaid, Osama Alomar, Mohammed Abuzaid, Mohammad Alsabban, Tusneem Elhassan, Abdullah Salem,

Yahya Alyamani, Ismail A. Al-Badawi

Review ArticlesA Quick Review of Redox State in Cancer: Focus to Bladder ................................................................................................................... 59Hamid Mazdak, Mehdi Gholampour, Zahra Tolou_Ghamari

Case ReportsAbdominoscrotal Lymphangioma Masquerading as a Communicating Hydrocele: A Case Report ....................................................... 63Ahmed Al Rashed, Zarine Gazali, Vijay Kumar Malladi, Arbinder Kumar Singal

Hurthle Cell Adenoma with Micro-Papillary Carcinoma and Parathyroid Adenoma in a Transplant Recipient with Graft Failure: A Case Report ...................................................................................................................................................................... 66Shameema Sharfudeen, Tasneem Amir, Waddah Eskaf, Mahmoud Elsayed Ghanem, Aysha Al Jassar, Kusum Kapila

Feature ArticleThe State of Cancer Care in the United Arab Emirates in 2020: Challenges and Recommendations, A report by the United Arab Emirates Oncology Task Force .................................................................................................................... 71 Humaid Al-Shamsi, et. al.

Conference Highlights/Scientific Contributions• Highlights of “Management of Breast and Colorectal Cancer: Recent Updates” Kuwait Conference .............................................. 88

• News Notes ........................................................................................................................................................................................... 92

• Scientific events in the GCC and the Arab World for 2020 ................................................................................................................. 96

12

Abstract

Introduction: A phase II study was conducted in patients, unsuited for surgery, with locally advanced squamous cell carcinoma of oral cavity (stage III or IV) and without distant metastasis. The objectives were to evaluate overall response (OR) rate and safety of subjects treated with induction regimen docetaxel and cisplatin, followed by definitive chemoradiotherapy (CRT) in this setting.

Methods and Materials: Induction regimen consisted of docetaxel 75mg/m2 and cisplatin 75mg/m2 on day 1; cycles repeated every 21 days for three cycles with supportive G-CSF treatment beginning at first cycle. Definitive CRT consisted of weekly cisplatin 30mg/m2 for four weeks starting concomitantly with 60 Gy/30 fractions of conventional radiotherapy for six weeks. Primary and secondary efficacy criteria were OR rate at three weeks after cycle three and eight weeks after last cycle of CRT respectively.

Results: Three centers enrolled 35 patients. Primary efficacy endpoint: OR rate of evaluable patients after induction (n=27) was 88.9% (95% CI:71.9-96.2). Complete response (CR) was not achieved by any patient; partial response (PR) was achieved by 88.9% (24/27). From intent to treat (ITT) analysis OR rate was 68.6% (24/35). Secondary efficacy endpoint: OR rate of evaluable patients after definitive CRT (n=19) was 78.9%(95%CI:56.7–91.5) with CR and PR achieved by 2(10.5%) and 13(68.4%) patients respectively. From ITT analysis CR rate was 5.7% (2/35) and OR rate was 42.9% (15/35). During induction most common hematological toxicity was leukopenia in eight patients, with ≥Grade 3 leukopenia reported in three patients. During CRT most common adverse events were alopecia, stomatitis and nausea.

Conclusion: We observed an ITT response rate of 68.6% with induction regimen docetaxel plus cisplatin, with a manageable safety profile. Hence, further investigation in this setting is warranted.

Keywords: docetaxel, cisplatin, head and neck cancer, squamous cell carcinoma, phase II

Original Article

Open label, Non-randomized, Interventional Study to Evaluate Response Rate After Induction Therapy with

Docetaxel and Cisplatin in Locally Advanced Squamous Cell Carcinoma of Oral Cavity

S. H. Manzoor Zaidi1, Ahmad Ijaz Masood2, Syed Ijaz Hussain Shah3, Irfan Hashemy4.

1Baqai Institute of Oncology, Karachi, Pakistan 2 Clinical Oncology Department, Nishtar Medical College and Hospital, Multan, Pakistan

3 Clinical Oncology Department, Allied Hospital, Faisalabad, Pakistan 4 Medical Affairs, Sanofi-Aventis Pakistan limited, Karachi

Corresponding author: Irfan Hashemy, Executive Medical Manager, Medical Affairs, Sanofi-

Aventis Pakistan limited, Karachi, Pakistan, Postal Address: Sanofi-Aventis Pakistan limited, Plot 23, Sector 22, Korangi Industrial Area, Karachi-74900

Pakistan, Telephone: +92 300 2220204, Email address: irfan.hashemy@sanofi.com

IntroductionSquamous cell carcinoma of the head and neck

(SCCHN) is one of the most common cancers worldwide, with more than 90% of tumors in the head and neck being squamous carcinomas.(1) Among head and neck cancers, oral cavity cancers are highly prevalent in Southern Asia and the leading cause of cancer deaths in Pakistani males. (2) Risk factors for the development of SCCHN include tobacco smoking, alcohol use and betel chewing.(3) In Pakistan, a local cancer registry reported that head and

neck cancers are the most common in males accounting for 15.70% of the cancers.(4) GLOBOCAN estimated that oral cavity and lip cancers accounted for 18881 new

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G. J. O. Issue 32, 2020

cases in 2018, with an age standardized incidence rate of 12.2 per 100,000 population.(5) Most cases of oral cavity cancers are locally advanced and have a poor prognosis.(6)

Locally advanced SCCHN (LA-SCCHN) is generally treated by a combination of chemotherapy, radiotherapy and/or surgery.(7) Selection of treatment is based on considerations of disease control, anticipated functional and cosmetic outcomes, patient general condition and availability of resources and expertise.(8) Surgery for oral cancers can be disfiguring and both surgery and radiotherapy have significant functional side effects, notably impaired ability to eat, drink and talk.(9) Primary radiotherapy and/or chemotherapy may be selected for the following reasons a) in early stage disease to avoid anticipated functional and cosmetic defect, b) for unresectable disease, c) for high operative risk patients due to comorbidity or poor performance status, d) recurrent disease when previous multiple surgeries have been undertaken and further surgery would be technically improbable, and e) patient’s preference.(8) Timing of the chemotherapy has for long been a matter of debate (10) but concurrent chemo radiation was widely adopted as standard of care for LA-SCCHN after the publication of a large meta-analysis including individual updated data on 10,741 patients in 63 randomized trials (11) An updated meta-analysis with 24 new trials concluded that the benefit of concomitant chemotherapy was confirmed and was greater than the benefit of induction chemotherapy.(12) Induction chemotherapy has some appealing theoretical advantages: optimal drug delivery to the tumor through undisrupted vasculature, early eradication of micrometastases and improved tolerance of cytotoxic drugs. (13) Tumor shrinkage may render unresectable tumors resectable or reduce the extensiveness of the intended surgery for resectable tumors. Induction chemotherapy offers the opportunity of assessing tumor response and selecting the patients who are candidate for organ preservation.

The cisplatin plus fluorouracil (FU) combination was the induction regimen of choice for two decades. Randomized trials had demonstrated superior objective response rates with cisplatin plus 5-FU (approximately 30%) compared with single-agent cisplatin, 5-FU, or methotrexate (10% to 20%) in advanced SCCHN. However, this advantage was not reflected in improved overall survival rates for combination therapy compared with monotherapy. (11) Furthermore, the cisplatin plus 5-FU combination was associated with significantmucosal toxicity and prolonged administration time, factors that are problematic in this patient population and that detract from the palliative intent of the therapy.

Combination of cisplatin, fluorouracil and a taxane has superseded cisplatin plus 5-FU which can be considered

the standard regimen when induction chemotherapy is appropriate. (14,15) Phase II data of docetaxel plus 5-FU regimen failed to show the desired response in patients with SCCHN (16) while another phase II trial of docetaxel plus cisplatin regimen as an induction chemotherapy in LA-SCCHN had shown that the combination is useful and with manageable toxicity.(17) However, to date there is scant induction data in Pakistan measuring response rate and safety of docetaxel and cisplatin combination in SCCHN patients unsuited for surgery. Thus, there was a need to have this study in patients with locally advanced squamous cell carcinoma of oral cavity (stage III or IV) without distant metastasis. The primary objective of the study was to evaluate overall response (OR) rate and the secondary objective was to assess the safety and tolerability of the induction regimen docetaxel and cisplatin followed by definitive chemoradiotherapy (CRT) in this setting.

Methods and Materials

Patient population

The study was conducted at three hospitals in Pakistan from May 2014 to October 2015. Patients diagnosed with squamous cell carcinoma of oral cavity in stage III–IV without evidence of distant metastases and no prior chemotherapy or radiation therapy were selected for the study. Patients had to be considered not suitable for surgery. Selected patients were between the age groups of 18 years and 65 years with Eastern Cooperative Oncology Group (ECOG) ≤ 1, life expectancy > 3 months and adequate organ function. We excluded patients who had any previous definitive surgery for SCCHN, chemotherapy or radiotherapy or any other diagnosed case of cancer. Patients were excluded if they had associated complaints of peripheral neuropathy > grade 1 or other serious diseases such as unstable ischemic heart disease, acute myocardial infarction six months prior to inclusion, history of significant neurological or psychiatric disorder or active peptic ulcer. We also excluded patients who were being treated concomitantly with corticosteroids (except as pre-medication), severe weight loss (> 20 % of body weight) in the preceding three months and hearing loss (> grade 2). Pregnant women and sexually active females without adequate contraception were also excluded from the study.

The study was undertaken in accordance with principles of the Declaration of Helsinki and Good Clinical Practice guidelines. It was approved by the institutional review boards of each participating hospital, and written informed consent was obtained from all participants.

14

Induction therapy with docetaxel and cisplatin in head & neck cancer, S. H. Manzoor Zaidi, et. al.

Treatment and data collection

The treatment duration for each patient was around six months. Patients included in the study were treated with induction regimen followed by definitive CRT. Within the induction period there were three cycles (docetaxel plus cisplatin) every 21 days. The post-induction follows up was on day 21 after the third cycle. This was followed by definitive CRT consisting of radiotherapy for six weeks and cisplatin every week for four cycles. Following definitive CRT the follow up was at eight weeks after radiotherapy. During the induction period, patients received a one-hour intravenous infusion of docetaxel at 75 mg/m2 {capped at a body surface area (BSA) of 2.0 m2} followed by a 30-minute intravenous infusion of cisplatin at 75 mg/m2 (capped at a BSA of 2.0 m2). Docetaxel and cisplatin treatments were repeated every 21 days for three cycles, provided that the patient’s blood count had returned to normal (absolute neutrophil count ≥1500 / mm3; platelet count ≥ 100,000/ mm3) by the start of the next scheduled chemotherapy cycle. Patients were pre-medicated with dexamethasone at 8 mg twice daily for three days, commencing one day before docetaxel infusion. Patients were premedicated with intravenous dexamethasone at 20 mg and either ondansetron or granisetron was administered before cisplatin infusion. Patients undergoing induction chemotherapy were given supportive Granulocyte Colony-Stimulating Factor (G-CSF) treatment beginning at the first cycle. During definitive CRT, intravenous cisplatin was administered at a dose of 30 mg/m2 weekly starting concomitantly with conventional radiotherapy to the primary tumor and to the clinically positive nodes for a period of six weeks. Intravenous cisplatin was continued for four weeks. Gross disease dose of conventional radiotherapy was 60 Gy/30 fractions over six weeks and sub clinical dose was 45-50 Gy/30 fractions. A boost of 4 – 6 Gy in 2 -3 fractions to the gross tumor was optional. The equipment used was telecobalt.

Primary and secondary efficacy criteria were OR rate at three weeks after cycle three of the induction period, and at eight weeks after last cycle of definitive CRT respectively. Proportion of patients who achieved complete response and partial response were evaluated using the RECIST criteria version 1.1 (18). Radiologic tumor measurements with CT scans at baseline, at the end of the induction period and at the end of definitive CRT were performed. At each visit, a physical examination, laboratory tests, and adverse events (AEs) assessment were performed. The AEs were classified based upon their occurrence and severity. The National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.03 (19) was used to grade the adverse events.

Statistical analysis

Population characteristics were summarized using descriptive statistics such as mean, standard deviation and median for continuous variables, and frequencies and percentages for categorical variables. Based on a European study (20), we assumed the OR rate of docetaxel plus cisplatin regimen to be 54%. For a 95% confidence level and a margin of error of 17.5% the sample size required was 32. Accounting for a dropout rate of approximately 10%, we conducted this study on 35 subjects. Intention to Treat (ITT) analysis was done based on proportion of patients who achieved complete response and partial response using the RECIST criteria version 1.1 at three weeks after cycle three and at eight weeks after completion of last cycle of CRT. To determine proportion of patients, the number of patients in each of the given six categories was divided by the ITT population. These categories were complete response (CR), partial response (PR), stable disease (SD), progressive disease (PD), unknown & not done

Results

Baseline characteristics

Thirty-five patients were enrolled in this study. There were 24 (68.6 %) males and 11(31.4%) females. The overall mean and median age of these patients was 44.4±11.8, and 45 years respectively. The mean and median age of male patients was 44.6±10.3, and 45 years respectively and that of females was 43.9±15.3, and 46 years respectively. TNM staging information showed that six (17.1%) patients had stage III disease and 29 (82.9%) patients had stage IV disease. Eighteen (51.4%) patients had a T4 status and 15 (42.9%) patients had a N2 status. (Table 1)

Efficacy Evaluation

Of the 35 patients 27 were assessable for response of induction chemotherapy. After the first cycle of induction chemotherapy two patients died, two patients were lost to follow up and one patient was dropped from the study due to nephrotoxicity. After the second and third chemotherapy cycles one more patient was lost to follow up and two patients died respectively. The OR rate of the evaluable patients (n=27) was 88.9% (95% CI: 71.9 - 96.2). A CR was not achieved by any patients and PR was achieved by 24 (88.9%) of 27 patients. Stable disease (SD) and progressive disease (PD) were shown for one patient and two patients, respectively. From the intent to treat analysis CR rate was not achieved by any patients and the OR rate was 68.6% (24 of 35). (Table 2)

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G. J. O. Issue 32, 2020

during CRT. The OR rate of the evaluable patients was 78.9% (95% CI: 56.7 – 91.5). A CR was achieved by two patients (10.5%) and a PR was achieved by 13 (68.4%) of 19 patients. Progressive disease (PD) were shown for four patients (14.8%). From the intent to treat analysis CR rate was 5.7 % (2 of 35) and the OR rate was 42.9% (15 of 35) at the end of definitive CRT. (Table 2)

Safety Evaluation

All 35 patients were included for safety evaluation. For the induction period, 94 cycles of chemotherapy were analyzed. The mean dose intensity of docetaxel was 23.93±2.29 mg/m2/week and the mean dose intensity of cisplatin was 23.54±2.90 mg/m2/week. The mean and median relative dose intensity for docetaxel was 95.20±11.12, and 96.8 respectively and that of cisplatin was 93.75±13.07 and 96.8 respectively. During induction, 26 patients had at least one adverse event (any grade), while nine patients had at least one AE of ≥ Grade 3. The most common hematological toxicity during induction was leukopenia which occurred in eight patients, and three patients suffered from leukopenia of ≥Grade 3. The common non-hematologic toxicities (all grades) were nausea, stomatitis and alopecia which occurred in 21, 18 and 18 patients respectively. During definitive CRT, 22 patients had at least one AE (any grade), while four patients had at least one AE of ≥Grade 3. The most common adverse events (all grades) during CRT were alopecia, stomatitis and nausea which occurred in 14, 13 and 13 patients respectively.

A summary of the most common treatment emergent AEs is depicted in Table 3 & 4. There was one case of febrile neutropenia. Nausea, vomiting and diarrhea of ≥Grade 3 occurred in one, three and five patients respectively. Seven patients died during the study period. One patient presented with complaints of vomiting, drowsiness and decreased level of consciousness. The most likely cause of death was subdural hematoma due

†BPM: Beats per minute, ‡ cm: centimeter, §kg: kilogram, ‖s.d: Standard deviation

Table 1. Baseline Patients Characteristics

Characteristic

Age (years, mean±s.d /median)

Gender

Male

Female

ECOG performance status 1

Stage of Primary tumor

T2

T3

T4

Nodal status

N0

N1

N2

N3

Overall Stage

III

IV

Histopathology

Well differentiated

Moderately differentiated

Poorly/undifferentiated

Degree of differentiation not assessable

Vitals signs

Blood pressure systolic (mm Hg mean ±s.d)

Blood pressure diastolic (mm Hg mean ±s.d)

Heart rate (†bpm mean ±s.d)

Temperature (°C mean ±s.d)

Body weight (§kg)

Height (‡cm)

Total (N = 35) (%)

44.4 ± 11.8 / (45)

24 (68.6)

11 (31.4)

35 (100)

02 (5.7)

15 (42.9)

18 (51.4)

2 (5.7)

14 (40)

15 (42.9)

4 (11.4)

06 (17.1)

29 (82.9)

15 (42.9)

13 (37.1)

1 (2.9)

6 (17.1)

118.1 ± 7.5

76.9 ± 5.2

81.9 ± 4.5

36.9 ± 0.3

62.3 ± 21.6

164.1 ± 10.5

Of the 27 patients assessable after induction phase, 19 were assessable eight weeks after completion of definitive CRT. After the post induction follow up visit, one patient refused to participate. After week six of CRT three patients died, and one patient refused to participate. Three patients were excluded due to protocol violation

Table 2. Summary of response rate

Response

Induction phase

(n= 35)

Definitive CRT

(n=27)

Complete response

0

(0%)

2

(7.4%)

Partial response

24

(68.6%)

13

(48.1%)

Progre-ssivedisease

2

(5.7%)

4

(14.8%)

Stable disease

1

(2.8%)

0

(0%)

Not assessed

8

(22.9%)

8

(29.6%)

Overall response rate (ITT)

24

(68.6%)

15

(42.9%)

16

Induction therapy with docetaxel and cisplatin in head & neck cancer, S. H. Manzoor Zaidi, et. al.

to head injury. In case of one patient, the probable cause of death was diarrhea and hypotension. Another patient died in a road traffic accident. For the rest of the cases, the cause of death is not known. These fatal events were considered as not associated to the investigational drugs.

DiscussionSquamous cell carcinoma of the head and neck

(SCCHN) presents at a locally advanced stage in many patients. (21) Chemotherapy, which is one fundamental therapy mode for local disease control of inoperable disease or if organ preservation is desired, has become an important factor of first line treatment regimens either during or prior to radiotherapy. Patients with locoregionally advanced inoperable, recurrent or metastatic disease still have a poor prognosis, which enforces the need for new treatment approaches and new drug therapies, adjusted to the different settings of the disease. One innovative progress for such patients with locally

advanced tumor was the implementation of docetaxel in chemotherapeutic regimes in optimal combination with concurrent chemoradiotherapy or in neoadjuvant setting of induction phase treatment. (22) Docetaxel combined with the conventional chemotherapy regimen, containing cisplatin and 5-FU (TPF), is now acknowledged as being the gold standard of induction treatment. (23) Various studies suggest survival advantage due to the induction chemotherapy followed by chemoradiotherapy, which is known as sequential therapy, over chemoradiotherapy alone. (22,23) The DeCIDE trial (24) showed decreased adherence in patients receiving TPF and during subsequent chemoradiotherapy. Thus, TPF followed by cisplatin/radiotherapy may be suitable only for highly selected patients with good to excellent performance status and no contraindications to cisplatin or for those who received a protocol driven reduced total dose of cisplatin during induction chemoradiotherapy. (25-27)

In the present study we assessed the response rate and safety profile of induction regimen docetaxel and cisplatin followed by definitive chemoradiotherapy with the primary endpoint of overall response rate and secondary endpoint of safety profile among SCCHN patients in Pakistan. In our clinical experience, many patients are not suitable for full treatment dosages on account of poor nutritional status and general condition. Therefore, during definitive CRT, protocol driven reduced dosages of radiotherapy and cisplatin were administered to maximize patient safety and improve adherence to treatment. In this study of patients with squamous cell carcinoma of oral cavity in stage III–IV without evidence of distant metastases, the combination of docetaxel and cisplatin showed activity during the induction phase with an intent-to-treat response rate of 68.6%. For the evaluable patients, the overall response rate was 88.9% (95% CI: 71.9 - 96.2). Following definitive CRT, this intent-to-treat response rate declined to 42.9% and for the assessable patients the response rate was 78.9% (95% CI: 56.7 - 91.5).

Noronha et al reported 65.4% OR rate for docetaxel and cisplatin induction chemotherapy in South Asian Population which is comparable to the outcomes in the present study.(28) Specht et al (29) and Glisson et al (30)

evaluated the same doses of docetaxel and cisplatin as those used in the present trial and observed a response rate of 33% and 40% respectively. The OR rate of the present trial for ITT population (42.9%) at the end of study is comparable to these studies. However, both these trials included SCCHN patients with different primary disease sites, as well as distant metastasis. The main limitation of the study is the relatively small patient population. Additionally, follow up evaluation was not undertaken to determine if the response rate can result in survival improvement.

Table 3. Treatment Emergent Adverse Events - Induction

phase

Treatment Emergent Adverse Events -

Definitive CRT

Alopecia

Nausea

Stomatitis

Vomiting

Grade

≤ 2

14

13

13

9

3

0

0

0

0

4

0

0

0

0

5

0

0

0

0

All

14

13

13

9

Table 4. Treatment Emergent Adverse Events – Definitive CRT

Treatment Emergent Adverse Events -

Induction phase

Leukopenia

Alopecia

Diarrhea

Nausea

Stomatitis

Vomiting

3

3

1

4

1

0

3

4

0

0

0

0

0

0

5

0

0

1

0

0

0

All

8

18

14

21

18

13

Grade

≤ 2

5

17

9

20

18

10

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G. J. O. Issue 32, 2020

Overall, the toxicity of docetaxel and cisplatin was generally manageable. During the induction phase, leukopenia was the most common hematological toxicity reported in eight of 35 patients. The non-hematological toxicities were generally tolerable.

ConclusionIn conclusion, we observed an intent-to-treat

response rate of 68.6% with induction regimen docetaxel plus cisplatin, with a manageable safety profile in our setting. Although, induction chemotherapy remains controversial as a routine treatment in patients with inoperable disease, further investigation is warranted.

AcknowledgementWe are grateful to the following physicians who

participated in this study: Muhammad Khalid (Faisalabad); Tahseen Khursheed (Karachi); Sarah Khan and Farwa Nasir (Multan). We also acknowledge Iqbal Mujtaba from Sanofi Pakistan for statistical assistance. The authors were responsible for all content and editorial decisions and received no honoraria related to the development of this manuscript. Trial registration: ClinicalTrials.gov (NCT02061631)

Funding and Conflict of InterestThis study was funded by Sanofi-Aventis Pakistan

limited. S. H. Manzoor Zaidi has received honoraria from Sanofi, Eli Lilly and Roche. Ahmed Ijaz Masood has received research funding from GlaxoSmithKline, honoraria from Sanofi and GlaxoSmithKline. Syed Ijaz Hussain Shah has received honoraria from Sanofi. Irfan Hashemy is a full-time employee of Sanofi.

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