ESMO Preceptorship Program Head & Neck Cancer NPC: Epidemiology, diagnosis and work-up

Transcription

1 ESMO Preceptorship Program Head & Neck Cancer NPC: Epidemiology, diagnosis and work-up Dr. John Woo Consultant, ENT Department, PWH Honorary Clinical Professor, Department of Otorhinolaryngology, H&N Surgery The Chinese University of Hong Kong

2 Prevalence of Nasopharyngeal Carcinoma

3 Prevalence of Nasopharyngeal Carcinoma

4 Epidemiology of Nasopharyngeal Carcinoma Endemic in Southern China! Guang Dong Tumour!

5 Epidemiology of Nasopharyngeal Carcinoma Still one of the commonest cancers in Hong Kong with an annual incidence of ~1000 over the past decades but on a down trend

6 Epidemiology of Nasopharyngeal Carcinoma In 1999 Rank Site Cases Mortality 1 Lung 3,707 3,168 2 Colon 2, Breast 1, Liver 1,572 1,420 5 Nasopharynx 1, Hong Kong Cancer Registry

7 Epidemiology of Nasopharyngeal Carcinoma NPC in 2015: 876 new case The commonest H&N cancer 10 th commonest of all cancers 10 th commonest cancer mortality Hong Kong Cancer Registry, 2015

8 Age Specific Incidence Rate of NPC & Other Cancers Hong Kong Cancer Registry, 1999

9 NPC Trends of the Past Decades Incidence trend over the past decades

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11 Age standardized incidence rate of NPC in Hong Kong over the past decades Time period Incidence (male) Incidence (female) : 28.5 / 100, / 100, : 20.2 / 100, / 100, : 12.0 / 100, / 100,000 Hong Kong Cancer Registry

12 Age standardized incidence rate of NPC in Hong Kong over the past decades Time period Incidence (male) Incidence (female) : 28.5 / 100, / 100, : 20.2 / 100, / 100, : 12.0 / 100, / 100,000 Hong Kong Cancer Registry

13 Age standardized incidence rate of NPC in Hong Kong over the past decades A total decrease of 29% for men and 30% for women. The peak incidence occurs in the year age group, and this sex & age-distribution pattern has remained much the same throughout the twenty-year period (Lee et al 2003).

14 Age standardized incidence rate of NPC in Hong Kong over the past decades Over the same period: 1. In Malaysia, no significant trend in the incidence rate for NPC has been observed. 2. In Singapore, a similar trend was observed but at a much slower rate than Hong Kong.

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16 Taiwan Cancer Registry 2016

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18 Figures from cancer registry of Hong Kong and Singapore

19 Age standardized incidence rate of NPC in Hong Kong over the past decades Time period Incidence (male) Incidence (female) : 28.5 / 100, / 100, : 20.2 / 100, / 100, : 12.0 / 100, / 100,000 Hong Kong Cancer Registry

20 Age standardized incidence rate of NPC in Hong Kong over the past decades This down trend cannot be explained by genetic drift as ~95% population are still from Canton province. EBV infection is still as prevalent as ever. EBV is still Every Body s Virus!

21 Age standardized incidence rate of NPC in Hong Kong over the past decades The traditional Chinese culture in Hong Kong has changed a lot over the last 2 3 decades! The way we keep, cook and use our food have changed a lot!

22 What remains unchanged The sex and age distribution pattern remains unchanged! Hong Kong Cancer Registry, 2015

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24 Common cancers in young persons Below the age of 45 NPC is the commonest cancer in male NPC is the 3 rd commonest cancer in female Hong Kong Cancer Registry, 2015

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28 Nasopharyngeal Carcinoma Diagnosis

29 Nasopharyngeal Carcinoma Process of Diagnosis Patient awareness Primary Care Practitioners Specialists

30 Nasopharyngeal Carcinoma Process of Diagnosis Patients General Practitioners Specialists

31 Key to early diagnosis Guided biopsy at first consultation!

32 Diagnosis of NPC Fact: Used to be late!

33 Diagnosis of NPC Why so late?

34 Late diagnosis of NPC Early disease has no or nonspecific symptoms Nasopharynx is difficult to examine by traditional means Patient & doctor factors involved

35 Staging at Diagnosis (1988) (Modified Ho s Classification) 200 consecutive patients diagnosed in % I II III IV V PWH/ENT Survey, 1988

36 PWH/ENT Survey, 1988

37 PWH/ENT Survey, 1988

38 Diagnosis of NPC Will better education in general, especially health education uplift the public awareness of NPC and earlier diagnosis?

39 Staging at Diagnosis (1996) (Modified Ho s Classification) 157 consecutive patients diagnosed in % I II III IV V PWH/ENT Survey, 1996

40 Awareness of NPC % Never Family Friends Media Source PWH/ENT Survey, 1996

41 Education Level and No. of Drs. Seen before Diagnosis % None Primary Secondary Tertiary 1 Dr. 2 Drs. 3 Drs 4-6 Dr. >6 Drs Education Level PWH/ENT Survey, 1996

42 Diagnosis of NPC Fact: What about now?

43 Diagnosis of NPC Fact: Still being late!

44 Stage distribution of NPC in Hong Kong at diagnosis 17.4% at stage I&II Hong Kong Cancer Registry 2015

45 Diagnosis of NPC Is early diagnosis possible?

46 Diagnosis of NPC Public & health education is probably not a solution to achieve early diagnosis!

47 Early Diagnosis of NPC What about a mass screening program?

48 NPC Screening for general population A major project set off from 2011 Prof. Dennis Lo, Prof. Allen Chan and their research Team Department of Chemical Pathology, Collaborating Departments: Department of Clinical Oncology and Radiotherapy Department of Diagnostic Radiology and Organ Imaging Department of Otorhinolaryngology, Head and Neck Surgery Prince of Wales Hospital, The Chinese University of Hong Kong Shatin, Hong Kong SAR, China.

49 NPC Screening for general population Conducted 2 large scale Mass Screening Programs between pilot study completed and published in Cancer 2013 Feb 21 1 mass screening program completed and published in N Engl J Med 2017

50 Early detection of nasopharyngeal carcinoma by plasma Epstein-Barr virus DNA analysis in a surveillance program. Chan KC, Hung EC, Woo JK, Chan PK, Leung SF, Lai FP, Cheng AS, Yeung SW, Chan YW, Tsui TK, Kwok JS, King AD, Chan AT, van Hasselt AC, Lo YM. Cancer 2013 Feb 21. doi: /cncr Objectives: Assessing the value of screening of volunteers for early detection of NPC using plasma EBV DNA as marker. Methodology: In total, 1318 volunteers ages 40 to 60 years were prospectively recruited. Plasma EBV DNA and serology for viral capsid antigen immunoglobulin A (IgA) were measured. Participants who had detectable plasma EBV DNA or positive IgA serology underwent nasal endoscopic examination and a follow-up plasma EBV DNA analysis in approximately 2 weeks. All participants were followed for 2 years to record the development of NPC.

51 Early detection of nasopharyngeal carcinoma by plasma Epstein-Barr virus DNA analysis in a surveillance program. Chan KC, Hung EC, Woo JK, Chan PK, Leung SF, Lai FP, Cheng AS, Yeung SW, Chan YW, Tsui TK, Kwok JS, King AD, Chan AT, van Hasselt AC, Lo YM. Cancer 2013 Feb 21. doi: /cncr Cost effective analysis: 1318 subjects recruited Plasma EBV DNA analysis 69 (5.2%) positive 19/69 (1.4% of 1318) had persistently positive result over a median of 16 days Over a period of 2 years, a total of 1387 EBV DNA analysis + 69 NP endoscopy performed and 3 early cases of NPC detected Serology IgA EBV viral capsid antigen 86 (6.5%) positive

52 Early detection of nasopharyngeal carcinoma by plasma Epstein-Barr virus DNA analysis in a surveillance program. Chan KC, Hung EC, Woo JK, Chan PK, Leung SF, Lai FP, Cheng AS, Yeung SW, Chan YW, Tsui TK, Kwok JS, King AD, Chan AT, van Hasselt AC, Lo YM. Cancer 2013 Feb 21. doi: /cncr Results: 3 individuals with NPC were identified at enrolment. All of them were positive for EBV DNA and remained positive in follow-up analysis. Only 1 of those patients was positive for EBV serology. In 1 patient who had NPC with a small tumor confined to the mucosa, the tumor was not detectable on endoscopic examination. Because of a 2-fold increase in plasma EBV DNA on the follow-up analysis, that patient underwent magnetic resonance imaging, which revealed the tumor. Among the participants who did not have NPC but had initially positive plasma EBV DNA results, approximately 66% had negative EBV DNA results after a median of 2 weeks. Conclusion: Plasma EBV DNA analysis proved useful for detecting early NPC in individuals without a clinical suspicion of NPC. Repeating the test in those who had initially positive results differentiated those with NPC from those who had false-positive results. Cancer 2013; American Cancer Society.

53 What did we learn from the pilot study Enrolment to the study Yearly phone FU - development of NPC - development of other cancers Time line Plasma EBV DNA 4 weeks 5.5% Positive plasma EBV DNA FU plasma EBV DNA test 1.5% Persistently positive plasma EBV DNA on two occasions Nasal endoscopy and MRI assessment

54 Prospective NPC mass screening with the revised protocol Methodology: Recruitment of asymptomatic male subjects between the age of Inclusion for NPC workup if plasma EBV DNA positive at 2 time points 4 weeks apart NPC workup include NP endoscopy and MRI Target recruitment of 20,000 subjects in 3 years

55 Subject recruitment Weekly community visits in all 18 districts

56 Results 20,174 subjects recruited 1,112 (5.5%) of 20,178 subjects with initial positive plasma EBV DNA 309 (1.53%) subjects with positive results on two occasions [4 weeks apart] - Endoscopic examination of nasopharynx - MRI examination - 9 subjects refused further investigation 34 NPC cases identified

57 Stage distribution 100% Percentage of patients in different stages 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% NPC patients identified by screening NPC patients in 2013 Hong Kong Cancer Registry Stage I Stage II Stage III Stage IV

58 Progression-free survival Survival probability (%) Number at risk Hazard ratio = (95% C.I.: ) Patients identified by screening Patients in a historical cohort Time (months)

59 Yearly FU Two test-negative subjects reported to have NPC diagnosed on yearly FU Case I NPC diagnosed at 4 months after screening Stage II disease Case II NPC diagnosed at 22 months after screening Stage III disease

60 Nine test-positive subjects refused further investigation One subjected reported to have developed NPC at 32 months after recruitment presented with metastatic disease died two months after diagnosis of NPC

61 Summary Plasma EBV DNA serves as a marker for screening of NPC Significant higher proportion of early stage disease (Stages I & II) patients Better progression-free survival for NPC patients detected by screening

62 Early Diagnosis of NPC A real possibility with effective screening and workups!

63 Workups for high risk NPC subjects High index of suspicion Screening based on EBV-NPC association General Vs Targeted population EBV IgA serology Vs plasma EBV DNA High risk NPC subjects Persistently raised NPC related EBV markers Positive family history for NPC +/- other symptoms and signs of NPC

64 Workups for high risk NPC subjects High risk NPC subjects Persistently raised NPC related EBV markers Positive family history for NPC +/- other symptoms and signs of NPC Effective Work Up Thorough assessment of the mucosal surface of NP by nasendoscopy (~90% of NPC were visible) Thorough assessment for deep seated NPC by MRI with iv contrast (MR much more accurate than CT)

65 Workups for high risk NPC subjects High risk NPC subjects Persistently raised NPC related EBV markers Positive family history for NPC +/- other symptoms and signs of NPC Nasendoscopy Nasendoscopy and NP biopsy of any suspicious lesions MRI with iv contrast Can pick up submucosal NPC / retropharyngeal nodes

66 Hidden / Submucosal Tumors Can easily be missed by an inexperienced / hurried endoscopist

67 Hidden / Submucosal Tumors Can easily be missed by an inexperienced / hurried endoscopist

68 Workups for high risk NPC subjects High risk NPC subjects Persistently raised NPC related EBV markers Positive family history for NPC +/- other symptoms and signs of NPC Nasendoscopy missed 1 submucosal T1N0 NPC but MRI picked it up

69 Workups for high risk NPC subjects High risk NPC subjects Persistently raised NPC related EBV markers Positive family history for NPC +/- other symptoms and signs of NPC MRI missed 1 T1N0 NPC at the right choana but Nasendoscopy picked it up

70 Workups for high risk NPC subjects High risk NPC subjects Persistently raised NPC related EBV markers Positive family history for NPC +/- other symptoms and signs of NPC Nasendoscopy would have missed it too if the endoscopy was done just through the left nostril alone!

71 Workups for high risk NPC subjects High risk NPC subjects Persistently raised NPC related EBV markers Positive family history for NPC +/- other symptoms and signs of NPC As a diagnostic tool for very early NPC in a high risk subject, nasendoscopy and MRI are complimentary to each other!

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73 Early Diagnosis of NPC Literature review

74 Endoscopic NP Biopsy ~90% NPC were endoscopically obvious in our series

75 Endoscopic NP Biopsy Biopsy must be targeted!

76 Targeted NP Biopsy ~90% NPC were endoscopically obvious

77 Targeted NP Biopsy Can the target be made more obvious?

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79 Summary: The nasopharynx of 156 patients who failed serological screening for or presented with symptoms of nasopharyngeal carcinoma was graded under white light and narrow band imaging endoscopy and a biopsy taken Narrow band imaging endoscopy patterns alone for suspected nasopharyngeal carcinoma is not more useful than white light endoscopy of nasopharyngeal morphology, nor does it add to or surpass the diagnostic accuracy of white light endoscopy in this regard Ultimately high index of suspicion and multiples biopsies are key to successful diagnosis.

80 Summary: The nasopharynx of 156 patients who failed serological screening for or presented with symptoms of nasopharyngeal carcinoma was graded under white light and narrow band imaging endoscopy and a biopsy taken Narrow band imaging endoscopy patterns alone for suspected nasopharyngeal carcinoma is not more useful than white light endoscopy of nasopharyngeal morphology, nor does it add to or surpass the diagnostic accuracy of white light endoscopy in this regard Ultimately high index of suspicion and multiples biopsies are key to successful diagnosis.

81 Workups for high risk NPC subjects High risk NPC subjects Persistently raised NPC related EBV markers Positive family history for NPC +/- other symptoms and signs of NPC Nasendoscopy bil-nostril nasendoscopy and; MRI with iv contrast

82 Follow ups for high risk NPC subjects Subsequent follow ups By what means How frequently For how long

83 Familial nasopharyngeal carcinoma in Hong Kong: epidemiology and implication in screening Wai Tong Ng, Cheuk Wai Choi, Michael C. H. Lee, Siu Hong Chan, Tsz Kok Yau, Anne W. M. Lee Familial Cancer (2009) 8: Objective: Review the characteristics of familial vs non-familial NPC Stage at presentation and treatment results for patients with or without a screening program Materials and Method: Retrospectively review all [1,202] NPC patients diagnosed between March 1994 and November 2005 in PYNEH. Analysis groups: Group 1 [125]: with 1 st degree NPC relative - subgroups1a: under a family screening program - subgroup 1b: not under any screening program Group 2 [1077]: without 1 st degree NPC relative none of these were under any screening program

84 Familial nasopharyngeal carcinoma in Hong Kong: epidemiology and implication in screening Wai Tong Ng, Cheuk Wai Choi, Michael C. H. Lee, Siu Hong Chan, Tsz Kok Yau, Anne W. M. Lee Familial Cancer (2009) 8: Results: Demographics: In the present study, the familial NPC patients with first-degree family history were on average about 2 years younger than the sporadic ones. Although with slightly more female patients, however, not statistical significant. It seemed that familial NPC did not have any notable demographical characteristics for it to be distinct from sporadic cases. Stage of disease at diagnosis: 37% in group 1 presenting at stage I II - sub-gp. 1a [52.9%] - sub-gp. 1b [34.3%] 23% in group 2 presenting at stage I-II (P\0.01)

85 Familial nasopharyngeal carcinoma in Hong Kong: epidemiology and implication in screening Wai Tong Ng, Cheuk Wai Choi, Michael C. H. Lee, Siu Hong Chan, Tsz Kok Yau, Anne W. M. Lee Familial Cancer (2009) 8: Conclusions: 1 st degree relatives of NPC patients have significant higher risk of developing NPC [4-8 fold more] Familial NPC patients were generally diagnosed at an earlier age than sporadic cases. Familial NPC patients under a surveillance program were diagnosed earlier than those not under surveillance. *Any surveillance is better than none

86 Follow ups for high risk NPC subjects Subsequent follow ups By what means - The surveillance program should as at least as accurate as the initial screening program How frequently For how long

87 Follow ups for high risk NPC subjects Subsequent follow ups By what means - Plasma EBV DNA / IgA EBV serology + nasendoscopy - +/- MRI +/- iv contrast when indicated otherwise How frequently For how long

88 Follow ups for high risk NPC subjects Subsequent follow ups By what means - EBV IgA serology / Plasma DNA + nasendoscopy - +/- MRI +/- iv contrast How frequently For how long

89 An analysis of the efficacy of serial screening for familial nasopharyngeal carcinoma based on Markov chain models Cheuk Wai Choi Michael C. H. Lee.Wai Tong Ng Lai Yau Law Tsz Kok Yau Anne W. M. Lee Familial Cancer (2011) 10: Objectives: To compared cost-effectiveness of different screening programs for familial NPC based on Markov chain models Materials and Method: A retrospective analysis of 1 st degree family members of patients with NPC taken from the data base of an on going screening program. A total of 1,072 out of a total of 1,199 family members of NPC patients screened between 1994 to 2005 were included. Among them, 127 participants with fluctuating EBV serological test results were excluded from this study due to the non-reversible assumption of the Markov chain model.

90 An analysis of the efficacy of serial screening for familial nasopharyngeal carcinoma based on Markov chain models Cheuk Wai Choi Michael C. H. Lee.Wai Tong Ng Lai Yau Law Tsz Kok Yau Anne W. M. Lee Familial Cancer (2011) 10: Assumption: a point of no return for carcinogenesis

91 An analysis of the efficacy of serial screening for familial nasopharyngeal carcinoma based on Markov chain models Cheuk Wai Choi Michael C. H. Lee.Wai Tong Ng Lai Yau Law Tsz Kok Yau Anne W. M. Lee Familial Cancer (2011) 10: This study simulated and compared the outcomes of 4 screening strategies over a period of 12 years: (A) annual screening, (B) biennial screening, (C) triennial screening, and (D) triennial screening for participants tested EBV negative and annual screening once the participants are tested EBV positive.

92 An analysis of the efficacy of serial screening for familial nasopharyngeal carcinoma based on Markov chain models Cheuk Wai Choi Michael C. H. Lee.Wai Tong Ng Lai Yau Law Tsz Kok Yau Anne W. M. Lee Familial Cancer (2011) 10: Results: The early detection rates with strategies A, B, C and D are 88, 79, 71 and 87% respectively. The 5-year overall survival with screening is 10 12% higher than that without and is the highest with strategies A and D. Strategy D, however, requires only 64% screening tests compared with strategy A and has almost identical resultant disease stage distribution to strategy A. The study concluded that strategy D, i.e., triennial screening for participants tested EBV negative and annual screening once the participants are tested EBV positive offered the highest efficacy for NPC screening of family members of NPC patients among the four strategies studied.

93 An analysis of the efficacy of serial screening for familial nasopharyngeal carcinoma based on Markov chain models Cheuk Wai Choi Michael C. H. Lee.Wai Tong Ng Lai Yau Law Tsz Kok Yau Anne W. M. Lee Familial Cancer (2011) 10: Results: The early detection rates with strategies A, B, C and D are 88, 79, 71 and 87% respectively. The 5-year overall survival with screening is 10 12% higher than that without and is the highest with strategies A and D. Strategy D, however, requires only 64% screening tests compared with strategy A and has almost identical resultant disease stage distribution to strategy A. The study concluded that strategy D, i.e., triennial screening for participants tested EBV negative and annual screening once the participants are tested EBV positive offered the highest efficacy for NPC screening of family members of NPC patients among the four strategies studied.

94 Workups for high risk NPC subjects Subsequent follow ups By what means - EBV IgA serology / Plasma DNA + nasendoscopy - +/- MRI +/- iv contrast How frequently - annual follow ups should suffice For how long

95 Workups for high risk NPC subjects Subsequent follow ups By what means - EBV IgA serology / Plasma DNA + nasendoscopy - +/- MRI +/- iv contrast How frequently - annual follow ups should suffice For how long

96 Workups for high risk NPC subjects Subsequent follow ups By what means - EBV IgA serology / Plasma DNA + nasendoscopy - +/- MRI +/- iv contrast How frequently - annual follow ups should suffice For how long - can only be answered with more and longer term studies, and ultimately with the NPC Genomic Studies

97 Workups for high risk NPC subjects Subsequent follow ups By what means - EBV IgA serology / Plasma DNA + nasendoscopy - +/- MRI +/- iv contrast How frequently - annual follow ups should suffice For how long - life long follow up for those with positive family history and persistently raised markers

98 Conclusions: Effective workups for high risk NPC subjects plasma EBV DNA Bil-nostril nasendoscopy MRI with iv contrast Subsequent follow ups By what means - Plasma EBV DNA + nasendoscopy How frequently - Annually For how long - long term follow up for those with positive family history and persistently raised markers

99 Thanks

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102 Q & A