Management of Metastatic Nasopharyngeal Carcinoma

C H A P T E R

14 Management of Metastatic Nasopharyngeal Carcinoma Roger K.C. Ngan1, Kenneth W.S. Li2, James C.H. Chow2, Timothy T.C. Yip3 1

2

Department of Clinical Oncology, University of Hong Kong, Gleneagles Hong Kong Hospital, Hong Kong, China; Department of Clinical Oncology, Queen Elizabeth Hospital, Hong Kong, China; 3Laboratory Director, ACT Genomics Biotechnology (Hong Kong) Ltd, Hong Kong, China

O U T L I N E Introduction Prognostication of Metastatic Nasopharyngeal Carcinoma Prognostic Models

314 314 314

Approaches in Formulating Systemic Chemotherapy 316 First-Line Systemic Chemotherapy 316 Palliative Chemotherapy Beyond First-Line Treatment 318 Novel Therapy for Metastatic Nasopharyngeal Carcinoma

320

Monitoring of Therapeutic Response by Biomarkers During Systemic Therapy 323 EpsteineBarr Virus DNA 323 Circulating Tumor Cells and Other Potential Biomarkers 324

Nasopharyngeal Carcinoma https://doi.org/10.1016/B978-0-12-814936-2.00014-6

Local Treatment for Oligometastatic Nasopharyngeal Carcinoma Surgical Excision and Image-Guided Ablative Interventions Bone Metastases Liver Metastases Lung Metastases Stereotactic Ablative Radiotherapy

325 325 325 326 326 326

Role of Local Therapy in Metastatic Nasopharyngeal Carcinoma

327

Conclusions

327

References

328

Commentary on Chapter 14: Management of Metastatic Nasopharyngeal Carcinoma

333

References

334

313

Copyright © 2019 Elsevier Inc. All rights reserved.

314

14. MANAGEMENT OF METASTATIC NASOPHARYNGEAL CARCINOMA

INTRODUCTION Although excellent treatment outcomes can be achieved for localized nasopharyngeal cancer (NPC) by intensive chemoradiotherapy, disease relapses are observed in approximately 30% of patients, predominated by distant failures.1 In a report on 3328 patients who all received intensity-modulated radiotherapy and more than 70% who received additional chemotherapy, the actuarial distant failure rate was 16.3% at 5 years and 18.5% at 8 years.2 In addition, the proportion of patients with NPC presenting with de novo metastatic diseases varies from 4% to 4.6% in retrospective series,3e5 to 14.8% when prospectively staged by whole-body dual-modality 18-F fluorodeoxyglucose positron emission tomography (PET)/computed tomography (CT).6 Overall, up to 25%e30% NPC patients will present with either synchronous or metachronous distant metastasis.

PROGNOSTICATION OF METASTATIC NASOPHARYNGEAL CARCINOMA Patients with metastatic NPC can have very diversified clinical features, prognosis, and outcomes. There are reports of long-term survival of patients with oligometastases after intensive salvage treatment with radical intent,3,7e9 while patients with extensive (poly)metastases have much worse prognosis and short survival of a few months only.3 The significant variation in outcome calls for building relevant prognostic factors into models that could accurately predict the prognosis, with a view to formulating the most optimal and personalized treatment strategy for individual patients. Such prognostication could also help patient stratification in designing future clinical trials. The various prognostic factors reported in literature can be classified into four categories, namely patient-related, tumor-related, biomarker- and inflammatory marker-related, and treatment-related factors, which are summarized in Table 14.1.

Prognostic Models Leveraging on the various relevant clinical and laboratory parameters previously shown to be prognostic of outcome, different prognostic models or scoring systems have been formulated to stratify patients with metastatic NPC into different risk groups, allowing more accurate prediction of individual patient’s prognosis. The factors incorporated by the five models are summarized in Table 14.2 for easy reference and comparison. Notably, different factors are incorporated in each of the models, some factors being more commonly used than others although they may be differentially scored across different models. Such models may be able to provide both the oncologist and the patient with an understanding of the anticipated prognosis of their metastatic cancer before embarking on the palliative treatment. Ong et al.16 developed a prognostic index score, which was later modified and validated by Toh et al.17 in a separate patient cohort. The total prognostic index score was the total sum of the assigned scores of the following independent prognostic variables: poor performance status (PS) (score 5), hemoglobin <12 g/L (score 4), and disease-free interval
6 months (score 10) or metastases at initial diagnosis (score 1). The maximum score was 19. Patients were stratified into three prognostic groups (good [0e3], intermediate [4e8], poor [9]) with significantly different median overall survival (OS) of 19.6, 14.3, and 9.2 months, respectively (P ¼ .003). The short disease-free interval has an overwhelming impact on the OS in this prognostic index score. Jin et al.10 proposed another prognostic model with a maximum score of 12 contributed from six independent adverse prognostic factors, including hemoglobin <12 g/L (score 1), lactate dehydrogenase (LDH) > 245 IU/L (score 3), alkaline phosphatase (ALP) > 110IU/L (score 1), EpsteineBarr virus (EBV) DNA 1000 copies/mL (score 3), Karnofsky performance score (KPS) < 80 (score 3) and age 45 (score 1). According to the total score, three different prognostic groups of low risk (score 0e4), intermediate risk,5e8 and high risk9e12 could be identified, with significantly different median OS of 25.5, 15.1, and 7 months, respectively (P < .001). A 10-signature classifier was developed by Jiang et al.,36 using a support vender machine that identified 10 useful prognostic factors consisting of three clinical indices (oligometastases, N stage, and distant lymph node metastasis) and 7 laboratory markers (EBV-viral capsid antigen IgA, neutrophil count, monocyte count, platelet count, hemoglobin, glutamic-pyruvic transaminase, and glutamyltranspetidase levels). The classifier assigns patients to either a

315

PROGNOSTICATION OF METASTATIC NASOPHARYNGEAL CARCINOMA

TABLE 14.1

Prognostic Factors in Metastatic Nasopharyngeal Carcinoma

Prognostic Factors

Outcome

Remarks

PATIENT FACTORS 1. Age

Worse OS for older age3,10e13

2. Performance status

Worse OS for PS > 1,14,15 ECOG > 116e18 or KPS < 8010,11,13,19,20

3. Gender

Worse OS for male14

Doubtful prognostic value as many other negative studies3,10e13,15,17e29

4. BMI

Better OS for higher BMI21

One negative study11

TUMOUR FACTORS 1. Number of metastases (solitary vs. multiple)

Better OS for solitary11,12,19e22,29e33

2. Site or organ of metastases

Worse OS for liver3,11,12,16,20,21,28,30e33 Better OS for lung and worse OS for bone11,28,30,31

Inconsistent finding

Worse OS for lung and better OS for bone16 3. Number of organ involvement (single vs. multiple)

Worse OS for multiple11,18,31

4. Timing of metastases (synchronous vs. metachronous)

Worse OS for metachronous metastases3,16,17,30

5. DFS from initial definitive treatment

Worse OS for short DFS (<6e9 months)3,16,17,28

6. PET-CT metabolic tumor volume

Worse OS if >110 mL14

7. N stage

Worse OS for more advanced N stage11,21,29,30,32

OS even worse than metachronous metastases16,17

BIOMARKERS 1. EBV DNA

Worse OS for high level10,14,15,19,23e25,27 Better OS if undetectable posttreatment level27 or faster clearance rate15,19

2. LDH

Worse OS for high level10,11,18,20,26,34

3. Fibrinogen

Worse OS for high pretreatment level35

4. Hb

Worse OS for anemia10,16e18,24

5. ALP

Worse OS for high level10

6. Apolipoprotein A-I

Better OS for high level21

INFLAMMATORY MARKERS 1. CRP

Worse OS for high baseline CPR24 or CPR/albumin ratio25

2. GPS

Worse OS for higher score23,25

3. NLR

Worse OS for high ratio13,23

4. LMR

Better OS for high ratio12,22

5. Albumin

Worse OS for hypoalbuminaemia19 Continued

316 TABLE 14.1

14. MANAGEMENT OF METASTATIC NASOPHARYNGEAL CARCINOMA

Prognostic Factors in Metastatic Nasopharyngeal Carcinomadcont’d

Prognostic Factors

Outcome

Remarks

TREATMENT FACTORS 1. Response to chemotherapy

Better OS for CR13,20/PR20

2. Number of cycles of chemotherapy

Better OS for 4 cycles20,32

3. Locoregional RT

Better OS for addition of RT after completion of chemotherapy among patients with synchronous metastases20,29,32

4. Radical treatment intent

Better OS for treatment with curative intent28

Potential bias as number of cycles of chemotherapy could be associated with treatment response

ALP, alkaline phosphatase; BMI, body mass index; CR, complete response; CRP, C-reactive protein; DFS, disease-free survival; EBV, EpsteineBarr virus; ECOG, Eastern Cooperative Oncology Group; GPS, Glascow Prognostic Score; Hb, hemoglobin; KPS, Karnofsky Performance Score; LDH, lactate dehydrogenase; LMR, lymphocyteto-monocyte ratio; N, nodal; NLR, neutrophil-to-lymphocyte ratio; OS, overall survival; PET-CT, positron emission tomography-computed tomography; PR, partial response; PS, performance status; RT, radiotherapy.

high-risk or a low-risk group, each having significantly different median OS, 13.8 months versus 38 months, respectively (P < .01). They also found that combination treatment of chemotherapy and locoregional therapy resulted in better OS than chemotherapy alone in the low-risk group (5-year OS 47% vs. 10%, P < .01), but not in the high-risk group. Zeng et al.11 reported a nomogram for predicting survival based on independent prognostic factors including age, nodal (N) category, KPS, LDH, number of metastatic locations, number of metastatic lesions, and presence of liver metastasis and bone metastasis. Four different groups with different median OS of 45.6, 26.2, 22.4, and 17 months, respectively (P < .01) could be classified according to the total score based on the factors in the nomogram. Chee et al.18 proposed a prognostic scoring system using four independent adverse prognostic factors: Eastern Cooperative Oncology Group (ECOG) >1, LDH >580 U/L, hemoglobin <12 g/dL, and multiorgan metastasis, each factor being given a score of 1. The scoring system identified three different prognostic groups, low risk (total score ¼ 0), intermediate risk (score 1e2), and high risk,3,4 with significantly different median survivals of 57.1, 18.1, and 8 months, respectively (P < .001).

APPROACHES IN FORMULATING SYSTEMIC CHEMOTHERAPY First-Line Systemic Chemotherapy Palliative chemotherapy, though never directly compared with best supportive care, is often employed to achieve disease response, alleviate cancer symptoms, and prolong survival. Cisplatin and 5-fluorouracil (PF), used extensively as induction chemotherapy as well as palliative chemotherapy in non-nasopharyngeal head and neck squamous cell carcinoma, has been a widely adopted initial regimen of choice for metastatic NPC. Data from early retrospective or single-armed phase II studies demonstrated activity of this combination with response rates ranging between 66% and 76%.37,38 In general, more toxic polychemotherapy regimens comprising more than two drugs are only rarely used in endemic areas, as outcome reported in nonrandomized phase II studies over platinum doublets was not superior.39e41 The classical PF regimen necessitates 120-h infusion of 5-fluorouracil (5-FU) and an even longer period of hospitalization, which will be difficult in busy public hospitals in the Asian endemic regions, leading to adoption of modified PF regimens consisting of shortened PF infusion lasting for 72 or 96 h. As the PF regimen in various versions has been incorporated in the neoadjuvant or adjuvant treatment in locoregionally advanced diseases,42e45 patients presenting with metachronous metastasis are often considered at least partially PF-resistant, particularly in those with a relatively short relapse-free interval. Therefore, replacing 5-FU in the platinum doublet with other partner drugs such as gemcitabine, capecitabine, taxanes, and pemetrexed were investigated, with results reported in various nonrandomized phase II studies often from single institutions.46e49 Except for gemcitabine-cisplatin (GP), none of these

TABLE 14.2

Prognostic Models for Metastatic Nasopharyngeal Carcinoma Prognostic Index Score by Ong et al.16 and Toh et al.17

Prognostic Score Model by Jin et al.10

x

Ten-Signature Classifier by Jiang et al.36

Nomogram by Zeng et al.11

Prognostic Scoring System by Chee et al.18

x

x

x

x

x

PATIENT-RELATED FACTORS 1. Poor PS 2. Older age TUMOR-RELATED FACTORS x

2. Short DFS

x

3. N stage

x

x

4. Multiple metastases

x

x

5. Metastases to multiple sites/ organs

x

6. Distant LN metastases

x

x

7. Liver metastases

x

8. Bone metastases

x

BIOMARKER FACTORS 1. Low Hb

x

x

2. High EBV DNA

x

3. High ALP

x

4. High LDH

x

x

x

x

5. High EBV-viral capsid antigen IgA

x

6. High neutrophil count

x

7. High monocyte count

x

8. High platelet count

x

9. High ALT

x

10. High GGT

x

x

APPROACHES IN FORMULATING SYSTEMIC CHEMOTHERAPY

1. Synchronous metastases

ALP, alkaline phosphatase; ALT, glutamic-pyruvic transaminase; DFS, disease-free survival; EBV, EpsteineBarr Virus; GGT, glutamyltranspeptidase; Hb, hemoglobin; LDH, lactate dehydrogenase; LN, lymph node; N stage, nodal stage; PS, performance status.

317

318

14. MANAGEMENT OF METASTATIC NASOPHARYNGEAL CARCINOMA

second-generation platinum doublets has ever been compared in a randomized phase III study with the classical PF regimen. The activity of the GP regimen was first evaluated in a phase II study by Ngan et al. from Hong Kong, which demonstrated an excellent disease response rate of 73% and satisfactory symptom control with this ambulatory regimen in 44 patients.46 In the study, cisplatin (50 mg/m2) and gemcitabine (1000 mg/m2) were given on day 1 and day 8 to leverage on the synergism of the two drugs, and then gemcitabine on day 15 of a 4-weekly cycle. Overnight hospitalization could be avoided with this ambulatory regimen. After more than a decade, its efficacy as firstline treatment was confirmed in a multicenter phase III randomized clinical trial published in 2016, in which 362 patients with recurrent or metastatic NPC were randomly assigned to receive either GP (Gemcitabine 1 g/m2 days 1 and 8, cisplatin 80 mg/m2 day 1, every 3 weeks) or PF (5-FU 4 g/m2 over 96 h, cisplatin 80 mg/m2 day 1, every 3 weeks).50 Prior chemotherapy as part of the primary treatment was allowed if at least 6 months had elapsed before disease recurrence. At a median follow-up period of 19.4 months, the GP regimen demonstrated a superior median progression-free survival (PFS) (7.0 months vs. 5.6 months, hazard ratio 0.55, 95% CI 0.44e0.68). This regimen also showed a higher response rate (64% vs. 42%) and longer median OS (29.1 months vs. 20.9 months, hazard ratio 0.62, 95% CI 0.45e0.84). In terms of treatment-related adverse events, there were more grade 3e4 leucopenia, neutropenia, and thrombocytopenia after GP, while mucosal inflammation was more common in the PF group. Based on the promising results from this important trial, the GP combination is now underpinned as the preferred first-line regimen of choice for metastatic or recurrent NPC, while other second-generation platinum doublets are often used as subsequent lines of chemotherapy (see later). To achieve better treatment response, patients with de novo metastatic NPC are often treated with standard platinum-based doublets such as GP if they are medically fit. Cisplatin can be replaced by carboplatin in the combination when renal function or advanced age compromises its use. With favorable interim response observed, it is common practice to continue up to four to six cycles of the palliative chemotherapy, followed by high dose radiotherapy delivering up to 50e60 Gy or more to the nasopharynx and cervical region without concurrent chemotherapy.51,52 With the advent of high-precision image-guided technology in radiotherapy, delivering tumoricidal doses of stereotactic ablative radiotherapy (SABR) to the residual metastatic lesions after chemotherapy for those with oligometastases is an attractive proof-of-concept approach, especially when high-dose locoregional radiotherapy is also planned.53 For patients presenting with metachronous distant polymetastases, which constitute the majority of patients with stage IVB diseases, and for patients with advanced locoregional recurrences not amenable to curative local therapy, GP should be offered as first-line chemotherapy for palliation of symptoms to medically fit patients where appropriate, similar to patients with de novo metastasis. A median PFS of up to 6e10 months and a median OS of up to 12e15 months can be expected, with anticipated symptom control in those 50%e80% patients who experience favorable chemotherapy response. As the majority of patients in the modern era already received concurrent cisplatin chemoradiotherapy with or without neoadjuvant or adjuvant cisplatin-containing chemotherapy (such as PF with or without docetaxel), which could have delivered a total cisplatin dose ranging from 300 to 540 mg/m2, carboplatin is often used to replace cisplatin in first-line chemotherapy, either at commencement or during mid-course, whenever high-grade adverse neurological (ototoxicity or peripheral neuropathy) or renal toxicity appears.

Palliative Chemotherapy Beyond First-Line Treatment Upon progression after first-line chemotherapy, which inevitably occurs in nearly all patients, other nonplatinum single-agent chemotherapy such as capecitabine, gemcitabine, taxanes, pemetrexed, irinotecan, or non-platinum doublets such as gemcitabine/vinorelbine, ifosfamide/5-FU/leucovorin, or ifosfamide/doxorubicin can be offered (Table 14.3).47,54e63 Typically, a modest response rate of around 10%e40% will be achieved, with median PFS of 3e 6 months, which is much shorter than that achieved after first-line chemotherapy. Gemcitabine was shown to be active in chemotherapy pretreated but gemcitabine-naive patients. Results of parallel groups of chemonaı¨ve and chemotherapy pretreated metastatic NPC patients treated with single-agent gemcitabine (1250 mg/m2, days 1 and 8, every 3 weeks) were reported.57 Satisfactory response rate (48%) and median time to progression (5.1 months) were reported among pretreated patients. Of note, grades 3e4 neutropenia rate was 37%, much higher in this patient subgroup than in those who are chemonaı¨ve (4%). Nevertheless, the clinically important activity of gemcitabine alone offers itself a competitive option as an alternative regimen for treating those patients who develop metastasis shortly after primary chemoradiotherapy (with cisplatin) when platinum-based chemotherapy is not preferred. Apart from monotherapy, gemcitabine-vinorelbine combination (GV) has also

TABLE 14.3

Phase II Studies on Palliative Chemotherapy Regimens (as First-Line or Later Line) for Recurrent and/or Metastatic Nasopharyngeal Carcinoma Number of PatientsLine of Therapya

Study

Regimen

CR Rate (%)

OR Rate (%)

Median PFS (Months)

Median OS (Months)

SINGLE-AGENT REGIMEN Foo 200257

2e3

Gemcitabine

3.7

48.1

5.1

10.5

32

1

Gemcitabine

0

43.8

5.1

16

17

1

Capecitabine

5.9

23.5

4.9

7.6

23

2e4

Capecitabine

9

48

14

1-year OS 62%

28

2e10

Irinotecan

0

14.3

3.9

11.4

30

b

2e4

Docetaxel

0

36.7

5.3

12.8

Zhang 2012

35

2

Pemetrexed

0

2.9

1.5

13.3

67

13

1

TAS-106

0

0

1.6

9.2

56

3e7

Metronomic oral cyclophosphamide

0

8.9

4.5

9.2

Zhang 2008

47

Chua 2003

56

Ciuleanu 2008 60

Poon 2004

59

Ngeow 2011

63

Tsao 2013

66

Lee 2017

PLATINUM DOUBLET REGIMEN Yeo 199665

42

1

5-FU þ Carboplatin

17

38

NA

12.1

Yeo 199864

27

1

Paclitaxel þ Carboplatin

11

59

6.0

13.9

Ngan 200246

44

1

Gemcitabine þ Cisplatin

20.5

72.8

10.6

15.0

Yau 201268

15

1

Pemetrexed þ Cisplatin

7

20

6.9

NA

NONPLATINUM DOUBLET REGIMEN Chua 200055

18

1

Ifosfamide þ 5-FU þ Leucovorin

6

56

6.5

1-year OS 51%

Huang 200258

36

1

Ifosfamide þ Doxorubicin

14.7

67.6

6

NA

Wang 200661

39

2 (platinum-refractory)

Gemcitabine þ Vinorelbine

3

37

5.6

11.9

Chen 201254

61

2

Gemcitabine þ Vinorelbine

1.6

37.7

5.2

14.1

APPROACHES IN FORMULATING SYSTEMIC CHEMOTHERAPY

27 62

a

Lines of palliative chemotherapy (chemotherapy used in definitive setting not included). One chemonaı¨ve patient included due to protocol violation. 5-FU, 5-fluorouracil; CR, complete response; NA, not available; NPC, nasopharyngeal carcinoma; OR, overall response; OS, overall survival; PFS, progression-free survival.

b

319

320

14. MANAGEMENT OF METASTATIC NASOPHARYNGEAL CARCINOMA

been evaluated in two separate phase II studies in the second line or beyond setting, one of which focused on treatment-refractory patients who experienced disease progression during cisplatin-containing palliative chemotherapy. This GV regimen, which produced a promising response rate of 37% and PFS of approximately 5 months, could be considered in patients who are still fit for combination chemotherapy beyond first-line, and relatively free of platinum-related cumulative toxicities.54,61 Efficacy of capecitabine, an oral derivative of 5-FU, was evaluated as a single agent in a small single-center study.47 Seventeen recurrent or metastatic NPC patients who received prior platinum-based chemotherapy as part of definitive treatment or in palliative setting were treated with capecitabine (1250 mg/m2 twice daily, days 1e14, every 3 weeks), giving an overall response rate of 23.5% and a median time to progression of 4.9 months. Treatment-related adverse events were mild and capecitabine was generally well tolerated among relapsed patients. Severe or prolonged myelosuppression was rare, which may represent a potential advantage in patients who have been heavily pretreated with primary chemoradiotherapy or first-line chemotherapy, whose marrow reserves are often limited and are vulnerable to chemotherapy toxicity. The activity of taxanes has also been reported in a single-arm phase II study evaluating the efficacy of weekly docetaxel (30 mg/m2, days 1, 8, 15, every 4 weeks) in recurrent or metastatic NPC who have failed at least one line of palliative chemotherapy.59 A response rate of 37% and a median PFS of 5.3 months were observed among the 30 patients recruited. Due to the overlapping toxicity of neuropathy between taxanes and cisplatin, it is of value to screen for preexisting peripheral numbness before treatment initiation. Dose-reduction or alternative treatment options may be required in selected cisplatin pretreated patients who have ongoing residual neuropathy. When the distant failure is detected very shortly after primary chemoradiotherapy (such as within 6 months), the conventional sequence of chemotherapy can be reversed such that nonplatinum chemotherapy regimens recommended as second-line therapies described earlier can be offered for first-line use. Failing the non-platinum regimens, platinum-based regimens such as gemcitabine-carboplatin, 5-FU-carboplatin, or paclitaxel-carboplatin can be offered as second or further lines of systemic treatment.46,64,65 Upon progression after second-line chemotherapy, symptomatic treatment or palliative radiotherapy can be offered if the patient cannot tolerate further lines of chemotherapy. Whenever indicated in otherwise medically fit patients, rechallenge with platinum-based chemotherapy (carboplatin alone, carboplatin-containing doublet, or carboplatin-cetuximab), or unexposed drugs and regimens recommended for second-line therapy can be considered if prior response and prolonged disease-free interval is observed. Metronomic oral cyclophosphamide was reported to be an active agent in heavily pretreated patients who were fit for third-line therapy or beyond; reasonable objective response (8.9%) and disease control rate (57.1%), as well as favorable toxicity profile were observed.66 The PFS gain was significantly longer in patients with good performance status, suggesting the importance of careful patient selection. Currently, as evidence to guide treatment selection among chemorefractory patients is limited, recruitment of these patients into clinical trials studying novel targeted therapeutic agents and immunotherapy as subsequent lines of treatment should be encouraged.

NOVEL THERAPY FOR METASTATIC NASOPHARYNGEAL CARCINOMA In parallel with the progress achieved in cytotoxic chemotherapy, development of novel systemic therapies for metastatic NPC has also been evolving rapidly in recent years pursuant to the advent of molecular diagnostics and new drug development. Novel therapies developed for both EBV specific and EBV nonspecific targets have been tested albeit in small phase II studies. While immunotherapy (EBV-directed or immune checkpoint inhibitors) will be discussed elsewhere, other EBV nonspecific targeted therapies including drugs targeting cell surface receptors like epidermal growth factor receptor (EGFR), vascular endothelial growth factor receptor (VEGFR), plateletderived growth factor receptor (PDGFR), and other intracellular pathways such as phosphatidylinositol 3-kinase (PI3k)/protein kinase B (also known as Akt), will be discussed later. As most of the studies were conducted on available drugs targeting these receptors/pathways initially developed for other cancers, rather than exclusively driven by proof-of-concept NPC-specific molecular science unraveled in the laboratory, it is by no means surprising that breakthrough results have been lacking. Nevertheless, overexpression of EGFR and VEFGR were demonstrated in NPC.69e71 Results and toxicity of multiple small studies on small molecules and monoclonal antibodies targeting EGFR and VEGFR have been reported, which are summarized in Table 14.4 alongside those ongoing studies registered in the public domain.72e80 Without concomitant chemotherapy, the best response rates reported were usually 10% or less, which are unimpressive overall compared with those reported for cytotoxic chemotherapy used in similar settings after failing first-line chemotherapy.

TABLE 14.4

Results of Targeted Drugs Used in Phase II Clinical Studies for Recurrent and/or Metastatic Nasopharyngeal Carcinoma

Study (Patient No.) & Year Reported

Line and Role of Therapy

Regimen

Overall Response %

Median PFS or TTP (Months)

Median OS (Months)

Selected Severe Toxicity (>G3)

2.7

7.7

52% (>10%: anemia, thrombocytopenia, acneiform rash, dyspnoea)

ANTI-EGFR THERAPY Chan60,75 2005

Cetuximab þ carboplatin / cetuximab

11.7

(32% related to cetuximab, none G5) >3rd, monotherapy

Gefitinib

0

4

16

nil

2008

>2nd, monotherapy

Gefitinib

0

2.7

12

Acneiform rash 33%

2012

Maintenance after first-line GP

Erlotinib, after GP

0 (only 15 received erlotinib)

6.3 (from start of GP, not erlotinib)

NR

Acneiform rash 20%

Chua19,72 2008 16,73

Ma

19,74

You

Leucopenia, HFS 13% each Infection 7% (none G5)

ANTI-VEGF OR ANTI-PDGFR Xue54,76 2013

1st, combined with chemotherapy and then maintenance

Sorafenib þ PF / Sorafenib

77.8

7.2

11.8

HFS reaction 19% Leucopenia 7% Bleeding 2% (G5)

27,77

Elser

2007

Lim33,78 2011

2nd, monotherapy

Sorafenib

3.7

3.2

7.7

Fatigue 15% lymphopenia 19%

>2nd, monotherapy

Pazopanib

6.1

4.4

10.8

Fatigue, HF (15% each) Bleeding 3% (G5)

13,79

Hui

40,80

Hui

2011

>2nd, monotherapy

2016

>2nd, monotherapy

Sunitinib Axitinib

10.0 a

2.7 (18.9 )

3.5

10.5

Bleeding 43% (14% G5)

5.0

10.4

Hypertension 8%

NOVEL THERAPY FOR METASTATIC NASOPHARYNGEAL CARCINOMA

2nd, combined with chemotherapy and then maintenance

Continued

321

322

TABLE 14.4

Results of Targeted Drugs Used in Phase II Clinical Studies for Recurrent and/or Metastatic Nasopharyngeal Carcinomadcont’d Line and Role of Therapy

NCT02250599 (ongoing)

1st, combined with chemotherapy and then maintenance

Bevacizumab þ carboplatin-paclitaxel

NCT03213587

>2nd, monotherapy or maintenance post-first- or second-line chemotherapy

NCT03180476

Median PFS or TTP (Months)

Median OS (Months)

Selected Severe Toxicity (>G3)

na

na

na

na

Apatinib

na

na

na

na

>3rd, monotherapy

Donafenib, Famitinib

na

na

na

na

>2nd, monotherapy

MK-2206

5.0

3.5

10.0

33% (rash, hyperglycemia, fatigue)

Regimen

Overall Response %

NCT03130270 (all ongoing) NCT02698111 NCT01392235 (all ongoing) AKT INHIBITOR Ma31,82 2015

ONGOING STUDIES ON OTHER DRUGS NCT00305734

1st, monotherapy, then combined with chemotherapy

Bortezomib / bortezomib þ gemcitabine at PD

na

na

na

na

NCT00367718

>2nd, monotherapy

Bortezomib

na

na

na

na

NCT00336063

2nd, doublet

SAHA and Azacitidine

na

na

na

na

NCT02269943

>2nd, monotherapy

Azacitidine

na

na

na

na

a

Including unconfirmed partial responses. G, grade; GP, gemcitabine-cisplatin or gemcitabine-carboplatin; HFS, hand-foot-syndrome; na, not available; OS, overall survival; PD, progression of disease; PF, cisplatin-5 fluorouracail; PFS, progression-free survival; SAHA, Suberoylanailide hydroxamic acid; TTP, time to progression.

14. MANAGEMENT OF METASTATIC NASOPHARYNGEAL CARCINOMA

Study (Patient No.) & Year Reported

MONITORING OF THERAPEUTIC RESPONSE BY BIOMARKERS DURING SYSTEMIC THERAPY

323

Reported toxicity of anti-EGFR therapies including gefitinib (as monotherapy) and erlotinib (as maintenance therapy after GP chemotherapy) was usually trivial, while significant toxicity of grade 3 or higher was not uncommon when cetuximab was combined with chemotherapy.72e75 On the other hand, life-threatening and even fatal toxicities consisting of uncontrolled bleeding from the upper aerodigestive tract including the nasopharynx were reported in some studies using anti-VEGF therapy (sunitinib, sorafenib) and anti-PDGFR therapy (pazopanib) as monotherapy or combined with chemotherapy.76e80 The safety of combining the monoclonal antibody bevacizumab (targeting VEFG itself rather than VEFGR) with chemotherapy reported in primary treatment of locally advanced NPC (RTOG 0615 study) will need further confirmation in an ongoing study combining bevacizumab and carboplatin-paclitaxel for metastatic NPC (NCT02250599).81 There are a number of other newer drugs that can inhibit the VEGF and other pathways, including small molecules such as apatinib (VEGFR2 inhibitor), famitinib (inhibitor of VEGFR-2/3, c-kit, PDGFR-b), donafenib (Raf kinase inhibitor), as well as larger molecules of endostatin (inhibitor of bFDF, FGF-2, and VEGF), which are being investigated in ongoing phase I/II clinical trials. Last, low response rate at 5%, short median PFS of 3.5 months, and frequent high-grade adverse events were reported for an Akt inhibitor used as a second or later line monotherapy82 (Table 14.4). More adventurous approaches that target the epigenetic changes such as DNA hypermethylation and histone modification involved in EBV carcinogenesis have also been initiated. Azacitidine, a methyltransferase inhibitor, which when given at low doses, can lead to hypomethylation of DNA, was shown to be able to demethylate various EBV promoters and activate expression of a previously silent viral antigen.83 Suberoylanailide hydroxamic acid (SAHA), a histone deacetylase inhibitor, which is shown to be able to activate the lytic cycle of EBV from the latent cycle and therefore lead to apoptosis and suppression of proliferation,84 is now being combined with azacitidine in a multicentered phase I/II study for locally recurrent NPC (NCT00336063). Synergism of a proteasome inhibitor, bortezomib, with SAHA was reported on NPC cell lines and xenografts,85 and bortezomib itself is also investigated as first-line therapy in recurrent or metastatic NPC, to which gemcitabine will be added upon progression, in a clinical study that has been completed but results are pending (NCT00305734). As immunotherapy using adoptive EBV-specific autologous cytotoxic T cells or immune checkpoint inhibitors is working its way into the second-line therapy or even as sequential or consolidation therapy after first-line Gemcitabine-platinum chemotherapy, the role of these existing or emerging targeted drugs should be carefully evaluated, given the generally disappointing results and not uncommon prohibitive toxicities hitherto reported. The recent introduction of affordable next-generation sequencing (NGS) genetic tests, however, may allow better selection for patients with actionable genetic or cellular targets for targeted drugs, which can be prescribed as either maintenance therapy following first-line chemotherapy or as later lines of therapy when conventional chemotherapy or immunotherapy has failed.

MONITORING OF THERAPEUTIC RESPONSE BY BIOMARKERS DURING SYSTEMIC THERAPY EpsteineBarr Virus DNA Radiological or clinical monitoring is still the gold standard in assessing response to cytotoxic or targeted therapy based on the Response Evaluation Criteria in Solid Tumors (RECIST) criteria, although immune-related RECIST (irRECIST) is increasingly used in immunotherapy. Assaying circulating cell-free EBV DNA (believed to be of tumor origin) in blood for patients with recurrence,86 which is relatively noninvasive and much less expensive, serves as an attractive biomarker supplementary to radiological studies such as PET-CT scan that invariably involves radiation. In a retrospective review of studies measuring plasma EBV DNA concentrations for BamH1-W fragment by real-time quantitative polymerase chain reaction (PCR), the prevalence rate of detectable EBV DNA ranged from 86% to 96% for distant metastasis and 51%e67% for local and/or regional recurrence.87 Indeed, use of plasma or serum EBV DNA for BamH1-W fragment, EBNA1 gene, and EBER1 DNA of the EBV genome, have been reported for monitoring outcomes of recurrent or metastatic NPC to systemic treatments.19,27,73,86e90 Ngan et al. evaluated the role of serum EBV DNA (EBER-1) during chemotherapy in 19 patients with metastatic or recurrent NPC, and reported that all four patients who had complete response had a drop of EBV DNA after chemotherapy to background level. However, this pattern of EBV DNA fall was also observed in four of another nine patients with partial response and two of four patients with stable disease.88 Apart from the prognostic value of EBV DNA in predicting survival after chemotherapy, the implication of the potential benefit in guiding ongoing systemic therapy will be even more relevant. Wang et al. from Taiwan first

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reported in 2010 the ability of prospectively correlating the clearance rate of plasma EBV DNA (BamH1-W), measured during the first month of commencing chemotherapy, with treatment response to chemotherapy and overall survival.19 The protocol mandated taking three to five blood samples during the first month, and then correlating the half-life (t1/2) of clearance of the EBV DNA with PET or CT studies performed during and after chemotherapy. All the 14 complete responders (out of 34 patients treated by chemotherapy) in the study had a t1/2 of <8 days. Together with other factors, t1/2 of EBV DNA clearance, but not the concentration, could independently predict the overall survival in Cox multivariate analysis. The authors suggested prolonged t1/2 of EBV DNA clearance measured in the first month of chemotherapy may guide the consideration of switching to other chemotherapy regimens. Similar assay of EBV DNA kinetics was also performed during primary radiotherapy for newly diagnosed nonmetastatic NPC, and during surgery for recurrent NPC.15,91 In a larger cohort of 127 patients with NPC metastasis treated by first-line chemotherapy in China, the level of plasma EBV DNA (BamH1-W) after cycle 1 became undetectable in 47 patients, and their median PFS (9.6 vs. 3.9 months) and OS (19.6 vs. 14.5 months) were statistically superior compared with those having persistent level detectable after chemotherapy.89 Though not statistically confirmed, outcome of those with later disappearance of plasma EBV DNA (13 patients after cycle 2 and 22 patients further beyond) was not as optimal. Without the need to take multiple blood samples during the first month, the authors concluded EBV DNA assay at a single time point after cycle 1 could be more convenient in their clinical practice and as predictive as t1/2 measurement. In this study, response was correlated with the disappearance of EBV DNA level after overall treatment completion rather than after cycle 1, and the pretreatment DNA level was also found to be prognostic of both PFS and OS. EBV DNA t1/2 measurement was reported to be predictive of survival in another Taiwanese study. GP chemotherapy was used in 41% of 73 patients, and multiple blood samples were prospectively taken during the first 6 weeks. Both EBV DNA concentration and t1/2 were significant prognostic factors.90 The survival (>70% at 2 years) was best in patients with both low pretreatment EBV DNA level (<5000 copies/mL) and short t1/2 (<7 days) of clearance. A dual endpoint consisting of quantitative measurement of PET-CT-based response assessment (>50% drop in sum of SUVmax of target lesion) at 4 weeks, and t1/2 of <10 days for EBV DNA clearance, was found to correlate well with the CT-based chemotherapy response defined by RECIST performed at 10 weeks posttreatment.27 Whether introduction of early intensification of systemic therapy based on this early endpoint defined previously will improve the final response rate and survival calls for further investigation. For those patients with metastatic NPC in the endemic region with detectable plasma EBV DNA, choice of chemotherapy particularly in the first-line setting will probably not be affected by the pretreatment EBV DNA concentration although it may be prognostic. Until EBV DNA is validated to be a standalone biomarker (not necessitating a companion radiological study such as PET-CT scan) predictive of response to chemotherapy when measured during the early cycle(s) of chemotherapy in terms of clearance rate or complete disappearance, evidence is still lacking to support an early switch of systemic therapy based on the results of such early assays. Significant drop or complete disappearance of the EBV DNA level was observed in a majority of responders to chemotherapy as reported in various studies.27,88 However, undetectable EBV DNA could also be observed in those with stable disease,27,88 making complete DNA clearance from blood a less reliable classifier to distinguish between partial responders from those nonresponders who have stable disease without clinical progression. It is not sure if there is persistence of predominantly shorter DNA fragments after chemotherapy in those nonresponders, which might be detected by specially designed primers of smaller size.87 However, resurgent or persistently high levels of EBV DNA can still be indicative of the need to perform an early radiological study for confirming response (or progression) to decide on the need for second-line therapy. With persistent detectable EBV DNA level after completing the planned systemic therapy, it is uncertain whether offering further local or systemic therapy to the radiologically evident residual lesions that have achieved significant radiological partial response could benefit patients with advanced locoregional recurrence or oligometastasis.

Circulating Tumor Cells and Other Potential Biomarkers Circulating tumor cells (CTCs) in blood have been shown to be detectable in patients with various solid tumors including lung, colorectal, prostate, and breast cancers,92 which are being explored as a predictive or prognostic blood biomarker.93e95 Longitudinal analysis of CTCs may also be useful in monitoring chemotherapy response in patients with metastatic colorectal cancers.96 Enumeration of CTCs has been reported in pretreatment blood samples of largely nonmetastatic NPC.97e99 Although the detection rates of canonical (cytokeratin-positive and CD45negative) and potential (both markers negative) CTCs were satisfactory at 76% and 94%, respectively, in the pretreatment samples in a study designed to capture both epithelial and mesenchymal CTCs in 46 patients, the correlation of

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CTC counts with clinical stage, short-term radiotherapy response, and overall survival was poor, which was outperformed by EBV DNA assays performed on the same samples.97 Among 38 patients with poorly differentiated squamous cell nasopharyngeal cancers, CTCs could be detected in 52.6% of the preradiotherapy blood samples in another study.98 The CTC numbers were significantly decreased 1 month after radiotherapy treatment, but no correlation between CTC number or detection and tumor, node, metastases (TNM) stages or other clinical parameters was observed.98 In another study, epithelial CTCs were detected in pretreatment blood samples of 22 out of 33 patients (67%).99 There was no correlation between CTC number or positivity and TNM stages or other clinical parameters. Interestingly, CTC counts were correlated with EBV VCA-IgA titres and EBV DNA load, and CTCs could be enumerated in four of five patients with stage IVc (metastatic) disease. Thus far, CTC in NPC is still immature enumeration, and there is no data reported for chemotherapy surveillance. C-reactive protein (CRP) kinetics during chemotherapy was shown to predict prognosis of patients with metastatic NPC. Patients having a nonelevated CRP level during treatment had the most favorable 3-year overall survival of 68%, compared with only 0.03% among those having an elevated pretreatment level that was not normalized after chemotherapy.24 Serial serum LDH levels were also found to correlate with clinical response to chemotherapy. Response rate was 66.7% and no progressive disease was observed among 21 patients having normalized LDH level after chemotherapy, while all six patients with rising LDH levels developed progressive disease.34 However, both markers are less sensitive and specific than EBV DNA.

LOCAL TREATMENT FOR OLIGOMETASTATIC NASOPHARYNGEAL CARCINOMA Patients with oligometastatic NPC (defined as one to five sites of metastases) have a better 5-year OS rate than those with multiple (poly)metastatic disease (6 lesions) (38.7% vs. 7.0%).100 Metastases from NPC are reported in bones (67.7%), liver (32.3%), and lung (16.0%), of which 19.4% are solitary metastasis and up to 66.7% are oligometastases.100 Among patients with bone-only metastases, worse survival was observed in those with >3 metastatic sites, as well as those with metastasis to the spine.101 Other poor prognostic factors reported include age >40, subsequent local recurrence, metachronous metastasis, and disease-free interval
24 months.102 Patients with liver metastases are often regarded portending a poor prognosis, as the 5-year OS was reported to be around 22.6%e23.6%.33 However, satisfactory 3-year OS rate of more than 50% was reported in patients with less than three liver metastases after aggressive treatment.31 Compared with metastasis in other organs, superior survival was observed in patients with lung metastases only (HR 0.24, P ¼ .0003).103 Indeed, among 198 patients with lung-only metastasis, Cao et al. could identify a subgroup with prolonged OS and lung metastases survival based on a sophisticated scoring system that computed the total scores from a multitude of adverse prognostic factors. A score of 1 will be assigned each to the presence of advanced T stage (T3/4), advanced N stage (N2/3), bilateral lung involvement, metachronous metastases, and disease-free interval
24 months to predict OS, and also age > 45, VCA-IgA titer > 1:320, multiple metastases (vs. solitary) to predict lung metastases survival. The 5-year OS rate was 60% for those with a score of 0e1, which was only 7% for those with a score of 4e8.104

Surgical Excision and Image-Guided Ablative Interventions Bone Metastases Tokuhashi et al. reported a revised preoperative scoring system to predict patient survival in patients with spinal metastases from all types of cancer, with a concordance rate exceeding 75%. Surgical treatment most benefits the group of patients with a favorable score of 12e15.105 Though only a small proportion of patients (1.6%) experienced spinal cord compression in a cohort of more than 600 metastatic NPC patients, the complication would lead to poor quality of life and poor survival.106 Prompt surgical decompression or fixation should therefore be recommended in this group of patients followed by consolidation radiotherapy, particularly in those with good Tokuhashi score. Percutaneous vertebroplasty and kyphoplasty can also be used to treat patients with vertebral metastases eligible for these new interventional approaches. Vertebroplasty involves direct injection of methylmethacrylate cement into compromised vertebral bodies, whereas kyphoplasty requires the use of an inflatable balloon to raise the fracture endplate and create a void in the vertebral body to restore vertebral height, followed by injection of cement.107 Significant pain relief was reported after the procedure (VAS  7.0 preprocedure vs. VAS < 4.0

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postprocedure).108 CT image guidance has led to a reduction in analgesics use and better quality of life compared with open procedures. The minimally invasive CT-guided vertebroplasty combined with radiofrequency ablation (RFA) conferred satisfactory pain relief and PFS in a Chinese study.35 Moreover, combination of vertebroplasty with consolidation radiotherapy was also reported to be significantly reducing the VAS pain score from 8.2 to 3, and improving the vertebral body compression ratios (anterior vertebral body height subtracted from posterior body height) and kyphotic angles in two Korean studies.109,110 Whether SABR could be safely combined with vertebroplasty, achieving similar efficacy, remains unanswered and warrants future studies. Liver Metastases A retrospective Chinese study compared the outcomes of 15 patients with NPC undergoing partial hepatectomy with another 15 patients given transcatheter hepatic artery chemoembolization (after primary radiotherapy with or without adjuvant chemotherapy for NPC) for liver metastases during the period of 1993e2010. Patients in the surgical group had superior OS and PFS at years 1, 3, and 5; both the median OS (45.2 months vs. 14.1 months, P ¼ .039) and PFS (21.2 months vs. 4.2 months, P ¼ .007) were improved.111 RFA was combined with chemotherapy to compare with RFA alone in another retrospective Chinese study using propensity score matching, which included 37 NPC patients treated by the combination and another 37 patients by chemotherapy alone. The adjusted hazard ratio in OS and PFS of combination group to chemotherapy group was 0.53 (95% CI, 0.30e0.93) and 0.60 (95% CI, 0.36e0.97), respectively. The median OS was 32.5 months in the combination group versus 18.8 months in the chemotherapy group. On multivariate analysis, number of liver metastases >3, presence of extrahepatic metastases, and number of chemotherapy cycles <4 were found to negatively impact the OS.112 Outcomes of CT-guided local microwave treatments delivered to 15 Chinese NPC patients during 2007e12 were also reported. A total of 27 ablations were performed in 24 liver metastatic lesions that measured from 1.9 to 4.2 cm. The treatment was delivered with a power setting at 50e60 W and the cumulative ablation time varied from 4 to 12 min. All lesions exhibited complete necrosis after the procedure. At a median follow-up period of 22.4 months, the median PFS was 37.5 months and the median OS was 41.4 months. Only one patient developed pneumothorax after the procedure, which resolved after chest drain insertion, and two other patients had postprocedural pain requiring hospitalization.113 Lung Metastases Ma et al. reported statistically better local control and survival for patients after surgical excision with or without chemotherapy, compared with chemotherapy alone in 105 patients with solitary lung metastases from NPC.114 Superior short-term survival outcome was also reported in 12 patients by Cheng et al., who received lung metastatectomy, which was compared to 65 patients as historical controls, with the 2-year actuarial OS of 80% and 24.1%, respectively (P ¼ .0002).115 Pan et al. reported outcomes of 10 NPC patients with 23 pulmonary metastatic lesions 35 mm or less treated with 25 local RFA. The median OS was 77.1 months, compared with 32.4 months observed in a matched cohort without RFA treatment. Procedure-related complications were, however, not insignificant as postprocedural pain was reported in two patients requiring intramuscular tramadol injection, and there were five episodes of pneumothorax after 13 procedures, with three requiring chest drain insertion.9 The efficacy of microwave treatment in lung metastases was studied by Qi et al. in a total of 29 lesions diagnosed in 17 NPC patients (1e4 lesions per patient), with the largest lesion diameter being 4.2 cm. The treatment was performed at a power setting of 50e70 W and an ablation time of 5e10 min. Complete response was achieved in 27 of the 29 lesions. Unlike RFA, the microwave ablation procedure was relatively safe, resulting in two minor pneumothorax not requiring chest drain insertion and four minor episodes of lung parenchyma bleeding.116

Stereotactic Ablative Radiotherapy With the advent of high-precision image-guided intensity-modulated radiotherapy (IMRT), SABR has been widely practiced in recent years in patients with limited metastases located in different organs over the body. However, only case reports of SABR for patients with metastatic NPC are available.53 SABR treatment for oligometastatic NPC generally follows the principles of SABR delivery for metastases from other primary cancers, but the treatment can be even more attractive as NPC is more radiosensitive. Various international guidelines on contouring and radiation dosimetry were published as reference in irradiating vertebral metastases,117e119 due to the close proximity of the critical organ at risk of the spinal cord usually

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within millimeters of the metastatic lesions. Irrespective of cancer types, overall results were promising with 80%e95% local control rate reported at 12e18 months120e123 and around 50% complete pain response.123 Treatment can be delivered either with linear accelerator-based systems with on-board verification systems such as Cone beam CT or Exactrac, or with robotic linear accelerator systems such as the Cyberknife.124 Commonly used radiation dose fractionation schedules can be variable, ranging from 15 to 24 Gy delivered in one fraction to 27e30 Gy in three fractions.120e122 A higher radiation dose of 30e75 Gy in three to eight fractions can be achieved by SABR for liver and lung metastases compared with vertebral metastases, mainly due to the need to adhere to the stringent spinal cord dose constraint in irradiating vertebral metastases.125,126 The 1-year and 2-year local control rates were reported as 70%e100% and 60%e90% in metastatic lesions <3 cm, respectively, in patients with liver metastases from lung, breast, and colorectal cancers.126 A model for predicting tumor control probability suggested a biological equivalent dose (BED) of 209  67 Gy10 was required for 90% tumor control at 2 years with no prior chemotherapy, and 286  78 Gy10 with prior chemotherapy. It was also reported that the response of breast cancer was significantly better compared with other cancers, with 90% tumor control probability at 2 years achievable with a relatively lower BED127 The commonest severe max of 157  80 Gy10 or 80  62 Gy10 with and without prior chemotherapy, respectively. hepatic toxicity of liver SABR is radiation-induced liver disease (RILD), which typically occurs at 2e3 weeks after radiotherapy. However, <5% RILD occurrence was reported in patients who are not hepatitis-B carriers and have normal baseline liver function, if no more than 700 mL of uninvolved normal liver had received 15 Gy or more in three fractions in accordance with the recommendations of the Quantitative Analyses of Normal Tissue Effects in the Clinic (QUANTEC).128 Similarly, outcomes of SABR on lung limited metastases are also favorable, with 2-year weighted local control being 77.9% reported in a systemic review.125 Local control was superior with BED 100Gy10 (77% at 3 years, vs. 45% with BED < 100Gy10) and for lesions < 11cc (72.9% at 2 years vs. 45.6% for lesions > 27cc).129 With the inherent radiosensitivity of NPC, higher rate of long-term local control may be achieved by the same SABR dose or better therapeutic ratio by SABR dose deescalation, which warrants future investigation.

ROLE OF LOCAL THERAPY IN METASTATIC NASOPHARYNGEAL CARCINOMA Several retrospective studies20,29,32,51,130,131 showed that the addition of locoregional radiotherapy to chemotherapy could prolong the survival of patients presenting with synchronous metastases. Two studies51,52 suggested dose response relationship for OS outcome. Rusthoven et al.51 reported that increasing radiation dose was associated with improved OS as a continuous variable and survival benefit was observed among patients receiving 50 Gy. Lin et al.52 also found that patients receiving >65 Gy had better median OS (27 vs. 12 months, P ¼ .05). With the introduction of IMRT, Hu132 reported favorable outcome in patients treated with platinum-based chemotherapy followed by definitive radiotherapy, reporting a median OS of 31.2 months and a few long-term survivors with solitary metastasis being disease-free for 52 to >101 months. In addition, Yin et al.133 showed that IMRT might be superior to conventional radiotherapy in 2-year OS (76.6% vs. 44.4%, P ¼ .297). However, inherent caveats of the retrospective studies may not be able to correct for confounding factors (other than locoregional radiotherapy), which may contribute to the favorable outcome of such patients. Chen et al.131 reported that patients who received combined treatment were younger, having earlier T staging (T1-2), solitary metastasis or single organ involvement, no metastasis to the liver or secondary metastases. Moreover, whether all patients with synchronous metastasis can benefit remains controversial. While benefits were observed from additional locoregional radiotherapy regardless of the anatomic site or number (single vs. multiple organs) of metastases in one study,51 patients with poor prognosis defined by presence of liver metastases33 or a 10-signature classifier36 in two other studies, respectively, did not benefit.

CONCLUSIONS New advances in both drug development and radiation technology can now offer opportunities for intensification of systemic and local treatments for patients with metastatic NPC, which are expected to improve the generally dismal outlook. The challenge to oncologists remains in defining the optimal sequence of various systemic and local therapeutic approaches for individual patients who may have diversified prognosis.

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64. Yeo W, Leung TW, Chan AT, et al. A phase II study of combination paclitaxel and carboplatin in advanced nasopharyngeal carcinoma. Eur J Cancer. 1998;34(13):2027e2031. 65. Yeo W, Leung TW, Leung SF, et al. Phase II study of the combination of carboplatin and 5-fluorouracil in metastatic nasopharyngeal carcinoma. Cancer Chemother Pharmacol. 1996;38(5):466e470. 66. Lee VH, Kwong DL, Lam KO, et al. Metronomic oral cyclosphosphamide as third-line systemic treatment or beyond in patients with inoperable locoregionally advanced recurrent or metastatic nasopharyngeal carcinoma. Medicine. 2017;96(15):e6518. 67. Tsao A, Hui EP, Juergens R, et al. Phase II study of TAS-106 in patients with platinum-failure recurrent or metastatic head and neck cancer and nasopharyngeal cancer. Cancer Med. 2013;2(3):351e359. 68. Yau TK, Shum T, Lee AW, Yeung MW, Ng WT, Chan L. A phase II study of pemetrexed combined with cisplatin in patients with recurrent or metastatic nanopharyngeal carcinoma. 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Phase II trial of sorafenib in patients with recurrent or metastatic squamous cell carcinoma of the head and neck or nasopharyngeal carcinoma. J Clin Oncol. 2007;25(24):3766e3773. 78. Lim WT, Ng QS, Ivy P, et al. A Phase II study of pazopanib in Asian patients with recurrent/metastatic nasopharyngeal carcinoma. Clin Cancer Res. 2011;17(16):5481e5489. 79. Hui EP, Ma BB, King AD, et al. Hemorrhagic complications in a phase II study of sunitinib in patients of nasopharyngeal carcinoma who has previously received high-dose radiation. Ann Oncol. 2011;22(6):1280e1287. 80. Hui EP, Ma BBY, Loong HHF, et al. Efficacy, safety, and pharmacokinetics of axitinib in nasopharyngeal carcinoma: a preclinical and phase II correlative study. Clin Cancer Res. 2018;24(5):1030e1037. 81. Lee NY, Zhang Q, Pfister DG, et al. Addition of bevacizumab to standard chemoradiation for locoregionally advanced nasopharyngeal carcinoma (RTOG 0615): a phase 2 multi-institutional trial. Lancet Oncol. 2012;13(2):172e180. 82. Ma BB, Goh BC, Lim WT, et al. Multicenter phase II study of the AKT inhibitor MK-2206 in recurrent or metastatic nasopharyngeal carcinoma from patients in the mayo phase II consortium and the cancer therapeutics research group (MC1079). Investig N Drugs. 2015;33(4):985. 83. Chan AT, Tao Q, Robertson KD, et al. Azacitidine induces demethylation of the Epstein-Barr virus genome in tumors. J Clin Oncol. 2004;22(8): 1373e1381. 84. Hui KF, Ho DN, Tsang CM, Middeldorp JM, Tsao GS, Chiang AK. Activation of lytic cycle of Epstein-Barr virus by suberoylanilide hydroxamic acid leads to apoptosis and tumor growth suppression of nasopharyngeal carcinoma. Int J Cancer. 2012;131(8):1930e1940. 85. Hui KF, Lam BH, Ho DN, Tsao SW, Chiang AK. Bortezomib and SAHA synergistically induce ROS-driven caspase-dependent apoptosis of nasopharyngeal carcinoma and block replication of Epstein-Barr virus. Mol Cancer Therapeut. 2013;12(5):747e758. 86. Lo YM, Chan LY, Chan AT, et al. Quantitative and temporal correlation between circulating cell-free Epstein-Barr virus DNA and tumor recurrence in nasopharyngeal carcinoma. Cancer Res. 1999;59(21):5452e5455. 87. Yip TT, Ngan RK, Fong AH, Law SC. Application of circulating plasma/serum EBV DNA in the clinical management of nasopharyngeal carcinoma. Oral Oncol. 2014;50(6):527e538. 88. Ngan RK, Lau WH, Yip TT, et al. Remarkable application of serum EBV EBER-1 in monitoring response of nasopharyngeal cancer patients to salvage chemotherapy. Ann N Y Acad Sci. 2001;945:73e79. 89. Lo YM, Leung SF, Chan LY, et al. Kinetics of plasma Epstein-Barr virus DNA during radiation therapy for nasopharyngeal carcinoma. Cancer Res. 2000;60(9):2351e2355. 90. To EW, Chan KC, Leung SF, et al. Rapid clearance of plasma Epstein-Barr virus DNA after surgical treatment of nasopharyngeal carcinoma. Clin Cancer Res. 2003;9(9):3254e3259. 91. Ma B, Hui EP, King A, et al. Prospective evaluation of plasma Epstein-Barr virus DNA clearance and fluorodeoxyglucose positron emission scan in assessing early response to chemotherapy in patients with advanced or recurrent nasopharyngeal carcinoma. Br J Cancer. Apr 2018; 118(8):1051e1055. 92. Farace F, Massard C, Vimond N, et al. A direct comparison of CellSearch and ISET for circulating tumour-cell detection in patients with metastatic carcinomas. Br J Cancer. 2011;105(6):847e853. 93. Doyen J, Alix-Panabieres C, Hofman P, et al. Circulating tumor cells in prostate cancer: a potential surrogate marker of survival. Crit Rev Oncol-Hematol. 2012;81(3):241e256. 94. Cohen SJ, Punt CJ, Iannotti N, et al. Relationship of circulating tumor cells to tumor response, progression-free survival, and overall survival in patients with metastatic colorectal cancer. J Clin Oncol. 2008;26(19):3213e3221.

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Commentary on Chapter 14: Management of Metastatic Nasopharyngeal Carcinoma Danny Rischin Department of Medical Oncology, Peter MacCallum Cancer Centre; Sir Peter MacCallum Department of Oncology, University of Melbourne, Victoria, Australia

In Chapter 14 Ngan and colleagues provide a comprehensive review of the management of metastatic nasopharyngeal cancer (NPC), focusing on the role of chemotherapy and targeted therapies. The emerging potential role of immunotherapy is discussed in a separate chapter. In addition, they review the literature on prognostic models and circulating EpsteineBarr virus (EBV)-DNA in the metastatic setting, as well as the management of patients with oligometastases. Locoregional control has improved significantly in the intensity-modulated radiotherapy era, but there have been limited advances in the management of distant metastases. Distant metastases now represent the predominant site of failure following chemoradiation, and furthermore the incidence of distant metastases at presentation is higher than previously recognized based on better baseline imaging including positron emission tomography 18Ffluorodeoxyglucose scans. As the authors note around 25% patients with NPC may be diagnosed with either synchronous or metachronous distant metastases. Chemotherapy has been the mainstay of treatment for patients with metastatic disease over the last 30 years. In contrast to the large number of trials investigating the optimal way to combine chemotherapy with radiotherapy in locoregionally advanced nasopharyngeal cancer, there has been a paucity of trials in metastatic disease with no randomized trials published prior to 2016. The reasons for this are unclear but may include the understandable focus on improving outcomes in the curative setting, the lack of pharmaceutical sponsor support for trials in NPC and lack of other sources of funding, and few promising agents deemed worthy of investigation in phase 3 trials. The platinum/5-fluorouracil (5FU) combination became the standard of care for incurable metastatic/locally recurrent NPC, based on phase 2 data and consistent with clinical practice in nonnasopharyngeal head and neck cancer. However, this regimen requires either a central venous catheter device with its inherent associated inconvenience and morbidity, or prolonged hospitalization, and is also associated with significant toxicity particularly with the original 5-day 5FU schedule. Gemcitabine was demonstrated to have significant activity in metastatic NPC both as a single agent and in combination with cisplatin as far back as 2002. However, it was not until 2016 that the landmark phase 3 trial by Zhang et al. established cisplatin/gemcitabine as the new standard of care with superior efficacy compared to cisplatin 5FU, and an acceptable toxicity profile.1 It was noteworthy that in subgroup analysis benefit was seen irrespective of prior exposure to cisplatin/5FU in the adjuvant or neoadjuvant setting. In clinical practice it is often difficult to administer cisplatin in patients heavily pretreated with cisplatin as part of primary treatment, so carboplatin/gemcitabine is frequently used. Ongoing areas of uncertainty with regard to first-line chemotherapy for recurrent/metastatic disease include the optimal regimen for patients relapsing within 6 months of primary chemoradiation, the optimal regimen if gemcitabine used as part of primary treatment and the relative activity of chemotherapy in irradiated versus nonirradiated sites as almost all patients enrolled on the Zhang trial had distant metastases. The authors quite reasonably suggest that a nonplatinum regimen be considered for patients relapsing within 6 months of primary chemoradiation. The authors summarize well the available phase 2 data for second-line (and beyond) chemotherapy following progression on platinum-based chemotherapy or early relapse after chemoradiation. Drugs such as taxanes and capecitabine have activity though the duration of response is usually short. As there is no proven survival advantage in the second-line setting, patients should be considered for clinical trials, and decisions to treat should be based primarily on alleviating symptoms and improving quality of life. The benefit of nonplatinum combinations compared to single agents has not been established. The disappointing results achieved with targeted therapies in NPC with none found to have significant clinical benefit is comprehensively described by the authors and catalogued in Table 14.4. The epidermal growth factor receptor inhibitors were found to have minimal activity and drugs targeting the vascular endothelial growth factor demonstrated limited activity and an increased risk of hemorrhage. Although recent sequencing studies have identified a greater degree of somatic mutations and structural variation in NPC than had been recognized, there are few currently actionable mutations.2,3 As molecular profiling becomes more available, the opportunity exists for identifying potential therapies based on an individual’s tumor profile. It remains to be established whether there is a

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subgroup of patients with metastatic NPC who may benefit from this approach. Genomic aberrations resulting in activation of the NF-kB pathway have been found to be quite frequent in NPC, raising the possibility that NF-kB pathway inhibition could be an effective strategy in NPC.2,3 As the authors have highlighted, NPC s have a high hypermethylation frequency,4 and epigenetic modifiers represent a novel approach that is being investigated and warrants further study. Another approach being explored is EBV targeting therapies such as EBNA1 inhibition.5 A review of known prognostic factors and prognostic models/nomograms in metastatic NPC is included in the chapter. While these nomograms can identify different prognostic groups, the factors included are quite variable and all the models require further prospective validation. Furthermore, the clinical utility of these nomograms remains unclear, with none of them being widely adopted in clinical practice. The settings in which understanding of prognostic factors is most influencing practice are management of patients with oligometastases, and in determining whether locoregional treatment should be given to patients who present with de novo distant metastases. It has been known for some time that some patients who present with oligometastases and are treated with chemotherapy can be long-term survivors.6 Accurate identification of patients with oligometastases suitable for curative treatment approaches is vital. Favorable prognostic factors identified in retrospective series for patients presenting with oligometastases include having only one organ involved, limited number of lesions (variable definition two to five lesions), no hepatic metastases, good performance status, and good response to chemotherapy.7 Suitable patients will generally be treated with curative intent including chemotherapy, full dose (chemo)radiation to the primary and neck, and local treatment of metastases (e.g., stereotactic ablative radiotherapy [SABR]). As discussed in the chapter, multiple retrospective studies have also suggested that there may be a role for locoregional treatment in a broader group of patients presenting with de novo metastatic disease. However, this is clearly not appropriate for all patients. Factors influencing the decision to administer high-dose locoregional radiation after chemotherapy for patients with metastatic disease at diagnosis include the extent of metastatic disease, extent of locoregional disease, sites of metastases, response to chemotherapy, and predicted prognosis. There have been numerous approaches to local treatment of oligometastases. However, most of the studies have been small retrospective single institution studies. The authors review the studies investigating surgical excision, SABR, and image-guided ablative interventions. Surgical excision and local radiotherapy including SABR are standard approaches for management of oligometastases across different cancers. It is difficult to draw definitive conclusions about the efficacy of some of the other interventions that are described in the chapter including radiofrequency ablation, microwave therapy, and vertebroplasty. Caution should be exercised in the interpretation of the single-arm studies of vertebroplasty for bone metastases reporting pain relief. Placebo controlled randomized trials of vertebroplasty for osteoporotic vertebral compression fractures failed to confirm the benefit claimed in noncomparative studies.8 The authors provide a detailed account about what is known about using circulating EBV DNA for therapeutic monitoring in metastatic NPC. While changes in EBV DNA levels may correlate with response or progression on systemic therapy, I agree with their conclusion that the clinical utility of using EBV DNA as a stand-alone test in this setting has not been established. Caution should be exercised in widespread adoption of serial measurement of EBV DNA in metastatic NPC until there is evidence that any resultant changes in practice (e.g., early change in systemic therapy regimen) is demonstrated to lead to improved outcomes. There may be a role for therapeutic monitoring with EBV DNA in circumstances where the disease is difficult to follow on imaging. Other potential markers including circulating tumor cells, C-reactive protein, and lactate dehydrogenase are discussed, but none have been definitively shown to be useful for therapeutic monitoring in metastatic NPC. Finally, the determination of the role of immunotherapy in metastatic NPC9,10 may change treatment paradigms and the sequencing of regimens. Based on the benefit of combining an immune checkpoint inhibitor with chemotherapy in other cancers (e.g., nonesmall cell lung cancer),11 this is one approach that warrants investigation in the first-line metastatic indication. With the advent of activity of immune checkpoint inhibitors in NPC, we are already witnessing pharmaceutical sponsor support for randomized trials in metastatic NPC. Hopefully, the establishment of the Head and Neck Intergroup will also facilitate collaboration and future trials in metastatic NPC.12

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