Abstract
Objective
Although standard of care for primary nasopharyngeal carcinoma (NPC) is chemoradiotherapy, there remains no consensus on management of recurrent or metastatic disease. We characterized recent clinical trials on NPC to assess trends in NPC treatment and establish promising areas for future research.
Study Design
Retrospective database study.
Setting
ClinicalTrials.gov database.
Methods
Retrospective review of all NPC trials from November 1999 to June 2021. For each study, the following variables were extracted: study characteristics, intervention, outcome measures, and inclusion criteria. Secondary searches via PubMed and Google scholar determined trial publication status.
Results
A total of 448 clinical trials were identified: 72 (16%) observational and 376 (84%) interventional, of which there were 30 (8%) Phase I, 183 (49%) Phase II, 86 Phase III (23%), and 5 (1%) Phase IV trials. Fifty‐four percent of trials included only primary NPC while 111 (25%) exclusively studied recurrent cancers. The most common interventions were cisplatin (n = 64) and intensity modulated radiation therapy (n = 54); there were 38 trials involving PD‐1 monoclonal antibodies. Thirty‐four studies examined quality of life measures, including xerostomia and mucositis. Of the completed studies, 53.2% have published manuscripts. Poor patient accrual was the most common reason for premature study termination.
Conclusions
Novel immunotherapies have been increasingly incorporated into NPC studies in recent years, however, chemotherapy and radiation, despite their numerous side effects, are still widely used due to their clinical effectiveness. Future trials are warranted to determine the optimal therapeutic regimens to decrease relapse rates and side effects.
Keywords: chemoradiotherapy, clinical trial, immunotherapy, nasopharyngeal carcinoma, nasopharyngeal neoplasms
Nasopharyngeal carcinoma clinical trials.
Key points
Significant findings of the study: Through a comprehensive review of the ClinicalTrials.gov database, we found that only 25% of registered nasopharyngeal carcinoma (NPC) trials have been completed. Current trials focus on the addition of immunotherapy to traditional radiation and chemotherapy regimens.
What this study adds: Despite advances in cancer therapy, there are limited completed and published Phase 3 trials in NPC, warranting future studies to examine optimal combination therapies to increase recurrence‐free and overall survival.
INTRODUCTION
Nasopharyngeal carcinoma (NPC) is a disease characterized by a unique geographical distribution, with a particular prevalence in Southeast Asia: for every case of NPC in the United States (US) and Europe, there are 30 cases in Southern China (incidence of <1 case per 100,000 persons and 30 cases per 100,000 persons in the United States/Europe and Southern China, respectively). 1 , 2 , 3 , 4 , 5 NPC is associated with multiple risk factors, including lifestyle, diet, genetic predisposition, and environmental exposures. 2 , 3
Five‐year survival rates of patients with NPC are highly dependent on ethnicity, gender, age at diagnosis, tumor grade, and TNM stage. While younger patients (15–45 years old) have a favorable prognosis and a 5‐year survival rate of 72%, this rate is only 36% for older patients (65–74 years old). 5 Due to a deeper understanding of NPC pathogenesis, better population screening guidelines, advancements in radiotherapy and systemic chemotherapy regimens, and lifestyle and environmental changes, the incidence and mortality of NPC have gradually but steadily declined over the last decade. 6
Although treatment outcomes for these tumors have improved significantly, there is still room for improvement in current diagnostic and therapeutic options, particularly in the exploration of immunotherapy, induction chemotherapy, and minimally invasive surgical techniques. Clinical trials are essential to the advancement of such modalities.
In 1997, the ClinicalTrials.gov database was created by the National Library of Medicine (NLM) to increase public access to clinical trial information, encourage study reporting, and foster transparency of the process. 7 The legal requirements for registering and reporting clinical trials and their results were expanded in 2007, making the ClinicalTrials.gov database the most comprehensive publicly‐available repository of all past and present clinical trials occurring worldwide. 8
While prior studies have evaluated other subsets of oncologic‐based clinical trials, none thus far present an up‐to‐date evaluation of the landscape of clinical studies on NPC. 9 , 10 , 11 , 12 We aimed to present a comprehensive summary of NPC‐related clinical trials based on the ClinicalTrials.gov database, which can identify the strengths and gaps in NPC research conducted to date and guide future research to accelerate improvements in patient survival and outcomes.
MATERIALS AND METHODS
Our study was deemed exempt from review by the University of Pennsylvania institutional review board (IRB) due to the publicly accessible nature of the data that was analyzed.
Search strategy and trial selection
We conducted a retrospective review via the ClinicalTrials.gov database of all clinical trials studying NPC between November 1999 and June 2021. We used the “Studies by Topic” function, and abstracted all clinical trials that resulted via the topics “Nasopharyngeal Carcinoma,” “Nasopharyngeal Diseases,” and “Nasopharyngeal Neoplasms.” The search included synonyms and related MeSH terms. Eligible trials were those that listed NPC as the primary disorder being investigated. Studies that did not exclusively study NPC were excluded (Figure 1). Two reviewers independently assessed each ClinicalTrials.gov record for eligibility and discussed any disagreements.
Figure 1.
Flow diagram demonstrating database search results and strategy for nasopharyngeal carcinoma (NPC) clinical trial selection
Data extraction
For each study, the following variables were extracted: study status, location, trial design, intervention, outcome measures, and inclusion criteria. Trial data were collected from ClinicalTrials.gov database export and the Clinical Trials Transformation Initiative (CTTI) Database for Aggregate Analysis of ClinicalTrials.gov (AACT). 13 , 14 Data were accessed on July 25, 2021. The CTTI is a public–private partnership that created a publicly accessible database from ClinicalTrials. 15 , 16 The AACT gathers detailed trial information into a format accessible for data analysis.
Both lead sponsors and collaborators were considered in our evaluation of study sponsorship. Lead sponsors and collaborators listed for the studies were divided into the following three categories: the National Institutes of Health (“NIH”), private industry (“Industry”), and “Other.”
Interventions used in each trial were classified via manual review by KX and EDR. Each intervention was classified as drug, radiation, diagnostic, or other. Drugs reported were further classified as either chemotherapy, immunotherapy, small‐molecule drugs, biologic drugs (e.g., monoclonal antibodies), or other. Of note, several trials implemented multiple drug classes or interventions and were thus counted under multiple interventions.
Patient eligibility for each trial was ascertained by manual review of the inclusion/exclusion criteria provided on the ClinicalTrials.gov database. Studies were broadly classified as those for either primary or recurrent NPC. Primary NPC included newly diagnosed cancers that had never been treated before or had just finished the first line of curative therapy. Recurrent NPC included cancers that had failed previous treatment regimes. The “Other” category includes studies that did not specify or unclearly specified which NPCs were included.
Clinical trials were manually reviewed for their primary outcome measure, including: quality of life, response rate, overall survival, progression‐free survival (PFS), failure‐free survival (FFS), drug tolerability, adverse events, and other. One trial could have multiple primary outcomes.
Publication status evaluation
Finally, we utilized publication matching methods from prior ClinicalTrials.gov studies in the literature to determine the publication status of completed studies. 17 , 18 We conducted a systematic search of PubMed and Google Scholar using the National Clinical Trial ID, study title, and study sponsors. The PubMed citations provided in each trial's registry records were also reviewed to identify published manuscripts and abstracts for completed clinical trials.
RESULTS
Overall study characteristics can be found in Table 1. There were 448 clinical trials related to nasopharyngeal cancer between November 1, 1999 and June 28, 2021. Of those trials, there were 210 active studies, 111 completed studies, 26 studies that were prematurely terminated, and 101 studies that were lost to follow‐up. Forty‐one percent of the interventional studies were Phase 2 studies, and the mean study enrollment was 151 participants. Of the observational studies, 57% were cohort models, with a mean enrollment of 1978 participants. The NIH sponsored 24 of the 448 studies.
Table 1.
Characteristics of 448 nasopharyngeal carcinoma trials divided into interventional and observational studies and compared across study status
| Study status | ||||||
|---|---|---|---|---|---|---|
| Interventional studies (n = 376) | Total No. (%) | Active No. (%) | Completed No. (%) | Prematurely ended No. (%) | Unknown No. (%) | |
| Total trials | 376 (100.0) | 180 (47.8) | 86 (22.9) | 23 (6.1) | 87 (23.1) | |
| Phase | Phase 1 | 30 (6.7) | 9 (4.3) | 13 (11.7) | 3 (11.5) | 5 (5.0) |
| Phase 1/Phase 2 | 22 (4.9) | 8 (3.8) | 8 (7.2) | 3 (11.5) | 3 (3.0) | |
| Phase 2 | 183 (40.8) | 80 (38.1) | 49 (44.1) | 12 (46.2) | 42 (41.6) | |
| Phase 2/Phase 3 | 11 (2.5) | 7 (3.3) | 1 (0.9) | 0 (0) | 3 (3.0) | |
| Phase 3 | 86 (19.2) | 58 (27.6) | 7 (6.3) | 4 (15.4) | 17 (16.8) | |
| Phase 4 | 5 (1.1) | 1 (0.5) | 1 (0.9) | 0 (0) | 3 (3.0) | |
| N/A | 39 (8.7) | 17 (8.1) | 7 (6.3) | 1 (3.8) | 14 (13.9) | |
| Model | Factorial assignment | 5 (1.3) | 2 (1.1) | 1 (1.2) | 1 (4.3) | 1 (1.1) |
| Parallel assignment | 191 (50.8) | 105 (58.3) | 29 (33.7) | 5 (21.7) | 52 (59.8) | |
| Sequential assignment | 3 (0.8) | 1 (0.6) | 2 (2.3) | 0 (0) | 0 (0) | |
| Single group assignment | 166 (44.1) | 72 (40.0) | 50 (58.1) | 15 (65.2) | 29 (33.3) | |
| N/A | 11 (2.9) | 0 (0) | 4 (4.7) | 2 (8.7) | 5 (5.7) | |
| Allocation | Nonrandomized | 36 (9.6) | 11 (6.1) | 11 (12.8) | 4 (17.4) | 10 (11.5) |
| Randomized | 192 (51.1) | 101 (56.1) | 31 (36.0) | 7 (30.4) | 53 (60.9) | |
| N/A | 148 (39.4) | 68 (37.8) | 44 (51.2) | 12 (52.2) | 22 (25.3) | |
| Masking | None (open‐label) | 330 (87.8) | 165 (91.7) | 76 (88.4) | 20 (87.0) | 69 (79.3) |
| Single | 19 (5.1) | 7 (3.9) | 3 (3.5) | 0 (0) | 9 (10.3) | |
| Double | 9 (2.4) | 4 (2.2) | 1 (1.2) | 1 (4.3) | 3 (3.4) | |
| Triple | 4 (1.1) | 1 (0.6) | 0 (0) | 0 (0) | 3 (3.4) | |
| Quadruple | 7 (1.9) | 3 (1.7) | 3 (3.5) | 0 (0) | 1 (1.1) | |
| N/A | 7 (1.9) | 0 (0) | 3 (3.5) | 2 (8.7) | 2 (2.3) | |
| Enrollment a | Trials w/enrollment information | 373 (99.2) | 180 (100.0) | 84 (97.7) | 23 (100.0) | 86 (98.9) |
| Mean (SD) | 151 (190) | 182 (179) | 84 (113) | 72 (137) | 174 (253) | |
| Minimum | 0 | 2 | 3 | 0 | 2 | |
| Median | 90 | 126 | 55 | 9 | 95 | |
| Maximum | 2000 | 1324 | 803 | 465 | 2000 | |
| Location b | North America | 46 (12.2) | 15 (8.3) | 23 (26.7) | 7 (30.4) | 1 (1.1) |
| Asia/Pacific | 349 (92.8) | 175 (97.2) | 75 (87.2) | 18 (78.2) | 81 (93.1) | |
| Europe | 30 (8.0) | 4 (2.2) | 16 (18.6) | 9 (39.1) | 1 (1.1) | |
| Sponsorship | NIH | 19 (5.1) | 5 (2.8) | 11 (12.8) | 2 (8.7) | 1 (1.1) |
| Industry | 49 (13.0) | 23 (12.8) | 15 (17.4) | 6 (26.1) | 5 (5.7) | |
| Other | 308 (81.9) | 152 (84.4) | 60 (69.8) | 15 (65.2) | 91 (93.1) | |
| Study status | ||||||
|---|---|---|---|---|---|---|
| Observational studies (n = 72) | Total No. (%) | Active No. (%) | Completed No. (%) | Prematurely Ended No. (%) | Unknown No. (%) | |
| Total trials | 72 (100.0) | 30 (41.7) | 25 (34.7) | 3 (4.2) | 14 (19.4) | |
| Study design | Case–control | 10 (13.9) | 3 (10.0) | 2 (8.0) | 1 (33.3) | 4 (28.6) |
| Case‐crossover | 1 (1.4) | 0 (0) | 0 (0) | 0 (0) | 1 (7.1) | |
| Case‐only | 14 (19.4) | 4 (13.3) | 8 (32.0) | 0 (0) | 2 (14.3) | |
| Cohort | 41 (56.9) | 22 (73.3) | 12 (48.0) | 2 (66.7) | 5 (35.7) | |
| Defined population | 1 (1.4) | 0 (0) | 0 (0) | 0 (0) | 1 (7.1) | |
| Family‐based | 2 (2.8) | 0 (0) | 2 (8.0) | 0 (0) | 0 (0) | |
| Other | 2 (2.8) | 1 (3.3) | 1 (4.0) | 0 (0) | 0 (0) | |
| N/A | 1 (1.4) | 0 (0) | 0 (0) | 0 (0) | 1 (7.1) | |
| Enrollment a | Number of trials w/enrollment information | 72 (100.0) | 30 (100.0) | 25 (100.0) | 3 (100.0) | 14 (100.0) |
| Mean (SD) | 1978 (5358) | 2268 (5865) | 1340 (2835) | 1487 (1806) | 2600 (7953) | |
| Minimum | 9 | 20 | 17 | 9 | 20 | |
| Median | 200 | 200 | 300 | 952 | 200 | |
| Maximum | 30,000 | 25,000 | 12,206 | 3,500 | 30,000 | |
| Location b | North America | 8 (11.1) | 2 (6.7) | 4 (16.0) | 2 (66.7) | 0 (0) |
| Asia/Pacific | 45 (62.5) | 18 (60.0) | 14 (56.0) | 2 (66.7) | 11 (78.6) | |
| Europe | 5 (6.9) | 2 (6.7) | 2 (8.0) | 0 (0) | 1 (7.1) | |
| Sponsorship | NIH | 5 (6.9) | 0 (0) | 3 (12.0) | 2 (66.7) | 0 (0) |
| Industry | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | |
| Other | 67 (93.1) | 30 (100.0) | 22 (88.0) | 1 (33.3) | 14 (100.0) | |
Abbreviation: NIH, National Institutes of Health.
Enrollment numbers include anticipated and actual enrollment numbers, whichever provided by investigator.
Each trial can have multiple locations. Only the most common locations are included.
A comprehensive summary of the study eligibility criteria, interventions, and primary outcome measures can be found in Table 2. The most common interventions were drug regimens (44%), of which chemotherapy was the most common (40%). Studies predominantly examined primary NPC (54%) and PFS (31%) was the most common primary outcome measure.
Table 2.
Study interventions and primary outcome measures
| Study status | |||||||
|---|---|---|---|---|---|---|---|
| Study design | Total No. (%) | Active No. (%) | Completed No. (%) | Prematurely ended No. (%) | Unknown No. (%) | ||
| Total trials | 448 (100.0) | 210 (46.9) | 111 (24.8) | 26 (5.8) | 101 (22.5) | ||
| Type of intervention | Drug only | 195 (43.5) | 70 (33.3) | 57 (51.4) | 16 (61.5) | 52 (51.5) | |
| Drug and radiation | 145 (32.4) | 92 (43.8) | 20 (18.0) | 6 (23.1) | 27 (26.7) | ||
| Radiation only | 29 (6.5) | 18 (8.6) | 9 (8.1) | 1 (3.8) | 1 (1.0) | ||
| Other | 79 (17.6) | 30 (14.3) | 25 (22.5) | 3 (11.5) | 21 (20.8) | ||
| Drug regimen | Chemotherapy only | 181 (40.4) | 72 (34.3) | 49 (44.1) | 11 (42.3) | 49 (48.5) | |
| IT only | 56 (12.5) | 42 (20.0) | 8 (7.2) | 4 (15.4) | 2 (2.0) | ||
| IT and chemotherapy | 38 (8.5) | 33 (15.7) | 2 (1.8) | 1 (3.8) | 2 (2.0) | ||
| No drug regimen | 108 (24.1) | 48 (22.9) | 34 (30.6) | 4 (15.4) | 22 (21.8) | ||
| Other drug regimen | 65 (14.5) | 15 (7.1) | 18 (16.2) | 6 (23.1) | 26 (25.7) | ||
| Eligibility | Recurrent NPC | 111 (24.8) | 56 (26.7) | 28 (25.2) | 13 (50.0) | 14 (13.9) | |
| Primary NPC | 240 (53.6) | 119 (56.7) | 48 (43.2) | 9 (34.6) | 64 (63.4) | ||
| Both | 94 (21.0) | 34 (16.2) | 34 (30.6) | 4 (15.4) | 22 (21.8) | ||
| Other | 3 (0.7) | 1 (0.5) | 1 (0.9) | 0 (0) | 1 (1.0) | ||
| Primary outcome measuresa | Quality of life | 34 (7.6) | 14 (6.7) | 6 (5.4) | 0 (0) | 14 (13.9) | |
| Response rate | 104 (23.2) | 44 (21.0) | 34 (30.6) | 7 (26.9) | 19 (18.8) | ||
| Overall survival | 55 (12.3) | 30 (14.3) | 8 (7.2) | 5 (19.2) | 12 (11.9) | ||
| Progression‐free survival | 137 (30.6) | 75 (35.7) | 23 (20.7) | 4 (15.4) | 35 (34.7) | ||
| Drug tolerability | 36 (8.0) | 12 (5.7) | 12 (10.8) | 3 (11.5) | 9 (8.9) | ||
| Life expectancy | 7 (1.6) | 2 (1.0) | 2 (1.8) | 1 (3.8) | 2 (2.0) | ||
| Adverse events | 31 (6.9) | 13 (6.2) | 9 (8.1) | 5 (19.2) | 4 (4.0) | ||
| Disease‐free survival | 20 (4.5) | 13 (6.2) | 4 (3.6) | 1 (3.8) | 2 (2.0) | ||
| Other | 64 (14.3) | 25 (11.9) | 23 (20.7) | 5 (19.2) | 11 (10.9) | ||
| Missing | 15 (3.3) | 1 (0.5) | 6 (5.4) | 2 (7.7) | 6 (5.9) | ||
Abbreviations: IT, immunotherapy; NPC, nasopharyngeal carcinoma.
Some studies had multiple primary outcome measures.
The most common reason for early termination was poor accrual (Table 3). Seventy out of the 111 completed studies published results, including 59 manuscripts and 11 abstracts. Details regarding published studies are summarized in Table 4.
Table 3.
Reported reasons for studies terminated prematurely
| Prematurely ended studies | No. (%) |
|---|---|
| Reason for termination | |
| Poor accrual | 12 (46.2) |
| Loss of sponsor | 3 (11.5) |
| Not human subject research | 2 (7.7) |
| Lack of efficacy | 1 (3.8) |
| Reassessing new guidelines | 1 (3.8) |
| Intolerable intervention | 1 (3.8) |
| Not disclosed | 6 (23.1) |
| Phase | |
| Phase 1 | 3 (11.5) |
| Phase 1/Phase 2 | 3 (11.5) |
| Phase 2 | 12 (46.2) |
| Phase 3 | 4 (15.4) |
| N/A | 4 (15.4) |
| Total | 26 (100.0) |
Table 4.
Comparison of study characteristics and designs of published versus unpublished completed studies
| Publication status | ||||
|---|---|---|---|---|
| Publication status | Total No. (%) | Not published No. (%) | Publisheda No. (%) | |
| Completed interventional studies | 86 (100.0) | 30 (34.9) | 56 (65.1) | |
| Phase | Phase 1 | 13 (15.1) | 5 (16.7) | 8 (14.3) |
| Phase 1/Phase 2 | 8 (9.3) | 3 (10.0) | 5 (8.9) | |
| Phase 2 | 49 (57.0) | 16 (53.3) | 33 (58.9) | |
| Phase 2/Phase 3 | 1 (1.2) | 1 (3.3) | 0 (0) | |
| Phase 3 | 7 (8.1) | 1 (3.3) | 6 (10.7) | |
| Phase 4 | 1 (1.2) | 0 (0) | 1 (1.8) | |
| N/A | 7 (8.1) | 4 (13.3) | 3 (5.4) | |
| Allocation | Nonrandomized | 11 (12.8) | 5 (16.7) | 6 (10.7) |
| Randomized | 31 (36.0) | 10 (33.3) | 21 (37.5) | |
| N/A | 44 (51.2) | 15 (50.0) | 29 (51.8) | |
| Masking | None (open label) | 76 (88.4) | 26 (86.7) | 50 (89.3) |
| Single | 3 (3.5) | 0 (0) | 3 (5.4) | |
| Double | 1 (1.2) | 0 (0) | 1 (1.8) | |
| Quadruple | 3 (3.5) | 1 (3.3) | 2 (3.6) | |
| N/A | 3 (3.5) | 3 (10.0) | 0 (0) | |
| Completed observational studies | 25 (100.0) | 11 (44.0) | 14 (56.0) | |
| Model | Case–control | 2 (8.0) | 1 (9.1) | 1 (7.1) |
| Case‐only | 8 (32.0) | 3 (27.3) | 5 (35.7) | |
| Cohort | 12 (48.0) | 5 (45.5) | 7 (50.0) | |
| Family‐based | 2 (8.0) | 2 (18.2) | 0 (0) | |
| Other | 1 (4.0) | 0 (0) | 1 (7.1) | |
| All completed studies | 111 (100.0) | 41 (36.9) | 70 (63.1) | |
| Regionb | Asia & Pacific | 90 (81.1) | 29 (70.7) | 61 (87.1) |
| Europe | 18 (16.2) | 2 (4.9) | 16 (22.9) | |
| North America | 27 (24.3) | 12 (29.3) | 15 (21.4) | |
| Sponsor | Industry | 15 (13.5) | 3 (7.3) | 12 (17.1) |
| NIH | 14 (12.6) | 7 (17.1) | 7 (10.0) | |
| Other | 82 (73.9) | 31 (75.6) | 51 (72.9) | |
| Intervention | Drug | 57 (51.4) | 18 (43.9) | 39 (55.7) |
| Radiation | 9 (8.1) | 14 (34.1) | 11 (15.7) | |
| Drug and radiation | 20 (18.0) | 7 (17.1) | 13 (18.6) | |
| Other | 25 (22.5) | 2 (4.9) | 7 (10.0) | |
| Drug regimen | Chemotherapy | 49 (44.1) | 15 (36.6) | 34 (48.6) |
| Immunotherapy | 8 (7.2) | 3 (7.3) | 5 (7.1) | |
| Immunotherapy and chemotherapy | 2 (1.8) | 0 (0) | 2 (2.9) | |
| Not drug | 34 (30.6) | 16 (39.0) | 18 (25.7) | |
| Other | 18 (16.2) | 7 (17.1) | 11 (15.7) | |
| Eligibility | Recurrent NPCs | 28 (25.2) | 9 (22.0) | 19 (27.1) |
| Primary NPCs | 48 (43.2) | 15 (36.6) | 33 (47.1) | |
| Both | 34 (30.6) | 16 (39.0) | 18 (25.7) | |
| Other | 1 (0.9) | 1 (2.4) | 0 (0) | |
|
Primary outcome measuresc |
Quality of life | 6 (5.4) | 1 (2.4) | 5 (7.1) |
| Response rate | 33 (29.7) | 12 (29.3) | 21 (30.0) | |
| Overall survival | 8 (7.2) | 1 (2.4) | 7 (10.0) | |
| Progression‐free survival | 23 (20.7) | 9 (22.0) | 14 (20.0) | |
| Drug tolerability | 11 (9.9) | 4 (9.8) | 7 (10.0) | |
| Life expectancy | 2 (1.8) | 1 (2.4) | 1 (1.4) | |
| Adverse events | 9 (8.1) | 2 (4.9) | 7 (10.0) | |
| Disease free survival | 4 (3.6) | 1 (2.4) | 3 (4.3) | |
| Other | 23 (20.7) | 11 (26.8) | 12 (17.1) | |
| Missing | 6 (5.4) | 4 (9.8) | 2 (2.9) | |
Abbreviation: NPC, nasopharyngeal carcinoma.
Any published work, including both abstracts and manuscripts.
Clinical trials could have multiple locations, the most common locations across all trials were included.
Some studies had more than one primary outcome measure.
DISCUSSION
Clinical trials are critical to advancing research from the bench to the bedside. To our knowledge, this is the most comprehensive analysis of clinical trials involving NPC. Our analysis of all registered trials as of July 2021 identified 448 studies, including 210 active studies, 111 completed studies, 26 prematurely terminated studies, and 101 studies of unknown status. Overall, 155 (35%) studies were open‐label, randomized trials, and 352 (79%) studies were conducted in Asia where the prevalence of NPC is much higher. We also identified the persistence of chemotherapy and radiation studies despite a rapid increase in immunotherapy studies in the past several years.
The 111 completed studies were finished between November 1999 to July 2020 with median length of 4.2 years (interquartile range: 2.7–7.1). Of the 111 completed studies, a comprehensive literature search identified 59 (53%) published manuscripts and 11 (10%) abstracts. This is concordant with previously reported publication rates for completed interventional studies. 9 , 10 , 11 Eleven studies had data published before completion; for the remaining manuscripts, the median time to publication was 2 years. Six Phase 3 studies published results. In the immunotherapy field, Yang et al. 19 and Mai et al. 20 reported that the addition of an anti‐PD‐1 monoclonal antibody to gemcitabine‐cisplatin chemotherapy provided superior PFS and a manageable safety profile. Mai et al. 20 studied toripalimab (study population 289 patients) and Yang et al. 19 studied camrelizumab (263 patients). Both reported similar hazard ratios and increases in PFS. In the chemotherapy field, Lee et al. 21 demonstrated that an induction‐concurrent regimen of cisplatin and capecitabine significantly improved PFS and overall survival compared to concurrent‐adjuvant sequence. In terms of toxicity, Tang et al. 22 demonstrated the noninferiority of nedaplatin, which has fewer toxic effects, to cisplatin in concurrent chemoradiotherapy. Publications of Phase 2 studies demonstrate the promising work that is ongoing involving monoclonal antibody drugs and reducing treatment side effects. These studies will continue to inform future work in the NPC field.
Of the 210 active studies, the average anticipated competition date is November 2023, with a latest expected date of December 2035. These active studies are predominately Phases 2 and 3 studies investigating drug and radiation combinations. Cisplatin (n = 64) and IMRT (n = 54) are the most common interventions, followed by gemcitabine (n = 27) and docetaxel (n = 18). The active studies also reflect changes in the landscape of NPC treatment in the last decade with the advent of immunotherapy. Thirty‐eight trials implement monoclonal antibodies targeting PD‐1 expression, with toripalimab (n = 10), camrelizumab (n = 10), and pembrolizumab (n = 7) being the most common. Toripalimab (Shanghai Junshi Bioscience Co., Ltd.) and Camrelizumab (Jiangsu Hengrui Pharmaceuticals Co., Ltd.) are both recombinant, humanized monoclonal antibodies targeting PD‐1. 22 , 23 As discussed above, there are two major publications indicating the effectiveness of these two compounds. 19 , 20 Pembrolizumab is an anti‐PD‐1 monoclonal antibody developed by Merck & Co. 24 Results from these trials will elucidate their efficacy in NPC to guide future treatment regimens.
Of the 26 studies that were suspended, terminated, or withdrawn, 20 provided reasons for termination. Twelve were terminated due to slow patient accrual, seven (58%) of which took place in the United States or Europe. The low prevalence of NPC in the United States and Europe could have contributed to their insufficient recruitment rate. 6 Other reasons for termination included difficulty with funding (sponsors or collaborators), issues with trial administration or principal investigators, and poor drug tolerability.
Overall, 101 studies were listed with an “Unknown” completion status. ClinicalTrials.gov classifies these “Unknown” studies as those that were once classified as active but have passed their completion date and have not been verified in the past 2 years. This generally indicates a study that has lost support or will soon be terminated. “Unknown” trials can also indicate different reporting requirements between countries. Trials that are lost to updates represent an area of lost opportunity, as understanding the factors that contribute to trial termination can help investigators design successful future trials.
Finally, we investigated trends for the 266 interventional studies that are active or completed (Figure 2). The use of chemotherapy and radiotherapy dominated trials since 1996, on average composing 54% and 43% of studies each year. From 2009 to 2012, there was a large increase in trials incorporating small‐molecule drugs and biologics, targeting receptors in tumor growth signaling pathways. Of the studies started after 2020, 65% of studies included a small‐molecule or biologic drug. Between 2010 and 2012, there was a spike in studies with small‐molecule/biologic interventions. Starting in 2017, there was an exponential rise in immunotherapy interventions. In 2020, 50% of the studies included immunotherapy. These trends demonstrate that novel immunotherapies have been increasingly incorporated into therapeutic regimens, however, chemotherapy and radiotherapy, despite their numerous side effects, are still widely used. Studies evaluating small‐molecule and monoclonal antibody drugs targeting receptor tyrosine kinase pathways continue to be initiated but remain infrequent.
Figure 2.
Interventions used in nasopharyngeal carcinoma clinical trials over time. Chemo, chemotherapy; MAB, monoclonal antibody; SM, small molecule.
Future work in the NPC field must include basic science research to improve treatment options that can be applied to patients. 3 Also, there is room for growth in biomarkers to track disease outcome, progression, and treatment response. 6 When examining clinical trial characteristics, future studies are warranted to evaluate trial reporting guidelines at different regions, characterization of trial results, and the redundancy in trials.
CONCLUSION
There are an increasing number of immunotherapy, quality of life, and drug tolerability trials in NPC treatment. Simultaneously, studies continue to investigate chemotherapy and radiation therapy regimens to better manage recurrent NPCs. Our study highlights the limited number of completed and published Phase 3 studies this field. Due to the unique geographical distribution of NPC, while there are a limited amount of relevant NIH‐funded studies, many prominent universities and pharmaceutical companies in Asia are investigating novel treatment regimens to improve clinical outcomes. This is the first study to provide a comprehensive analysis and detailed insight into new precision therapies for NPC. Our analysis identifies the landscape of current NPC trials and key trends and stakeholders in the research process.
AUTHOR CONTRIBUTIONS
Katherine Xu and Emma De Ravin were equally involved in conceptualization, methodology, data collection and analysis, and manuscript writing. Neeraj Suresh was involved in data collection and data analysis. Robert M. Brody was involved in interpretation of data, concept, and design. Karthik Rajasekaran was involved in concept and design, analysis, and interpretation of data, critical review, and final approval.
CONFLICT OF INTEREST
The authors declare no conflict of interest.
ETHICS STATEMENT
The above manuscript is the authors’ own original work and reflects the authors’ own research. Analysis in a truthful and complete manner and properly credits the meaningful contributions of co‐authors and co‐researchers. Institutional Review Board (IRB) approval was neither sought nor required as this study does not involve protected health information or human subjects.
ACKNOWLEDGMENTS
The authors declare that no funds, grants, or other support were received for the preparation of this manuscript.
Xu K, De Ravin E, Suresh N, Brody RM, Rajasekaran K. A comprehensive review and characterization of nasopharyngeal carcinoma clinical trials. World J Otorhinolaryngol Head Neck Surg. 2023;9:174‐182. 10.1002/wjo2.80
Katherine Xu and Emma De Ravin contributed equally to this study.
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available in the public domain on ClinicalTrials.gov.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data that support the findings of this study are available in the public domain on ClinicalTrials.gov.