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"NEJM Medical Frontiers" invited the team of Professor Ma Jun of Sun Yat-sen University Cancer Prevention and Treatment Center to review the important progress
in the field of head and neck cancer in 2022.
NEJM Medical Frontiers is a collaboration between Jiahui Medical Research and Education Group (J-Med) and the New England Journal of Medicine (NEJM
).
For the fifth consecutive year, we have launched a clinical research inventory of all important disease areas, so stay tuned
.
DONG Zhe, ZHANG Yuan, MA Jun*Sun Yat-sen University Cancer Center*Corresponding author: Common head and neck squamous cell carcinomas include nasopharyngeal cancer, oral cancer, oropharyngeal cancer and laryngeal cancer
.
Globally, there are about 800,000 new cases of squamous cell carcinoma of the head and neck each year, and more than 350,000 deaths [1].
There are about 140,000 new cases of head and neck squamous cell carcinoma in China every year, of which nasopharyngeal carcinoma is the most common, about 60,000 cases per year [2].
More than two-thirds of patients with squamous cell carcinoma of the head and neck are diagnosed with locally advanced or metastatic disease, and require a combination of surgery, radiotherapy, chemotherapy, immunotherapy and other treatments
.
The clinical research results of squamous cell carcinoma of the head and neck in 2022 mainly focus on the exploration of "attenuated" treatment mode, and individualized chemoradiotherapy for patients with different risk levels to improve the quality of
life of patients under the premise of ensuring efficacy.
With the application of magnetic resonance, intensity-modulated radiotherapy, induction chemotherapy and other diagnosis and treatment modes, the 5-year survival rate of
nasopharyngeal carcinoma patients has been continuously improved, and it is now as high as 85%~90%.
However, the acute and long-term toxic side effects of current radiotherapy and chemotherapy on patients cannot be ignored
.
Therefore, risk stratification of patients, and reducing toxicity and improving the quality of life of patients by reducing the intensity of treatment for low-risk patients, so that patients with nasopharyngeal carcinoma not only live longer, but also live better, is a highlight of this year's research progress in nasopharyngeal carcinoma
。
Low-risk nasopharyngeal carcinoma - reducing the intensity of chemotherapyAt present, intensity-modulated radiation therapy has become the main radiotherapy method for nasopharyngeal carcinoma, which significantly improves the efficacy
of nasopharyngeal carcinoma 。 For patients with stage II and T3N0 without adverse prognostic factors (cervical lymph node capsular invasion, maximum diameter ≥ 3 cm or located in the lower cervix, or plasma EBV DNA (EBV-DNA) ≥4000 copy number/ml) before treatment), the 5-year overall survival rate can reach more than 90%, the risk of metastasis and recurrence is low, and the benefit of combining concurrent chemotherapy on the basis of radiotherapy is limited, but the adverse reactions
such as vomiting in patients during treatment are increased.
A study published in 2022 by Professor Ma Jun's team from the Sun Yat-sen University Cancer Center found that for the above-mentioned low-risk nasopharyngeal carcinoma patients, radiotherapy alone was not inferior to concurrent chemoradiotherapy [3].
。 A total of 341 patients with nasopharyngeal carcinoma were randomized to the trial group (172; intensity-modulated radiotherapy alone) and (169 patients; Intensity-modulated radiotherapy combined with concurrent chemotherapy), after 46 months follow-up, patients in the radiotherapy alone group survived 3-year without failure compared to concurrent chemoradiotherapy (90.
5% vs.
91.
9%; non-inferior P<0.
0001); And the incidence of grade 3~4 toxicity was greatly reduced (17% vs.
46%)
.
In addition, the quality of life of patients in the radiotherapy alone group was significantly better than that in the concurrent chemoradiotherapy group
.
This research result greatly optimizes the treatment mode of this group of patients, reduces chemotherapy-related toxicity, and significantly improves the quality of life
.
Figure 1 Disease recurrence or mortality occurred in the radiotherapy alone group and the concurrent chemoradiotherapy group[3].
At the same time, whether it can reduce the chemotherapy intensity in low-risk patients with locally advanced nasopharyngeal carcinoma is also a research hotspot
.
In 2022, the team of Professor Mai Haiqiang of the Cancer Center of Sun Yat-sen University published a phase 2 randomized controlled clinical trial to screen low-risk patients with locally advanced (III.
-IV.
a) nasopharyngeal carcinoma using plasma EBV-DNA (<4000 copy number/ml), and the results showed that the efficacy of 2 courses of cisplatin concurrent chemotherapy was not inferior to 3 courses [4].
This study provides a basis for reducing chemotherapy intensity in patients with low-risk locally advanced nasopharyngeal carcinoma.
Smaller radiation range, less dose? ——Individualized radiotherapy 1.
There is a certain regularity in the metastasis of lymph nodes in patients with cervical lymph node negative semi-cervical prophylactic irradiation that is not inferior to full neck radiation for nasopharyngeal carcinoma, and most of the metastases occur in the ipsilateral lymph node drainage area, and rarely contralateral metastasis; And following the law of top-down transfer, jump transfer
rarely occurs.
Based on this theoretical basis, Professor Ma Jun's team conducted a prospective multi-center phase 3 clinical trial to compare selective upper neck irradiation on the negative side of cervical lymph nodes for nasopharyngeal carcinoma with total neck irradiation
.
A total of 446 patients were enrolled in the study, with a median follow-up of 53 months
.
Primary endpoint 3-year survival without lymph node recurrence was similar in the upper neck and full neck irradiation groups (97.
7% vs.
96.
3%; P=0.
85), non-inferiority test showed that the survival rate of the upper neck irradiation group was not inferior to that of the whole neck irradiation group
.
The incidence of late toxicity was lower in the upper neck irradiation group than in the full neck irradiation group, including any grade of hypothyroidism (30 versus 39 percent), skin toxicity (14 versus 25 percent), dysphagia (17 versus 32 percent), and neck tissue injury (23 versus 40 percent) [5].
The irradiation technology reduces the irradiation volume of the skin, organs, esophagus, thyroid and other important organs of the lower neck, significantly reduces the sequelae of radiotherapy such as hypothyroidism, dysphagia, neck tissue damage, etc.
, improves the quality of life of patients, and will benefit 70% of nasopharyngeal cancer patients
.
Figure 2 Survival rate of recurrence without region in the whole neck irradiation group and the upper neck irradiation group[5]
2.
Patients with metastasis in the medial group without retropharyngeal lymph nodes can be exempted from prophylactic irradiation in this area, although the rate of retropharyngeal lymph node metastasis is high, but it is mainly concentrated in the lateral group, and metastasis in the medial group is extremely rare; Previous radiotherapy norms used to prophylactic irradiation of retropharyngeal lymph nodes indiscriminately, resulting in impaired swallowing function and seriously affecting the quality of life of
patients.
Based on this, another study by Professor Ma Jun's team found that the exemption of patients with nasopharyngeal carcinoma from the prophylactic radiation of the retropharyngeal lymph node drainage area in the medial group can improve the quality of life of patients while not affecting the treatment effect [6].
A total of 568 patients with nasopharyngeal carcinoma were included in the study, and the experimental group (285 patients) was exempted from prophylactic irradiation in the retropharyngeal lymph node drainage area in the medial group; The control group (283 cases) used standard irradiation to prophylactic irradiation
of the retropharyngeal lymph node drainage area in the medial group.
At median 42-month follow-up, patients in the experimental group survived 3 years without local recurrence (primary endpoint; 95.
3% vs.
95.
5%) were not inferior to the control group, and the incidence of dysphagia decreased in acute (25.
5% vs.
35.
1%) and late (24.
0% vs.
34.
3%), and the patient-reported quality of life was significantly improved
.
The research results will further promote the precision and refinement of the radiotherapy target area for nasopharyngeal carcinoma and improve the quality of life of
patients.
Low-risk, chemotherapy-sensitive radiation therapy for nasopharyngeal carcinoma – try lowering the dose to 60 Gy
Radiotherapy-related toxicity often affects the quality of life of patients in the long term, and attempts to reduce the dose of radiotherapy are expected to bring benefits
to low-risk patients.
A single-arm, single-center phase 2 clinical trial by Professor Mai Haiqiang's team from Sun Yat-sen University Cancer Prevention and Treatment Center suggested that patients with low-risk locally advanced nasopharyngeal carcinoma who received low-dose (60 Gy) concurrent chemoradiotherapy after two cycles of induction chemotherapy could also achieve good efficacy [7].
。 The 116 patients with low-risk (plasma EBV-DNA<4000 copy number/ml) stage III nasopharyngeal carcinoma in this study received 60 Gy intensity-modulated radiotherapy and concurrent cisplatin chemotherapy after 2 courses of induction chemotherapy for TPF (paclitaxel liposomes, cisplatin, and fluorouracil) and plasma EBV-DNA dropped to undetectable and received 60 Gy intensity-modulated radiotherapy and concurrent cisplatin chemotherapy
.
At a median follow-up of 25.
8 months, the 2-year progression-free survival rate reached 94.
8%, and no long-term adverse events
above grade 3 were observed.
The trial also provides the basis for a randomised controlled trial of "lowering the dose of radiotherapy".
Exploration
of reducing the intensity of radiotherapy and chemotherapy for head and neck squamous cell carcinoma plays an important role in the treatment of locally advanced head and neck squamous cell carcinoma, and reducing the treatment intensity is also an important research direction
for locally advanced head and neck squamous cell carcinoma.
HPV-positive oropharyngeal carcinoma - After TOS combined with low-dose adjuvant radiotherapy, HPV-related oropharyngeal cancer has a good prognosis, and is sensitive
to chemoradiotherapy 。 ECOG-ACRIN E3311 is a large phase 2 randomized clinical trial of oropharyngeal squamous cell carcinoma patients with stage III.
-IV.
A (T1-2), HPV-positive, suitable for transoral surgery (TOS), and was divided into 3 risk groups according to the pathological results after surgery, including low-risk group (T1-2N0-1, negative margin, no lymph node capsular invasion) follow-up observation, high-risk group (positive margin, lymph node capsular invasion> 1 mm, Positive lymph nodes ≥5) received 66 Gy of postoperative radiotherapy and concurrent cisplatin chemotherapy
.
The other patients were intermediate-risk and randomized to receive postoperative radiotherapy
of 50 Gy and 60 Gy respectively.
A total of 445 patients were included, including 49 in the low-risk group, 258 in the intermediate-risk group, and 138 in the high-risk group [8].
At a median follow-up of 35.
2 months, the 2-year progression-free survival rates in the low-risk and high-risk groups were 96.
9% and 90.
7%,
respectively.
For the intermediate-risk group, the 2-year progression-free survival rate of 50 Gy and 60 Gy radiotherapy after surgery was more than 90%, 94.
9% (90% CI, 91.
3~98.
6) and 96.
0% (90% CI, 92.
8~99.
3), respectively, and the grade 3~4 adverse reaction rate was lower in the 50 Gy group (14% vs.
24%)
.
This study provides a preliminary basis
for reducing the dose of postoperative radiotherapy in patients with HPV-positive oropharyngeal cancer.
Figure 3 Progression-free survival in different risk groups[8].
Concurrent chemoradiotherapy after surgery for head and neck squamous cell carcinoma – which is less toxic than a single-week or three-week regimen?
The current standard treatment model for patients with high-risk head and neck squamous cell carcinoma after surgery is radiotherapy plus cisplatin for three weeks
.
JCOG1008 is a non-inferior phase 2/3 clinical trial that compares the efficacy and toxicity of cisplatin single-week regimens and three-week regimens in this population [9].
The multicenter trial included a total of 261 patients with high-risk head and neck squamous cell carcinoma who underwent radical surgery for III.
-IV.
b and were randomized to a single-week cisplatin regimen (129 patients; 40 mg/m² once weekly) and three-week regimen (132 patients; 100 mg/m² once every 3 weeks).
After a median follow-up of 2.
2 years, overall survival was not inferior to that of the three-week regimen (non-inferior unilateral P=0.
0027), while the incidence of neutropenia (35% vs.
49%) and infection (7% vs.
12%) was lower
in grade 3 or above.
In this study, the median cumulative cisplatin dose in the single-week regimen group was significantly lower than in the three-week regimen group (239 mg/m² vs.
280 mg/m²).
Figure 4 Overall survival in the cisplatin single-week regimen group and the three-week regimen group[9].
However, a similarly designed nasopharyngeal carcinoma clinical trial conducted by the Cancer Center of Sun Yat-sen University to Professor Yanqun's team has yielded different results
.
A total of 526 patients with locally advanced nasopharyngeal carcinoma were included in this trial, and although there was no significant difference in efficacy between the single-week regimen and the three-week regimen, acute hematologic toxicity and advanced ototoxicity were significantly reduced in the three-week regimen group [10].
Of note, in this study, the median cumulative cisplatin dose in the three-week regimen group was slightly lower than in the single-week regimen group (200 mg/m² vs.
220 mg/m²).
The two trials reached opposite conclusions and may suggest that the cumulative dose of cisplatin, rather than the frequency of use (single week and three weeks), is the determinant of
adverse effects.
Head and neck squamous cell carcinoma immunotherapy explores locally advanced head and neck squamous
cell carcinoma - immunotherapy fails to improve efficacy With the success of immunotherapy in recurrent metastatic head and neck squamous cell carcinoma, multiple studies have explored its value in locally advanced head and neck squamous cell carcinoma
。 A recent randomized controlled, double-blind, phase 3 clinical trial (KEYNOTE-412) compared the efficacy and safety of concurrent chemoradiotherapy in combination with pembrolizumab or placebo in the treatment of locally advanced head and neck squamous cell carcinoma [11].
In this study, a total of 804 patients were included with a median follow-up of 47.
7 months, and the results showed that although there was a trend of benefit in the combined immunization group, there was no statistical difference in event-free survival (HR, 0.
83; 95% CI, 0.
68~1.
03).
PREVIOUSLY, THE JAVELIN H&N 100 STUDY, WHICH IS SIMILAR TO THE KENNOTE-412 DESIGN, also received negative results
.
Therefore, concurrent chemoradiotherapy is still the standard of care for this group of patients, and the significance of immunotherapy needs further study
.
Figure 5 KEYNOTE-412 STUDY DESIGN [11].
Recurrent metastatic head and neck squamous cell carcinoma - Low-dose immunotherapy based on the results of KEYNOTE-048 clinical studies, pembrolizumab or pembrolizumab combined with chemotherapy has become the standard treatment mode for recurrent metastatic head and neck squamous cell carcinoma [12], but the high cost of PD-1 inhibitors makes immunotherapy
impossible for many patients.
A randomized controlled phase 3 clinical trial conducted by an Indian team found that low-dose nivolumab in combination with beating chemotherapy also significantly improved efficacy [13].
A total of 151 patients with recurrent metastatic head and neck squamous cell carcinoma were randomized to a control group (75 patients; methotrexate + celecoxib + erlotinib) and the experimental group (76 cases); The experimental group was combined with low-dose nivolumab (20 mg once every 3 weeks)
in addition to the control group.
The median follow-up was 10.
9 months
.
The results showed that low-dose nivolumab significantly improved one-year overall survival (43.
4% vs.
16.
3%), while grade 3 or higher adverse effects were comparable in both groups (46.
1% vs.
50%)
.
Although this study does not prove that the efficacy of low-dose nivolumab is not worse than that of standard doses, it has an important hint for reducing the cost of treatment for patients and reducing the social medical burden
.
Figure 6 Overall survival between experimental and control groups[13].
Figure 7 Progression-free survival in experimental and control groups[13].
References
1.
Bray F, Ferlay J, Soerjomataram I, et al.
Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.
CA Cancer J Clin 2018; 68:394-424.
2.
Chen W, Zheng R, Baade PD, et al.
Cancer statistics in China, 2015.
CA Cancer J Clin 2016; 66:115-32.
3.
Tang LL, Guo R, Zhang N, et al.
Effect of radiotherapy alone vs radiotherapy with concurrent chemoradiotherapy on survival without disease relapse in patients with low-risk nasopharyngeal carcinoma: A randomized clinical trial.
JAMA 2022; 328:728-36.
4.
Li XY, Luo DH, Guo L, et al.
Deintensified chemoradiotherapy for pretreatment epstein-barr virus DNA-selected low-risk locoregionally advanced nasopharyngeal carcinoma: A phase II randomized noninferiority trial.
J Clin Oncol 2022; 40:1163-73.
5.
Tang LL, Huang CL, Zhang N, et al.
Elective upper-neck versus whole-neck irradiation of the uninvolved neck in patients with nasopharyngeal carcinoma: an open-label, non-inferiority, multicentre, randomised phase 3 trial.
Lancet Oncol 2022; 23:479-90.
6.
Mao YP, Wang SX, Gao T, et al.
Sparing irradiation versus conventional irradiation to the medial retropharyngeal space in patients with nasopharyngeal carcinoma:an open-label, non-inferiority, multicentre, randomised phase III trial.
2022 ASTRO Abstract.
7.
Mai HQ, Guo SS, Sun XS, et al.
Reduced-dose radiotherapy for pretreatment EBV DNA selected low-risk stage III nasopharyngeal carcinoma: A single-arm, phase II trial.
2022 ASCO Abstract :6002.
8.
Ferris RL, Flamand Y, Weinstein GS, et al.
Phase II randomized trial of transoral surgery and low-dose intensity modulated radiation therapy in resectable p16+ locally advanced oropharynx cancer: An ECOG-ACRIN Cancer Research Group Trial (E3311).
J Clin Oncol 2022; 40:138-49.
9.
Kiyota N, Tahara M, Mizusawa J, et al.
Weekly cisplatin plus radiation for postoperative head and neck cancer (JCOG1008): A multicenter, noninferiority, phase II/III randomized controlled trial.
J Clin Oncol 2022; 40:1980-90.
10.
Xia WX, Lv X, Liang H, et al.
A randomized controlled trial comparing two different schedules for cisplatin treatment in patients with locoregionally advanced nasopharyngeal cancer.
Clin Cancer Res 2021; 27:4186-94
11.
Machiels JP, Tao J, Burtness B, et al.
LBA5 - Primary results of the phase III KEYNOTE-412 study: Pembrolizumab (pembro) with chemoradiation therapy (CRT) vs placebo plus CRT for locally advanced (LA) head and neck squamous cell carcinoma (HNSCC).
2022 ESMO Annual Meeting Abstract: 6530
12.
Burtness B, Harrington KJ, Greil R, et al.
Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE- 048): a randomised, open-label, phase 3 study.
Lancet 2019; 394:1915- 28.
13.
Patil VM; Noronha V; Menon N, et al.
Low-dose immunotherapy in head and neck cancer: a randomized study.
J Clin Oncol 2022; JCO2201015.
Introduction by experts
of the Cancer Center of Sun Yat-sen University.
He has won the honorary titles of leading talent of the "10,000 Talents Program" of the Organization Department of the CPC Central Committee, national expert of the 100 million talents project, and young and middle-aged experts with outstanding contributions from the Ministry of Health
.
He served as the convener of the special medical review group of the Academic Degree Committee of the State Council, the first chairman of the CSCO Nasopharyngeal Cancer Expert Committee, the chairman-elect of the Nasopharyngeal Cancer Professional Committee of the Chinese Anti-Cancer Association, and the standing member of the Radiation Oncology Branch of the Chinese Medical Association
.
He specializes in the comprehensive diagnosis and treatment of nasopharyngeal carcinoma, and his results have rewritten 11 international diagnosis and treatment guidelines and published in journals such as NEJM, Lancet, and BMJ
.
He has won 2 key projects of the National Natural Science Foundation of China, led the team to be selected into the innovation team of the Ministry of Education and the innovation team of the key field of the Ministry of Science and Technology, won 2 second prizes of the National Science and Technology Progress Award as the first completer, and won the top ten scientific and technological progress of Chinese colleges and universities and the first prize of Chinese medical science and technology for many times
.
Yuan Zhang, M.
D.
, is an associate researcher/attending physician of the Department of Radiotherapy, Sun Yat-sen University Cancer Hospital, and a master supervisor
.
He is engaged in research
related to induction chemotherapy for nasopharyngeal cancer.
The research results were published as the first author in the New England Journal of Medicine and JAMA Oncology, which ranked first in clinical medicine, and two research results were adopted by the world's authoritative NCCN guidelines for cancer treatment, defining induction chemotherapy as the standard treatment
for locally advanced nasopharyngeal cancer.
He presided over a number of funds such as the 2020 National Natural Science Foundation of China Youth Program, and as a key member, he won the 2019 Top Ten Progress in Life Science in China and the Top Ten Scientific and Technological Progress
in Colleges and Universities.
Dong Zhe is a doctoral student
at the Cancer Center of Sun Yat-sen University.
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