Head and neck nasopharynx definitive EBRT chemoradiation

Acute: Short term side effects during or within a few weeks post radiation therapy (usually temporary)
Skin reaction/dermatitis	Including itch, erythema, dry or moist desquamation. Read more about skin reactions.
Mucositis	Read more about mucositis.
Fatigue	Read more about fatigue.
Xerostomia	Read more about salivary gland dysfunction - xerostomia and/or hyposalivation (radiation induced).
Odynophagia
Dysgeusia	Read more about taste alteration.
Dysphagia
Ocular or periocular toxicity	Including keratitis sicca (dry eye syndrome), lacrimal duct stenosis/epiphora, corneal ulceration.
Anorexia	Loss of appetite and/or desire to eat. Read more about anorexia.
Alopecia	Read more about alopecia.

Late: Long term side effects - months to years post radiation therapy (may be permanent)
Skin changes	Including telangiectasia, atrophy and changes to skin pigmentation.
Fatigue	Read more about fatigue.
Xerostomia	Read more about salivary gland dysfunction - xerostomia and/or hyposalivation (radiation induced).
Dental caries	Read more about radiation induced oral complications.
Dysphagia	Including long-term feeding tube.
Dysgeusia	Read more about taste alteration
Trismus
Lymphoedema	Read more about lymphoedema.
Carotid atherosclerosis
Endocrine dysfunction
Soft tissue fibrosis and necrosis
Myelopathy/neuropathy	Read more about chronic progressive radiation myelopathy.
Cranial nerve palsy
Osteoradionecrosis of the jaw/skull base	Read more about osteoradionecrosis
Second malignancy
Alopecia	Read more about alopecia.
Cataract formation and blindness	Unilateral or bilateral.
Eustachian tube dysfunction
Hearing loss/ototoxicity	Includes vestibular changes, sensorineural and conductive hearing loss.
Brain/brainstem injury	Including neurocognitive effects. Brain stem and temporal lobe necrosis.

Source	Study and year published	Supports use Yes/No/NA	Is the radiation dose and fractionation consistent with the protocol	Comments
Meta analysis	Baujat et al. 200640	Yes	Yes	Absolute survival benefit of 4% at 2 years (from 77% to 81%) and 6% at 5 years (from 56% to 62%) for chemoradiation therapy (CRT) vs radiation therapy (RT) alone.
	Blanchard et al. 202241	Yes	Yes	Update of the MAC-NPC meta-analysis. Addition of chemotherapy reduced the risk of death, with a hazard ratio (HR) of 0.79 [95% confidence interval (CI): 0.73-0.85], and an absolute survival increase at 5 and 10 years of 6.1% (+3.9; +8.3) and + 8.4% (+5.7; +11.1), respectively.
	Langdenijik et al. 200442	Yes	Yes	Ten randomised control trials (RCT) included (n = 2450). Absolute survival benefit of 4% after 5 years for CRT vs RT alone.
	Ribassin-Majed et al. 201743	Yes	Yes	Addition of either induction or adjuvant chemotherapy to concomitant CRT reduces recurrence rates.
Phase III trials	Al-Sarraf et al. 1998 (Intergroup 0099)44	Yes	Yes	CRT found to be superior to RT alone. 3-year progression free survival (PFS) rate was 24% for RT alone versus 69% for CRT (p<.001). 3-year survival rate was 46% for RT alone and 76% for CRT (p<.001).
	Peng et al. 201245	Yes	Yes	Intensity-modulated RT (IMRT) versus 2D-CRT was associated with improved overall survival (OS) (five-year OS 79.6% versus 67.1%) and decreased toxicity.
	Chen et al. 201146	Yes	Yes
	Lee et al. 2017 (RTOG 0225)47	Yes	Yes
	Zhang et al. 202248	Yes	Yes	Induction chemotherapy group had a significantly higher 5-year OS (87.9% versus 78.8%, HR 0.51, 95% CI:0.34-0.78, p = .001) and a comparable risk of late toxicities (≥ grade 3, 11.3% versus 11.4%).
Guidelines	Date published/revised	Supports use	Is the dose and regimen consistent with the protocol?	Comments
NCCN	V.1.202349	Yes	Yes
ESMO-EURACAN	202150	Yes	Yes
CSCO	202151	Yes	Yes 70 Gy (GTV) 60 Gy (medium/intermediate risk) 50 Gy (low risk/elective sites)
CSCO/ASCO	20215	Yes	Yes

1

Peters, L. J., B. O'Sullivan, J. Giralt, et al. 2010. "Critical impact of radiotherapy protocol compliance and quality in the treatment of advanced head and neck cancer: results from TROG 02.02." J Clin Oncol 28(18):2996-3001.

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PURPOSE: To report the impact of radiotherapy quality on outcome in a large international phase III trial evaluating radiotherapy with concurrent cisplatin plus tirapazamine for advanced head and neck cancer. PATIENTS AND METHODS: The protocol required interventional review of radiotherapy plans by the Quality Assurance Review Center (QARC). All plans and radiotherapy documentation underwent post-treatment review by the Trial Management Committee (TMC) for protocol compliance. Secondary review of noncompliant plans for predicted impact on tumor control was performed. Factors associated with poor protocol compliance were studied, and outcome data were analyzed in relation to protocol compliance and radiotherapy quality. RESULTS: At TMC review, 25.4% of the patients had noncompliant plans but none in which QARC-recommended changes had been made. At secondary review, 47% of noncompliant plans (12% overall) had deficiencies with a predicted major adverse impact on tumor control. Major deficiencies were unrelated to tumor subsite or to T or N stage (if N+), but were highly correlated with number of patients enrolled at the treatment center (< five patients, 29.8%; > or = 20 patients, 5.4%; P < .001). In patients who received at least 60 Gy, those with major deficiencies in their treatment plans (n = 87) had a markedly inferior outcome compared with those whose treatment was initially protocol compliant (n = 502): -2 years overall survival, 50% v 70%; hazard ratio (HR), 1.99; P < .001; and 2 years freedom from locoregional failure, 54% v 78%; HR, 2.37; P < .001, respectively. CONCLUSION: These results demonstrate the critical importance of radiotherapy quality on outcome of chemoradiotherapy in head and neck cancer. Centers treating only a few patients are the major source of quality problems.

2

Kyaw, J. Y. A., A. Rendall, E. F. Gillespie, et al. 2023. "Systematic Review and Meta-analysis of the Association Between Radiation Therapy Treatment Volume and Patient Outcomes." Int J Radiat Oncol Biol Phys.

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Purpose

Evidence of a volume–outcome association in cancer surgery has shaped the centralization of cancer services; however, it is unknown whether a similar association exists for radiation therapy. The objective of this study was to determine the association between radiation therapy treatment volume and patient outcomes.

Methods and Materials

This systematic review and meta-analysis included studies that compared outcomes of patients who underwent definitive radiation therapy at high-volume radiation therapy facilities (HVRFs) versus low-volume facilities (LVRFs). The systematic review used Ovid MEDLINE and Embase. For the meta-analysis, a random effects model was used. Absolute effects and hazard ratios (HRs) were used to compare patient outcomes.

Results

The search identified 20 studies assessing the association between radiation therapy volume and patient outcomes. Seven of the studies looked at head and neck cancers (HNCs). The remaining studies covered cervical (4), prostate (4), bladder (3), lung (2), anal (2), esophageal (1), brain (2), liver (1), and pancreatic cancer (1). The meta-analysis demonstrated that HVRFs were associated with a lower chance of death compared with LVRFs (pooled HR, 0.90; 95% CI, 0.87- 0.94). HNCs had the strongest evidence of a volume–outcome association for both nasopharyngeal cancer (pooled HR, 0.74; 95% CI, 0.62-0.89) and nonnasopharyngeal HNC subsites (pooled HR, 0.80; 95% CI, 0.75-0.84), followed by prostate cancer (pooled HR, 0.92; 95% CI, 0.86-0.98). The remaining cancer types showed weak evidence of an association. The results also demonstrate that some centers defined as HVRFs are undertaking very few procedures per annum (<5 radiation therapy cases per year).

Conclusions

An association between radiation therapy treatment volume and patient outcomes exists for most cancer types. Centralization of radiation therapy services should be considered for cancer types with the strongest volume–outcome association, but the effect on equitable access to services needs to be explicitly considered.

3

Teitelbaum, J. I., K. Issa, I. R. Barak, et al. 2020. "Sinonasal Squamous Cell Carcinoma Outcomes: Does Treatment at a High-Volume Center Confer Survival Benefit?" Otolaryngol Head Neck Surg 163(5):986-991.

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Abstract

Objective

To determine whether treatment of sinonasal squamous cell carcinoma (SCC) at a high-volume facility affects survival.

Study Design

Retrospective database analysis.

Setting

National Cancer Database (2004-2014).

Subjects and Methods

The National Cancer Database was queried for sinonasal SCC from 2004 to 2014. Patient demographics, tumor characteristics and classification, resection margins, treatment regimen, and facility case-specific volume—averaged per year and grouped in tertiles as low (0%-33%), medium (34%-66%), and high (67%-100%)—were compared. Overall survival was compared with Cox proportional hazards regression analysis.

Results

A total of 3835 patients treated for sinonasal SCC between 2004 and 2014 were identified. Therapeutic options included surgery alone (18.6%), radiotherapy (RT) alone (29.1%), definitive chemoradiation (15.4%), surgery with adjuvant RT (22.8%), and combinations (14.1%) of the aforementioned treatments. Patients who underwent surgery with adjuvant RT had better overall survival (hazard ratio [HR], 0.74; P <. 001; 95% CI, 0.63-0.86). As for treatment volume per facility, 7.4% of patients were treated at a low-volume center, 17.5% at a medium-volume center, and 75.1% at a high-volume center. Univariate analysis showed that treatment at a high-volume facility conferred a significantly better overall survival (HR, 0.77; P =. 002). Multivariable Cox proportional hazards regression analysis, adjusting for age, sex, tumor classification, and treatment regimen, demonstrated that patients who underwent treatment at a high-volume facility (HR, 0.81; P <. 001) had significantly improved survival.

Conclusion

This study shows a better overall survival for sinonasal SCC treated at high-volume centers. Further study may be needed to understand the effect of case volume on the paradigms of sinonasal SCC management.

4

American Joint Commission on Cancer (AJCC). 2017. "Cancer Staging Handbook". 8th Edition. Springer, New York.

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5

Chen, Y. P., N. Ismaila, M. L. K. Chua, et al. 2021. "Chemotherapy in Combination With Radiotherapy for Definitive-Intent Treatment of Stage II-IVA Nasopharyngeal Carcinoma: CSCO and ASCO Guideline." J Clin Oncol 39(7):840-859.

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PURPOSE

The aim of this joint guideline is to provide evidence-based recommendations to practicing physicians and other healthcare providers on definitive-intent chemoradiotherapy for patients with stage II-IVA nasopharyngeal carcinoma (NPC).

METHODS

The Chinese Society of Clinical Oncology (CSCO) and ASCO convened an expert panel of radiation oncology, medical oncology, surgery, and advocacy representatives. The literature search included systematic reviews, meta-analyses, and randomized controlled trials published from 1990 through 2020. Outcomes of interest included survival, distant and locoregional disease control, and quality of life. Expert panel members used this evidence and informal consensus to develop evidence-based guideline recommendations.

RESULTS

The literature search identified 108 relevant studies to inform the evidence base for this guideline. Five overarching clinical questions were addressed, which included subquestions on radiotherapy (RT), chemotherapy sequence, and concurrent, induction, and adjuvant chemotherapy options.

RECOMMENDATIONS

Evidence-based recommendations were developed to address aspects of care related to chemotherapy in combination with RT for the definitive-intent treatment of stage II to IVA NPC.

6

Chan, A. T., V. Gregoire, J. L. Lefebvre, et al. 2012. "Nasopharyngeal cancer: EHNS-ESMO-ESTRO Clinical Practice Guidelines for diagnosis, treatment and follow-up." Ann Oncol 23 Suppl 7:vii83-85.

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7

Browman, G. P., G. Wong, I. Hodson, et al. 1993. "Influence of cigarette smoking on the efficacy of radiation therapy in head and neck cancer." N.Engl.J Med. 328(3):159-163.

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BACKGROUND. Smoking is a risk factor for several cancers and may also limit the efficacy of treatment. In this study, we evaluated the influence of cigarette smoking during radiation therapy on the efficacy of treatment in patients with head and neck cancer. METHODS. Using a questionnaire, we obtained information on smoking behavior at base line and weekly during therapy in 115 patients with head and neck cancer who were treated with radiation therapy with or without fluorouracil. The side effects of therapy were evaluated weekly, and response was assessed 13 weeks after treatment was completed. The main outcomes measured were treatment response and survival. RESULTS. The prognostic variables were similar among the patients who smoked and those who did not smoke during treatment. The 53 patients who continued to smoke during radiation therapy had a lower rate of complete response (45 percent vs. 74 percent, P = 0.008) and poorer two-year survival (39 percent vs. 66 percent, P = 0.005) than the 62 patients who did not smoke or who had quit before treatment. Among the nonsmoking patients, mortality was influenced by the length of time between quitting and treatment, with a risk reduction (relative to that for patients who continued to smoke) of 40 percent for patients who had quit less than 12 weeks before diagnosis and of 70 percent for patients who had quit more than 1 year before diagnosis. After adjustment for other variables with proportional-hazards regression analysis, smoking remained an independent prognostic factor (P = 0.002), with a relative risk of 2.5 (95 percent confidence interval, 1.4 to 4.4) favoring the patients who abstained from smoking. The results could not be explained by the type of chemotherapy received, the presence of coexisting morbid conditions, differences in the side effects of radiation, or the number of interruptions of treatment. CONCLUSIONS. Patients with head and neck cancer who continue to smoke during radiation therapy have lower rates of response and survival than patients who do not smoke during radiation therapy

8

Hendry, J. H., S. M. Bentzen, R. G. Dale, et al. 1996. "A modelled comparison of the effects of using different ways to compensate for missed treatment days in radiotherapy." Clin Oncol (R Coll Radiol) 8(5):297-307.

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There is much evidence for the detrimental effect on tumour control of missed treatment days during radiotherapy, amounting for example to approximately a 1.6% absolute decrease in local control probability per day of treatment prolongation in the case of head and neck squamous cell cancer. Various methods to compensate for missed treatment days are compared quantitatively in this article, using the linear-quadratic formalism. The overall time and fraction size can be maintained by either treating on weekend days (the preferred way (Method 1a), although with unsocial hours and at extra cost) or using two fractions per day to "catch up' (Method 1b). The latter might incur a small loss of tolerance regarding late reactions, when intervals of 6-8 h are used rather than 24 h, and there may be logistical/scheduling difficulties with larger numbers of patients in some centres when using this method. A second type of strategy retains overall treatment time, and also one fraction per day, but the size of the dose per fraction is increased. For example, this may be done for the same number of "post-gap' days as gap days (Method 2). However, with this method, calculated isoeffect doses regarding late reactions indicate a probable decrease in tumour control rate (Method 2a). Otherwise, isoeffective doses regarding tumour control result in an increase in late reactions (Method 2b). In addition, this method is unsuitable for short regimens already using high doses per fraction. To reduce this problem, overall treatment time can also be retained by using fewer fractions, all of greater size in the case of planned gaps (statutory holidays), or larger remaining fractions after unplanned gaps (Method 2c). The problem also with this method is that equivalence for tumour control gives an increase in late reactions. The least satisfactory strategy (Method 3) is to accept the protraction caused by the missed treatment days, and give either the same prescribed number of (slightly larger) fractions or the planned treatment followed by one (or more) extra fraction to compensate for the gap. This would retain the expected local control rate, but there would be an increase in late reactions. An example of this, using average parameter values, is that a 3-day gap (necessitating four extra days to complete treatment with one fraction of 2.4 Gy) might maintain a 70% local control rate for glottic carcinoma, but severe reactions might rise from 1% to 4% and minor/moderate reactions from 37% to 50%. In this example, the inclusion of an extra weekend would increase the required extra dose and hence may further increase the morbidity rates. A final point is that the effect of treatment interruptions for an individual patient is expected to be greater than that for a group of patients because of interpatient heterogeneity tending to flatten dose-response curves. Calculations show that the above value of 1.6% loss of local control per day for a group of patients may reflect values for individual patients that range around a median value of as much as 5% per day, so stressing further the importance of gaps in treatment. It is concluded that, wherever possible, treatment days should not be missed. If they are missed, it is important to compensate for them, preferably by one of the first of the above methods (1a or 1b), in order to keep as close as possible to the original/standard prescription in terms of total dose, dose per fraction and overall time.

9

Hua, Y. J., Y. F. Ou-Yang, X. Zou, et al. 2021. "The Effect of Prolonged Duration of Intensity Modulated Radiotherapy for Nasopharyngeal Carcinoma." Front Oncol 11:648637.

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Abstract

Purpose: Radiotherapy is the most important primary treatment for patients with nasopharyngeal carcinoma. Generally, the treatment duration of radiotherapy takes six or six and half weeks with 30 to 33 fractions. The current study was conducted to evaluate the association between prognosis and the duration of radiotherapy in nasopharyngeal carcinoma patients.

Methods: Patients with primary nasopharyngeal carcinoma who were treated with intensity-modulated radiotherapy and concurrent cisplatin-based chemotherapy, with or without induction chemotherapy between January, 2008 and December, 2013 at a single institution were retrospectively reviewed.

Results: In total, 1292 patients were included. At a median follow-up of 71.0 months (range 2.0-126.0 months), locoregional recurrence, distant failure and death were observed in 8.8%, 12.2% and 15.6% of all patients, respectively. Estimated 5-year locoregional relapse-free survival, distant metastasis-free survival, progression-free survival and overall survival in patients with radiation ≤ 7 weeks versus patients with radiation >7 weeks were: 93.2% versus 87.0% (P < 0.001), 89.4% versus 84.4% (P = 0.016), 79.8% versus 70.6% (P < 0.001) and 87.2% versus 78.4% (P < 0.001), respectively.

Conclusions: Prolonged duration of radiotherapy with a significantly higher risk of distant metastasis and death in nasopharyngeal carcinoma patients. Understanding this point, healthcare providers should make efforts to avoid prolonged duration of radiotherapy to minimize the risk of treatment failure.

Keywords: chemotherapy; duration; intensity-modulated radiotherapy; nasopharyngeal carcinoma; prognosis; radiation.

10

Lee, A. W., W. T. Ng, J. J. Pan, et al. 2019. "International Guideline on Dose Prioritization and Acceptance Criteria in Radiation Therapy Planning for Nasopharyngeal Carcinoma." Int J Radiat Oncol Biol Phys 105(3):567-580.

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Abstract

Purpose: The treatment of nasopharyngeal carcinoma requires high radiation doses. The balance of the risks of local recurrence owing to inadequate tumor coverage versus the potential damage to the adjacent organs at risk (OARs) is of critical importance. With advancements in technology, high target conformality is possible. Nonetheless, to achieve the best possible dose distribution, optimal setting of dose targets and dose prioritization for tumor volumes and various OARs is fundamental. Radiation doses should always be guided by the As Low As Reasonably Practicable principle. There are marked variations in practice. This study aimed to develop a guideline to serve as a global practical reference.

Methods and materials: A literature search on dose tolerances and normal-tissue complications after treatment for nasopharyngeal carcinoma was conducted. In addition, published guidelines and protocols on dose prioritization and constraints were reviewed. A text document and preliminary set of variants was circulated to a panel of international experts with publications or extensive experience in the field. An anonymized voting process was conducted to rank the proposed variants. A summary of the initial voting and different opinions expressed by members were then recirculated to the whole panel for review and reconsideration. Based on the comments of the panel, a refined second proposal was recirculated to the same panel. The current guideline was based on majority voting after repeated iteration for final agreement.

Results: Variation in opinion among international experts was repeatedly iterated to develop a guideline describing appropriate dose prioritization and constraints. The percentage of final agreement on the recommended parameters and alternative views is shown. The rationale for the recommendations and the limitations of current evidence are discussed.

Conclusions: Through this comprehensive review of available evidence and interactive exchange of vast experience by international experts, a guideline was developed to provide a practical reference for setting dose prioritization and acceptance criteria for tumor volumes and OARs. The final decision on the treatment prescription should be based on the individual clinical situation and the patient's acceptance of optimal balance of risk.

Copyright © 2019 Elsevier Inc. All rights reserved.

11

Tang, L. L., R. Guo, N. Zhang, et al. 2022. "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 328(8):728-736.

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Abstract

Importance  Concurrent chemoradiotherapy has been the standard treatment for stage II nasopharyngeal carcinoma (NPC) based on data using 2-dimensional conventional radiotherapy. There is limited evidence for the role of chemotherapy with use of intensity-modulated radiation therapy (IMRT).

Objective  To assess whether concurrent chemotherapy can be safely omitted for patients with low-risk stage II/T3N0 NPC treated with IMRT.

Design, Setting, and Participants  This multicenter, open-label, randomized, phase 3, noninferiority clinical trial was conducted at 5 Chinese hospitals, including 341 adult patients with low-risk NPC, defined as stage II/T3N0M0 without adverse features (all nodes <3 cm, no level IV/Vb nodes; no extranodal extension; Epstein-Barr virus DNA <4000 copies/mL), with enrollment between November 2015 and August 2020. The final date of follow-up was March 15, 2022.

Interventions  Patients were randomly assigned to receive IMRT alone (n = 172) or concurrent chemoradiotherapy (IMRT with cisplatin, 100 mg/m² every 3 weeks for 3 cycles [n = 169]).

Main Outcomes and Measures  The primary end point was 3-year failure-free survival (time from randomization to any disease relapse or death), with a noninferiority margin of 10%. Secondary end points comprised overall survival, locoregional relapse-free survival, distant metastasis-free survival, adverse events, and health-related quality of life (QOL) measured by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (QLQ-C30; range, 0-100 points; minimum clinically important difference ≥10 for physical function, symptom control, or health-related QOL; higher score indicates better functioning and global health status or worse symptoms).

Results  Among 341 randomized patients (mean [SD] age, 48 [10] years; 30% women), 334 (98.0%) completed the trial. Median follow-up was 46 months (IQR, 34-58). Three-year failure-free survival was 90.5% for the IMRT-alone group vs 91.9% for the concurrent chemoradiotherapy group (difference, −1.4%; 1-sided 95% CI, −7.4% to ∞; P value for noninferiority, <.001). No significant differences were observed between groups in overall survival, locoregional relapse, or distant metastasis. The IMRT-alone group experienced a significantly lower incidence of grade 3 to 4 adverse events (17% vs 46%; difference, −29% [95% CI, −39% to −20%]), including hematologic toxicities (leukopenia, neutropenia) and nonhematologic toxicities (nausea, vomiting, anorexia, weight loss, mucositis). The IMRT-alone group had significantly better QOL scores during radiotherapy including the domains of global health status, social functioning, fatigue, nausea and vomiting, pain, insomnia, appetite loss, and constipation.

Conclusions and Relevance  Among patients with low-risk NPC, treatment with IMRT alone resulted in 3-year failure-free survival that was not inferior to concurrent chemoradiotherapy.

12

Gregoire, V., M. Evans, Q. T. Le, et al. 2018. "Delineation of the primary tumour Clinical Target Volumes (CTV-P) in laryngeal, hypopharyngeal, oropharyngeal and oral cavity squamous cell carcinoma: AIRO, CACA, DAHANCA, EORTC, GEORCC, GORTEC, HKNPCSG, HNCIG, IAG-KHT, LPRHHT, NCIC CTG, NCRI, NRG Oncology, PHNS, SBRT, SOMERA, SRO, SSHNO, TROG consensus guidelines." Radiother Oncol 126(1):3-24.

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PURPOSE: Few studies have reported large inter-observer variations in target volume selection and delineation in patients treated with radiotherapy for head and neck squamous cell carcinoma. Consensus guidelines have been published for the neck nodes (see Gregoire et al., 2003, 2014), but such recommendations are lacking for primary tumour delineation. For the latter, two main schools of thoughts are prevailing, one based on geometric expansion of the Gross Tumour Volume (GTV) as promoted by DAHANCA, and the other one based on anatomical expansion of the GTV using compartmentalization of head and neck anatomy. METHOD: For each anatomic location within the larynx, hypopharynx, oropharynx and oral cavity, and for each T-stage, the DAHANCA proposal has been comprehensively reviewed and edited to include anatomic knowledge into the geometric Clinical Target Volume (CTV) delineation concept. A first proposal was put forward by the leading authors of this publication (VG and CG) and discussed with opinion leaders in head and neck radiation oncology from Europe, Asia, Australia/New Zealand, North America and South America to reach a worldwide consensus. RESULTS: This consensus proposes two CTVs for the primary tumour, the so called CTV-P1 and CVT-P2, corresponding to a high and lower tumour burden, and which should be associated with a high and a lower dose prescription, respectively. CONCLUSION: Implementation of these guidelines in the daily practice of radiation oncology should contribute to reduce treatment variations from clinicians to clinicians, facilitate the conduct of multi-institutional clinical trials, and contribute to improved care of patients with head and neck carcinoma.

13

Lee, A.W., W.T. Ng, J.J. Pan, et al. 2018. "International guideline for the delineation of the clinical target volumes (CTV) for nasopharyngeal carcinoma." Radiotherapy and Oncology 126(1):25-36.

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Purpose: Target delineation in nasopharyngeal carcinoma (NPC) often proves challenging because of the notoriously narrow therapeutic margin. High doses are needed to achieve optimal levels of tumour control, and dosimetric inadequacy remains one of the most important independent factors affecting treatment outcome.
Method: A review of the available literature addressing the natural behaviour of NPC and correlation between clinical and pathological aspects of the disease was conducted. Existing international guidelines as well as published protocols specified by clinical trials on contouring of clinical target volumes (CTV) were compared. This information was then summarized into a preliminary draft guideline which was then circulated to international experts in the field for exchange of opinions and subsequent voting on areas with the greatest controversies.
Results: Common areas of uncertainty and variation in practices among experts experienced in radiation therapy for NPC were elucidated. Iterative revisions were made based on extensive discussion and final voting on controversial areas by the expert panel, to formulate the recommendations on contouring of CTV based on optimal geometric expansion and anatomical editing for those structures with substantial risk of microscopic infiltration.
Conclusion: Through this comprehensive review of available evidence and best practices at major institutions, as well as interactive exchange of vast experience by international experts, this set of consensus guidelines has been developed to provide a practical reference for appropriate contouring to ensure optimal target coverage. However, the final decision on the treatment volumes should be based on full consideration of individual patients’ factors and facilities of an individual centre (including the quality of imaging methods and the precision of treatment delivery).

14

Biau, J., M. Lapeyre, I. Troussier, et al. 2019. "Selection of lymph node target volumes for definitive head and neck radiation therapy: a 2019 Update." Radiother Oncol 134:1-9.

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Highlights

• Updated proposal for the selection of nodal target volumes in definitive radiotherapy is provided.
• Recommendations for both negative and positive neck are provided.
• The locations addressed are: oral cavity, oropharynx, hypopharynx, larynx, nasopharynx, paranasal sinuses, nasal cavity and carcinoma of unknown primary.
• Recommendations are according to the latest neck node level terminology and staging.

Abstract

Background and purpose: In 2000, a panel of experts published a proposal for the selection of lymph node target volumes for definitive head and neck radiation therapy (Radiother Oncol, 2000; 56: 135-150). Hereunder, this selection is updated and extended to also cover primary sites not previously covered.

Patients and methods: The lymphatic spread of head and neck cancers into neck lymph nodes was comprehensively reviewed based on radiological, surgical and pathological literature regarding both initial involvement and patterns of failure. Then a panel of worldwide head and neck radiotherapy experts agreed on a consensus for the selection of both high- and low-risk lymph node target volumes for the node negative and the node positive neck.

Results: An updated selection of lymph node target volumes is reported for oral cavity, oropharynx, hypopharynx, larynx, nasopharynx, paranasal sinuses, nasal cavity and carcinoma of unknown primary as a function of the nodal staging (UICC 8th edition).

Conclusions: The selection of lymph node target volumes for head and neck cancers treated with IMRT/VMAT or other highly conformal techniques (e.g. proton therapy) requires a rigorous approach. This updated proposal of selection should help clinicians for the selection of lymph nodes target volumes and contribute to increase consistency.

15

Gregoire, V., K. Ang, W. Budach, et al. 2014. "Delineation of the neck node levels for head and neck tumors: a 2013 update. DAHANCA, EORTC, HKNPCSG, NCIC CTG, NCRI, RTOG, TROG consensus guidelines." Radiother Oncol 110(1):172-181.

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In 2003, a panel of experts published a set of consensus guidelines for the delineation of the neck node levels in node negative patients (Radiother Oncol, 69: 227-36, 2003). In 2006, these guidelines were extended to include the characteristics of the node positive and the post-operative neck (Radiother Oncol, 79: 15-20, 2006). These guidelines did not fully address all nodal regions and some of the anatomic descriptions were ambiguous, thereby limiting consistent use of the recommendations. In this framework, a task force comprising opinion leaders in the field of head and neck radiation oncology from European, Asian, Australia/New Zealand and North American clinical research organizations was formed to review and update the previously published guidelines on nodal level delineation. Based on the nomenclature proposed by the American Head and Neck Society and the American Academy of Otolaryngology-Head and Neck Surgery, and in alignment with the TNM atlas for lymph nodes in the neck, 10 node groups (some being divided into several levels) were defined with a concise description of their main anatomic boundaries, the normal structures juxtaposed to these nodes, and the main tumor sites at risk for harboring metastases in those levels. Emphasis was placed on those levels not adequately considered previously (or not addressed at all); these included the lower neck (e.g. supraclavicular nodes), the scalp (e.g. retroauricular and occipital nodes), and the face (e.g. buccal and parotid nodes). Lastly, peculiarities pertaining to the node-positive and the post-operative clinical scenarios were also discussed. In conclusion, implementation of these guidelines in the daily practice of radiation oncology should contribute to the reduction of treatment variations from clinician to clinician and facilitate the conduct of multi-institutional clinical trials.

16

Ko, H. C., V. Gupta, W. F. Mourad, et al. 2014. "A contouring guide for head and neck cancers with perineural invasion." Pract Radiat Oncol 4(6):e247-258.

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PURPOSE: Perineural invasion (PNI) is a frequent pathological finding in head and neck cancers. When adjuvant radiation to cranial nerves at risk in head and neck cancers with PNI is considered, there is a need for consensus on which nerves are at risk and how to contour these nerves. This contouring guide attempts to address this need. METHODS AND MATERIALS: Representative patient diagnostic computed tomographic (CT) scans with contrast of the neck were used to create example contours. The cranial nerves V2, V3, VII, and XII, and sample primary tumor sites were initially delineated using the Varian Eclipse planning system by 5 radiation oncologists. All of the images were then reviewed with a diagnostic radiologist to establish consensus for delineating the cranial nerves. RESULTS: We provided detailed contouring and planning guidelines on a CT atlas, with figures to help illustrate internerve connections, based on clinical experience, literature-based patterns of failure, and established anatomic connections between cranial nerves. Tumor bed, cranial nerve, and elective target volumes are depicted. CONCLUSIONS: These planning guidelines and atlas provide anatomic, clinical, and technical recommendations for guiding radiation oncologists in the planning and delivery of intensity modulated radiation therapy for head and neck cancer with PNI.

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Biau, J., V. Dunet, M. Lapeyre, et al. 2019. "Practical clinical guidelines for contouring the trigeminal nerve (V) and its branches in head and neck cancers." Radiother Oncol 131:192-201.

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PURPOSE: The trigeminal nerve (V) is a major route of tumor spread in several head and neck cancers. However, only limited data are currently available for its precise contouring, although this is absolutely necessary in the era of intensity-modulated radiation therapy (IMRT). The purpose of this article is to present practical clinical guidelines for contouring the trigeminal nerve (V) in head and neck cancers at risk of spread along this nerve. METHOD: The main types of head and neck cancers associated with risks of spread along the trigeminal nerve (V) and its branches were comprehensively reviewed based on clinical experience, literature-based patterns of failure, anatomy and radio-anatomy. A consensus for contouring was proposed based on a multidisciplinary approach among head and neck oncology experts including radiation oncologists (JBi, ML, MO, VG and JB), a radiologist (VD) and a surgeon (CS). These practical clinical guidelines have been endorsed by the GORTEC (Head and Neck Radiation Oncology Group). RESULTS: We provided contouring and treatment guidelines, supported by detailed figures and tables to help, for the trigeminal nerve and its branches: the ophthalmic nerve (V1), the maxillary nerve (V2) and the manidibular nerve (V3). A CT- and MRI-based atlas was proposed to illustrate the whole trigeminal nerve pathway with its main branches. CONCLUSION: Trigeminal nerve (V) invasion is an important component of the natural history of various head and neck cancers. Recognizing the radio-anatomy and potential routes of invasion is essential for optimal contouring, as presented in these guidelines.

18

Mayo, C., E. Yorke and T. E. Merchant. 2010. "Radiation associated brainstem injury." Int J Radiat Oncol Biol Phys 76(3 Suppl):S36-41.

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Publications relating brainstem radiation toxicity to quantitative dose and dose-volume measures derived from three-dimensional treatment planning were reviewed. Despite the clinical importance of brainstem toxicity, most studies reporting brainstem effects after irradiation have fewer than 100 patients. There is limited evidence relating toxicity to small volumes receiving doses above 60-64 Gy using conventional fractionation and no definitive criteria regarding more subtle dose-volume effects or effects after hypofractionated treatment. On the basis of the available data, the entire brainstem may be treated to 54 Gy using conventional fractionation using photons with limited risk of severe or permanent neurological effects. Smaller volumes of the brainstem (1-10 mL) may be irradiated to maximum doses of 59 Gy for dose fractions 64 Gy.

19

Toledano, I., P. Graff, A. Serre et al. 2012. "Intensity-modulated radiotherapy in head and neck cancer: Results of the prospective study GORTEC 2004–03." Radiotherapy and Oncology 103:57-62.

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Background and purpose: In 2003, the French Authority for Health (HAS) recommended the use of intensity modulated radiotherapy (IMRT) in prospective trial before its routine use. The Oncology and Radiotherapy Group for Head and Neck Cancer (GORTEC) proposed to evaluate prospectively acute and late toxicities, locoregional control and overall survival for patients treated for head and neck cancer (HNC) with IMRT and bilateral neck irradiation.
Materials and methods: Between 2002 and 2008, 208 patients with HNC were treated with IMRT in 8 centres. There were 38 nasopharynx, 117 oropharynx, 25 pharyngo-larynx, 24 oral cavity and 4 unknown primary (28.5% stage I–II and 71% Stage III–IV). Ninety-three patients (46%) had postoperative IMRT and 78 patients (37.5%) received concurrent chemotherapy. The doses were 70 Gy to the gross tumour, 66 Gy to the high-risk postoperative sites and 50 Gy to the subclinical disease. Toxicities were graded according to the RTOG–EORTC scales. 
Results: The median follow-up was 25.3 months (range: 0.4–72 months). There were 29 local–regional failures: 24 were in-field, three were marginal and one was out-field. The two-year loco-regional control and overall survival were 86% and 86.7%, respectively. At 18 months, gradeP2 xerostomia was 16.1%. A mean dose to the spared parotid below 28 Gy led to significantly less grade P2 xerostomia (8.5% vs 24%) with a relative risk of 1.2 [95% CI: 1.02–1.41, p = 0.03]. GradeP2 xerostomia increased by approximately 3% per Gy of mean parotid dose up to 28, Gy then 7% per Gy above 33 Gy.
Conclusions: IMRT forHNcancer seems to reduce late toxicities without jeopardising local control and overall survival.

20

Emami, B. 2013. "Tolerance of normal tissue to therapeutic radiation." Reports of Radiotherapy and Oncology 1(1):35-48.

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21

Scoccianti, S., B. Detti, D. Gadda, et al. 2015. "Organs at risk in the brain and their dose-constraints in adults and in children: a radiation oncologist's guide for delineation in everyday practice." Radiother Oncol 114(2):230-238.

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PURPOSE: Accurate organs at risk definition is essential for radiation treatment of brain tumors. The aim of this study is to provide a stepwise and simplified contouring guide to delineate the OARs in the brain as it would be done in the everyday practice of planning radiotherapy for brain cancer treatment. METHODS: Anatomical descriptions and neuroimaging atlases of the brain were studied. The dosimetric constraints used in literature were reviewed. RESULTS: A Computed Tomography and Magnetic Resonance Imaging based detailed atlas was developed jointly by radiation oncologists, a neuroradiologist and a neurosurgeon. For each organ brief anatomical notion, main radiological reference points and useful considerations are provided. Recommended dose-constraints both for adult and pediatric patients were also provided. CONCLUSIONS: This report provides guidelines for OARs delineation and their dose-constraints for the treatment planning of patients with brain tumors.

22

Bhandare, N., A. Jackson, A. Eisbruch, et al. 2010. "Radiation therapy and hearing loss." Int J Radiat Oncol Biol Phys 76(3 Suppl):S50-57.

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A review of literature on the development of sensorineural hearing loss after high-dose radiation therapy for head-and-neck tumors and stereotactic radiosurgery or fractionated stereotactic radiotherapy for the treatment of vestibular schwannoma is presented. Because of the small volume of the cochlea a dose-volume analysis is not feasible. Instead, the current literature on the effect of the mean dose received by the cochlea and other treatment- and patient-related factors on outcome are evaluated. Based on the data, a specific threshold dose to cochlea for sensorineural hearing loss cannot be determined; therefore, dose-prescription limits are suggested. A standard for evaluating radiation therapy-associated ototoxicity as well as a detailed approach for scoring toxicity is presented.

23

RTOG 0615 (2006). Radiation Therapy Oncology Group (RTOG) trial protocol 0615: A Phase II Study of Concurrent Chemoradiotherapy Using Three-Dimensional Conformal Radiotherapy (3D-CRT) or Intensity-Modulated Radiation Therapy (IMRT) + Bevacizumab (BV) For Locally or Regionally Advanced Nasopharyngeal Cancer.

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24

Kubota, H., D. Miyawaki, N. Mukumoto, et al. 2021. "Risk factors for osteoradionecrosis of the jaw in patients with head and neck squamous cell carcinoma." Radiat Oncol 16(1):1.

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Abstract

Background

To evaluate factors associated with osteoradionecrosis of the jaw (ORNJ) in patients with head and neck squamous cell carcinoma (HNSCC), focusing on jaw-related dose–volume histogram (DVH) parameters.

Methods

We retrospectively reviewed the medical records of 616 patients with HNSCC treated with curative-intent or postoperative radiation therapy (RT) during 2008–2018. Patient-related (age, sex, history of smoking or alcohol use, diabetes mellitus, performance status, pre-RT dental evaluation, pre- or post-RT tooth extraction), tumor-related (primary tumor site, T-stage, nodal status), and treatment-related (pre-RT surgery, pre-RT mandible surgery, induction or concurrent chemotherapy, RT technique) variables and DVH parameters (relative volumes of the jaw exposed to doses of 10 Gy–70 Gy [V10–70]) were investigated and compared between patients with and without ORNJ. The Mann–Whitney U test was used to compare RT dose parameters. Univariate and multivariate Cox regression analyses were used to assess factors associated with ORNJ development. Kaplan–Meier analyses were performed for cumulative ORNJ incidence estimation.

Results

Forty-six patients (7.5%) developed ORNJ. The median follow-up duration was 40 (range 3–145) months. The median time to ORNJ development was 27 (range 2–127) months. DVH analysis revealed that V30–V70 values were significantly higher in patients with than in those without ORNJ. In univariate analyses, primary tumor site, pre-RT mandible surgery, post-RT tooth extraction, and V60 > 14% were identified as important factors. In multivariate analyses, V60 > 14% (p = 0.0065) and primary tumor site (p = 0.0059) remained significant. The 3-year cumulative ORNJ incidence rates were 2.5% and 8.6% in patients with V60 ≤ 14% and > 14%, respectively (p < 0.0001), and 9.3% and 1.4% in patients with oropharyngeal or oral cancer and other cancers, respectively (p < 0.0001).

Conclusions

V60 > 14% and oropharyngeal or oral cancer were found to be independent risk factors for ORNJ. These findings might be useful to minimize ORNJ incidence in HNSCC treated with curative RT.

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van Dijk, L. V., A. A. Abusaif, J. Rigert, et al. 2021. "Normal Tissue Complication Probability (NTCP) Prediction Model for Osteoradionecrosis of the Mandible in Patients With Head and Neck Cancer After Radiation Therapy: Large-Scale Observational Cohort." Int J Radiat Oncol Biol Phys 111(2):549-558.

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Abstract

Purpose:

Osteoradionecrosis (ORN) of the mandible represents a severe, debilitating complication of radiation therapy (RT) for head and neck cancer (HNC). At present, no normal tissue complication probability (NTCP) models for risk of ORN exist. The aim of this study was to develop a multivariable clinical/dose-based NTCP model for the prediction of ORN any grade (ORN_I-IV) and grade IV (ORN_IV) after RT (±chemotherapy) in patients with HNC.

Methods and Materials:

Included patients with HNC were treated with (chemo-)RT between 2005 and 2015. Mandible bone radiation dose-volume parameters and clinical variables (ie, age, sex, tumor site, pre-RT dental extractions, chemotherapy history, postoperative RT, and smoking status) were considered as potential predictors. The patient cohort was randomly divided into a training (70%) and independent test (30%) cohort. Bootstrapped forward variable selection was performed in the training cohort to select the predictors for the NTCP models. Final NTCP model(s) were validated on the holdback test subset.

Results:

Of 1259 included patients with HNC, 13.7% (n = 173 patients) developed any grade ORN (ORN_I-IV primary endpoint) and 5% (n = 65) ORN_IV (secondary endpoint). All dose and volume parameters of the mandible bone were significantly associated with the development of ORN in univariable models. Multivariable analyses identified D_30% and pre-RT dental extraction as independent predictors for both ORN_I-IV and ORN_IV best-performing NTCP models with an area under the curve (AUC) of 0.78 (AUC_validation = 0.75 [0.69–0.82]) and 0.81 (AUC_validation = 0.82 [0.74–0.89]), respectively.

Conclusions:

This study presented NTCP models based on mandible bone D_30% and pre-RT dental extraction that predict ORN_I-IV and ORN_IV (ie, needing invasive surgical intervention) after HNC RT. Our results suggest that less than 30% of the mandible should receive a dose of 35 Gy or more for an ORN_I-IV risk lower than 5%. These NTCP models can improve ORN prevention and management by identifying patients at risk of ORN.

26

Timmerman, R. 2022. "A Story of Hypofractionation and the Table on the Wall." Int J Radiat Oncol Biol Phys 112(1):4-21.

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No abstract available

27

Mayo, C., M. K. Martel, L. B. Marks, et al. 2010. "Radiation dose-volume effects of optic nerves and chiasm." Int J Radiat Oncol Biol Phys 76(3 Suppl):S28-35.

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Publications relating radiation toxicity of the optic nerves and chiasm to quantitative dose and dose-volume measures were reviewed. Few studies have adequate data for dose-volume outcome modeling. The risk of toxicity increased markedly at doses >60 Gy at approximately 1.8 Gy/fraction and at >12 Gy for single-fraction radiosurgery. The evidence is strong that radiation tolerance is increased with a reduction in the dose per fraction. Models of threshold tolerance were examined.

28

RTOG 0920 (2009). "Radiation Therapy Oncology Group (RTOG) trial protocol 0920: A Phase III Study of Postoperative Radiation Therapy (IMRT) +/- Cetuximab for Locally-Advanced Resected Head and Neck Cancer."

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29

Eisbruch, A., R. K. Ten Haken, H. M. Kim, et al. 1999. "Dose, volume, and function relationships in parotid salivary glands following conformal and intensity-modulated irradiation of head and neck cancer." Int J Radiat Oncol Biol Phys 45(3):577-587.

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PURPOSE: To determine the relationships between the three-dimensional dose distributions in parotid glands and their saliva production, and to find the doses and irradiated volumes that permit preservation of the salivary flow following irradiation (RT). METHODS AND MATERIALS: Eighty-eight patients with head and neck cancer irradiated with parotid-sparing conformal and multisegmental intensity modulation techniques between March 1994 and August 1997 participated in the study. The mean dose and the partial volumes receiving specified doses were determined for each gland from dose-volume histograms (DVHs). Nonstimulated and stimulated saliva flow rates were selectively measured from each parotid gland before RT and at 1, 3, 6, and 12 months after the completion of RT. The data were fit using a generalized linear model and the normal tissue complication probability (NTCP) model of Lyman-Kutcher. In the latter model, a "severe complication" was defined as salivary flow rate reduced to < or =25% pre-RT flow at 12 months. RESULTS: Saliva flow rates data were available for 152 parotid glands. Glands receiving a mean dose below or equal to a threshold (24 Gy for the unstimulated and 26 Gy for the stimulated saliva) showed substantial preservation of the flow rates following RT and continued to improve over time (to median 76% and 114% of pre-RT for the unstimulated and stimulated flow rates, respectively, at 12 months). In contrast, most glands receiving a mean dose higher than the threshold produced little saliva with no recovery over time. The output was not found to decrease as mean dose increased, as long as the threshold dose was not reached. Similarly, partial volume thresholds were found: 67%, 45%, and 24% gland volumes receiving more than 15 Gy, 30 Gy, and 45 Gy, respectively. The partial volume thresholds correlated highly with the mean dose and did not add significantly to a model predicting the saliva flow rate from the mean dose and the time since RT. The NTCP model parameters were found to be TD50 (the tolerance dose for 50% complications rate for whole organ irradiated uniformly) = 28.4 Gy, n (volume dependence parameter) = 1, and m (the slope of the dose/response relationship) = 0.18. Clinical factors including age, gender, pre-RT surgery, chemotherapy, and certain medical conditions were not found to be significantly associated with the salivary flow rates. Medications (diuretics, antidepressants, and narcotics) were found to adversely affect the unstimulated but not the stimulated flow rates. CONCLUSIONS: Dose/volume/function relationships in the parotid glands are characterized by dose and volume thresholds, steep dose/response relationships when the thresholds are reached, and a maximal volume dependence parameter in the NTCP model. A parotid gland mean dose of < or =26 Gy should be a planning goal if substantial sparing of the gland function is desired.

30

Moroney, L. B., J. Helios, E. C. Ward, et al. 2017. "Patterns of dysphagia and acute toxicities in patients with head and neck cancer undergoing helical IMRT+/-concurrent chemotherapy." Oral Oncol 64:1-8.

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BACKGROUND: There is limited prospective data reporting the extent of treatment related toxicities associated with helical Intensity Modulated Radiotherapy (H-IMRT) for head and neck cancer (HNC). The study aim was to investigate severity, peak incidence and recovery patterns of dysphagia and related toxicities in patients undergoing H-IMRT+/-chemotherapy to examine when patients are experiencing symptoms requiring supportive clinical care. METHODS: Prospective study of 212 patients undergoing H-IMRT. Dysphagia and associated acute toxicities were monitored weekly during treatment and at weeks 2, 4 and 12 post treatment using the CTCAE v4, Functional Oral Intake Score and National Dysphagia Diet Descriptors. RESULTS: 75% experienced Grade 2-3 dysphagia. Over 70% had grade 2-3 dysguesia, xerostomia, and thick saliva, and >50% experienced grade 2-3 pharyngeal mucositis, oral mucositis, and nausea. 13% patients declined to NBM requiring complete enteral nutrition, 25% required enteral nutrition but maintained some form of oral intake. Symptoms peaked in final week of treatment, consistently improving thereafter, with the majority better than baseline by 12 weeks post-treatment. Concurrent chemotherapy at least doubles the odds of experiencing most symptoms excepting xerostomia, taste and fluid level. CONCLUSION: Despite advancements in radiation techniques, results confirm a high proportion of HNC patients experience dysphagia and related toxicities requiring supportive care during H-IMRT. Patients receiving H-IMRT alone experience a lower incidence of symptoms compared with those receiving concurrent chemotherapy. The data confirms the ongoing need for active on treatment monitoring with implications for the timing and intensity of patient support services.

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Wopken, K., H. P. Bijl and J. A. Langendijk. 2018. "Prognostic factors for tube feeding dependence after curative (chemo-) radiation in head and neck cancer: A systematic review of literature." Radiother Oncol 126(1):56-67.

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BACKGROUND: Tube feeding dependence is a commonly observed debilitating side-effect of curative (chemo-) radiation in head and neck cancer patients that severely affects quality of life. Prevention of this side-effect can be obtained using advanced radiation techniques, such as IMRT. For radiotherapy treatment plan optimization, it has become increasingly important to develop prediction models that enable clinicians to predict the risk of tube feeding dependence for individual patients. To develop such a tool, information regarding the most relevant prognostic factors for tube feeding dependence is necessary. OBJECTIVES: The primary aim of this systematic review, conducted according to PRISMA guidelines, was to identify prognostic factors that are consistently found to be associated with tube feeding dependence at >/=6months after treatment. The secondary aim was to identify prognostic factors found to be associated with tube feeding placement and use at <6months. DATA SOURCES: Articles were identified through a search in MEDLINE, EMBASE and the Cochrane Library. Approximately 2600 articles were screened and selected by inclusion and exclusion criteria. RESULTS: Fourteen retrospective studies were identified that fulfilled the inclusion criteria and reported on prognostic factors for tube feeding dependence at >/=6months. The studies reported on patient and disease variables, treatment variables and DVH parameters. Two of these studies reported on a model for tube feeding dependence, one including DVH parameters. Additionally, 18 studies were identified that reported on prognostic factors for tube feeding placement and use at <6months. CONCLUSIONS: Prognostic factors that were consistently associated with the risk of tube feeding dependence at >/=6months for head and neck cancer patients treated with (chemo-) radiotherapy were DVH parameters, including dose to the larynx, the pharyngeal constrictor muscle inferior and superior, and the dose to the contralateral parotid gland. Furthermore, advanced tumor and nodal stage, pretreatment weight loss, (concomitant) chemotherapy and prophylactic gastrostomy policy were prognostic for tube feeding dependence >/=6months. For tube feeding use at less than 6months, prognostic DVH parameters included dose and volume to the oral mucosa, dose to the contralateral submandibular gland, and also dose to the larynx and the pharyngeal constrictor muscle inferior and superior. Prognostic patients/disease and treatment factors for tube feeding placement and use at less than 6months were similar to the prognostic factors for tube feeding dependence at >/=6months, but also included several unique variables such as the use of narcotics prior to treatment and living alone at the time of treatment.

32

Levendag, P. C., D. N. Teguh, P. Voet, et al. 2007. "Dysphagia disorders in patients with cancer of the oropharynx are significantly affected by the radiation therapy dose to the superior and middle constrictor muscle: a dose-effect relationship." Radiother Oncol 85(1):64-73.

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Abstract

Purpose/objective: To assess the relationship between the radiation therapy (RT) dose received by the muscular components of the swallowing (sw) apparatus and - dysphagia related - quality of life (QoL) in oropharyngeal cancer.

Materials/methods: Between 2000 and 2005, 81 patients with SCC of the oropharynx were treated by 3DCRT or IMRT, with or without concomitant chemotherapy (CHT); 43 out of these 81 patients were boosted by brachytherapy (BT). Charts of 81 patients were reviewed with regard to late dysphagia complaints; 23% experienced severe dysphagia. Seventeen patients expired. Fifty-six out of 64 (88%) responded to quality of life (QoL) questionnaires; that is, the Performance Status Scales of List, EORTC H&N35, and the M.D. Anderson Dysphagia Inventory. The superior (scm), middle (mcm), and inferior constrictor muscle (icm), the cricopharyngeus muscle and the inlet of the esophagus, are considered of paramount importance for swallowing. The mean dose was calculated in the muscular structures. Univariate analysis and multivariate analysis were performed using the proportional odds model.

Results: Mean follow-up was 18 months (range 2-34) for IMRT, and 46 months for 3DCRT (range 2-72). At 3-years, a LRC of 84%, DFS of 78% and OS of 77% were observed. A significant correlation was observed between the mean dose in the scm and mcm, and severe dysphagia complaints (univariate analysis). A steep dose-effect relationship, with an increase of the probability of dysphagia of 19% with every additional 10 Gy, was established. In the multivariate analysis, BT (dose) was the only significant factor.

Conclusion: A dose-effect relationship between dose and swallowing complaints was observed. One way to improve the QoL is to constrain the dose to be received by the swallowing muscles.

33

Batth, S. S., J. J. Caudell and A. M. Chen. 2014. "Practical considerations in reducing swallowing dysfunction following concurrent chemoradiotherapy with intensity-modulated radiotherapy for head and neck cancer." Head Neck 36(2):291-298.

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Abstract

Data have emerged that the addition of concurrent chemotherapy to radiation can lead to swallowing dysfunction that may have an impact on patient quality of life and lead to significant morbidities such as poor nutritional status, enteral feeding tube dependence, and aspiration pneumonia. Although intensity-modulated radiation therapy (IMRT) for head and neck cancer was initially developed to spare the parotid gland to reduce xerostomia, attention has recently focused on its utility to selectively decrease radiation dose to specified anatomic structures responsible for a functional swallow. Recent reports have proposed a variety of dose thresholds or constraints to these swallowing-related structures, which may guide IMRT planning with the aim of reducing dysphagia. This critical review of the current literature assesses the feasibility of IMRT to maintain swallowing function and appraises the various dosimetric parameters that have been proposed to help minimize long-term dysphagia.

Keywords: IMRT; dosimetry; dysphagia; head and neck cancer; swallowing dysfunction.

34

Kirkpatrick, J. P., A. J. van der Kogel and T. E. Schultheiss. 2010. "Radiation dose-volume effects in the spinal cord." Int J Radiat Oncol Biol Phys 76(3 Suppl):S42-49.

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Dose-volume data for myelopathy in humans treated with radiotherapy (RT) to the spine is reviewed, along with pertinent preclinical data. Using conventional fractionation of 1.8-2 Gy/fraction to the full-thickness cord, the estimated risk of myelopathy is <1% and <10% at 54 Gy and 61 Gy, respectively, with a calculated strong dependence on dose/fraction (alpha/beta = 0.87 Gy.) Reirradiation data in animals and humans suggest partial repair of RT-induced subclinical damage becoming evident about 6 months post-RT and increasing over the next 2 years. Reports of myelopathy from stereotactic radiosurgery to spinal lesions appear rare ( <1%) when the maximum spinal cord dose is limited to the equivalent of 13 Gy in a single fraction or 20 Gy in three fractions. However, long-term data are insufficient to calculate a dose-volume relationship for myelopathy when the partial cord is treated with a hypofractionated regimen.

35

Murdoch-Kinch, C. A., H. M. Kim, K. A. Vineberg, et al. 2008. "Dose-effect relationships for the submandibular salivary glands and implications for their sparing by intensity modulated radiotherapy." Int J Radiat Oncol Biol Phys 72(2):373-382.

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PURPOSE: Submandibular salivary glands (SMGs) dysfunction contributes to xerostomia after radiotherapy (RT) of head-and-neck (HN) cancer. We assessed SMG dose-response relationships and their implications for sparing these glands by intensity-modulated radiotherapy (IMRT). METHODS AND MATERIALS: A total of 148 HN cancer patients underwent unstimulated and stimulated SMG salivary flow rate measurements selectively from Wharton's duct orifices, before RT and periodically through 24 months after RT. Correlations of flow rates and mean SMG doses were modeled throughout all time points. IMRT replanning in 8 patients whose contralateral level I was not a target incorporated the results in a new cost function aiming to spare contralateral SMGs. RESULTS: Stimulated SMG flow rates decreased exponentially by (1.2%)(Gy) as mean doses increased up to 39 Gy threshold, and then plateaued near zero. At mean doses < or =39 Gy, but not higher, flow rates recovered over time at 2.2%/month. Similarly, the unstimulated salivary flow rates decreased exponentially by (3%)(Gy) as mean dose increased and recovered over time if mean dose was <39 Gy. IMRT replanning reduced mean contralateral SMG dose by average 12 Gy, achieving < or =39 Gy in 5 of 8 patients, without target underdosing, increasing the mean doses to the parotid glands and swallowing structures by average 2-3 Gy. CONCLUSIONS: SMG salivary flow rates depended on mean dose with recovery over time up to a threshold of 39 Gy. Substantial SMG dose reduction to below this threshold and without target underdosing is feasible in some patients, at the expense of modestly higher doses to some other organs.

36

Su, S. F., S. M. Huang, F. Han, et al. 2013. "Analysis of dosimetric factors associated with temporal lobe necrosis (TLN) in patients with nasopharyngeal carcinoma (NPC) after intensity modulated radiotherapy." Radiat Oncol 8:17.

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BACKGROUND: The radiation tolerance dose-volume in brain remains unclear for nasopharyngeal carcinoma (NPC) patients treated with intensity modulated radiotherapy (IMRT). We performed this study to investigate dosimetric factors associated with temporal lobe necrosis (TLN) in NPC patients treated with IMRT. METHODS: From 2001 to 2008, 870 NPC patients were treated with IMRT. For the whole group, 40 patients have developed MRI-diagnosed TLN, and 219 patients were followed-up more than 60 months. Predictive dosimetric factors for TLN were identified by using univariate and multivariate analysis in these 259 patients. RESULTS: By univariate analyses, rVX ( percent of temporal lobes receiving >/= X Gy) and aVX ( absolute volumes of temporal lobes receiving >/= X Gy, values of X considered were 10, 20, 30, 40, 50, 60, 66 and 70) were all significantly associated with TLN. Multivariate analysis by logistic regression showed that rV40 and aV40 were significant factors for TLN. All dosimetric factors in current serials were highly correlated one another (p < 0.001). The 5-year incidence of TLN for rV40 <10% or aV40 <5 cc is less than 5%. The incidence for rV40 >/= 15% or aV40c >/= 10c is increased significantly and more than 20%. CONCLUSIONS: In this study, all dosimetric factors were highly correlated, rV40 and aV40 were independent predictive factors for TLN, IMRT with rV40 <10% or aV40 <5 cc in temporal lobe is relatively safe.

37

Brouwer, C. L., R. J. Steenbakkers, J. Bourhis, et al. 2015. "CT-based delineation of organs at risk in the head and neck region: DAHANCA, EORTC, GORTEC, HKNPCSG, NCIC CTG, NCRI, NRG Oncology and TROG consensus guidelines." Radiother Oncol 117(1):83-90.

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PURPOSE: The objective of this project was to define consensus guidelines for delineating organs at risk (OARs) for head and neck radiotherapy for routine daily practice and for research purposes. METHODS: Consensus guidelines were formulated based on in-depth discussions of a panel of European, North American, Asian and Australian radiation oncologists. RESULTS: Twenty-five OARs in the head and neck region were defined with a concise description of their main anatomic boundaries. The Supplemental material provides an atlas of the consensus guidelines, projected on 1mm axial slices. The atlas can also be obtained in DICOM-RT format on request. CONCLUSION: Consensus guidelines for head and neck OAR delineation were defined, aiming to decrease interobserver variability among clinicians and radiotherapy centers.

38

Hall, W. H., M. Guiou, N. Y. Lee, et al. 2008. "Development and validation of a standardized method for contouring the brachial plexus: preliminary dosimetric analysis among patients treated with IMRT for head-and-neck cancer." Int J Radiat Oncol Biol Phys 72(5):1362-1367. NULL

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Hall, W. H., M. Guiou, N. Y. Lee, et al. 2008. Development and Validation of A Standardized Method for Contouring The Brachial Plexus: Preliminary Dosimetric Analysis Among Patients Treated with IMRT for Head-and-Neck Cancer. Int.J Radiat.Oncol Biol.Phys. PURPOSE: Although Radiation Therapy Oncology Group protocols have proposed a limiting dose to the brachial plexus for patients undergoing intensity-modulated radiotherapy for head-and-neck cancer, essentially no recommendations exist for the delineation of this structure for treatment planning. METHODS AND MATERIALS: Using anatomic texts, radiologic data, and magnetic resonance imaging, a standardized method for delineating the brachial plexus on 3-mm axial computed tomography images was devised. A neuroradiologist assisted with identification of the brachial plexus and adjacent structures. This organ at risk was then contoured on 10 consecutive patients undergoing intensity-modulated radiotherapy for head-and-neck cancer. Dose-volume histogram curves were generated by applying the proposed brachial plexus contour to the initial treatment plan. RESULTS: The total dose to the planning target volume ranged from 60 to 70 Gy (median, 70). The mean brachial plexus volume was 33 +/- 4 cm(3) (range, 25.1-39.4). The mean irradiated volumes of the brachial plexus were 50 Gy (17 +/- 3 cm(3)), 60 Gy (6 +/- 3 cm(3)), 66 Gy (2 +/- 1 cm(3)), 70 Gy (0 +/- 1 cm(3)). The maximal dose to the brachial plexus was 69.9 Gy (range, 62.3-76.9) and was >/=60 Gy, >/=66 Gy, and >/=70 Gy in 100%, 70%, and 30% of patients, respectively. CONCLUSIONS: This technique provides a precise and accurate method for delineating the brachial plexus organ at risk on treatment planning computed tomography scans. Our dosimetric analysis suggest that for patients undergoing intensity-modulated radiotherapy for head-and-neck cancer, brachial plexus routinely receives doses in excess of historic and Radiation Therapy Oncology Group limits

39

Christianen, M. E., J. A. Langendijk, H. E. Westerlaan, et al. 2011. "Delineation of organs at risk involved in swallowing for radiotherapy treatment planning." Radiother Oncol 101(3):394-402.

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BACKGROUND AND PURPOSE: Radiotherapy, alone or combined with chemotherapy, is a treatment modality used frequently in head and neck cancer. In order to report, compare and interpret the sequelae of radiation treatment adequately, it is important to delineate organs at risk (OARs) according to well-defined and uniform guidelines. The aim of this paper was to present our institutional Computed Tomography (CT)-based delineation guidelines for organs in the head and neck at risk for radiation-induced swallowing dysfunction (SWOARs). MATERIAL AND METHODS: After analyses of the human anatomy of the head and neck area and literature review, CT-based guidelines for delineation of the most relevant SWOARs were described by a panel of experts. RESULTS AND CONCLUSIONS: This paper described institutional guidelines for the delineation of potential SWOARs, accompanied by CT-based illustrations presenting examples of the delineated structures and their corresponding anatomic borders. This paper is essential to ensure adequate interpretation of future reports on the relationship between dose distribution in these SWOARs and different aspects of post-treatment swallowing dysfunction.

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Baujat, B., H. Audry, J. Bourhis, et al. 2006. "Chemotherapy in locally advanced nasopharyngeal carcinoma: an individual patient data meta-analysis of eight randomized trials and 1753 patients." Int.J.Radiat.Oncol Biol.Phys. 64(1):47-56.

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OBJECTIVES: To study the effect of adding chemotherapy to radiotherapy (RT) on overall survival and event-free survival for patients with nasopharyngeal carcinoma. METHODS AND MATERIALS: This meta-analysis used updated individual patient data from randomized trials comparing chemotherapy plus RT with RT alone in locally advanced nasopharyngeal carcinoma. The log-rank test, stratified by trial, was used for comparisons, and the hazard ratios of death and failure were calculated. RESULTS: Eight trials with 1753 patients were included. One trial with a 2 x 2 design was counted twice in the analysis. The analysis included 11 comparisons using the data from 1975 patients. The median follow-up was 6 years. The pooled hazard ratio of death was 0.82 (95% confidence interval, 0.71-0.94; p = 0.006), corresponding to an absolute survival benefit of 6% at 5 years from the addition of chemotherapy (from 56% to 62%). The pooled hazard ratio of tumor failure or death was 0.76 (95% confidence interval, 0.67-0.86; p < 0.0001), corresponding to an absolute event-free survival benefit of 10% at 5 years from the addition of chemotherapy (from 42% to 52%). A significant interaction was observed between the timing of chemotherapy and overall survival (p = 0.005), explaining the heterogeneity observed in the treatment effect (p = 0.03), with the highest benefit resulting from concomitant chemotherapy. CONCLUSION: Chemotherapy led to a small, but significant, benefit for overall survival and event-free survival. This benefit was essentially observed when chemotherapy was administered concomitantly with RT

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Blanchard, P., A. W. M. Lee, A. Carmel, et al. 2022. "Meta-analysis of chemotherapy in nasopharynx carcinoma (MAC-NPC): An update on 26 trials and 7080 patients." Clin Transl Radiat Oncol 32:59-68.

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Abstract

Purpose: Chemotherapy, when added to radiotherapy, improves survival in locally advanced nasopharyngeal carcinoma (NPC). This article presents the second update of the Meta-Analysis of Chemotherapy in NPC.

Methods: Published or unpublished randomized trials assessing radiotherapy (±a second chemotherapy timing) with/without chemotherapy in non-metastatic NPC patients were identified. Updated data were sought for studies included in the previous rounds of the meta-analysis. The primary endpoint was overall survival. All trials were analyzed following the intent-to-treat principle using a fixed-effects model. Treatments were classified in five subsets according to chemotherapy timing. The statistical analysis plan was pre-specified.

Results: Eighteen new trials were identified. Individual patient data were available for seven. In total, the meta-analysis now included 26 trials and 7,080 patients. The addition of chemotherapy reduced the risk of death, with a hazard ratio (HR) of 0.79 (95% confidence interval (CI) [0.73; 0.85]), and an absolute survival increase at 5 and 10 years of 6.1% [+3.9; +8.3] and + 8.4% [+5.7; +11.1], respectively. The largest effect was observed for concomitant + adjuvant, induction (with concomitant in both arms) and concomitant chemotherapy, with respective HR [95%CI] of 0.68 [0.59; 0.79] (absolute survival increase at 5 years: 12.3% (7.0%;17.6%)), 0.73 [0.63; 0.86] (6.0% (2.5%;9.5%)) and 0.81 [0.70; 0.92] (5.2% (0.8%;9.6%)). The benefit of chemotherapy was also demonstrated by improvement in progression-free survival, cancer mortality, locoregional control and distant control. There was a significant interaction between patient age and chemotherapy effect.

Conclusion: This updated meta-analysis confirms the benefit of concomitant chemotherapy and concomitant + adjuvant chemotherapy, and suggests that addition of induction or adjuvant chemotherapy to concomitant chemotherapy improves tumor control and survival. The benefit of chemotherapy decreases with increasing patient age.

Keywords: Chemotherapy; Individual patient data; Meta-analysis; Nasopharynx carcinoma; Randomized trials.

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Langendijk, J. A., C. R. Leemans, J. Buter, et al. 2004. "The additional value of chemotherapy to radiotherapy in locally advanced nasopharyngeal carcinoma: a meta-analysis of the published literature." J.Clin Oncol. 22(22):4604-4612.

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PURPOSE: The purpose of this meta-analysis was to determine the additional value of neoadjuvant, concurrent, and/or adjuvant chemotherapy to radiation in the treatment of locally advanced nasopharyngeal carcinoma (NPC) with regard to the overall survival (OS) and the incidence of local-regional recurrences (LRR) and distant metastases (DM). PATIENTS AND METHODS: To be eligible, full published studies had to deal with biopsy-proven NPC and have patients randomly assigned to receive conventional radiotherapy (66 to 70 Gy in 7 weeks) or radiotherapy combined with chemotherapy. RESULTS: Ten randomized clinical studies were identified, including 2,450 patients. The pooled hazard ratio (HR) of death for all studies was 0.82 (95% CI, 0.71 to 0.95; P = .01) corresponding to an absolute survival benefit of 4% after 5 years. Three categories of trials were defined according to the sequence of chemotherapy, including neoadjuvant chemotherapy, at least concomitant chemoradiotherapy, and adjuvant chemotherapy. A significant interaction term (P = .02) was found among these three categories. The largest effect was found for concomitant chemotherapy, with a pooled HR of 0.48 (95% CI, 0.32 to 0.72), which corresponds to a survival benefit of 20% after 5 years. Comparable results were found for the incidence of LRR and DM. CONCLUSION: The results of this study indicate that concomitant chemotherapy in addition to radiation is probably the most effective way to improve OS in NPC

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Ribassin-Majed, L., S. Marguet, A. W. M. Lee, et al. 2017. "What Is the Best Treatment of Locally Advanced Nasopharyngeal Carcinoma? An Individual Patient Data Network Meta-Analysis." J Clin Oncol 35(5):498-505.

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Purpose The role of adjuvant chemotherapy (AC) or induction chemotherapy (IC) in the treatment of locally advanced nasopharyngeal carcinoma is controversial. The individual patient data from the Meta-Analysis of Chemotherapy in Nasopharynx Carcinoma database were used to compare all available treatments. Methods All randomized trials of radiotherapy (RT) with or without chemotherapy in nonmetastatic nasopharyngeal carcinoma were considered. Overall, 20 trials and 5,144 patients were included. Treatments were grouped into seven categories: RT alone (RT), IC followed by RT (IC-RT), RT followed by AC (RT-AC), IC followed by RT followed by AC (IC-RT-AC), concomitant chemoradiotherapy (CRT), IC followed by CRT (IC-CRT), and CRT followed by AC (CRT-AC). P-score was used to rank the treatments. Fixed- and random-effects frequentist network meta-analysis models were applied. Results The three treatments with the highest probability of benefit on overall survival (OS) were CRT-AC, followed by CRT and IC-CRT, with respective hazard ratios (HRs [95% CIs]) compared with RT alone of 0.65 (0.56 to 0.75), 0.77 (0.64 to 0.92), and 0.81 (0.63 to 1.04). HRs (95% CIs) of CRT-AC compared with CRT for OS, progression-free survival (PFS), locoregional control, and distant control (DC) were, respectively, 0.85 (0.68 to 1.05), 0.81 (0.66 to 0.98), 0.70 (0.48 to 1.02), and 0.87 (0.61 to 1.25). IC-CRT ranked second for PFS and the best for DC. CRT never ranked first. HRs of CRT compared with IC-CRT for OS, PFS, locoregional control, and DC were, respectively, 0.95 (0.72 to 1.25), 1.13 (0.88 to 1.46), 1.05 (0.70 to 1.59), and 1.55 (0.94 to 2.56). Regimens with more chemotherapy were associated with increased risk of acute toxicity. Conclusion The addition of AC to CRT achieved the highest survival benefit and consistent improvement for all end points. The addition of IC to CRT achieved the highest effect on DC.

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Al-Sarraf, M., M. LeBlanc, P. G. Giri, et al. 1998. "Chemoradiotherapy versus radiotherapy in patients with advanced nasopharyngeal cancer: phase III randomized Intergroup study 0099." J.Clin Oncol 16(4):1310-1317.

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PURPOSE: The Southwest Oncology Group (SWOG) coordinated an Intergroup study with the participation of Radiation Therapy Oncology Group (RTOG), and Eastern Cooperative Oncology Group (ECOG). This randomized phase III trial compared chemoradiotherapy versus radiotherapy alone in patients with nasopharyngeal cancers. MATERIALS AND METHODS: Radiotherapy was administered in both arms: 1.8- to 2.0-Gy/d fractions Monday to Friday for 35 to 39 fractions for a total dose of 70 Gy. The investigational arm received chemotherapy with cisplatin 100 mg/m2 on days 1, 22, and 43 during radiotherapy; postradiotherapy, chemotherapy with cisplatin 80 mg/m2 on day 1 and fluorouracil 1,000 mg/m2/d on days 1 to 4 was administered every 4 weeks for three courses. Patients were stratified by tumor stage, nodal stage, performance status, and histology. RESULTS: Of 193 patients registered, 147 (69 radiotherapy and 78 chemoradiotherapy) were eligible for primary analysis for survival and toxicity. The median progression-free survival (PFS) time was 15 months for eligible patients on the radiotherapy arm and was not reached for the chemo-radiotherapy group. The 3-year PFS rate was 24% versus 69%, respectively (P < .001). The median survival time was 34 months for the radiotherapy group and not reached for the chemo-radiotherapy group, and the 3-year survival rate was 47% versus 78%, respectively (P = .005). One hundred eighty-five patients were included in a secondary analysis for survival. The 3-year survival rate for patients randomized to radiotherapy was 46%, and for the chemoradiotherapy group was 76% (P < .001). CONCLUSION: We conclude that chemoradiotherapy is superior to radiotherapy alone for patients with advanced nasopharyngeal cancers with respect to PFS and overall survival

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Peng, G., T. Wang, K. Y. Yang, et al. 2012. "A prospective, randomized study comparing outcomes and toxicities of intensity-modulated radiotherapy vs. conventional two-dimensional radiotherapy for the treatment of nasopharyngeal carcinoma." Radiother Oncol 104(3):286-293.

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BACKGROUND AND PURPOSE: To compare clinical outcomes and toxicities of two-dimensional conventional radiation therapy (2D-CRT) and intensity modulated radiation therapy (IMRT) for the treatment of nasopharyngeal carcinoma (NPC). MATERIALS AND METHODS: Between July 2003 and October 2008, 616 patients with non-metastatic stage I to IVb NPC were prospectively randomized to receive 2D-CRT (n=310; mean age, 44.8+/-13.6 years) or IMRT (n=306; mean age, 46.7+/-12.5 years). Clinical outcomes and acute and late toxicities were determined and compared. RESULTS: The 2 groups were comparable with respect to all parameters of demographics and disease characteristics (all, p >0.05). Median follow-up was 42 months (range, 1-83 months). The 5-year actuarial local control rate was 90.5% in the IMRT group and 84.7% in the 2D-CRT group. The local control rates were 91% for stage T3 and 81.5% for stage T4 disease in the IMRT group and 80% and 62.2% in the 2D-CRT group, respectively. The 5-year actuarial nodal relapse-free survival (NRFS) rate was 92.4% in the IMRT and 92.9% in the 2D-CRT group (p >0.05). The NRFS was 93.9% for N2 disease in the IMRT group and 91.4% in the 2D-CRT group (p=0.02). The 5-year overall survival (OS) rate was 79.6% for the IMRT group and 67.1% for the 2D-CRT group (p=0.001). When stratified for stage, a significant difference was only noted for stage III disease. In terms of radiation-induced toxicities, patients in IMRT group had significantly lower radiation-induced toxicities than those in 2D-CRT group. CONCLUSION: IMRT provides improved local-recurrence free survival, especially in late-stage NPC patients and is associated with a lower incidence of toxicities.

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Chen, Q. Y., Y. F. Wen, L. Guo, et al. 2011. "Concurrent chemoradiotherapy vs radiotherapy alone in stage II nasopharyngeal carcinoma: phase III randomized trial." J Natl Cancer Inst 103(23):1761-1770.

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BACKGROUND: Concurrent chemoradiotherapy (CCRT) has been shown to improve outcomes for stage III-IV nasopharyngeal carcinoma (NPC) patients compared with radiotherapy (RT) alone, but the effectiveness of the combined therapy for stage II NPC patients is unknown. METHODS: Patients with Chinese 1992 stage II NPC were randomly assigned to receive either RT alone (n = 114) or CCRT (n = 116). The CCRT patients were given concurrent cisplatin (30 mg/m(2) on day 1) weekly during RT. The primary endpoint was overall survival (OS). Secondary endpoints were progression-free survival (PFS), distant metastasis-free survival, and locoregional relapse-free survival. All patients were analyzed by the intent-to-treat principle. The Cox proportional hazards model was used to calculate hazard ratios (HRs) with 95% confidence intervals (CIs) and in multivariable analyses to test the independent statistical significance of treatment intervention. Toxic effects and the response to treatment were analyzed using the chi(2) test. All statistical tests were two-sided. RESULTS: With a median follow-up of 60 months, adding chemotherapy statistically significantly improved the 5-year OS rate (94.5% vs 85.8%; HR of death = 0.30, 95% CI = 0.12 to 0.76; P = .007), PFS (87.9% vs 77.8%; HR of progression = 0.45, 95% CI = 0.23 to 0.88; P = .017), and distant metastasis-free survival (94.8% vs 83.9%; HR of distant relapse = 0.27, 95% CI = 0.10 to 0.74; P = .007); however, there was no statistically significant difference in the 5-year locoregional relapse-free survival rate (93.0% vs 91.1%; HR of locoregional relapse = 0.61, 95% CI = 0.25 to 1.51; P = .29). Multivariable analysis showed that the number of chemotherapy cycles was the only independent factor that was associated with OS, PFS, and distant control in stage II NPC. The CCRT arm experienced statistically significantly more acute toxic effects (P = .001), although the rate of late toxic effects did not increase statistically significantly. CONCLUSION: Concurrent chemotherapy and radiotherapy is associated with a considerable survival benefit for patients with stage II NPC.

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Lee, A. W. M., S. Y. Tung, W. T. Ng, et al. 2017. "A multicenter, phase 3, randomized trial of concurrent chemoradiotherapy plus adjuvant chemotherapy versus radiotherapy alone in patients with regionally advanced nasopharyngeal carcinoma: 10-year outcomes for efficacy and toxicity." Cancer 123(21):4147-4157.

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BACKGROUND: Concurrent-adjuvant chemoradiotherapy (CRT) became a recommended treatment for locoregionally advanced nasopharyngeal carcinoma (NPC) with the first report of a significant survival benefit from the Intergroup 0099 study. However, data on late toxicities are lacking. Previous reports from the current NPC-9901 trial have raised concerns about a failure to improve overall survival (OS) because of an inadequate impact on distant control and increases in toxicities/noncancer deaths. Validation of the long-term therapeutic ratio is needed. METHODS: In this phase 3, randomized trial, patients with nonkeratinizing NPC (stage T1-4/N2-3/M0) were randomly assigned to radiotherapy alone (176 patients) or to CRT (172 patients) with concurrent cisplatin followed by adjuvant cisplatin plus fluorouracil. RESULTS: The early findings of significant improvements in tumor control were maintained: the CRT group achieved significantly higher 10-year overall failure-free (62% vs 50%; P = .01) and progression-free survival rates (56% vs 42%; P = .006) because of superior locoregional control (87% vs 74%; P = .003), whereas the impact on distant control remained insignificant (68% vs 65%; P = .24). The initial differences in toxicities diminished with longer follow-up: 52% versus 47% at 10 years for late toxicities (P = .20), 4.1% versus 2.8% for deaths due to treatment toxicity, and 15.1% versus 13.1% for deaths due to incidental/unknown causes. The OS rate for the CRT group reached statistical superiority at 10 years (62% vs 49%; P = .047). CONCLUSIONS: Long-term results have confirmed that CRT can significantly improve OS without excessive late toxicities for patients with regionally advanced NPC. However, more potent therapy is needed for improving distant control, especially for patients with stage IVA/B disease. Cancer 2017;123:4147-4157. (c) 2017 American Cancer Society.

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Zhang, Y., L. Chen, G. Q. Hu, et al. 2022. "Final Overall Survival Analysis of Gemcitabine and Cisplatin Induction Chemotherapy in Nasopharyngeal Carcinoma: A Multicenter, Randomized Phase III Trial." J Clin Oncol 40(22):2420-2425.

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ABSTRACT

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically on the based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.

We previously reported significantly improved failure-free survival using gemcitabine plus cisplatin induction chemotherapy in locoregionally advanced nasopharyngeal carcinoma. Here, we present the final overall survival (OS) analysis. In this multicenter, randomized trial, patients were assigned to be treated with concurrent chemoradiotherapy alone (standard therapy, n = 238) or gemcitabine and cisplatin induction chemotherapy before concurrent chemoradiotherapy (n = 242). With a median follow-up of 69.8 months, the induction chemotherapy group had a significantly higher 5-year OS (87.9% v 78.8%, hazard ratio, 0.51 [95% CI 0.34 to 0.78]; P = .001) and a comparable risk of late toxicities (≥ grade 3, 11.3% v 11.4%). Notably, the depth of the tumor response to induction chemotherapy correlated significantly and positively with survival (complete response v partial response v stable/progressive disease, 5-year OS, 100% v 88.4% v 61.5%, P = .005). Besides, patients with a low pretreatment cell-free Epstein-Barr virus DNA load (< 4,000 copies/mL) might not benefit from induction chemotherapy (5-year OS, 90.6% v 91.4%, P = .77). In conclusion, induction chemotherapy before concurrent chemoradiotherapy improved OS significantly in patients with locally advanced nasopharyngeal carcinoma, without increasing the risk of late toxicities. Tumor response to induction chemotherapy and pretreatment cell-free Epstein-Barr virus DNA might be useful to guide individualized treatment.

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National Comprehensive Cancer Network (NCCN) Guidelines Version 1.2023 Head and Neck Cancers. www.nccn.org

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Bossi, P., A. T. Chan, L. Licitra, et al. 2021. "Nasopharyngeal carcinoma: ESMO-EURACAN Clinical Practice Guidelines for diagnosis, treatment and follow-up(†)." Ann Oncol 32(4):452-465.

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Tang, L. L., Y. P. Chen, C. B. Chen, et al. 2021. "The Chinese Society of Clinical Oncology (CSCO) clinical guidelines for the diagnosis and treatment of nasopharyngeal carcinoma." Cancer Commun (Lond) 41(11):1195-1227.

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Abstract

Nasopharyngeal carcinoma (NPC) is a malignant epithelial tumor originating in the nasopharynx and has a high incidence in Southeast Asia and North Africa. To develop these comprehensive guidelines for the diagnosis and management of NPC, the Chinese Society of Clinical Oncology (CSCO) arranged a multi-disciplinary team comprising of experts from all sub-specialties of NPC to write, discuss, and revise the guidelines. Based on the findings of evidence-based medicine in China and abroad, domestic experts have iteratively developed these guidelines to provide proper management of NPC. Overall, the guidelines describe the screening, clinical and pathological diagnosis, staging and risk assessment, therapies, and follow-up of NPC, which aim to improve the management of NPC.

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Lee, N., J. Harris, A. S. Garden, et al. 2009. "Intensity-modulated radiation therapy with or without chemotherapy for nasopharyngeal carcinoma: radiation therapy oncology group phase II trial 0225." J Clin Oncol 27(22):3684-3690.

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PURPOSE: To investigate the feasibility of intensity-modulated radiation therapy (IMRT) with or without chemotherapy, and to assess toxicities, failure patterns, and survivals in patients with nasopharyngeal carcinoma (NPC). PATIENTS AND METHODS: Radiation consisted of 70 Gy given to the planning target volumes of primary tumor plus any N+ disease and 59.4 Gy given to subclinical disease, delivered over 33 treatment days. Patients with stage T2b or greater or with N+ disease also received concurrent cisplatin (100 mg/m(2)) on days 1, 22, and 43 followed by adjuvant cisplatin (80 mg/m(2)) on day 1; fluorouracil (1,000 mg/m(2)/d) on days 1 through 4 administered every 4 weeks for three cycles. Tumor, clinical status, and acute/late toxicities were assessed. The primary objective was to test the transportability of IMRT to a multi-institutional setting. RESULTS: Between February 2003 and November 2005, 68 patients with stages I through IVB NPC (of which 93.8% were WHO types 2 and 3) were enrolled. Prescribed IMRT (target delineation) was given to 83.8%, whereas 64.9% received chemotherapy per protocol. The estimated 2-year local progression-free (PF), regional PF, locoregional PF, and distant metastasis-free rates were 92.6%, 90.8%, 89.3%, and 84.7%, respectively. The estimated 2-year PF and overall survivals were 72.7% and 80.2%, respectively. Acute grade 4 mucositis occurred in 4.4%, and the worst late grade 3 toxicities were as follows: esophagus, 4.7%; mucous membranes, 3.1%; and xerostomia, 3.1%. The rate of grade 2 xerostomia at 1 year from start of IMRT was 13.5%. Only two patients complained of grade 3 xerostomia, and none had grade 4 xerostomia. CONCLUSION: It was feasible to transport IMRT with or without chemotherapy in the treatment of NPC to a multi-institutional setting with 90% LRPF rate reproducing excellent reports from single institutions. Minimal grade 3 and lack of grade 4 xerostomia were encouraging.

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Blanchard, P., A. Lee, S. Marguet, et al. 2015. "Chemotherapy and radiotherapy in nasopharyngeal carcinoma: an update of the MAC-NPC meta-analysis." Lancet Oncol 16(6):645-655.

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BACKGROUND: A previous individual patient data meta-analysis by the Meta-Analysis of Chemotherapy in Nasopharynx Carcinoma (MAC-NPC) collaborative group to assess the addition of chemotherapy to radiotherapy showed that it improves overall survival in nasopharyngeal carcinoma. This benefit was restricted to patients receiving concomitant chemotherapy and radiotherapy. The aim of this study was to update the meta-analysis, include recent trials, and to analyse separately the benefit of concomitant plus adjuvant chemotherapy. METHODS: We searched PubMed, Web of Science, Cochrane Controlled Trials meta-register, ClinicalTrials.gov, and meeting proceedings to identify published or unpublished randomised trials assessing radiotherapy with or without chemotherapy in patients with non-metastatic nasopharyngeal carcinoma and obtained updated data for previously analysed studies. The primary endpoint of interest was overall survival. All trial results were combined and analysed using a fixed-effects model. The statistical analysis plan was pre-specified in a protocol. All data were analysed on an intention-to-treat basis. FINDINGS: We analysed data from 19 trials and 4806 patients. Median follow-up was 7.7 years (IQR 6.2-11.9). We found that the addition of chemotherapy to radiotherapy significantly improved overall survival (hazard ratio [HR] 0.79, 95% CI 0.73-0.86, p<0.0001; absolute benefit at 5 years 6.3%, 95% CI 3.5-9.1). The interaction between treatment effect (benefit of chemotherapy) on overall survival and the timing of chemotherapy was significant (p=0.01) in favour of concomitant plus adjuvant chemotherapy (HR 0.65, 0.56-0.76) and concomitant without adjuvant chemotherapy (0.80, 0.70-0.93) but not adjuvant chemotherapy alone (0.87, 0.68-1.12) or induction chemotherapy alone (0.96, 0.80-1.16). The benefit of the addition of chemotherapy was consistent for all endpoints analysed (all p<0.0001): progression-free survival (HR 0.75, 95% CI 0.69-0.81), locoregional control (0.73, 0.64-0.83), distant control (0.67, 0.59-0.75), and cancer mortality (0.76, 0.69-0.84). INTERPRETATION: Our results confirm that the addition of concomitant chemotherapy to radiotherapy significantly improves survival in patients with locoregionally advanced nasopharyngeal carcinoma. To our knowledge, this is the first analysis that examines the effect of concomitant chemotherapy with and without adjuvant chemotherapy as distinct groups. Further studies on the specific benefits of adjuvant chemotherapy after concomitant chemoradiotherapy are needed. FUNDING: French Ministry of Health (Programme d'actions integrees de recherche VADS), Ligue Nationale Contre le Cancer, and Sanofi-Aventis.

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Wang, Y., W. Ding, C. Chen, et al. 2015. "Meta-analysis of concurrent chemoradiotherapy in the treatment of locoregionally advanced nasopharyngeal carcinoma." J Cancer Res Ther 11 Suppl 2:C191-195.

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BACKGROUND: With radiotherapy (RT) alone, the five-year overall survival (OS) rate for advanced nasopharyngeal carcinoma (NPC) can only reach 40%, the ratio of distant metastasis (DM) is 36-40%. This meta-analysis was performed to compare the clinical efficacy of concurrent chemoradiotherapy (CCRT) with RT alone in the treatment of locoregionally advanced NPC. METHODS: The related literature were retrieved and reviewed by two independent investigators from the followed electronic databases: Review manager 5.3 software (Cochrane Collaboration, London, United Kingdom) was applied for statistical analysis. RESULTS: A total of 16 trials with 2576 patients were recruited according to the criterion. The odds ratios of 3 and 5 years OS was 0.53 (95% confidence interval [95% CI]: 0.44-0.64) and 0.58 (95% CI: 0.48-0.71), which confirmed the significant improvement of CCRT compared with RT alone (P < 0.001). CCRT also reduced the risk of locoregional control failure and DM in locoregionally advanced NPC patients. CONCLUSIONS: The results suggested that CCRT was more beneficial when compared with RT alone in locoregionally advanced NPC patients. Further study is needed to perform to confirm this effect.

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Chen, Y., M. Z. Liu, S. B. Liang, et al. 2008. "Preliminary results of a prospective randomized trial comparing concurrent chemoradiotherapy plus adjuvant chemotherapy with radiotherapy alone in patients with locoregionally advanced nasopharyngeal carcinoma in endemic regions of china." Int J Radiat Oncol Biol Phys 71(5):1356-1364.

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PURPOSE: A prospective randomized trial was performed to evaluate the efficacy of concurrent chemotherapy and adjuvant chemotherapy in patients with locoregionally advanced nasopharyngeal carcinoma (NPC) in endemic regions of China. METHODS AND MATERIALS: Between July 2002 and September 2005, 316 eligible patients were randomly assigned to receive either radiotherapy alone (RT) or chemoradiotherapy concurrent with adjuvant chemotherapy (CRT). All patients received 70 Gy in 7 weeks using standard RT portals and techniques. The CRT patients were given concurrent cisplatin (40 mg/m(2) on Day 1) weekly during RT, followed by cisplatin (80 mg/m(2) on Day 1) and fluorouracil (800 mg/m(2) on Days 1-5) every 4 weeks (Weeks 5, 9, and 13) for three cycles after completion of RT. All patients were analyzed by intent-to-treat analysis. RESULTS: The two groups were well-balanced in all prognostic factors and RT parameters. The CRT group experienced significantly more acute toxicity (62.6% vs. 32%, p = 0.000). A total of 107 patients (68%) and 97 patients (61%) completed all cycles of concurrent chemotherapy and adjuvant chemotherapy, with a median follow-up time of 29 months. The 2-year overall survival rate, failure-free survival rate, distant failure-free survival rate, and locoregional failure-free survival rate for the CRT and RT groups were 89.8% vs. 79.7% (p = 0.003), 84.6% vs. 72.5% (p = 0.001), 86.5% vs. 78.7% (p = 0.024), and 98.0% vs. 91.9% (p = 0.007), respectively. CONCLUSIONS: This trial demonstrated the significant survival benefits of concurrent chemotherapy plus adjuvant chemotherapy in patients with locoregionally advanced NPC in endemic regions of China.

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Zhang, Y., L. Chen, G. Q. Hu, et al. 2019. "Gemcitabine and Cisplatin Induction Chemotherapy in Nasopharyngeal Carcinoma." N Engl J Med 381(12):1124-1135.

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BACKGROUND: Platinum-based concurrent chemoradiotherapy is the standard of care for patients with locoregionally advanced nasopharyngeal carcinoma. Additional gemcitabine and cisplatin induction chemotherapy has shown promising efficacy in phase 2 trials. METHODS: In a parallel-group, multicenter, randomized, controlled, phase 3 trial, we compared gemcitabine and cisplatin as induction chemotherapy plus concurrent chemoradiotherapy with concurrent chemoradiotherapy alone. Patients with locoregionally advanced nasopharyngeal carcinoma were randomly assigned in a 1:1 ratio to receive gemcitabine (at a dose of 1 g per square meter of body-surface area on days 1 and 8) plus cisplatin (80 mg per square meter on day 1), administered every 3 weeks for three cycles, plus chemoradiotherapy (concurrent cisplatin at a dose of 100 mg per square meter every 3 weeks for three cycles plus intensity-modulated radiotherapy) or chemoradiotherapy alone. The primary end point was recurrence-free survival (i.e., freedom from disease recurrence [distant metastasis or locoregional recurrence] or death from any cause) in the intention-to-treat population. Secondary end points included overall survival, treatment adherence, and safety. RESULTS: A total of 480 patients were included in the trial (242 patients in the induction chemotherapy group and 238 in the standard-therapy group). At a median follow-up of 42.7 months, the 3-year recurrence-free survival was 85.3% in the induction chemotherapy group and 76.5% in the standard-therapy group (stratified hazard ratio for recurrence or death, 0.51; 95% confidence interval [CI], 0.34 to 0.77; P = 0.001). Overall survival at 3 years was 94.6% and 90.3%, respectively (stratified hazard ratio for death, 0.43; 95% CI, 0.24 to 0.77). A total of 96.7% of the patients completed three cycles of induction chemotherapy. The incidence of acute adverse events of grade 3 or 4 was 75.7% in the induction chemotherapy group and 55.7% in the standard-therapy group, with a higher incidence of neutropenia, thrombocytopenia, anemia, nausea, and vomiting in the induction chemotherapy group. The incidence of grade 3 or 4 late toxic effects was 9.2% in the induction chemotherapy group and 11.4% in the standard-therapy group. CONCLUSIONS: Induction chemotherapy added to chemoradiotherapy significantly improved recurrence-free survival and overall survival, as compared with chemoradiotherapy alone, among patients with locoregionally advanced nasopharyngeal carcinoma. (Funded by the Innovation Team Development Plan of the Ministry of Education and others; ClinicalTrials.gov number, NCT01872962.).

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Zhang, L., C. Zhao, B. Ghimire, et al. 2010. "The role of concurrent chemoradiotherapy in the treatment of locoregionally advanced nasopharyngeal carcinoma among endemic population: a meta-analysis of the phase III randomized trials." BMC Cancer 10:558.

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BACKGROUND: The main objective of this meta-analysis was to determine the clinical benefit of concurrent chemoradiotherapy (CCRT) compared with radiation alone (RT) in the treatment of nasopharyngeal carcinoma (NPC) patients in endemic geographic areas. METHODS: Using a prospective meta-analysis protocol, two independent investigators reviewed the publications and extracted the data. Published randomized controlled trials (RCTs) in which patients with NPC in endemic areas were randomly assigned to receive CCRT or RT alone were included. RESULTS: Seven trials (totally 1608 patients) were eligible. Risk ratios (RRs) of 0.63 (95% CI, 0.50 to 0.80), 0.76 (95% CI, 0.61 to 0.93) and 0.74 (95% CI, 0.62 to 0.89) were observed for 2, 3 and 5 years OS respectively in favor of the CCRT group. The RRs were larger than that detected in the previously reported meta-analyses (including both endemic and non-endemic), indicating that the relative benefit of survival was smaller than what considered before. CONCLUSIONS: This is the first meta-analysis of CCRT vs. RT alone in NPC treatment which included studies only done in endemic area. The results confirmed that CCRT was more beneficial compared with RT alone. However, the relative benefit of CCRT in endemic population might be less than that from previous meta-analyses.

58

Chen, L., C. S. Hu, X. Z. Chen, et al. 2017. "Adjuvant chemotherapy in patients with locoregionally advanced nasopharyngeal carcinoma: Long-term results of a phase 3 multicentre randomised controlled trial." Eur J Cancer 75:150-158.

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AIM OF THE STUDY: Previous results from our trial showed that adjuvant cisplatin and fluorouracil chemotherapy did not significantly improve survival after concurrent chemoradiotherapy (CCRT) in locoregionally advanced nasopharyngeal carcinoma (NPC) at 2 years. Here, we present the data of long-term survival and late toxicities to further assess the ultimate therapeutic index of adjuvant chemotherapy (AC). METHODS: Patients with stage III-IVB (except T3-4N0) NPC were randomly assigned to receive CCRT plus AC or CCRT only at seven institutions in China. Patients in both groups received cisplatin 40 mg/m(2) weekly up to 7 weeks concurrently with radiotherapy. The CCRT plus AC group subsequently received adjuvant cisplatin 80 mg/m(2) and fluorouracil 800 mg/m(2)/d for 120 h every 4 weeks for three cycles. The primary end-point was failure-free survival. RESULTS: Two hundred and fifty-one patients were randomised to the CCRT plus AC group and 257 to the CCRT only group. After a median follow-up of 68.4 months, estimated 5-year failure-free survival rate was 75% in the CCRT plus AC group and 71% in the CCRT only group (hazard ratio 0.88, 95% confidence interval 0.64-1.22; p = 0.45). 66 (27%) of 249 patients in the CCRT plus AC group and 53 (21%) of 254 patients in the CCRT only group developed one or more late grade 3-4 toxicities (p = 0.14). CONCLUSION: Adjuvant cisplatin and fluorouracil chemotherapy still failed to demonstrate significant survival benefit after CCRT in locoregionally advanced NPC based on the long-term follow-up data, and addition of adjuvant cisplatin and fluorouracil did not significantly increase late toxicities. REGISTRATION NUMBER: NCT00677118.

59

Kam, M. K., S. F. Leung, B. Zee, et al. 2007. "Prospective randomized study of intensity-modulated radiotherapy on salivary gland function in early-stage nasopharyngeal carcinoma patients." J Clin Oncol 25(31):4873-4879.

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PURPOSE: This randomized trial compared the rates of delayed xerostomia between two-dimensional radiation therapy (2DRT) and intensity-modulated radiation therapy (IMRT) in the treatment of early-stage nasopharyngeal carcinoma (NPC). PATIENTS AND METHODS: Between November 2001 and December 2003, 60 patients with T1-2bN0-1M0 NPC were randomly assigned to receive either IMRT or 2DRT. Primary end point was incidence of observer-rated severe xerostomia at 1 year after treatment based on Radiotherapy Oncology Group /European Organisation for the Research and Treatment of Cancer late radiation morbidity scoring criteria. Parallel assessment with patient-reported outcome, stimulated parotid flow rate (SPFR), and stimulated whole saliva flow rate (SWSFR) were also made. RESULTS: At 1 year after treatment, patients in IMRT arm had lower incidence of observer-rated severe xerostomia than patients in the 2DRT arm (39.3% v 82.1%; P = .001), parallel with a higher fractional SPFR (0.90 v 0.05; P < .0001), and higher fractional SWSFR (0.41 v 0.20; P = .001). As for patient's subjective feeling, although a trend of improvement in patient-reported outcome was observed after IMRT, recovery was incomplete and there was no significant difference in patient-reported outcome between the two arms. CONCLUSION: IMRT is superior to 2DRT in preserving parotid function and results in less severe delayed xerostomia in the treatment of early-stage NPC. Incomplete improvement in patient's subjective xerostomia with parotid-sparing IMRT reflects the need to enhance protection of other salivary glands.

60

Pow, E. H., D. L. Kwong, A. S. McMillan, et al. 2006. "Xerostomia and quality of life after intensity-modulated radiotherapy vs. conventional radiotherapy for early-stage nasopharyngeal carcinoma: initial report on a randomized controlled clinical trial." Int J Radiat Oncol Biol Phys 66(4):981-991.

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PURPOSE: To compare directly the effect of intensity-modulated radiotherapy (IMRT) vs. conventional radiotherapy (CRT) on salivary flow and quality of life (QoL) in patients with early-stage nasopharyngeal carcinoma (NPC). METHODS AND MATERIALS: Fifty-one patients with T2, N0/N1, M0 NPC took part in a randomized controlled clinical study and received IMRT or CRT. Stimulated whole (SWS) and parotid (SPS) saliva flow were measured and Medical Outcomes Short Form 36 (SF-36), European Organization for Research and Treatment of Cancer (EORTC) core quetionnaire, and EORTC head-and-neck module (QLQ-H &N35) were completed at baseline and 2, 6, and 12 months after radiotherapy. RESULTS: Forty-six patients (88%) were in disease remission 12 months after radiotherapy. At 12 months postradiotherapy, 12 (50.0%) and 20 patients (83.3%) in the IMRT group had recovered at least 25% of preradiotherapy SWS and SPS flow respectively, compared with 1 (4.8%) and 2 patients (9.5%), respectively, in the CRT group. Global health scores showed continuous improvement in QoL after both treatments (p < 0.001). However, after 12 months subscale scores for role-physical, bodily pain, and physical function were significantly higher in the IMRT group, indicating a better condition (p < 0.05). Dry mouth and sticky saliva were problems in both groups 2 months after treatment. In the IMRT group, there was consistent improvement over time with xerostomia-related symptoms significantly less common than in the CRT group at 12 months postradiotherapy. CONCLUSIONS: IMRT was significantly better than CRT in terms of parotid sparing and improved QoL for early-stage disease. The findings support the case for assessment of health-related QoL in relation to head-and-neck cancer using a site-specific approach.

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Lee, A. W., S. Y. Tung, D. T. Chua, et al. 2010. "Randomized trial of radiotherapy plus concurrent-adjuvant chemotherapy vs radiotherapy alone for regionally advanced nasopharyngeal carcinoma." J Natl Cancer Inst 102(15):1188-1198.

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BACKGROUND: Current practice of adding concurrent-adjuvant chemotherapy to radiotherapy (CRT) for treating advanced nasopharyngeal carcinoma is based on the Intergroup-0099 Study published in 1998. However, the outcome for the radiotherapy-alone (RT) group in that trial was substantially poorer than those in other trials, and there were no data on late toxicities. Verification of the long-term therapeutic index of this regimen is needed. METHODS: Patients with nonkeratinizing nasopharyngeal carcinoma staged T1-4N2-3M0 were randomly assigned to RT (176 patients) or to CRT (172 patients) using cisplatin (100 mg/m(2)) every 3 weeks for three cycles in concurrence with radiotherapy, followed by cisplatin (80 mg/m(2)) plus fluorouracil (1000 mg per m(2) per day for 4 days) every 4 weeks for three cycles. Primary endpoints included overall failure-free rate (FFR) (the time to first failure at any site) and progression-free survival. Secondary endpoints included overall survival, locoregional FFR, distant FFR, and acute and late toxicity rates. All statistical tests were two-sided. RESULTS: The two treatment groups were well balanced in all patient characteristics, tumor factors, and radiotherapy parameters. Adding chemotherapy statistically significantly improved the 5-year FFR (CRT vs RT: 67% vs 55%; P = .014) and 5-year progression-free survival (CRT vs RT: 62% vs 53%; P = .035). Cumulative incidence of acute toxicity increased with chemotherapy by 30% (CRT vs RT: 83% vs 53%; P < .001), but the 5-year late toxicity rate did not increase statistically significantly (CRT vs RT: 30% vs 24%; P = .30). Deaths because of disease progression were reduced statistically significantly by 14% (CRT vs RT: 38% vs 24%; P = .008), but 5-year overall survival was similar (CRT vs RT: 68% vs 64%; P = .22; hazard ratio of CRT = 0.81, 95% confidence interval = 0.58 to 1.13) because deaths due to toxicity or incidental causes increased by 7% (CRT vs RT: 1.7% vs 0, and 8.1% vs 3.4%, respectively; P = .015). CONCLUSIONS: Adding concurrent-adjuvant chemotherapy statistically significantly reduced failure and cancer-specific deaths when compared with radiotherapy alone. Although there was no statistically significant increase in major late toxicity, increase in noncancer deaths narrowed the resultant gain in overall survival.

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Version 5

Date

Summary of changes

06/11/2023

Reviewed and approved at the head and neck reference committee meeting 8th June 2023.  Summary of changes:​ Evidence table: Update meta-analysis Blanchard et al. 2015 to 2021. Include Zhang et al. 2022 a phase III trial. Updated NCCN guidelines to V1.2023. Include ESMO-EURACAN guidelines 2020. Include CSCO guidelines - 2021. Include ASCO guidelines - 2021.                 Efficacy: Update “Role of concurrent chemotherapy” sub section – update meta-analysis MAC-NPC to Blanchard et al. 2022 and remove Figures 1 and 2 (2015) update with Survival curves (Lancet Oncology, 2022). Delete "Radiation therapy quality' subsection. Include new subsection “Role of induction chemotherapy”. Include summary of Zhang et al. 2022 and Blanchard et al. 2021. Indications and patient population: Update AJCC reference from 7th to 8th edition. Include statement : Consider radiation therapy alone for low risk cT2N0.(CSCO/ASCO 2021) Moved  'Prior radiation therapy to the head and neck' from cautions to exclusions subsection and changed to more generic 'Previous high dose radiation therapy to same site' Remove links to eviQ chemotherapy based protocols as they now sit in related pages section. Include link to new protocol ID 3888 'Head and neck nasopharynx EBRT chemoradiation (post-induction chemotherapy)' after existing statement on post-induction chemoradiation. Clinical information: Changed ‘could’ to ‘should’ perform CT scan of head and neck +/- chest. Referrals to allied health specialities amalgamated into single statement. Include impact of timely diagnosis on head and neck cancers, and link to ‘Head & Neck Cancer, Australia's - Optimal Care Pathway’. Include flag to check the patient does not have claustrophobia or anxiety prior to simulation. Include word 'strongly' i.e "Patients should be strongly encouraged to cease smoking...". Simulation: Head position changed to ‘Head neutral’. Immobilisation and supports - remove ‘ankle supports’. Radiopaque markers - include ‘Consider wire’ option with notes- ‘Consider use of wire to delineate surgical scars or skin involvement’. Bolus - notes to read ‘Consider bolus for primary target volumes (PTV) close to the skin. Other imaging – note updated to include fusion and registration for tumour delineation. CT acquisition – notes updated to include consider metal artefact reduction. Medications – option included to ‘Consider pre-medication for mask anxiety’. Simulation note: regarding the use of a 3-5 mm soft tissue equivalent spacer removed. Dose prescription: Dose prescription table: Replace IMRT heading with VMAT. Prescription notes - Include statement - Increasing overall treatment time can compromise both locoregional control and overall survival (references to include : Hendry, J. H., S. M. Bentzen, R. G. Dale, et al. 1996 and Hua, Y. J., Y. F. Ou-Yang, X. Zou, et al. 2021).  Update 'Patients should be compensated for non-treatment days' to include methods of compensation e.g. bi-daily, treatment acceleration and/or hypofractionation. Include statement noting alternative 33 fraction schedules to be considered (references Chen et al.2021and Lee et al.2009). Target volumes: Target volume table: Update column headings to ‘Volumes’ and ‘Description’. Changes to CTV 56 based on new randomised phase 3 trial (Tang et al. 2022), include contralateral IV and Vb optional if ipsilateral neck involved. Target volume notes – Change heading to ‘Target volume guides’. Remove eviQ additional clinical information ‘ID 3222 Diagram and definition of neck node levels’. Include Biau et al 2019. Lymph node target volumes for definitive head and neck radiation therapy: a 2019 Update. Include resources for contouring patients with perineural spread. Organs at risk (OAR) Remove base of tongue as an OAR. Brachial plexus – remove dose references in ‘additional information’ and replace with statement about target volumes taking priority. Brainstem – remove – ‘Small volumes (1-10cc) max dose <59Gy for fraction doses <2Gy’ in additional information column and replace with statement : ‘Higher doses may be appropriate depending on clinical situation’. Carotid – include as new OAR structure , ALARA as ideal constraint, and minimise dose when no elective nodal irradiation involved. Cervical oesophagus - remove dose constraints from ‘additional information’. Globe - Include statement in ‘additional information’ re tighter constraints for anterior chamber. Glottis /supraglottic larynx – true structure constraint (ideal) = Mean ≤35 Gy. Remove ‘additional information’ comment about patients who have had total laryngectomy. Lacrimal gland – change from max dose to mean dose (i.e. mean dose ≤30 Gy). Lens - Ideal constraint to read D0.03cc ≤6 Gy (reduced from <10 Gy). In ‘additional information’ include option acceptable D0.03cc ≤15 Gy. Lips – Ideal constraint update mean to ≤30 Gy remove max dose <40 Gy. In ‘additional information’ remove alternative dose constraints. Split mandible and temporal mandibular joints (TMJ) into 2 distinct OAR. Mandible – remove actual maximum dose and replace with ‘Avoid hotspots falling in mandible’. Remove ‘additional information’ re: hot spots and include ‘Limiting volumes of intermediate doses may reduce risk of osteoradionecrosis’: V60 Gy < 14% V42 Gy < 30% (without pre-treat dental extractions) V50 Gy < 30% (with dental extractions) V56 Gy < 30% (without dental extractions). TMJ – Ideal constraint include max dose ≤65 Gy and 1cc ≤60 Gy. ‘Additional information’ – include contouring information for TMJ. Parotid glands – ‘Additional information’ – remove points referring to sparing one parotid and 20cc combined dose. Pharyngeal constrictors - Additional information – remove ‘up to 60Gy’ and include predicted risks of dysphagia. Include superior, middle and inferior pharyngeal constrictors as individual OAR. Ideal constraint is mean dose  ≤55 Gy. Temporal lobe/brain- ‘Ideal’- include nasopharyngeal or PNI options – D 0.03 cc ≤65 Gy for T1-T2 tumours. D0.03 cc ≤70 Gy for T3-T4 tumours. Additional information delete content ‘Max < 70 Gy may be considered’. Remove thyroid as an OAR  Pituitary – include as new OAR. Ideal for nasopharyngeal cancers D0.03cc ≤60Gy Additional information include – ‘Acceptable’ D0.03cc ≤65Gy. OAR notes – Include new subheading 'Suggested OAR contouring atlases'. ​Target verification: Modality – remove MV. Match point include note to check 'body contour'. Target verification notes: Consensus to remove following statement: 'Consideration should be given to dose delivered from verification imaging and whether this needs to be accounted for in treatment planning, particularly with respect to critical OARs'.   ​Side Effects  Include “Fatigue” as Late: Long-term side effect. Add neuropathy to myelopathy as a late side effect. Related Patient information protocol changes: Update content with current requisite eviQ shared content “What is aim of treatment? and  “Radiation therapy is given to destroy cancer cells and shrink the tumour”. Update “How long will this treatment take? section” with current requisite eviQ shared content sections When is treatment delivered and how long does each treatment take? and How long is a treatment course? Important information - agreed to update content with current requisite eviQ shared content. It includes more detailed information on fertility specifically in the “How does treatment affect fertility?” section.Other information about your treatment: agreed to modify content to only include mask information ( i.e. your mask and what if I feel nervous or claustrophobic). All other content previously in this section moved to 'General advice for people with cancer' section which supersedes FAQs section to bring into line with current requisite eviQ shared content. Review in 2 years.

Version 4

Date	Summary of changes
06/10/2020	Online external review. Minor updates to protocol. Review in 2 years.

Version 3

Date	Summary of changes
01/10/2014	New Protocol, approved and published on eviQ,Review Group 1.
31/05/2017	Transferred to new eviQ website. Version number increased 2.0.
13/07/2018	Reviewed at reference committee meeting 25th May 2018.  Approved and published on eviQ. Review group 2. Updated version number: 3.0.