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Accelerated fractionation (AF) compared to conventional fractionation (CF) improves loco-regional control in the radiotherapy of advanced head and neck cancers: Results of the EORTC 22851 randomized trial
Abstract
A 5 week-hyperfractionated and accelerated radiotherapy regimen without reduction of the total dose was developed to fight tumour repopulation during treatment and tumour hypoxia. The purpose of the study was to try to improve loco-regional control in high risk head and neck carcinoma treated with curative radiotherapy.
From 1985 to 1995, a randomised controlled trial of the EORTC Cooperative Group of Radiotherapy (EORTC 22851) compared the experimental regimen (72 Gy/45 fractions/5 weeks) to standard fractionation and overall treatment time (70 Gy/35 fractions/7 weeks) in T2, T3 and T4 head and neck cancers (hypopharynx excluded). The end-point criteria were local and loco-regional control, overall and disease-free survival, and acute and late toxicities. Five hundred twelve patients were accrued.
Patients in the AF (accelerated fractionation) arm did significantly better with regard to loco-regional control (P = 0.02) resulting at 5 years in a 13% gain (95% CI 3-23% gain) in loco-regional control over the CF (conventional fractionation) arm. This improvement is of larger magnitude in patients with poorer prognosis (N2-3 any T, T4 any N) than in patients with more favourable stage. Multivariate analysis confirmed AF as an independent prognostic factor of good prognosis for loco-regional control (P = 0.03). Specific survival shows a trend (P = 0.06) in favour of the AF arm. ACUTE AND LATE TOXICITIES: Acute and late toxicity were increased in the AF arm. Late severe functional irradiation damage occurred in 14% of patients of the AF arm versus 4% in the CF arm. Two cases of radiation-induced myelitis occurred after doses of 42 and 48 Gy to the spinal cord.
This trial shows that accelerated radiotherapy improves loco-regional control in head and neck squamous cell carcinomas. A less toxic scheme should, however, be investigated and documented before using accelerated radiotherapy as a standard regimen of curative radiotherapy for head and neck cancers.
... Over-acceleration could result in significant mucosal consequential damage due to overly intense dose accumulation throughout the scheduled time-frame (e.g. CAIR [12,13]; EORTC 22851 [14], BCCA 9113 [15]). Head and neck cancer (HNC) patients are at high risk of death from competing risks, such as treatment-related sequelae (e.g. ...
... Notwithstanding the improved outcome with the HF arm of this study, the current message from the study is not intended to influence practice with a specific RT protocol. Instead this randomized trial is illustrative by remaining the only pure clinical test of the hypotheses of the effects of increased total dose using smaller than conventional doses per fraction that is not also confounded by the influence of accelerated proliferation, since the schedule is completed within 4 weeks, but without excessive dose accumulation that may result in consequential injury with delayed healing of acute toxicity [13][14][15]. ...
... Therefore, smaller dose fractions should reduce late toxicity to allow higher total RT doses without increasing late toxicity. Several HF schedules have been tested in the clinical trial setting [14,26,[31][32][33]. The present trial schedule, a hyperfractionated accelerated RT schedule with augmented RT dose, is based on Withers et al's [4] initial observation that head and neck tumor clonogen repopulation accelerates at 4 (±1) weeks after the start of RT, and Table 2 Multivariable analysis for overall survival and loco-regional control. ...
Purpose/objectives:
To examine the therapeutic ratio and mortality profile over time in a radiotherapy randomized trial in stage III-IV larynx/pharynx cancer with long-term follow-up.
Materials/methods:
From 1988 to 1995, 331 cases were randomized to either hyperfractionated (HF) (58 Gy/40 fractions, twice daily) or conventional (CF) (51 Gy/20 fractions, once daily) radiotherapy. Overall survival (OS), locoregional (LRC), distant control (DC), ≥Grade 3 late toxicity (LT), and relative mortality risk profile over time were compared between both arms.
Results:
Median follow-up was 13.6 years. HF had a 10% improved OS at 5-years (40% vs 30%, p = 0.04), but the benefit diminished to 3% at 10-years (21% vs 18%). A trend towards higher LRC with HF remained (5-year: 49% vs 40%; 10-year: 49% vs 39%, p = 0.05). DC rates were unchanged (5-year: 87% vs 85%; 10-year: 87 vs 84%, p = 0.56). LT rates were similar (HF vs CF: 5-year: 9% vs 12%; 10-year: 11% vs 14%, p = 0.27). Multivariable analysis confirmed that HF reduced mortality risk by 31% [HR 0.69 (0.55-0.88), p < 0.01] and locoregional failure risk by 35% [HR 0.65 (0.48-0.89), p < 0.01]. Index cancer mortality (5-year: 46% vs 51%; 10-year: 49% vs 55%) was lower in the HF arm. Competing mortality (mostly smoking-related) was also numerically lower with HF at 5-years (14% vs 19%) but became similar at 10-years (30% vs 28%).
Conclusions:
This trial confirms that HF with augmented total dose has a durable 10% effect size on LRC with comparable LT. OS benefit is evident at 5-years (10%) but relative mortality risk profile changes in longer follow-up.
... Recently, improvements in locoregional control and survival along with organ preservation have been achieved by various aggressive approaches such as altered fractionation radiotherapy, concurrent chemoradiotherapy with or without targeted therapies [1][2][3][4]. However, this has also resulted in increased rates and severity of acute [1,5,6] and long-term [1,6] toxicities. ...
... Recently, improvements in locoregional control and survival along with organ preservation have been achieved by various aggressive approaches such as altered fractionation radiotherapy, concurrent chemoradiotherapy with or without targeted therapies [1][2][3][4]. However, this has also resulted in increased rates and severity of acute [1,5,6] and long-term [1,6] toxicities. ...
... At the end of a minimum of 4 years' posttreatment, 11 (27.5%) patients had documented clinically proven strictures with a median time of 9 months (range, 5.5-16) of treatment completion in the 3DCRT group compared to 8 months (range, [6][7][8][9][10][11][12][13][14][15][16][17][18] in the IMRT group. All of them were treated with definitive radiotherapy and had received concurrent chemotherapy or enteral tube feedings during EBRT. ...
Purpose
To quantify and compare dose-volume and dose-length parameters of cervical esophagus between three-dimensional conformal radiotherapy (3DCRT) and intensity-modulated radiation therapy (IMRT) and to correlate with incidence of cervical strictures in head and neck cancer irradiation with radical intent.
Materials and Methods
Forty consecutive head and neck cancers patients who received radical radiation therapy either with 3DCRT (n = 20) or IMRT (n = 20) between December 2011 and August 2012 were retrospectively analyzed and followed up for at least 4 years post-treatment completion.
Results
The volumes of cervical esophagus receiving ≥54 Gy (V54) and ≥60 Gy (V60) and lengths receiving circumferential dose of ≥50 Gy (L50) and ≥54 Gy (L54) were significantly higher in patients treated with IMRT as compared to 3DCRT (P ≤ .05). At the end of minimum 4 years' post-treatment, nine patients had documented symptomatic strictures; three patients were treated with 3DCRT and six patients with IMRT technique.
Conclusion
IMRT technique in entire-neck irradiation is associated with increased spillage dose to the cervical esophagus, and thereby increased risk for late sequelae. The cervical esophagus has to be considered as an organ at risk and constraints need to be given in IMRT planning, particularly for lower-neck irradiation.
... State of the art regarding radiation dose fractionation has evolved from once daily treatment to hyper fractionation and accelerated fractionation. [1][2][3][4] These newer strategies lead to a 7%-10% improvement in locoregional control relative to once daily treatment scheme. Most randomized clinical trials show the superiority of combined RT and chemotherapy to RT alone for the treatment of locally advanced, nonmetastatic squamous carcinoma of head and neck. ...
... [15] There are less consistent results of randomized trials of accelerated fractionation as accelerated treatment is given by different ways. [2,4,16] We adopted the concept of pure acceleration using, six instead of 5 treatment days in a week because it has shown to significantly increase the locoregional control rate with a trend toward improved DFS. In our study, there was no significant difference between accelerated fractionation and conventional fractionation, which is similar to the previous findings. ...
... Similar to other studies, in our study also mucous membrane was the most common site of Grade 3 acute reactions. [1,2,17,19] Grade 3 mucosal toxicity was also the most common late side effect. Contrary to this, according to RTOG 9003 trial, the pharynx and the salivary gland were the most common sites to have Grade 3 late effects. ...
Introduction:
The worldwide incidence of head and neck malignancy exceeds half a million cases annually. In radiotherapy (RT), conventional fractionation comprises giving five fractions per week from Monday to Friday. Accelerated RT includes administration of six fractions per week is being advocated. It gives better locoregional control and the median overall treatment time is 39 days as compared to 46 days in conventional group. Our study involved comparison of conventional versus accelerated RT with concurrent chemotherapy, in evaluation of local control and toxicity in the two arms.
Materials and methods:
Sixty patients of locally advanced squamous cell carcinoma head and neck region were studied. All the patients received cisplatin (30 mg/m2) weekly during the therapy. The patients received RT dose of 70 Gray (Gy) in 35 fractions (#). The patients were randomly assorted into two groups: Group 1 - Study group (n = 30) - Six fractions RT per week (Monday-Saturday). Group 2 - Control group (n = 30) - Five fractions RT per week (Monday-Friday). During and after the treatment, locoregional control, acute and late radiation toxicity were assessed. Results and Observation: There was no significant difference between the two schedules regarding locoregional control rate. The Grade 3 or higher acute toxicities were significantly higher in the accelerated arm although there was no significant difference in late toxicities between the two arms.
Conclusion:
Accelerated fractionation regimen was not more efficacious than conventional fractionation in the treatment of previously untreated head and neck carcinoma.
... Studies showed that the prolongation of the overall treatment time resulted in worse outcomes of radiotherapy and doubling time of tumour cells might be reduced during RT to 5 days [10] . Clinical studies on head and neck cancers irradiation have shown the importance of treatment time for local control of disease [10][11][12][13] . Radiotherapy plans based on physical dose distributions do not necessarily reflect on the biological effects under various irradiation schemes. ...
... The linear-quadratic (LQ) model is used by radiologists as a convenient tool to quantify biological effects of radiotherapy [14][15][16] . Inadequate BED delivery to the treated volume is frequently identified as a possible cause of failure in the radiotherapy of cancers [10][11][12][13]17,18] . EQD 2 (biologically equivalent dose in 2 Gy fraction) is logistically and conceptually equivalent to BED, but has numerical values which can be directly related to clinical experience as the method converts treatments into isoeffective schedules of 2 Gy fractions [19] . ...
... The purpose of this paper is to share our experience of the use of brachytherapy boost in NPC which is most cost effective in our setting. The predictive quality of linear quadratic model in the radiotherapy of patients with NPC has been discussed in literatures [10][11][12][13] . Jones et al. [37] suggested that the concept of biological effective dose is useful for quantifying the treatment expectations; however, a careful interpretation of results is required before clinical decision. ...
Abstract: The aim of this study is to evaluate the decrease of EQD2 (biologically equivalent dose in 2 Gy fraction)
and its correlation with local control of tumour in the treatment of the advanced nasopharyngeal carcinoma (NPC)
when the overall treatment time is prolonged. A retrospective study was carried out on 43 advanced NPC (stage Ⅲ
and Ⅳ) treated with fractionated High Dose Rate (HDR)–Brachytherapy boost, following external beam radiation
therapy and chemotherapy in the period from 2009 to 2015. All patients were irradiated using a cobalt unit and a
technique that employed two laterals, opposed fields with a dose of (66 ± 4) Gy. It was followed by HDR –Intra
Luminal Radiotherapy after having a gap. The total EQD2 prescribed was (84.75 ± 7) Gy (range, 75–100.5 Gy).
The probabilities of disease recurrence within a median follow-up of 24 months (range, 10–78 months) are
expected as 0.12, 0.48 and 0.97 (P=0.05) for the overall treatment time of 75, 150 and 250 days respectively. The
relative risk of local recurrence of Stage IV NPC patient is about 2.30 times higher than stage Ⅲ patients. The
increase of total treatment time may be of different origin resulting in the fall of EQD2. It was observed that the
recurrence of disease is significant (P < 0.05) when the overall treatment time is above 100 days where EQD2 lost
becomes more than 0.10 Gy/day. The relative risk of disease recurrence of Stage Ⅳ is observed higher than stage
Ⅲ nasopharyngeal patients.
... Studies showed that the prolongation of the overall treatment time resulted in worse outcomes of radiotherapy and doubling time of tumour cells might be reduced during RT to 5 days [10] . Clinical studies on head and neck cancers irradiation have shown the importance of treatment time for local control of disease [10][11][12][13] . Radiotherapy plans based on physical dose distributions do not necessarily reflect on the biological effects under various irradiation schemes. ...
... The linear-quadratic (LQ) model is used by radiologists as a convenient tool to quantify biological effects of radiotherapy [14][15][16] . Inadequate BED delivery to the treated volume is frequently identified as a possible cause of failure in the radiotherapy of cancers [10][11][12][13]17,18] . EQD 2 (biologically equivalent dose in 2 Gy fraction) is logistically and conceptually equivalent to BED, but has numerical values which can be directly related to clinical experience as the method converts treatments into isoeffective schedules of 2 Gy fractions [19] . ...
... The purpose of this paper is to share our experience of the use of brachytherapy boost in NPC which is most cost effective in our setting. The predictive quality of linear quadratic model in the radiotherapy of patients with NPC has been discussed in literatures [10][11][12][13] . Jones et al. [37] suggested that the concept of biological effective dose is useful for quantifying the treatment expectations; however, a careful interpretation of results is required before clinical decision. ...
The aim of this study is to evaluate the decrease of EQD2 (biologically equivalent dose in 2 Gy fraction) and its correlation with local control of tumour in the treatment of the advanced nasopharyngeal carcinoma (NPC) when the overall treatment time is prolonged. A retrospective study was carried out on 43 advanced NPC (stage Ⅲ and Ⅳ) treated with fractionated High Dose Rate (HDR)–Brachytherapy boost, following external beam radiation therapy and chemotherapy in the period from 2009 to 2015. All patients were irradiated using a cobalt unit and a technique that employed two laterals, opposed fields with a dose of (66 ± 4) Gy. It was followed by HDR –Intra Luminal Radiotherapy after having a gap. The total EQD2 prescribed was (84.75 ± 7) Gy (range, 75–100.5 Gy). The probabilities of disease recurrence within a median follow-up of 24 months (range, 10–78 months) are expected as 0.12, 0.48 and 0.97 (P=0.05) for the overall treatment time of 75, 150 and 250 days respectively. The relative risk of local recurrence of Stage IV NPC patient is about 2.30 times higher than stage Ⅲ patients. The increase of total treatment time may be of different origin resulting in the fall of EQD2. It was observed that the recurrence of disease is significant (P < 0.05) when the overall treatment time is above 100 days where EQD2 lost becomes more than 0.10 Gy/day. The relative risk of disease recurrence of Stage Ⅳ is observed higher than stage Ⅲ nasopharyngeal patients.
... Treatments were ranked using the P score, which measures the mean extent of certainty that a treatment is better than the competing treatments. 11 A P score of 100% indicates that a treatment is certain to be the best and 0% indicates that a treatment is certain to be the worst. We computed the 5-year absolute benefit using the survival rate at 5 years for the locoregional therapy-only groups as the reference, and we computed the HR (95% CI) using the method by Stewart and Parmar 12 for overall survival and event-free survival. ...
... The network is presented in figure 1. A description of treatment modalities is given in the appendix (p 2), a list of trials included in each treatment comparison is given in the appendix (pp 3-4), and the main characteristics of each trial are presented in the appendix (pp [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21] Some trials had no data or events for specific secondary endpoints and were excluded from the corresponding analysis (appendix pp [39][40]. The results of event-free survival are in agreement with overall survival; heterogeneity was still present (p=0•054), and no inconsistency (p=0•52) was detected for this endpoint (table 1). ...
BACKGROUND: Randomised, controlled trials and meta-analyses have shown the survival benefit of concomitant chemoradiotherapy or hyperfractionated radiotherapy in the treatment of locally advanced head and neck cancer. However, the relative efficacy of these treatments is unknown. We aimed to determine whether one treatment was superior to the other. METHODS: We did a frequentist network meta-analysis based on individual patient data of meta-analyses evaluating the role of chemotherapy (Meta-Analysis of Chemotherapy in Head and Neck Cancer [MACH-NC]) and of altered fractionation radiotherapy (Meta-Analysis of Radiotherapy in Carcinomas of Head and Neck [MARCH]). Randomised, controlled trials that enrolled patients with non-metastatic head and neck squamous cell cancer between Jan 1, 1980, and Dec 31, 2016, were included. We used a two-step random-effects approach, and the log-rank test, stratified by trial to compare treatments, with locoregional therapy as the reference. Overall survival was the primary endpoint. The global Cochran Q statistic was used to assess homogeneity and consistency and P score to rank treatments (higher scores indicate more effective therapies). FINDINGS: 115 randomised, controlled trials, which enrolled patients between Jan 1, 1980, and April 30, 2012, yielded 154 comparisons (28 978 patients with 19 253 deaths and 20 579 progression events). Treatments were grouped into 16 modalities, for which 35 types of direct comparisons were available. Median follow-up based on all trials was 6·6 years (IQR 5·0-9·4). Hyperfractionated radiotherapy with concomitant chemotherapy (HFCRT) was ranked as the best treatment for overall survival (P score 97%; hazard ratio 0·63 [95% CI 0·51-0·77] compared with locoregional therapy). The hazard ratio of HFCRT compared with locoregional therapy with concomitant chemoradiotherapy with platinum-based chemotherapy (CLRTP) was 0·82 (95% CI 0·66-1·01) for overall survival. The superiority of HFCRT was robust to sensitivity analyses. Three other modalities of treatment had a better P score, but not a significantly better HR, for overall survival than CLRTP (P score 78%): induction chemotherapy with taxane, cisplatin, and fluorouracil followed by locoregional therapy (ICTaxPF-LRT; 89%), accelerated radiotherapy with concomitant chemotherapy (82%), and ICTaxPF followed by CLRT (80%). INTERPRETATION: The results of this network meta-analysis suggest that further intensifying chemoradiotherapy, using HFCRT or ICTaxPF-CLRT, could improve outcomes over chemoradiotherapy for the treatment of locally advanced head and neck cancer. FUNDINGS: French Institut National du Cancer, French Ligue Nationale Contre le Cancer, and Fondation ARC.
... Treatments were ranked using the P score, which measures the mean extent of certainty that a treatment is better than the competing treatments. 11 A P score of 100% indicates that a treatment is certain to be the best and 0% indicates that a treatment is certain to be the worst. We computed the 5-year absolute benefit using the survival rate at 5 years for the locoregional therapy-only groups as the reference, and we computed the HR (95% CI) using the method by Stewart and Parmar 12 for overall survival and event-free survival. ...
... The network is presented in figure 1. A description of treatment modalities is given in the appendix (p 2), a list of trials included in each treatment comparison is given in the appendix (pp 3-4), and the main characteristics of each trial are presented in the appendix (pp [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21] Some trials had no data or events for specific secondary endpoints and were excluded from the corresponding analysis (appendix pp [39][40]. The results of event-free survival are in agreement with overall survival; heterogeneity was still present (p=0•054), and no inconsistency (p=0•52) was detected for this endpoint (table 1). ...
Background
Randomised, controlled trials and meta-analyses have shown the survival benefit of concomitant chemoradiotherapy or hyperfractionated radiotherapy in the treatment of locally advanced head and neck cancer. However, the relative efficacy of these treatments is unknown. We aimed to determine whether one treatment was superior to the other.
Methods
We did a frequentist network meta-analysis based on individual patient data of meta-analyses evaluating the role of chemotherapy (Meta-Analysis of Chemotherapy in Head and Neck Cancer [MACH-NC]) and of altered fractionation radiotherapy (Meta-Analysis of Radiotherapy in Carcinomas of Head and Neck [MARCH]). Randomised, controlled trials that enrolled patients with non-metastatic head and neck squamous cell cancer between Jan 1, 1980, and Dec 31, 2016, were included. We used a two-step random-effects approach, and the log-rank test, stratified by trial to compare treatments, with locoregional therapy as the reference. Overall survival was the primary endpoint. The global Cochran Q statistic was used to assess homogeneity and consistency and P score to rank treatments (higher scores indicate more effective therapies).
Findings
115 randomised, controlled trials, which enrolled patients between Jan 1, 1980, and April 30, 2012, yielded 154 comparisons (28 978 patients with 19 253 deaths and 20 579 progression events). Treatments were grouped into 16 modalities, for which 35 types of direct comparisons were available. Median follow-up based on all trials was 6·6 years (IQR 5·0–9·4). Hyperfractionated radiotherapy with concomitant chemotherapy (HFCRT) was ranked as the best treatment for overall survival (P score 97%; hazard ratio 0·63 [95% CI 0·51–0·77] compared with locoregional therapy). The hazard ratio of HFCRT compared with locoregional therapy with concomitant chemoradiotherapy with platinum-based chemotherapy (CLRTP) was 0·82 (95% CI 0·66–1·01) for overall survival. The superiority of HFCRT was robust to sensitivity analyses. Three other modalities of treatment had a better P score, but not a significantly better HR, for overall survival than CLRTP (P score 78%): induction chemotherapy with taxane, cisplatin, and fluorouracil followed by locoregional therapy (ICTaxPF-LRT; 89%), accelerated radiotherapy with concomitant chemotherapy (82%), and ICTaxPF followed by CLRT (80%).
Interpretation
The results of this network meta-analysis suggest that further intensifying chemoradiotherapy, using HFCRT or ICTaxPF-CLRT, could improve outcomes over chemoradiotherapy for the treatment of locally advanced head and neck cancer.
Fundings
French Institut National du Cancer, French Ligue Nationale Contre le Cancer, and Fondation ARC.
... The French/American School, which developed the basis for radiotherapy on a stem cell rationale (among others boosting the most dense tumor areas and given smaller doses to elective volumes), was subsequently brought back to Europe by some of the pupils of Fletcher. Not least by Jean Claude Horiot, who through leadership in clinical multinational EORTC trials [14][15][16][17][18][19][20], eventually created a concept and basis upon which today's European radiotherapy is build. ...
... Substantial progress in radiotherapy was found in understanding the biological nature and variation among tumors and normal tissue. This was a time when collaboration especially was linked to large (often multinational and multidisciplinary) clinical trials [15,16,26,[36][37][38][39][40]. Translational research focused on identifying radiosensitivity through knowledge of hypoxia, tumor proliferation and radiosensi-tivity -it was the era of SF2, Tpot and pO2 measurements [22,24,[41][42][43][44][45][46][47]. ...
... Human literature data report attempts to improve similar poor outcomes for tonsillar SCC by combining conventional radiotherapy regimens and chemotherapy simultaneously, and by altering radiation fractionation using hyperfractionated and/or accelerated treatment schedules especially for the treatment of inoperable and advanced head and neck SCC. [72][73][74][75] Accelerated repopulation of tumor cells during the conventional fractionated radiotherapy regimen has been recognized as an important determinant of local control and possible cause of treatment failure in head and neck SCC, especially if the overall treatment time is prolonged. 45,46 This hypothesis is supported by laboratory and clinical data that have shown median potential doubling times in many SCC lesions of only approximately 4-days. ...
... However, this accelerated protocol is inherently associated with an increase in acute side effects. [73][74][75]77,78 Radiation treatment possibilities for the 3 canine cases presented here included the use of a standard definitive daily radiation therapy protocol consisting of 3 Gy per fraction in 16-18 treatment days to a total dose of 48-54 Gy. 9 Although an accelerated chemoradiotherapy protocol consisting of 3.5 Gy fractions to a total of 49 Gy delivered BID over 9-days has not been described for the treatment of canine oropharyngeal SCC, it was suggested as an alternative option. Again, the rationale for this latter protocol was related to the specific biological behavior of SCC, especially aggressive tonsillar SCC. ...
Accelerated radiation therapy protocols address the specific biology of aggressive oropharyngeal squamous cell carcinoma and this approach was applied in 5 feline and 3 canine oropharyngeal squamous cell carcinoma patients where surgery was not possible (4/5 feline and 2/3 canine cases) or was declined (1/5 feline and 1/3 canine cases). A protocol using 14 fractions of 3.5 Gy over 9-days, combined with carboplatin chemotherapy as a radiosensitiser (total dose 180 mg/m2 in feline and 300 mg/m2 in canine cases) resulted in a complete tumor response in most cases (4/5 feline and 3/3 canine cases) with acceptable acute and long-term side effects. Results achieved in feline cases correspond with published data where these specific radiotherapy protocols were employed. A complete response and long-term survival (> 2-years) was achieved in all canine patients. Although no standardized chemoradiotherapy protocols currently exist, this therapeutic approach can be a useful addition for the management of oropharyngeal squamous cell carcinoma of cats and dogs when the goals of treatment include maximizing tumor control while maintaining function and quality of life.
... Most of the loco-regional failures in patients undergoing intensity-modulated radiation therapy (IMRT) occur within areas receiving the highest prescribed radiation dose [94]. While an increased radiation dosage can enhance local control due to a dose-response relationship, intensified treatment targeting the entire GTV may increase toxicity, necessitating cautious consideration [95]. Tumor sub-volumes with increased metabolism and hypoxia often exhibit increased radio resistance, making them more resistant to standard treatment approaches, as documented in several studies where PET/CT with specific hypoxia tracers was used to personalize radiotherapy doses [96][97][98]. ...
Simple Summary
Among head–neck tumors, squamous cell carcinoma is the most frequent histotype and includes a range of malignancies with different sites of origin as well as different therapeutic strategies and clinical outcomes. In daily practice, patients with head–neck squamous cell carcinoma are seen in various clinical settings, requiring a multidisciplinary approach to therapeutic decisions and clinical care. ¹⁸F-FDG PET/CT plays a well-defined role in the management of these tumors for pre-treatment staging and radiotherapy planning as well as treatment-response assessment and post-therapy follow-up. This paper is an overview of the standard use of ¹⁸F-FDG PET/CT in the various clinical scenarios of head–neck squamous cell carcinoma. Also, emerging applications will be reviewed, including the use of radiopharmaceuticals other than ¹⁸F-FDG, PET/MRI implementation in clinical practice, and the use of radiomics and machine learning.
Abstract
This article provides an overview of the use of ¹⁸F-FDG PET/CT in various clinical scenarios of head–neck squamous cell carcinoma, ranging from initial staging to treatment-response assessment, and post-therapy follow-up, with a focus on the current evidence, debated issues, and innovative applications. Methodological aspects and the most frequent pitfalls in head–neck imaging interpretation are described. In the initial work-up, ¹⁸F-FDG PET/CT is recommended in patients with metastatic cervical lymphadenectomy and occult primary tumor; moreover, it is a well-established imaging tool for detecting cervical nodal involvement, distant metastases, and synchronous primary tumors. Various ¹⁸F-FDG pre-treatment parameters show prognostic value in terms of disease progression and overall survival. In this scenario, an emerging role is played by radiomics and machine learning. For radiation-treatment planning, ¹⁸F-FDG PET/CT provides an accurate delineation of target volumes and treatment adaptation. Due to its high negative predictive value, ¹⁸F-FDG PET/CT, performed at least 12 weeks after the completion of chemoradiotherapy, can prevent unnecessary neck dissections. In addition to radiomics and machine learning, emerging applications include PET/MRI, which combines the high soft-tissue contrast of MRI with the metabolic information of PET, and the use of PET radiopharmaceuticals other than ¹⁸F-FDG, which can answer specific clinical needs.
... Radiation therapy is an effective, non-invasive technique shown to improve overall survival and local control in patients with head and neck cancer (HNC), the 8th most common cancer globally. [1][2][3] However, the delivery of higher radiation doses is counterbalanced by toxicities to the healthy tissue, notably radiation-induced oral mucositis. [4][5][6] These toxicities can greatly reduce patients' quality of life and lead to treatment breaks. ...
Oral stents may reduce toxicities during radiation therapy for head and neck cancer (HNC). Although customized 3D-printed oral stents are more quickly fabricated and non-inferior (in terms of patient reported outcomes) compared to conventionally-fabricated stents, the design process is still relatively time-consuming, unstandardized, and requires experienced technicians. We hypothesized that semi-automating the 3D-printed stent design process can reduce design time and standardize the workflow. Using oral stent design principles established over decades by oral oncologists, we developed a customized computer program (Autostent) using MATLAB to semi-automate the design process. We then compared a previously described method utilizing non-automated computer-aided design with Autostent. Three users designed stents for four patients with HNC enrolled on a prospective observational study. These patients were selected based on differing dental anatomies, and each user designed stents for each patient thrice, using both the non- and semi-automated methods. The design time and stent volumes for the two methods were statistically analyzed. Semi-automation was found to significantly reduce the average design time by 23.6 minutes (51.2%, p=0.001), independent of user, dental anatomy, and trial number. Additionally, semi-automation reduced the average stent volume by 4.33 mL (12.9%, p=0.016, univariate analysis). While this was not statistically significant after accounting for the other experimental variables (p=0.40, multivariate analysis), semi-automation did reduce the variability in the stent volume across users (overall standard error of the mean reduced by 40%). Thus, the semi-automated workflow significantly reduced the design time and the variability in the stent volume across users compared to the non-automated workflow. This may lead to potential cost benefits, standardization of the device, and increased population-wide access to a device that could help reduce toxicities for HNC.
... En relación al fraccionamiento de RT empleado, encontramos mayores tasas de mucositis aguda moderada-severa entre los pacientes tratados con fraccionamientos alterados respecto al fraccionamiento convencional (58% vs 35.5%, p= 0.000). Esto coincide con algunos ensayos publicados comparando ambos fraccionamientos con mayores índices de toxicidad aguda, en especial mucosa, con el empleo de los fraccionamientos alterados (Horiot et al, 1997;Poulsen et al, 2001). ...
Causas de muerte en cáncer de cabeza y cuello tratados con diferentes esquemas de radioterapia.
... Regarding RT alone, accelerated hyperfractionated irradiation has been shown to be superior to normofractionated irradiation in terms of local control and OS (27,28). However, in terms of toxicity, hyperfractionation is significantly more toxic (27,29). Meta-analyses have shown a survival benefit for the addition of cisplatin-based chemotherapy to definitive RT in locally advanced HNSCC (30,31). ...
Background:
Comorbidity and frailty are relevant limitations of normofractionated combined radiochemotherapy for squamous cell head and neck cancer (HNSCC), especially in elderly patients. This retrospective study aimed to evaluate the efficacy and toxicity of moderately hypofractionated radiotherapy (HRT) without chemotherapy in patients ineligible for concurrent radiochemotherapy.
Patients and methods:
Between 2011 and 2018, 51 elderly/frail patients with HNSCC were treated with either definitive (n=23) or adjuvant (n=28) moderate HRT. A dose of 45 Gy was given to the primary tumour region and cervical nodes with a sequential boost up to 50 in the adjuvant and 55 Gy in the definitive cure setting (2.5 Gy/fraction). Patient outcomes of locoregional control, overall survival, and acute and late toxicity were analysed.
Results:
After a median follow-up of 6 months for the definitive HRT group and 28.5 months for the adjuvant HRT group, we found a median overall survival of 6 vs. 55 months (log-rank test: p<0.001) and a median locoregional control of 9 months vs. not reached (log-rank test: p=0.008), respectively. The 2-year rates of locoregional control were 28.5% for the definitive HRT group vs. 75.2% for the adjuvant HRT group. No acute or late grade 4-5 toxicity occurred; grade 3 toxicity was rarely documented.
Conclusion:
HRT in elderly/frail patients with HNSCC who are unfit for chemotherapy leads to acceptable local control with moderate toxicity in a short overall treatment time. Especially in the postoperative situation, HRT can be considered an appropriate alternative to normofractionated radio(chemo)therapy. Definitive HRT can be a treatment alternative, especially for multimorbid patients.
... Previous studies of radical dose escalation to the tumor in SCCHN have been limited by significant toxicities. [12][13][14] The success of a dose escalation approach may depend on identifying RT-resistant tumor subvolumes (eg, hypoxic tumor niches) that are spatially and temporally stable and being able to deliver higher doses to these subvolumes safely without exceeding normal tissue tolerance. Several trials are ongoing to evaluate the roles of magnetic resonance imaging (MRI)− and positron emission tomography (PET)−based adaptive RT for dose escalation to optimize local control for SCCHN (eg, NCT01341535, NCT02031250, and NCT03376386). ...
... Patients with advanced stage T3-T4 primary tumors have a worse prognosis compared with lower T stages, 27 and accelerated RT, resulting in a higher biologically effective dose, has been shown to be more beneficial in the treatment of more advanced tumors. 28 The efficacy of dose escalation to 73.1 Gy to the primary tumor was a secondary objective of this study. The prematurely stopped inclusion in the trial prevents this analysis. ...
PURPOSE
We performed an open-label randomized controlled phase III study comparing treatment outcome and toxicity between radiotherapy (RT) with concomitant cisplatin versus concomitant cetuximab in patients with locoregionally advanced head and neck squamous cell carcinoma (HNSCC; stage III-IV according to the Union for International Cancer Control TNM classification, 7th edition).
MATERIALS AND METHODS
Eligible patients were randomly assigned 1:1 to receive either intravenous cetuximab 400 mg/m ² 1 week before start of RT followed by 250 mg/m ² /wk, or weekly intravenous cisplatin 40 mg/m ² , during RT. RT was conventionally fractionated. Patients with T3-T4 tumors underwent a second random assignment 1:1 between standard RT dose 68.0 Gy to the primary tumor or dose escalation to 73.1 Gy. Primary end point was overall survival (OS) evaluated using adjusted Cox regression analysis. Secondary end points were locoregional control, local control with dose-escalated RT, pattern of failure, and adverse effects.
RESULTS
Study inclusion was prematurely closed after an unplanned interim analysis when 298 patients had been randomly assigned. At 3 years, OS was 88% (95% CI, 83% to 94%) and 78% (95% CI, 71% to 85%) in the cisplatin and cetuximab groups, respectively (adjusted hazard ratio, 1.63; 95% CI, 0.93 to 2.86; P = .086). The cumulative incidence of locoregional failures at 3 years was 23% (95% CI, 16% to 31%) compared with 9% (95% CI, 4% to 14%) in the cetuximab versus the cisplatin group (Gray’s test P = .0036). The cumulative incidence of distant failures did not differ between the treatment groups. Dose escalation in T3-T4 tumors did not increase local control.
CONCLUSION
Cetuximab is inferior to cisplatin regarding locoregional control for concomitant treatment with RT in patients with locoregionally advanced HNSCC. Additional studies are needed to identify possible subgroups that still may benefit from concomitant cetuximab treatment.
... Published studies revealed that almost of all HNC patients undergoing RT would experience oral mucositis (7). Evidence also suggested that about half of HNC patients experience grade 3 and above oral mucositis if exposure of the large mucosal surface to 66-70 Gy radiation in 6-7 weeks with 1.8-2 Gy per fraction (8)(9)(10). Oral mucositis leads to pain, difficulty swallowing, nutritional issues, increased risk of infection and treatment interruption. ...
Background: Oral mucositis is one of the most frequent, irreversible and distressing complications faced by head and neck cancer (HNC) patients undergoing radiotherapy. Several studies have investigated the role of honey in the prevention and alleviation of radiation-induced oral mucositis in HNC patients, however, a definitive conclusion has not yet been generated. We performed this updated systematic review and meta-analysis to inveterate whether honey can prevent and alleviate radiation-induced oral mucositis in HNC patients. Methods: We searched PubMed, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL) and China National Knowledge Infrastructure (CNKI) through October 2019. We searched and selected literature, extracted data and assessed risk of bias accordingly, and then conducted statistical analyses with RevMan software version 5.3. Results: Seven trials involving 412 patients were included in the final analysis. Meta-analyses showed that honey did not decrease the incidence of radiation-induced oral mucositis [(relative risk (RR), 0.69; 95% confidence interval (CI), 0.40-1.18; P=0.18]; however, relieved the severity of oral mucositis (RR, 0.22; 95% CI, 0.13-0.38; P<0.001), maintained or increased weight (RR, 1.92; 95% CI, 1.33-2.77; P<0.001) and reduced the treatment interruption related to oral mucositis (RR, 0.13; 95% CI, 0.02-0.97; P=0.05). Qualitative analysis also revealed a decreased incidence of oral mucositis in the honey group. Conclusions: Based on limited evidence, honey may have a clinical benefit against radiation-induced oral mucositis in HNC patients. However, future trials with large-scale and rigorous methods are warranted to further establish the role of honey in the management of radiation-induced oral mucositis.
... These studies test the validity of single time results by comparing them to those obtained from multiple time measurements when the steady-state assumption is questionable. The third issue considered is how better estimates of T G2ϩM alter the estimates of T pot , which has been the basis of several large-scale clinical trials (3,6,7,9,10,(15)(16)(17)21,25,34). More precisely, because most clinical studies are based on stratifying patients according to T pot values, the question studied is whether a tumor classified as fast growing (short T pot ) by older methods would still be fast growing by a new method of analysis. ...
Background
Estimating the duration of S phase (TS ) and the potential doubling time (Tpot ) from a single time measurement of the movement of cells using bivariate cytometry is common. However, these estimates require an assumption of the duration of G2 + M (TG2+M ). Inspection of the measured dynamic quantities, relative movement [RM(t)], fractions of labeled divided and undivided cells (flu(t) and fld(t)) suggests that TG2+M, TS, and Tpot can be determined simultaneously.
Methods
An equation connecting the growth of the cell population, time, and the dynamic quantities was determined. The equation cannot be solved analytically, but accurate approximations can be used to find Tpot. From this result, the value of TG2+M can be determined from fld(t), and TS can be determined from RM(t).
Results
Kinetic parameters obtained from single time estimates using the new method compared to those obtained from the analysis of multiple time‐point measurements of MCa‐K and MCa‐4 murine tumors are shown to be in close agreement. Moreover, estimates of TG2+M in MCa‐4 tumors, treated with paclitaxel, provide extra information on the changes in TG2+M. When applied to the rat R3327‐G prostate tumor model following androgen ablation, a correlation analysis of the Tpot values obtained by the new and previous single time‐point methods demonstrates that the rank order from shortest to longest Tpot values are largely preserved.
Conclusions
The new procedure makes direct estimation of TG2+M possible from single time‐dynamic measurements. The results from previous studies on TS and Tpot are largely unchanged, but extra information is now available. Cytometry 41:1–8, 2000 © 2000 Wiley‐Liss, Inc.
... 216 A more rapidly accelerated regimen of 72Gy in five weeks (three fractions per day at four hourly intervals) improves locoregional control, but also significantly increases grade 3 and 4 acute and late effects. 220 6.3.4 DECREASED TOTAl DOSE AND vERy ACCElERATED FRACTIONATION very rapid acceleration of radiotherapy with a decreased total dose, for example, continuous hyperfractionated accelerated radiotherapy (CHART, 54Gy in 36 fractions over 12 days) does not improve or reduce locoregional control or survival in patients with early (excluding T1N0) or locally advanced disease. ...
In 2005-6 I was surgical senior editor of the SIGN Guidelines. This guideline was withdrawn in 2015.
National Head and Neck Cancer Guideline for SIGN
... Several meta-analyses and randomized studies have proven the beneficial role of concomitant chemotherapy in combination with RT, especially regarding cisplatin chemotherapy, showing superior local control and OS rates in laryngeal/hypopharyngeal tumors as well as in other HNC either in the primary or postoperative setting [5,15,[25][26][27]. Besides an EQD2 > 70 Gy achieved by using fractionation doses >2Gy, we could identify a significant impact of cisplatin chemotherapy on LPFS only [28,29]. ...
Purpose
Salvage surgery of recurrent hypopharyngeal and laryngeal squamous cell carcinoma (SCC) results in limited local control and survival rates. As a result of recent technological progress, radiotherapy (RT) has become a valuable, potentially curative therapeutic option. Thus, we aimed to determine prognostic factors for survival outcome in order to optimize patient selection for salvage radiotherapy after failure of first-line treatment with surgery alone in this special patient cohort.
Methods
Seventy-five patients (85% male, median age of 64 years) underwent salvage RT in a secondary setting for recurrent hypopharyngeal or laryngeal SCC after prior surgery alone between 2007 and 2017. On average, patients were treated with one prior surgery (range 1–4 surgeries). Median time between surgery and salvage RT was 7 months (range 1–47 months) for initially advanced tumors (T3/4, N+, extracapsular spread) and 18 months (range 5–333 months) for initially early stage tumors. The majority of patients received concomitant chemotherapy (n = 48; 64%) or other kind of systemic treatment concurrent to radiotherapy (n = 10; 13%).
Results
Median follow-up was 41 months (range 3–120 months). Overall, fifteen patients were diagnosed with local failure (all were in-field) at last follow-up (20%). Median time to recurrence was 35 months (range 3–120 months) and 3-year local progression-free survival (LPFS) was 75%, respectively. Dose-escalated RT with 70.4 Gy applied in 2.1 Gy or 2.2 Gy fractions corresponding an EQD2 > 70 Gy (p = 0.032) and the use of concomitant cisplatin weekly chemotherapy (p = 0.006) had a significant positive impact on LPFS. 3-year OS and DPFS were 76 and 85%, respectively. No toxicity-related deaths occurred. Reported grade > 3 side effects were rare (n = 4/70, 6%).
Conclusion
Salvage radiotherapy resulted in excellent local control rates while radiation dose and the use of cisplatin weekly chemotherapy were identified as prognostic factors for LPFS. Nevertheless, patient selection for curative salvage treatment remains challenging.
... For any single radiation modality, the optimal number of fractions and the corresponding dose in each fraction depend on (i) the relative difference between the tumour's and the healthy tissue's biological response to that modality, (ii) the dose deposition profile of that modality with respect to the anatomy of the irradiated area and (iii) the tumour proliferation rate. The trade-offs in determining an optimal number of fractions and doses have been studied over the past several decades mainly for photon therapy (Rockwell, 1988;Fowler, 1990Fowler, , 2001Fowler, , 2007Fowler, , 2008Fowler & Ritter, 1995;Jones et al., 1995;Horiot et al., 1997Horiot et al., , 1992Fu et al., 2000;Garden, 2001;Armpilia et al., 2004;Ahamad et al., 2005;Trotti et al., 2005;Yang & Xing, 2005;Ho et al., 2009;Marzi et al., 2009;Arcangeli et al., 2010;Kader et al., 2011;Keller et al., 2012;Mizuta et al., 2012;Bertuzzi et al., 2013;Unkelbach et al., 2013a, b;Bortfeld et al., 2015;Saberian et al., 2015Saberian et al., , 2016Saberian et al., , 2017Badri et al., 2016). 364 S. NOUROLLAHI ET AL. ...
The goal in external beam radiotherapy (EBRT) for cancer is to maximize damage to the tumour while limiting toxic effects on the organs-at-risk. EBRT can be delivered via different modalities such as photons, protons and neutrons. The choice of an optimal modality depends on the anatomy of the irradiated area and the relative physical and biological properties of the modalities under consideration. There is no single universally dominant modality. We present the first-ever mathematical formulation of the optimal modality selection problem. We show that this problem can be tackled by solving the Karush-Kuhn-Tucker conditions of optimality, which reduce to an analytically tractable quartic equation. We perform numerical experiments to gain insights into the effect of biological and physical properties on the choice of an optimal modality or combination of modalities.
... 10 Many modified fractionation schemes have shown an improvement in overall survival (OS) and locoregional control (LRC) compared to standard fractionation in randomized clinical trials. [11][12][13][14][15][16][17][18] Several meta-analyses have compared two different radiotherapy methods with or without chemotherapy. [19][20][21][22][23] However, randomized comparisons of all these strategies have not been carried out so far. ...
Objectives
A Bayesian network meta-analysis (NMA) was conducted in patients with head and neck cancers (HNCs) to estimate the efficacy and safety of treatment with conventional fractionation radiotherapy (CF), conventional fractionation chemoradiotherapy (CF_CRT), hyperfractionated radiotherapy (HF), hyperfractionated chemoradiotherapy (HF_CRT), accelerated fractionation radiotherapy, accelerated fractionation chemoradiotherapy, accelerated hyperfractionated radiotherapy (HART) or accelerated hyperfractionated chemoradiotherapy (HACRT) to identify superior treatments to aid in clinical decisions.
Methods
PubMed, EMBASE and the Cochrane Central Register of Controlled Trials (CENTRAL) were searched for potentially eligible randomized controlled trials up to December 2016. Overall survival (OS), disease-free survival (DFS) and locoregional control (LRC) were considered efficacy outcomes, whereas acute toxicity and late toxicity on skin and mucosa were considered safety outcomes. The surface under the cumulative ranking curve (SUCRA) was calculated to rank each treatment in each index.
Results
Data from 72 trials with 21,868 participants were included in the analysis. Concerning OS, all treatments were associated with a significant advantage compared to CF alone, with HR effect sizes ranging from 0.64 to 0.83, and HACRT was significantly more effective than all the other treatments. The network comparisons of both HACRT vs HART and HF_CRT vs HF demonstrated a higher OS benefit, with an HR of 0.78 (95% credible interval [CrI]: 0.64–0.95) and 0.78 (95% CrI: 0.61–0.99), respectively. The results of SUCRA indicated that HACRT had the best ranking for OS and LRC, HF_CRT for DFS, HART for acute and late skin toxicity, CF_CRT for acute mucosal toxicity and HF_CRT for late mucosal toxicity.
Conclusion
The NMA results support the notion that HACRT is the preferable treatment modality for HNCs because it has better rankings in all three efficacy indexes, although it does present a high risk of acute mucosal toxicity.
... The response of the tissues to radiation depends on several factors, such as the sensitivity of the tumor to radiation, its location and oxygenation, as well as the quality and quantity of radiation, in addition to the total time given [9]. In order for the biological effect to reach a greater number of neoplastic cells and tolerance of normal tissues is respected, the total dose of radiation to be administered is usually fractionated in equal daily doses when external therapy is used [10]. ...
Cancer of the mouth begins in the oral cavity which includes: lips, jugal mucosa, teeth, gums, the first two-thirds of the tongue, floor of mouth, hard palate and retromolar trigone. Radiation therapy is a method capable of destroying tumor cells, employing a beam of ionizing radiation, seeking to eradicate all tumor cells with the least possible damage to the surrounding healthy cells at the expense of which the regenerated area will be regenerated. The objective of the present literature review was to report the main pathologies related to the performance of radiotherapy in patients with head and neck cancer. We selected articles published in the years from 1978 to 2017. The response of the tissues to radiation depends on several factors, such as the sensitivity of the tumor to radiation, its location and oxygenation, as well as the quality and quantity of radiation, in addition to the total time given. The oral complications of radiotherapy of head and neck neoplasms are common because they are rapidly renewing cells suffering greater action of the radiation agents, and can compromise the quality of life of the patient, besides negatively affecting the course of the cancer treatment until its suspension. Adverse reactions to radiation therapy are classified as acute, which occur during treatment or up to three months after the end, and late, which may manifest several months or years after the end of treatment. Oral mucositis is a clinically important and sometimes dose-limiting complication of cancer therapy. Mucositis lesions can be painful, affect nutrition and quality of life, and have a significant economic impact. Protocols for the treatment of the adverse effects of radiotherapy in the stomatognathic system are the responsibility of the dental surgeon. These include symptomatic relief, systemic medicines, physiotherapy, accumulating and oral lubricants, excellent oral hygiene and diet of certain types of food.
... Future research is required to investigate the longer term outcomes including late toxicity with comparison to the standard treatment (i.e. concurrent chemo-radiotherapy) [18][19][20][21][22][23][24][25][26][27][28][29][30][31]. ...
... [9] Regarding radiation dose fractionation has evolved from once daily dose to hyperfractionation and altered fractionation. [10] [11] A split course regimen was compared to the uninterrupted radiation therapy in laryngeal cancers. [12] The tumour proliferation in this was compensated by administration of higher doses. ...
... In contrast, using higher total doses (16-25.2 Gy, weekly) in association with strong AF schedules, such as in the EORTC 22851 (72 Gy in 5 weeks, between moderate and very accelerated) and Vancouver trials (66 Gy in 3.5 weeks) [38,41], increased acute toxicity, as seen in GORTEC, and may also increase late effects. It is important to note that those studies left lessons of severe adverse reactions [43]. ...
Early laryngeal, especially glottic, cancer is a good candidate for radiotherapy because obvious early symptoms (e.g. hoarseness) make earlier treatment possible and with highly successful localized control. This type of cancer is also a good model for exploring the basic principles of radiation oncology and several key findings (e.g. dose, fractionation, field size, patient fixation, and overall treatment time) have been noted. For example, unintended poor outcomes have been reported during transition from ⁶⁰Cobalt to linear accelerator installation in the 1960s, with usage of higher energy photons causing poor dose distribution. In addition, shell fixation made precise dose delivery possible, but simultaneously elevated toxicity if a larger treatment field was necessary. Of particular interest to the radiation therapy community was altered fractionation gain as a way to improve local tumor control and survival rate. Unfortunately, this interest ceased with advancements in chemotherapeutic agents because alternate fractionation could not improve outcomes in chemoradiotherapy settings. At present, no form of acceleration can potentially compensate fully for the lack of concurrent chemotherapy. In addition, the substantial workload associated with this technique made it difficult to add extra fractionation routinely in busy clinical hospitals. Hypofractionation, on the other hand, uses a larger single fractionation dose (2–3 Gy), making it a reasonable and attractive option for T1–T2 early glottic cancer because it can improve local control without the additional workload. Recently, Japan Clinical Oncology Group study 0701 reprised its role in early T1–T2 glottic cancer research, demonstrating that this strategy could be an optional standard therapy. Herein, we review radiotherapy history from ⁶⁰Cobalt to modern linear accelerator, with special focus on the role of alternate fractionation.
... Clinical studies with accelerated radiotherapy protocols (shortened overall treatment time, increased weekly dose) in head-and-neck cancer, have focused on oral mucositis as the dose-limiting early complication. Consistently, an aggravation was observed (30,31). Repopulation processes start within the first weeks of radiotherapy in patients (32,33) and preclinical models (34)(35)(36). ...
Effects of radiation exposure are observed in virtually all normal tissues. Early reactions occur primarily in turnover tissues (e.g., bone marrow, epidermis, mucosae of the gastrointestinal tract), where proliferative impairment results in progressive hypoplasia and eventually complete loss of functional cells, after a tissue dependent but dose independent latent time. These early radiation reponses are regularly preceded and accompanied by vascular and inflammatory reactions. In contrast, late reactions are based on combined parenchymal, vascular, and connective tissue changes; very late effects are dominated by vascular sequelae. In most instances, a significant involvement of the immune system can also be demonstrated for chronic radiation sequelae, and a contribution of neural changes is discussed. The orchestrated response of all tissue components results in loss of function within the exposed volume. Importantly, latent times of late effects are inversely dependent on dose. Hence modern, highly conformal treatment techniques with relatively low and inhomogeneous doses in the organs at risk (OAR) require very long follow-up intervals with a precise assessment and documentation of the complication endpoints for characterisation of the treatment-induced morbidity profile. Consequential late effects (CLEs) develop through interactions between early and late effects in the same organ; they follow the radiobiological principles of the early reactions. The clinical manifestation of radiation responses is defined by several parameters, summarized as the "R's of radiobiology". First, each individual symptom or endpoint of radiation-induced morbidity follows an individual dose-effect relationship (intrinsic 'R'adiosensitivity), in many instances related to the dose within specific subvolumes of the individual OAR, rather than e.g., the mean organ dose. The biological effectiveness of a certain (total) dose is modulated by exposure conditions: Changes in dose fractionation protocols ('R'recovery) predominantly impact on late responding tissues, while overall treatment time ('R'epopulation) predominantly affects early (and consequential late) reactions. Consequences of partial organ exposure (i'R'adiated volume") are related to tissue architecture. In mainly 'tubular' or 'serial' organs (e.g., gastrointestinal tract, but also vasculature), local exposure affects function in downstream compartments. In contrast, in predominantly 'parallel' organs, such as liver or lungs, only exposure of a significant (organ-dependent) fraction of the total volume results in clinical consequences. However, all organs in fact are composed of tubular and serial components. Translational studies into damage processing (molecular 'R'adiopathology), starting immediately after the onset of radiation exposure, but proceeding for long and very long time intervals even at subclinical levels, intra- and intercellular signals and signalling pathways may be identified that are relevant or even specific for the clinical manifestation of morbidity endpoints. These can serve as a basis to identify (early) biomarkers of the individual risk for specific tissue reactions and endpoints, and also for establishment of strategies to prevent/mitigate tissue effects after exposure.
... Similar results were found for progression-free survival (appendix p 10). After the exclusion of the nine comparisons with unusual Absolute difference at 10 years: -0·3% (95% CI -4·3 to 3·7) radiotherapy regimens (hypofractionated radiotherapy, 31,40 split course, 4,30,55,57 or both hyperfractionated and moderately accelerated radiotherapy) 44 or confounded chemotherapy schedules (ie, different chemotherapy regimens between groups), 36,39 no significant interaction was found between type of fractionation and overall survival (p=0·11; appendix pp [28][29]. ...
Background:
The Meta-Analysis of Radiotherapy in squamous cell Carcinomas of Head and neck (MARCH) showed that altered fractionation radiotherapy is associated with improved overall and progression-free survival compared with conventional radiotherapy, with hyperfractionated radiotherapy showing the greatest benefit. This update aims to confirm and explain the superiority of hyperfractionated radiotherapy over other altered fractionation radiotherapy regimens and to assess the benefit of altered fractionation within the context of concomitant chemotherapy with the inclusion of new trials.
Methods:
For this updated meta-analysis, we searched bibliography databases, trials registries, and meeting proceedings for published or unpublished randomised trials done between Jan 1, 2009, and July 15, 2015, comparing primary or postoperative conventional fractionation radiotherapy versus altered fractionation radiotherapy (comparison 1) or conventional fractionation radiotherapy plus concomitant chemotherapy versus altered fractionation radiotherapy alone (comparison 2). Eligible trials had to start randomisation on or after Jan 1, 1970, and completed accrual before Dec 31, 2010; had to have been randomised in a way that precluded prior knowledge of treatment assignment; and had to include patients with non-metastatic squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx undergoing first-line curative treatment. Trials including a non-conventional radiotherapy control group, investigating hypofractionated radiotherapy, or including mostly nasopharyngeal carcinomas were excluded. Trials were grouped in three types of altered fractionation: hyperfractionated, moderately accelerated, and very accelerated. Individual patient data were collected and combined with a fixed-effects model based on the intention-to-treat principle. The primary endpoint was overall survival.
Findings:
Comparison 1 (conventional fractionation radiotherapy vs altered fractionation radiotherapy) included 33 trials and 11 423 patients. Altered fractionation radiotherapy was associated with a significant benefit on overall survival (hazard ratio [HR] 0·94, 95% CI 0·90-0·98; p=0·0033), with an absolute difference at 5 years of 3·1% (95% CI 1·3-4·9) and at 10 years of 1·2% (-0·8 to 3·2). We found a significant interaction (p=0·051) between type of fractionation and treatment effect, the overall survival benefit being restricted to the hyperfractionated group (HR 0·83, 0·74-0·92), with absolute differences at 5 years of 8·1% (3·4 to 12·8) and at 10 years of 3·9% (-0·6 to 8·4). Comparison 2 (conventional fractionation radiotherapy plus concomitant chemotherapy versus altered fractionation radiotherapy alone) included five trials and 986 patients. Overall survival was significantly worse with altered fractionation radiotherapy compared with concomitant chemoradiotherapy (HR 1·22, 1·05-1·42; p=0·0098), with absolute differences at 5 years of -5·8% (-11·9 to 0·3) and at 10 years of -5·1% (-13·0 to 2·8).
Interpretation:
This update confirms, with more patients and a longer follow-up than the first version of MARCH, that hyperfractionated radiotherapy is, along with concomitant chemoradiotherapy, a standard of care for the treatment of locally advanced head and neck squamous cell cancers. The comparison between hyperfractionated radiotherapy and concomitant chemoradiotherapy remains to be specifically tested.
Funding:
Institut National du Cancer; and Ligue Nationale Contre le Cancer.
... It has been well demonstrated that hyperfractionation with dose escalation results in consistent survival benefit with an increase of severe acute side-effects, especially mucosal toxicity, compared with conventional fractionation (13)(14)(15). On the other hand, shortening the overall treatment time using accelerated fractionation improves locoregional control, but acute and late toxicities are also increased (16). Moreover, a recent metaanalysis showed an absolute survival benefit for altered fractionation of 3.4% at 5 years, but this benefit was limited to patients younger than 60 years of age (17). ...
Background:
To evaluate the treatment tolerance and clinical outcomes in patients aged 70 years and older with locally advanced oropharyngeal cancer treated by definitive intensity-modulated radiation therapy (IMRT).
Patients and methods:
We retrospectively analyzed 15 consecutive elderly patients, with histologically-proven squamous cell carcinoma of the oropharynx, staged T3-4 with or without involved lymph nodes at diagnosis, who received definitive sequential IMRT (70 Gy; 2 Gy/fraction). Adult Comorbidity Evaluation-27 (ACE-27) score was calculated and its influence on treatment tolerance and clinical outcomes was analyzed.
Results:
A total of 15 patients were included with a median age of 77 years (range=70-88 years). At baseline, 8 patients (53.3%) had an ACE-27 score of 1, and the remainder (n=7, 46.7%) had a comorbidity index of 0. All patients completed programmed IMRT treatment, without any reduction of total dose. Oral pain and mucositis were the most common acute side-effects, classified as grade 3 in 6 patients (40%) only. Xerostomia was reported in 13 patients (86.7%), without severe manifestation. There was no hematological toxicity. ACE-27 score was not related to higher severe acute toxicity. No patients experienced grade 3 or more late toxicity. Five-year overall survival and disease-free survival rates were 63.6% (95% confidence interval=32.7-83.3%) and 55% (95% confidence interval=24.4-77.6%), respectively. Comorbidity score did not influence survival outcomes, both overall survival (p=0.46) and disease-free survival (p=0.55).
Conclusion:
Treatment tolerance, as well as survival outcomes were good in elderly oropharyngeal cancer patients treated with definitive sequential IMRT. Due to age and comorbidity, no dose or volume reduction for IMRT should be considered in this setting of patients. A prospective randomized trial with a large sample size should be conducted to confirm our results.
... Accelerated RT improves locoregional control in squamous cell carcinoma of head and neck is shown in different clinical studies. [7] Although it increases treatment-associated acute morbidity, which when very severe, may lead to an increase in late radiation effects. This study was planned with the objectives that reducing overall treatment time would negate the effect of accelerated repopulation and would result in better locoregional control. ...
BACKGROUND: The radiotherapy (RT) dose and fractionation schedule for head and neck cancers for locoregional control and acceptable organ
toxicity are still debatable. Accelerated RT includes administration of six fractions per week with the same dose per fraction. AIM: Comparison
of conventional versus accelerated RT in terms of locoregional control, and acute and late radiation toxicity in squamous cell carcinoma
oropharynx (stage I and II). SETTINGS AND DESIGN: Prospective, double arm, phase 2, randomized study. MATERIALS AND METHODS: Sixty
patients of squamous cell carcinoma oropharynx (stage I and II) were randomized in two arms (accelerated fractionation, arm 1 and conventional
fractionation, arm 2). All patients received RT dose of 66 Gray (Gy) in 33 fractions (#). The patients in arm 1 received six fractions per week with
2 Gy/# (Monday–Saturday) and in arm 2, five fractions per week with 2 Gy/# (Monday–Friday). No chemotherapy was administered. During and
after the treatment, locoregional control, and acute and late radiation toxicity were assessed. RESULTS: At 1‑year follow‑up, 76% patients in arm
1 and 64% patients in arm 2 had complete response. The recurrence rate at the end of 1 year in arm 1 was 12% and it was 20% in arm 2.The
acute Grade 2 and 3 toxicities were higher in the accelerated arm and no significant difference in late toxicities was found. SPSS version 4.0 was
used for statistical analysis. CONCLUSION: Accelerated fractionation provides better locoregional control with higher but acceptable acute and
equal late radiation toxicity in squamous cell carcinoma oropharynx
This study attempts the identification of various tumour, host and treatment factors that may influence and can predict the probability of control of primary tumour in oral cancer patients treated by radical radiotherapy.
1. High fraction size schedule, such as the AF in this study, of 3 weeks duration is probably the most suitable for advanced oral cancers. The better results are probably due to the high fraction sizes which means lesser effect of missed doses
2. Effectiveness of large fraction sizes is related to less recovery (especially of the kinetic apparatus) during the inter-fraction interval.
3. The overall treatment time per se does not appear to be important; affecting fast and
slow proliferating tumours in opposite ways.
4. Missing treatments in the first two weeks is very critical. This is probably because for most of the tumours the Tk falls in this period.
5. 'Cumulative inter-fraction interval' (CIFI) concept is introduced. Analysis in terms of CIFI is the best way to identify the importance of treatment misses at any time during a course of radiotherapy.
6. Rapid proliferation and short Tk go hand in hand. Shown by findings in relation to CIFI, T duration, etc.
7. Hb is not a surrogate for oxygen carrying capacity of blood. It represents effect of ane interaction between the host and tumour related to iron metabolism and erythropoiesis affecting tumour growth. This interaction is better represented by MCH and MCHC.
8. A positive association between cytologically determined cell division index (CDI), which evaluates both amitotic and mitotic index, and tumour size suggest its potential usefulness as a cytoproliferative score to identify growth characteristics of tumours. The findings suggest that large tumours are more resistant not only because they contain larger absolute number of clonogenic cells but also, may be more probably, because they have a higher dividing/growth fraction and potential ability to repopulate during radiotherapy.
9. Serial cytological assay of acute nuclear changes ('SCANC'ing) is a useful predictive and research tool.
10. The finding that multinucleation had maximum relation with radiosensitivity suggest that death due to acytokinesis resulting from interference with the functioning of the kinetic apparatus, most probably the cell membrane, is an important cause of tumour cell kill in radiotherapy.
11. Histology does not influence tumour radiosensitivity.
12. The classical empirical factors such as Tsize, invasiveness and lymph node involvement do not have significant influence on radiosensitivity. Whatever apparent relation present is due to the indirect influence of proliferative characteristics and intrinsic radiosensitivity.
13. Time to recurrence analysis is potentially useful method to identify presence of radiation induced alterations in growth characteristics. It can complement findings of the other types of analysis.
14. Based on the findings of the study, mainly that acytokinesis is the most common mode of death in sensitive tumours and that treatment interruptions during the first two weeks are critical for most tumours since their ‘kick-off time to accelerated repopulation (Tk) during fractionated radiotherapy occurs within this period, a new type of cell kill called the k kill (k for kinesis) is introduced. The k kill is due to radiation induced damage to the kinetic apparatus of the cell which if present during cell division causes imbalance between karyokinesis and cytokinesis leading to multinucleation death commonly. This damage is proposed to be fraction size dependent and recovery can occur during interfraction intervals. This can explain many of the paradoxes in radiotherapy as well as the inter-relation between radiosensitivity and proliferation. The presence of the k kill is what led Bergonie and Tribondeau to promulgate their famous law.
Purpose:
To compare the objective and patient-reported toxicities of concomitant boost radiotherapy (CBRT) and concurrent chemoradiation (CRT) in patients with locally advanced head and neck cancers.
Methods and material:
In this prospective study, 46 patients with histologically proven stage III-IVA head and neck cancer were randomly assigned to receive either concurrent chemoradiation to a dose of 66 Gy in 33 fractions over 6.5 weeks with concurrent cisplatin (40 mg/m2 IV weekly; control arm) or accelerated radiotherapy with concomitant boost radiotherapy (study arm) to a dose of 67.5 Gy in 40 fractions in five weeks. Acute toxicity was evaluated using RTOG toxicity criteria. The assessment was done weekly after initiation of treatment, at the first follow-up (six weeks), and at three months. The four main patient-reported symptoms of pain, hoarseness of voice, dryness of mouth, and loss of taste were also compared between the two groups to assess patient quality of life during treatment.
Results:
The mean treatment duration was 37 days in the CBRT arm and 49 days in the CRT arm. Treatment-related interruptions were less in the study group,17.3% in the study, and 27.2% in the control with insignificant P-value. Grade III laryngeal toxicity was significantly higher in the study group (P=0.029). Other acute grade I-III toxicities (pharyngeal, skin, mucositis, and salivary) were comparable in both CRT and CBRT arms. Grade IV toxicities were seen only in the CBRT arm but were resolved at the first follow-up. Haematological toxicities and renal toxicities were significantly higher in the CRT arm, with significant P-values of 0.0004 and 0.018, respectively.
Conclusion:
In patients with locally advanced head and neck cancer, concomitant boost radiotherapy is well tolerated with acceptable local toxicity and minimal systemic toxicity as compared to conventional chemoradiation. It is a feasible option for patients with locally advanced head and neck cancer not fit for concurrent chemoradiation.
Background: Sarcopenia appears to be a negative prognostic factor for poor sur- vival outcomes and worse treatment tolerance in patients with head-and-neck squamous cell carcinoma (HNSCC). We evaluated sarcopenia's impact on overall survival (OS), disease-free survival (DFS) and chemo-radiation tolerance in pa- tients with head-and-neck cancer (HNC) treated with chemoradiotherapy (CRT) from a monocentric observational study.
Methods: We identified patients with HNC treated by CRT between 2009 and 2018 with pretreatment imaging using positron emission tomography–computed tomography scans (PET/CT). Sarcopenia was measured using the pretreatment PET/CT at the L3 vertebral body using previously published methods. Clinical variables were retrospectively retrieved.
Results: Of 216 patients identified, 54 patients (25.47%) met the criteria for sarco- penia. These patients had a lower mean body mass index before treatment (21.92 vs. 25.65cm/m2, p<0.001) and were more likely to have a history of smoking (88.89% vs. 71.52%, p = 0.01), alcohol use (55.56% vs. 38.61%, p = 0.03) and posi- tive human papilloma virus status (67.74% vs. 41.75%, p = 0.011). At 3years of follow-up, OS and DFS were 75% and 70% versus 82% and 85% for sarcopenic and non-sarcopenic patients, respectively (p = 0.1 and p = 0.00015). On multi- variate analysis, sarcopenia appeared as a pejorative factor on DFS (hazard ratio 2.174, p = 0.0001) in the overall cohort. Sarcopenic patients did not require more chemotherapy and radiation-treatment interruptions and did not suffer from more chemo-induced and radiation-induced grade 3–4 toxicities than their non- sarcopenic counterparts.
Conclusion: Sarcopenia in HNSCC patients is an independent adverse prognos- tic factor for DFS after definitive chemoradiotherapy.
Purpose:
We conducted a randomized Phase II multi-center clinical trial to test the hypothesis that physiologic MRI based radiation therapy (RT) dose escalation would improve the outcome of patients with poor prognosis head and neck cancer (HNC).
Methods:
MRI was acquired at baseline and at RT fraction 10 to create low blood volume (BV)/apparent diffusion coefficient (ADC) maps for RT boost subvolume definition in gross tumor volume (GTV). Patients were randomized to receive 70 Gy (standard RT) or 80 Gy to the boost subvolume (RT boost) with concurrent weekly platinum. The primary endpoint was disease free survival (DFS) with significance defined at a 1-sided 0.1 level, and secondary endpoints included loco-regional failure (LRF), overall survival (OS), comparison of adverse events and patient reported outcomes (PRO)s.
Results:
Among 81 randomized patients, neither the primary endpoint of DFS (hazard ratio (HR)= 0.849, p=0.31) nor OS (HR =1.19, p=0.66) were significantly improved in the RT Boost arm. However, the incidence of LRF was significantly improved with the addition of the RT boost (HR= 0.43, p=0.047). Two-year estimates (90% CI) of the cumulative incidence of LRF were 40% (27-53%) in the standard RT arm and 18% (10-31%) in the RT boost arm. Two-year estimates (90% CI) for DFS were 48% (34-60%) in the standard RT arm and 57% (43-69%) in the RT boost arm. There were no significant differences in toxicity or longitudinal differences seen in EORTC QLQ30/HN35 subscales between treatment arms in linear mixed effects models.
Conclusion:
Physiologic MRI based RT boost decreased LRF without a significant increase in grade 3+ toxicity or longitudinal PRO differences, but did not significantly improve DFS or OS. Additional improvements in systemic therapy are likely necessary to realize improvements in DFS and OS.
Background
The prescribed radiation dose to patients with oropharyngeal squamous cell carcinoma (OPSCC) is standardized, even if the prognosis for individual patients may differ. Easy-at-hand pre-treatment risk stratification methods are valuable to individualize therapy. In the current study we assessed the prognostic impact of primary tumor volume for p16-positive and p16-negative tumors and in relationship to other prognostic factors for outcome in patients with OPSCC treated with primary radiation therapy (RT).
Methods
Five hundred twenty-three OPSCC patients with p16-status treated with primary RT (68.0 Gy to 73.1 Gy in 7 weeks, or 68.0 Gy in 4.5 weeks), with or without concurrent chemotherapy, within three prospective trials were included in the study. Local failure (LF), progression free survival (PFS) and overall survival (OS) in relationship to the size of the primary gross tumor volume (GTV-T) and other prognostic factors were investigated. Efficiency of intensified RT (RT with total dose 73.1 Gy or given within 4.5 weeks) was analyzed in relationship to tumor volume.
Results
The volume of GTV-T and p16-status were found to be the strongest prognostic markers for LF, PFS and OS. For p16-positive tumors, an increase in tumor volume had a significantly higher negative prognostic impact compared with p16-negative tumors. Within a T-classification, patients with a smaller tumor, compared with a larger tumor, had a better prognosis. The importance of tumor volume remained after adjusting for nodal status, age, performance status, smoking status, sex, and hemoglobin-level. The adjusted hazard ratio for OS per cm³ increase in tumor volume was 2.3% (95% CI 0–4.9) for p16-positive and 1.3% (95% 0.3–2.2) for p16-negative. Exploratory analyses suggested that intensified RT could mitigate the negative impact of a large tumor volume.
Conclusions
Outcome for patients with OPSCC treated with RT is largely determined by tumor volume, even when adjusting for other established prognostic factors. Tumor volume is significantly more influential for patients with p16-positive tumors. Patients with large tumor volumes might benefit by intensified RT to improve survival.
Objectives
The number of citations an article receives is an important indication of its impact. The main objectives of this investigation provide readers with a practical guide in evaluating head and neck oncology literature and determine the characteristics of trends in ORL.
Methods
This was a retrospective bibliometric analysis that did not involve human participant. The Thomson Reuters Web of Science was searched to determine the citations of all published HNO articles. Most cited 300 article analyzed and a total of 100 articles were included in our investigation under the topic search “Head AND NECK AND (cancer OR carcinoma OR oncology).” Articles include malignancies other than head and neck are excluded. The top 100 cited articles were selected and analyzed by 2 independent investigators. Country, Institution, First Author, Journal name, study design, cites per year information gathered and analyzed.
Results
The journal with the highest number of top 100 cited articles was New England Journal Of Medicine with 19 paper, followed by The Journal of Clinical Oncology(17) and Cancer Research (12). The top article on the list (Radiotherapy plus cetuximab for squamous cell carcinoma of the head and neck-NEJM) has 2243 citations. A statistically significant association was found between the journal impact factor and the number of top 100 cited articles ( P < .05). The United States had the highest number of articles (63). John Hopkins is differed from other institutions with 15 contributing articles.
Conclusion
Our analysis provides an insight into the citation frequency of top cited articles published in HNO to help recognize the quality of the works, discoveries and the trends steering the study of HNO. This is also a modern reading list for young HNO scientist.
The time of a stochastic process first passing through a boundary is important to many diverse applications. However, we can rarely compute the analytical distribution of these first-passage times. We develop an approximation to the first and second moments of a general first-passage time problem in the limit of large, but finite, populations using Kramers–Moyal expansion techniques. We demonstrate these results by application to a stochastic birth-death model for a population of cells in order to develop several approximations to the normal tissue complication probability (NTCP): a problem arising in the radiation treatment of cancers. We specifically allow for interaction between cells, via a nonlinear logistic growth model, and our approximations capture the effects of intrinsic noise on NTCP. We consider examples of NTCP in both a simple model of normal cells and in a model of normal and damaged cells. Our analytical approximation of NTCP could help optimise radiotherapy planning, for example by estimating the probability of complication-free tumour under different treatment protocols.
Background and purpose
Customized mouth-opening-tongue-depressing-stents (MOTDs) may reduce toxicity in patients with head and neck cancers (HNC) receiving radiotherapy (RT). However, making MOTDs requires substantial resources, which limits their utilization. Previously, we described a workflow for fabricating customized 3D-printed MOTDs. This study reports the results of a prospective trial testing the non-inferiority of 3D-printed to standard and commercially-available (TruGuard) MOTDs as measured by patient reported outcomes (PROs).
Materials and methods
PROs were collected at 3 time points: (t1) simulation, (t2) prior to RT, (t3) between fractions 15–25 of RT. Study participants received a 3D-printed MOTDs (t1, t2, t3), a wax-pattern (t1), an acrylic-MOTDs (t2, t3) and an optional TruGuard (t1, t2, t3). Patients inserted the stents for 5–10 min and completed a PRO-questionnaire covering ease-of-insertion and removal, gagging, jaw-pain, roughness and stability. Inter-incisal opening and tongue-displacement were recorded. With 39 patients, we estimated 90% power to detect a non-inferiority margin of 2 at a significance level of 0.025. Matched pairs and t-test were used for statistics.
Results
41 patients were evaluable. The 3D-printed MOTDs achieved a significantly better overall PRO score compared to the wax-stent (p = 0.0007) and standard-stent (p = 0.0002), but was not significantly different from the TruGuard (p = 0.41). There was no difference between 3D-printed and standard MOTDs in terms of inter-incisal opening (p = 0.4) and position reproducibility (p = 0.98). The average 3D-printed MOTDs turn-around time was 8 vs 48 h for the standard-stent.
Conclusions
3D-printed stents demonstrated non-inferior PROs compared to TruGuard and standard-stents. Our 3D-printing process may expand utilization of MOTDs.
Background
A large tumor volume negatively impacts the outcome of radiation therapy (RT). Altered fractionation (AF) can improve local control (LC) compared with conventional fractionation (CF). The aim of the present study was to investigate if response to AF differs with tumor volume in oropharyngeal cancer.
Methods
Three hundred and twenty four patients with oropharyngeal cancer treated in a randomized, phase III trial comparing CF (2 Gy/d, 5 d/wk, 7 weeks, total dose 68 Gy) to AF (1.1 Gy + 2 Gy/d, 5 d/wk, 4.5 weeks, total dose 68 Gy) were analyzed.
Results
Tumor volume had less impact on LC for patients treated with AF. There was an interaction between tumor volume and fractionation schedule (P = .039). This differential response was in favor of CF for small tumors and of AF for large tumors.
Conclusion
AF diminishes the importance of tumor volume for local tumor control in oropharyngeal cancer.
Purpose:
Treatment of fast-growing, human papillomavirus-negative, head and neck cancers (HNCs) remains challenging from the perspectives of both tumor control and late sequelae. In this study, we use systematic radiobiological optimization to identify fractionation schemes that markedly improve the radiotherapeutic effectiveness balance between tumor control probability (TCP) and late normal tissue complication probability (LNTCP), as compared with standard fractionation.
Methods and materials:
We track the development after each treatment fraction of both tumor control and late sequelae. Toward the end of the treatment, accelerated repopulation of fast-growing HNC tumors means that further fractions minimally improve TCP but result in major LNTCP increases, providing the potential for optimization of the TCP-LNTCP balance. We used a recent improved model of accelerated repopulation, calibrated with extensive HNC clinical trials data, to identify optimally effective treatment regimens that both increase TCP and significantly decrease LNTCP. For comparison, we also used standard repopulation models.
Results:
An optimized hypofractionated schedule of 18 × 3.0 Gy is predicted to substantially increase TCP, particularly for late-stage HNC tumors (eg, ∼35% to 49% for late-stage tumors) while decreasing high-grade LNTCP (eg, ∼13% to <2%), as compared with a standard 35 × 2.0 Gy protocol. In addition, the treatment time is reduced from 47 to 24 days. Twice-daily treatments of 1.8 Gy per fraction provide still better outcomes. The hypofractionation predictions are robust, being almost independent of the details of the repopulation model.
Conclusions:
Hypofractionation or its close variant, accelerated hyperfractionation, efficiently overcomes tumor repopulation in fast-growing tumors and can be optimized toward the end of treatment when repopulation causes the TCP to increase only very slowly while LNTCP increases rapidly. Radiobiological modeling suggests that optimized 3.0 Gy per fraction hypofractionation (or 1.8 Gy per fraction, 2 fractions per weekday, accelerated hyperfractionation) is considerably more effective for HNC tumor control and for reduction of late effects than standard 2.0-Gy fractionation.
Purpose: To analyze the repopulation rate of cancer cells in vitro during conventional and accelerated irradiation, using the megacolony culture. Methods and Materials: Two cell lines-murine squamous cell carcinoma AT478 and human adenocarcinoma A549-were grown as epithelial megacolonies in vitro, and they were irradiated using Co-60 gamma source at the dose rate of 0.82 Gy/min. Single-dose irradiation, conventional fractionation, and continuous accelerated irradiation (CAIR) were applied to determine the dose-response relationship and to calculate the repopulation balancing dose. Radiosensitivity parameters and the rate of repopulation were calculated from the colony cure rates using direct maximum-likelihood regression and a linear-quadratic model. Cytogenetic radiation damage was measured as frequency of necrotic, apoptototic cells and cells with micronuclei. Mitotic index was used as a simple measure of cell proliferation kinetics. Results: When treatment time was increased, a significant drop in tumor control probability was detected. The loss of radiation dose calculated from LQ model parameters was equal to 0.8 Gy/day for both human and mouse cell lines. There was no evidence of a lag period for accelerated proliferation or altered proliferation during weekends. There were no significant differences in morphologic presentation of cellular radiation damage. Conclusion: In present in vitro experiments, we did not find any significant differences in repopulation or radiosensitivity between accelerated CAIR and conventional fractionation. Different mechanisms may be important for tumor cells repopulation in vitro and in vivo.
Due to the rapid increase in the availability of patient data, there is significant interest in precision medicine that could facilitate the development of a personalized treatment plan for each patient on an individual basis. Radiation oncology is particularly suited for predictive machine learning (ML) models due to the enormous amount of diagnostic data used as input and therapeutic data generated as output. An emerging field in precision radiation oncology that can take advantage of ML approaches is radiogenomics, which is the study of the impact of genomic variations on the sensitivity of normal and tumor tissue to radiation. Currently, patients undergoing radiotherapy are treated using uniform dose constraints specific to the tumor and surrounding normal tissues. This is suboptimal in many ways. First, the dose that can be delivered to the target volume may be insufficient for control but is constrained by the surrounding normal tissue, as dose escalation can lead to significant morbidity and rare. Second, two patients with nearly identical dose distributions can have substantially different acute and late toxicities, resulting in lengthy treatment breaks and suboptimal control, or chronic morbidities leading to poor quality of life. Despite significant advances in radiogenomics, the magnitude of the genetic contribution to radiation response far exceeds our current understanding of individual risk variants. In the field of genomics, ML methods are being used to extract harder-to-detect knowledge, but these methods have yet to fully penetrate radiogenomics. Hence, the goal of this publication is to provide an overview of ML as it applies to radiogenomics. We begin with a brief history of radiogenomics and its relationship to precision medicine. We then introduce ML and compare it to statistical hypothesis testing to reflect on shared lessons and to avoid common pitfalls. Current ML approaches to genome-wide association studies are examined. The application of ML specifically to radiogenomics is next presented. We end with important lessons for the proper integration of ML into radiogenomics.
Dans une démarche d'évaluation rigoureuse des innovations technologiques de la radiothérapie, notre travail de thèse a été construit autours de 2 thématiques : 1) Evaluation clinique des résultats de la radiothérapie conformationnelle avec modulation d'intensité (RCMI) appliquée au traitement des cancers ORL. La première étude rapporte les conclusions d'un enregistrement prospectif monocentrique du devenir au long cours des patients ORL traités par RCMI. Le contrôle locorégional est excellent et les niveaux de toxicité faibles. Des recommandations dosimétriques (dose aux parotides) adaptées à nos pratiques ont été établies. La deuxième étude rapporte les résultats d'une comparaison nationale multicentrique de la qualité de vie des patients traités pour un cancer ORL, soit par radiothérapie conventionnelle, soit par RCMI. Le bénéfice de la RCMI est remarquable dans les domaines du confort de la sphère buccale et de la prise alimentaire orale. 2) Evaluation de l'apport de l'imagerie embarquée (Cone Beam CT ou CBCT) dans la prise en charge des patients traités par RCMI pour un cancer ORL. Un premier projet propose, sur un panel de patients ORL traités par RCMI, le contrôle qualité de la distribution de la dose réellement délivrée. Le retentissement dosimétrique des variations anatomiques est discuté. L'apport d'outils dosimétriques spécifiques est étudié. Le second projet a pour objectif de quantifier la mobilité relative des régions anatomiques qui composent la sphère ORL et d'étudier l'impact dosimétrique lié au choix de différentes procédures de recalage. Une recommandation sur les modalités d'utilisation des images CBCT a pu être proposée.
Le traitement des carcinomes épidermoïdes de la sphère ORL jugés inopérables estbasé sur la radiothérapie exclusive conventionnelle, dont les résultats restentdécevants. La radiothérapie accélérée et l'association radiochimiothérapieconcomitante sont deux modalités nouvelles ayant pour but d'améliorer les résultatsde la radiothérapie. Après des rappels anatomo-cliniques et thérapeutiques, nous développons le rationnel des modifications de fractionnement et des associationsradiochimiothérapie. L'étude présentée porte sur une série de 67 patients traités au Centre Alexis Vautrin pour un cancer de la sphère ORL localement avancé. Nous analysons rétrospectivement les résultats de la radiothérapie accélérée normofractionnée (37 patients) et de la radiochimiothérapie concomitante (30 patients), essentiellement en terme de toxicité aiguë et tardive, et de faisabilité. Les résultats sont ensuite discutés et rapportés à ceux de la littérature.En conclusion, ces modalités thérapeutiques sont applicables, malgré une toxicitéplus importante pour l'accélération, mais qui reste gérable. Les perspectives d'avenirse développent avec l'arrivée des radioprotecteurs, les nouvelles drogues, telles queles taxanes, en association avec la radiothérapie, et les nouvelles modalités defractionnement et d'étalement associées à une chimiothérapie concomitante.
Background and purpose:
Accelerated repopulation (AR) can compromise tumor control after conventional radiotherapy for fast-growing tumors. Standard AR models assume it begins at a fixed time, with repopulation rates independent of the number of clonogens killed. We investigate the validity and significance of an alternative model where onset-time and rate of AR depend on the number of clonogens killed, and thus on dose and dose-fractionation.
Materials and methods:
We analyzed tumor control (TCP) from randomized trials for head and neck cancer (HNC, 7283 patients), featuring wide ranges of doses, times, and fractionation-schemes. We used the linear-quadratic model with the standard dose-independent AR model, or with an alternative dose-dependent model, where AR onset and rate depend on clonogen killing.
Results:
The alternative dose-dependent model of AR provides significantly-improved descriptions of a wide range of randomized clinical data, relative to the standard dose-independent model. This preferred model predicts that, for currently-used HNC fractionation schemes, the last 5 fractions do not increase TCP, but simply compensate for increased accelerated repopulation.
Conclusions:
The preferred dose-dependent AR model predicts that, for standard fractionation schemes currently used to treat HNC, the final week (5 fractions) could be eliminated without compromising TCP, but resulting in significantly decreased late sequelae due to the lower overall dose.
Aim
To investigate the impact of tomotherapy on the dose delivered to the lungs and other normal tissues.
Material and Methods
From February 2008 to May 2009, 35 patients with stage IIIA/IIIB non-small cell lung cancer were treated with helical tomotherapy at the S. Camillo-Forlanini Hospital. For our study we selected 20 patients who underwent chemotherapy followed by sequential radiotherapy. The planning target volume was delineated using planning CT scan and FDG-PET. The mean prescribed radiation dose was 67.5 Gy delivered in 30 fractions at a dose of 2.25 Gy per fraction.
Results
Median follow-up was 12.3 months. All patients developed acute esophageal toxicity, 15 of RTOG grade 1 and 5 of RTOG grade 2. At first follow-up 15 patients presented stable disease or partial response, 4 patients presented complete response, and 1 patient presented disease progression.
Conclusions
Helical tomotherapy is useful to achieve dose-per-fraction escalation without increasing the treatment-related morbidity. Our results applying dose escalation were encouraging considering that we delivered doses that may be difficult to achieve with 3-dimensional treatments with no excessive complication rates.
BACKGROUND: The Meta-Analysis of Radiotherapy in squamous cell Carcinomas of Head and neck (MARCH) showed that altered fractionation radiotherapy is associated with improved overall and progression-free survival compared with conventional radiotherapy, with hyperfractionated radiotherapy showing the greatest benefit. This update aims to confirm and explain the superiority of hyperfractionated radiotherapy over other altered fractionation radiotherapy regimens and to assess the benefit of altered fractionation within the context of concomitant chemotherapy with the inclusion of new trials. METHODS: For this updated meta-analysis, we searched bibliography databases, trials registries, and meeting proceedings for published or unpublished randomised trials done between Jan 1, 2009, and July 15, 2015, comparing primary or postoperative conventional fractionation radiotherapy versus altered fractionation radiotherapy (comparison 1) or conventional fractionation radiotherapy plus concomitant chemotherapy versus altered fractionation radiotherapy alone (comparison 2). Eligible trials had to start randomisation on or after Jan 1, 1970, and completed accrual before Dec 31, 2010; had to have been randomised in a way that precluded prior knowledge of treatment assignment; and had to include patients with non-metastatic squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx undergoing first-line curative treatment. Trials including a non-conventional radiotherapy control group, investigating hypofractionated radiotherapy, or including mostly nasopharyngeal carcinomas were excluded. Trials were grouped in three types of altered fractionation: hyperfractionated, moderately accelerated, and very accelerated. Individual patient data were collected and combined with a fixed-effects model based on the intention-to-treat principle. The primary endpoint was overall survival. FINDINGS: Comparison 1 (conventional fractionation radiotherapy vs altered fractionation radiotherapy) included 33 trials and 11 423 patients. Altered fractionation radiotherapy was associated with a significant benefit on overall survival (hazard ratio [HR] 0·94, 95% CI 0·90-0·98; p=0·0033), with an absolute difference at 5 years of 3·1% (95% CI 1·3-4·9) and at 10 years of 1·2% (-0·8 to 3·2). We found a significant interaction (p=0·051) between type of fractionation and treatment effect, the overall survival benefit being restricted to the hyperfractionated group (HR 0·83, 0·74-0·92), with absolute differences at 5 years of 8·1% (3·4 to 12·8) and at 10 years of 3·9% (-0·6 to 8·4). Comparison 2 (conventional fractionation radiotherapy plus concomitant chemotherapy versus altered fractionation radiotherapy alone) included five trials and 986 patients. Overall survival was significantly worse with altered fractionation radiotherapy compared with concomitant chemoradiotherapy (HR 1·22, 1·05-1·42; p=0·0098), with absolute differences at 5 years of -5·8% (-11·9 to 0·3) and at 10 years of -5·1% (-13·0 to 2·8). INTERPRETATION: This update confirms, with more patients and a longer follow-up than the first version of MARCH, that hyperfractionated radiotherapy is, along with concomitant chemoradiotherapy, a standard of care for the treatment of locally advanced head and neck squamous cell cancers. The comparison between hyperfractionated radiotherapy and concomitant chemoradiotherapy remains to be specifically tested. FUNDING: Institut National du Cancer; and Ligue Nationale Contre le Cancer.
The main purpose of this paper is to show that gaps in the radiation therapy of head and neck cancers have dramatic impact on the treatment results measured by tumour control probability (TCP). Our point of view is that the main reason of this effect is doubling of proliferation of cancer cells during treatment gaps. This assertion is proved by analysis of statistical models parameters of which are estimated basing on records of 1350 patients treated by radiotherapy.
Until today, radiotherapy and concomitant chemoradiation are considered standard of care for locally advanced and inoperable HNSCC. Altered fractionation versus standard fractionation led to a small but significant absolute OS benefit of 3.4 % at 5 years in patients with LAD-HNSCC corresponding to a HR reduction for death of 8 %. Hyperfractionation as a specific subtype of altered fractionation led to a highly significant absolute OS and LRC benefit of 8.2 % and 9.4 %, respectively, compared with standard fractionation corresponding to a HR reduction for death of 22 %. Hyperfractionation is a good alternative for definitive treatment of LAD-HNSCC in patients who are not fit for concurrent chemoradiation or who have a high Charlson comorbidity score.
All types of chemoradiation (induction, concurrent and adjuvant) versus radiation alone led to a general absolute overall survival benefit of 4.5 % corresponding to a HR reduction of death of 12 % (p = .0001) at 5 years. For 50 trials of concurrent chemoradiation, the absolute benefit was 6.5 % at 5 years with a corresponding HR reduction of death of 19 % (p < .0001). Platinum/5-FU-based chemoradiation versus radiation alone showed a reduction in local and distant failure rates of 13.5 % and 2.9 %, respectively, corresponding to HR reductions of about 25 % for death at 5 years. Mitomycin C-based chemoradiation is a reasonable alternative for elderly frail patients with large and hypoxic tumours, who are not candidates for platinum-based chemotherapy. Patients above the age of 70 years generally do not or only marginally benefit from altered fractionation or chemoradiation.
The use of logistic regression for the analysis of local control data is illustrated via a re-analysis of previously published data. A larger effect of overall time is found than in the original publication. In addition, the original analysis of 50 percent effective dose (ED50) is found to have obscured the relationship between local control and overall time for some doses.
Recently, Bataini et al. reported that overall time was the major treatment-related determinant of local control in 465 squamous carcinomas of the tonsillar region. They did not, however, quantify the relationship or relate it to the doubling time of tumorigenic cells, except qualitatively. This note reports an attempt at that quantification.
In the EORTC Radiotherapy Group, the feasibility of multiple fractions per day (MFD) was tested in a pilot study from 1978 to 1980. Three daily fractions of 1.6 Gy were given (4 h interval) during 2 weeks (total dose 48 Gy), with a boost to about 70 Gy after 3–4 weeks. In 53 of the 179 patients, misonidazole was given on every irradiation day (1 g/m ², total 13–14 g/m ²). Data on tolerance and early treatment results were published previously [21]; results with a minimum follow-up period of 3 years are now available. Survival (actuarial is 21% and locoregional tumor control was obtained in 34% of patients; no significant differences were seen between the subregions in the head and neck area. Survival is better in patients treated with misonidazole (probably due to selection), but locoregional control was identical as in patients treated without the sensitizer. In February 1984, 38 patients were alive, 35 without evidence of local tumor (5 after rescue surgery). Metastases were seen in 16% and a second tumor in 7% of patients. Seventeen patients (9%) died of causes, possibly related to treatment; necrosis was observed in 8 (4 with local tumor). Late effects in the long survivors were comparable to what is usually seen after high-dose radiotherapy. This study preceded a randomized trial, comparing classical radiotherapy to MFD with or without misonidazole [ 22
• Van den Bogaert W.
Controlled clinical trial on multiple daily fractionation (MDF) radiotherapy and anoxic cell sensitizers in the treatment of advanced head and neck tumors. in: EORTC protocol no. 22811. Radiotherapy Group, February 1981
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]. In February 1984, almost 500 patients were entered. As yet, no data are available on this trial.