This prospective, randomized phase II clinical trial evaluated whether daily adaptive radiotherapy (DART), delivered with a 1-mm PTV margin, improves patient-reported xerostomia at one year compared with standard non-adaptive IMRT using a 5-mm margin. Patients with head and neck squamous cell carcinoma were randomized to receive standard IMRT with daily IGRT (Arm 1) or DART (Arm 2). Patient-reported outcomes (PROs) were collected at baseline and during longitudinal follow-up. The Xerostomia Questionnaire (XQ) served as the primary endpoint.

Among the 50 enrolled patients (median age 61.2 years; predominantly male and Caucasian), most had T3–4 disease with nodal involvement and received concurrent chemoradiation. No statistically significant differences in XQ scores were observed between treatment arms when comparing changes from baseline to one year or when evaluating one-year scores directly. Overall one-year PROs were also not significantly different.

Acute dermatitis was significantly less common in the DART arm, although late toxicities were comparable. Secondary oncologic outcomes—including 2-year overall survival, progression-free survival, and locoregional and distant recurrence rates—showed no differences between the two approaches.

The authors concluded that while DART did not reduce one-year xerostomia, it achieved comparable tumor control and toxicity outcomes while enabling the use of substantially smaller PTV margins. These findings support the feasibility of integrating modern adaptive radiotherapy without compromising oncologic results.

 Reference (Pub-Med Link): Sher DJ, Avkshtol V, Lin MH, et al. Impact of daily adaptive head and neck radiotherapy on toxicity and quality of life: Results of the dartboard phase ii randomized trial. J Natl Cancer Inst 2025;117:2488-2494. https://doi.org/10.1093/jnci/djaf232

Key Institution: University of Texas Southwestern Medical Center

Keywords: Head and Neck

Treatment of hypopharynx and oropharynx with definitive chemoradiation is associated with adverse effects on patients’ quality of life. In this phase 3, multicenter, randomized controlled trial, the authors investigated the effects of dysphagia-optimized IMRT (DO-IMRT) which reduced the radiation dose to dysphagia- and aspiration-related structures. RT doses were 65 Gy to primary tumor and 54 Gy to high-risk clinical and nodal areas. A 50-Gy dose constraint to the pharyngeal constrictors outside of the high-dose target region was applied. MD Anderson Dysphagia inventory (MDADI) composite scores 12 months after RT showed better function the DO-IMRT group compared to standard IMRT group (mean scores 77.7 vs 70.6, p=0.037). Grade 3+ hearing impairment was similar in the two groups, but there was more G3+ dry mouth and dysphagia findings in the standard IMRT group vs DO-IMRT group (15% vs 5%, respectively). The authors conclude, “DO-IMRT should be considered a new standard of care for patients receiving radiotherapy for pharyngeal cancers.”

Reference (Pub-Med Link): Nutting C, Finneran L, Roe J, et al. Dysphagia-optimised intensity-modulated radiotherapy versus standard intensity-modulated radiotherapy in patients with head and neck cancer (dars): A phase 3, multicentre, randomised, controlled trial. The Lancet Oncology 2023;24:868-880. https://doi.org/10.1016/s1470-2045(23)00265-6

Key Institution: The Royal Marsden Hospital, Multi-institutional

Keywords: Head and Neck Cancer

Although the risk for xerostomia has improved with use of intensity-modulated radiation therapy (IMRT), it remains one of the most common side effects after irradiation of nasopharyngeal carcinoma, mainly due to the close proximity of level II cervical lymph nodes to the parotid gland. This randomized phase 2 trial examined whether sparing of the superficial lobe of the parotid reduces xerostomia in patients receiving radiation for nasopharyngeal carcinoma.

Eighty-two patients were included for xerostomia analysis and randomized to receive either superficial parotid lobe–sparing intensity-modulated radiation therapy (SPLS-IMRT) or conventional IMRT. For all patients, the whole parotid including deep and superficial lobes was contoured and the optimization objective was V36Gy <40%. In the experimental arm, the objective for the superficial lobe was lower with V26Gy <30%.

At 12 months, the rate of xerostomia was significantly lower in the superficial lobe sparing arm (83.4% v 95%). Grade 3 xerostomia decreased from 12.5% to 0%. There were no differences in disease-free or overall survival between the arms. The study shows that sparing the superficial parotid lobe is a potential way to reduce xerostomia while maintaining target volume coverage for nasopharyngeal carcinoma.

Reference (Pub-Med Link): Huang, H., Miao, J., Xiao, X., et al. (2022). Impact on xerostomia for nasopharyngeal carcinoma patients treated with superficial parotid lobe-sparing intensity-modulated radiation therapy (SPLS-IMRT): A prospective phase II randomized controlled study. Radiotherapy and Oncology : Journal of the European Society for Therapeutic  Radiology and Oncology, 175, 1–9. https://doi.org/10.1016/j.radonc.2022.07.006

Key Institution: Sun Yat-sen University Cancer Center
Keywords: Head & Neck

Concurrent radio-chemotherapy is effective for head and neck cancer, but also has a lot of side effects. Therefore, there is some effort to de-escalate therapy for different sub-types. Patients with low risk nasopharyngeal cancer have excellent treatment outcomes and could potentially benefit from treatment de-intensification.

This randomized, phase 3, multicenter trial aimed to examine if radiation alone (RT) has non-inferior failure-free survival compared to chemoradiation (CRT) for endemic nasopharyngeal carcinoma. 341 patients were enrolled, who had cT2N0-1 or cT3N0 squamous cell carcinoma of the nasopharynx that was considered low-risk based on the following criteria: all nodes <3cm, no level IV or VB metastases, no ENE, and an EBV DNA titer <4000 copies/mL. Radiation in both arms was delivered using IMRT with 4 different dose levels including a prescribed dose of 68-70 Gy in 30-33 fractions to the primary lesion. Patients in the chemoradiation arm received 100 mg/m2 cisplatin every 3 weeks for 3 cycles.

After 46 months median follow-up, the rate of locoregional failure was 7.6% with radiation therapy alone and 6.5% with chemoradiation, and the rate of distant metastasis was 4.7% v 2.4%. The 3-year failure free survival was deemed non-inferior with radiation therapy alone compared with chemoradiation (90.5% v 91.9%). There was no difference in overall survival between radiation therapy alone and chemoradiation (98.2% v 98.6%). Quality of life outcomes were significantly better with radiation alone. The overall rate of grade 3-4 toxicity with radiation therapy alone was less than half that of concurrent chemoradiation (17% v 46%). These included lower rates of hematologic toxicity as well as less nausea/vomiting (1% v 15%), weight loss (1% v 5%), and mucositis (10% v 19%). The authors found no difference in late grade 3-4 toxicity.

In summary, early results of this trial indicate that omission of chemotherapy for early stage, low-risk nasopharyngeal carcinoma has similar 3-year failure free survival as chemoradiation.

(Open Access)

Reference (Pub-Med Link): Tang, L.-L., Guo, R., Zhang, N., et al. (2022). Effect of Radiotherapy Alone vs Radiotherapy With Concurrent Chemoradiotherapy on Survival Without Disease Relapse in Patients With Low-risk Nasopharyngeal Carcinoma: A Randomized Clinical Trial. JAMA, 328(8), 728–736. https://doi.org/10.1001/jama.2022.13997

Key Institution: Multi-Center, China
Keywords: Head & Neck

In head and neck cancer, especially in elderly patients who are not candidates for concurrent chemotherapy there is renewed interest in hypofractionated radiation therapy, however there is limited data and lack of consensus to support its use. Additionally, swallowing outcomes for patients treated with radiotherapy alone are poorly described compared with those treated with chemo-radiotherapy, largely because they represent a group under-represented in clinical trials.

This multi-center retrospective observational study in UK compared long term swallowing function as well as outcomes (i.e., LRC and OS) between patients treated with curative intent mild hypofractionation (65-66 Gy in 30 fx over 6 weeks) and standard fractionation (70 Gy in 35 fx over 7 weeks) radiation alone for locally-advanced oropharyngeal squamous cell carcinoma (OPSCC). Swallowing function was assessed using MD Anderson Dysphagia Inventory (MDADI) questionnaire, which was sent to patients alive and cancer-free at a minimum of 2 years post-radiotherapy (n = 151, 65%).

LRC and OS were similar across schedules (p = 0.78 and 0.95 respectively, log-rank test). Enteral feeding rates during radiotherapy appeared higher in the 7-week group though this did not reach statistical significance (59% vs 48%, p = 0.08). Feeding rates were similar at 1 year post radiotherapy for both groups (10% vs 6%, p = 0.27). 107 patients returned MDADI questionnaires (71%); there were no differences between the 6- and 7-week groups for median global (60.0 vs 60.0, p = 0.99) and composite (65.8 vs 64.2, p = 0.44) MDADI scores.

This observational study of patients with oropharyngeal cancer who were treated with radiation therapy only, suggests that treatment outcomes and long-term swallowing function after mild hypofractionation over six weeks are comparable to standard fractionation over seven weeks

Reference (Pub-Med Link): Price, J. M., West, C. M., Dixon, L. M., et al.  (2022). Similar long-term swallowing outcomes for accelerated, mildly-hypofractionated radiotherapy compared to conventional fractionation in oropharyngeal cancer: A multi-centre study. Radiotherapy and Oncology, 172, 111–117. https://doi.org/10.1016/j.radonc.2022.05.013

This publication reports the longer term follow-up from the previously reported 3-year follow up of this randomized phase III trial investigating induction chemotherapy with gemcitabine and cisplatin followed by chemoradiation for patients with locoregionally advanced nasopharyngeal cancer. The study involved patients treated with concurrent chemoRT alone (238 pts) versus gemcitabine and cisplatin followed by concurrent chemoRT (242 pts).

Previous 3-year overall survival was shown to be improved with induction chemotherapy followed by chemoRT (94% vs 93%) compared to chemoRT alone. This 5-year overall survival study continues to see this trend with 88% vs 79% overall survival, respectively. The authors were able to correlate tumor response with the induction chemotherapy to the overall survival. Patients who had complete response had 100% overall survival at 5 years. Patients with partial response and stable disease were less likely to survive at 5 years with 88% and 62% overall survival. The authors did a subset analysis of patients with low pre-treatment EBV and found that overall survival for this cohort of patients was not different between the induction chemo and chemoRT versus chemoRT alone (91% vs 91%).

Reference (Pub-Med Link): Zhang, Y., Chen, L., Hu, G.-Q., et al. (2022). Final Overall Survival Analysis of Gemcitabine and Cisplatin Induction  Chemotherapy in Nasopharyngeal Carcinoma: A Multicenter, Randomized Phase III Trial. Journal of Clinical Oncology, 40(22), 2420–2425. https://doi.org/10.1200/JCO.22.00327

Key Institution: Sun Yat-sen University Cancer Center and other hospitals in China
Keywords: H&N

In this retrospective nonrandomized study, the authors analyzed 1483 adult patients with nonmetastatic locally advanced cancers treated with concurrent chemotherapy between 2011 and 2016 at the University of Pennsylvania. 391 patients received proton therapy and 1092 received photon therapy. The main research question was whether proton therapy can reduce the risk of severe adverse events associated with unplanned hospitalizations compared to photon therapy for patients also receiving chemotherapy. The authors found that patients treated with protons tended to be older, with more medical comorbidities. Despite this, patients treated with protons had a lower risk of developing 90-day adverse events of at least grade 3, grade 2, and were less likely to have a decline in overall performance status. There was no difference in disease-free or overall survival. Although this does appear favorable for proton therapy, there are several important limitations. The study is retrospective and although the authors did use statistical techniques to try to account for potential sources of bias, there may be unmeasured differences between the groups, and randomize prospective studies are needed to confirm these results.

Reference (PubMed Link): Baumann BC, Mitra N, Harton JG, et al. Comparative effectiveness of proton vs photon therapy as part of concurrent chemoradiotherapy for locally advanced cancer. JAMA Oncol 2019;6:237-46.

Key Institution: U Pennsylvania
Keywords: Proton therapy, photon therapy, locally advanced cancer, concurrent chemoradiation 

The purpose of this study was to compare clinical outcomes in patients with unresectable hepatocellular carcinoma (HCC) who receive ablative photon vs proton therapy.

This was a single-institution retrospective study looking at patients treated between 2008-2017 with unresectable HCC not treated with prior RT. This study looked at OS (main endpoint) as well as incidence of non-classic radiation-induced liver disease.

There were 133 patients on this study with a median follow-up of 14 months. There were 49 (37%) patients who received proton therapy. The study found that proton therapy was associated with a higher OS (HR 0.47, p=0.047). Proton therapy was also found to be associated with a lower risk of radiation-induced liver disease (OR 0.26, p=0.03). There was no difference in locoregional recurrence between the two arms.

The results showed that proton therapy was associated with improved OS compared to photon therapy, possibly owing to a reduction in the incidence of radiation-related liver disease. The findings of this retrospective study support a prospective study comparing proton and photon therapy for treatment of unresectable HCC.

Reference (PubMed Link): Sanford NN, Pursley J, Noe B, et al. Protons versus photons for unresectable hepatocellular carcinoma: Liver decompensation and overall survival. Int J Radiat Oncol Biol Phys 2019;105:64-72.

Key Institution: Harvard
Keywords: HCC, proton therapy, ablative radiation

There is substantial regional variation in the incidence of nasopharyngeal carcinoma worldwide, with the highest incidence in endemic populations in southern China, southeast Asia, northern Africa, and immigrant populations in the United States. Since the publication of the landmark Al-Sarraf trial (Intergroup 0099) in 1998, the standard of care for the vast majority of patients (all but M1 or T1N0) has been concurrent definitive chemoradiotherapy followed by adjuvant chemotherapy. An ongoing cooperative group trial in the United States is seeking to risk-stratify patients for selecting adjuvant chemotherapy, but the backbone of upfront chemoradiotherapy has remained the same for more than 20 years. More recently, however, there has been an interest in induction chemotherapy followed by chemoradiotherapy for patients with stage III-IVB disease; this month’s issue of the New England Journal of Medicine reports results from a phase III randomized-controlled trial reported by Zhang and colleagues.  

Zhang et al. conducted a multicenter randomized-controlled phase III trial in China, enrolling patients with newly-diagnosed stage III-IVB nasopharyngeal carcinoma. Patients were randomized to standard upfront chemoradiotherapy (70 Gy, concurrent with cisplatin) with or without three cycles of every-three-week induction gemcitabine and cisplatin. The primary outcome was recurrence-free survival, with overall survival as a secondary endpoint. From 2013-2016, 480 patients were enrolled. In the induction chemotherapy arm, 97% of patients completed all three cycles of gemcitabine/cisplatin, and 94% of patients completed at least two cycles of concurrent cisplatin. In the control arm, 98% of patients completed at least two cycles of concurrent cisplatin. All but two patients in the trial completed radiotherapy. These results indicate good adherence to definitive concurrent therapy despite three cycles of induction, suggesting feasibility of such an approach.  

The primary endpoint, recurrence-free survival, was statistically- and clinically-significantly prolonged with the addition of induction chemotherapy to chemoradiotherapy (3-year RFS, 85% vs 77%). Similarly, three-year overall survival was prolonged from 90% to 95%. This was primarily due to a reduction in distant recurrences, with no difference in locoregional recurrence-free survival. There were more grade 3+ adverse events in the induction therapy cohort (76% vs. 56%), primarily due to hematologic, gastrointestinal, and renal toxicity. There was no difference in the incidence of late effects except for grade 1-2 peripheral neuropathy.  

This trial will likely change the decades-old standard of care for patients with stage III-IVB disease, and again calls into question the controversial use of adjuvant chemotherapy. As a result, radiation oncologists will need to learn to manage these patients after induction chemotherapy, with more complex decision-making regarding adaptive planning and treatment of pre-induction or post-induction volumes.

Reference (PubMed Link): Zhang Y, Chen L, Hu GQ, et al. Gemcitabine and cisplatin induction chemotherapy in nasopharyngeal carcinoma. N Engl J Med 2019;381:1124-1135.

Key Institution: Multi-Institutional (Southern China)
Keywords: Nasopharyngeal Carcinoma, Chemoradiotherapy, Induction, Randomized, Intensity-Modulated Radiation Therapy

Patients with recurrent head and neck cancer have limited options for treatment, and generally poor outcomes.  The standard recommendation is for salvage surgery, but many patients are not eligible for this due to comorbidities, general medical deconditioning, or location of recurrence.  However, there has been concern with the role of reirradiation given retrospective reports of long term toxicity, and specifically the concern for carotid blowout syndrome (CBOS).  CBOS is defined as a complication of head and neck cancer in which the carotid artery or one of its major branches ruptures.  It is most often fatal.  SBRT is more attractive than conventionally fractionated treatment for a number of reasons including decreased acute toxicity and decreased treatment time.  Some small retrospective studies have previously suggested increased risk of CBOS for SBRT (8-17%) versus conventionally fractionated treatment (1-4%), as well as higher risk if >180 degrees of the carotid artery is encased.  This study examined whether there is any relation between SBRT and CBOS in the setting of reirradiation based on DMax, mean dose to the carotid, and additional risk factors such as degree of carotid encasement, skin involvement, and ulceration/necrosis. This is a single institution retrospective study of 75 patients and 150 carotid arteries.  All patients had previous conventionally fractionated head and neck radiation with a mean dose of 70Gy.  Their prior radiation doses, carotid hotspots, or carotid coverage were not accounted for in this study.  It only examined the SBRT reirradiation dose and hotspots.  Patients were treated to 40-50Gy in 5Fx delivered every other day.  A minority of patients (10.7%) had 2 or more courses of SBRT reirradiation and for these patients their cumulative SBRT dose was accounted for.  The median Dmax for the following volumes was: D0.1cc=40.8Gy, D1cc=26.8Gy, D2cc=15.4Gy.  The mean carotid dose was 15Gy, and median PTV size 39.3 cm^3. Interestingly this study only found a total of 4 carotid bleeding events (5.3%), which is lower than the previously reported 8-17% in the SBRT setting.  Of these, two were mucosal bleeds that were successfully embolized and 2 were truly fatal CBOS (2.6%).  This is within the range of 1-4% previously reported for conventional fractionation.  There was no true significant association between DMax, Dmean, or additional risk factors such as necrosis or carotid encasement.  There was however a trend (p=0.08) towards increased risk of bleeding with D0.1cc>47.6Gy.  Of note there was a true minority of patients who had carotid encasement >180 degrees (16%); the large majority (78.7%) had 0 carotid encasement.  The same is true for skin invasion (only 5.3%) and ulceration (9.3%).  These numbers are too small to form any real conclusions about safety of irradiating in these settings.  Additionally, it must be accounted for that this is a retrospective study that did not account for overlapping hotspots from previous radiation. Overall, this study does provide a preliminary reassurance that carotid reirradiation, especially in the SBRT setting, may pose less of a threat than previously thought for CBOS.  This opens the door for a modality of treatment that is often a head and neck patient’s only choice in a challenging setting of recurrence, especially if they have poor performance status or other comorbidities.  It cautions to proceed carefully and potentially limit D0.1CC to <47.6Gy.  More remains to be investigated for the true safety threshold of reirradiation, especially in the setting of overlapping hotspots from previous treatment, and carotid encasement. 

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