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This JCO Podcast provides observations and commentary on the JCO article, "Treatment of Childhood Nasopharyngeal Carcinoma with Induction Chemotherapy and Concomitant Chemoradiotherapy: Results of the Children\\u2019s Oncology Group ARAR0331 Study" by Rodriguez-Galindo et al. My name is Suzanne Wolden, and I am the Director of Pediatric Radiation Oncology at Memorial Sloan Kettering in New York City, USA.\\xa0 My oncologic specialty is Pediatric Radiation Oncology.

This important manuscript summarizes the results of Children\\u2019s Oncology Group protocol ARAR0331 for childhood nasopharyngeal carcinoma.\\xa0 The study enrolled 111 patients, of whom 75% were male and 47% were African American, with a median age of 15.\\xa0 Eligible patients had AJCC stage IIb-IVC disease and received three cycles of induction chemotherapy with 5-fluorouracil and cisplatin followed by concurrent cisplatin and radiotherapy.\\xa0 Three patients had progressive disease during induction chemotherapy, eight were removed from the study due to physician or parent preference, and another three were not evaluable.\\xa0 This left 97 patients evaluable for response and concurrent chemoradiotherapy.\\xa0 Responses and radiotherapy treatment plans were not centrally reviewed but were left to the judgement of the treating institution.\\xa0

All patients received 45 Gy to comprehensive head and neck fields encompassing the nasopharynx and bilateral level I-V lymph nodes.\\xa0 A boost to the nasopharynx and residual gross nodal disease was prescribed based on response.\\xa0 The full dose of 70.2 Gy indicated for stable disease was given to 18.6% of patients while 77.3% received the protocol specified dose for complete or partial response of 61.2 Gy or lower.\\xa0 Another 4.1% of patients received intermediate non-protocol doses of 63.9-66.6 Gy.\\xa0 The trial was amended to reduce the cycles of concurrent cisplatin during radiotherapy to two from three after unacceptable rates of renal and gastrointestinal toxicities were reported.\\xa0

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This trial was limited to patients age 18 years and younger and consisted primarily of American patients.\\xa0 It is notable that the demographics of nasopharynx cancer in these young patients differ significantly from adults with this diagnosis.\\xa0 Most patients are teens since nasopharynx cancer is vanishingly rare in younger children.\\xa0 The majority were male, and nearly half were African-American.\\xa0 Nasopharynx cancer is quite rare in teens of Asian descent, in stark contrast to the adult population.\\xa0 In international series, it has been noted that teens in countries around the Mediterranean also have a relatively high incidence of this rare cancer.\\xa0 The study illustrates that pediatric patients are much more likely than adults to have advanced disease and WHO type III, Epstein Barr virus-associated histology.

Despite a lack of central review, the response rate appears to be quite high to induction therapy as one might expect with WHO type III carcinoma.\\xa0 It is surprising that any patients had progressive disease, and I suspect that the rate of partial and complete response may have been even higher than what is inferred from the radiation boost doses given.\\xa0 Nonetheless, the strategy of induction therapy was highly successful in allowing a large majority of patients to receive reduced doses of radiation.\\xa0 It is important to note that all patients received 45 Gy to initial comprehensive fields rather than the 50 Gy typically used for adults and that smaller, more forgiving fractions of 1.8 Gy were used in comparison to the standard 2 Gy for adult head and neck cancer.\\xa0 While some patients received a standard adult boost dose of 70.2 Gy, 81.4% received a lower boost dose.\\xa0 In most cases, this was the protocol specified 61.2 Gy, a 13% dose reduction. \\xa0Even with these significantly lower doses, local control was exceptionally high, with only 5.5% of patients experiencing local failure with or without a distant relapse.

The successful reduction in radiotherapy doses in this study is incredibly important and by far the most newsworthy aspect of this paper.\\xa0 Even full or nearly grown teens experience dramatically more severe late effects of radiotherapy compared to older adults.\\xa0 The severity of soft tissue fibrosis 10 or more years after full doses of radiation to the head and neck is so great that many patients require feeding tubes and tracheostomies.\\xa0 The rate of second malignancy is also much higher in young patients.\\xa0

The rate of distant relapse of 10.5% was low, considering that patients with metastatic disease at diagnosis were enrolled.\\xa0 It is possible that with more advanced staging scans such as FDG-PET, metastatic lesions can be more easily detected and defined.\\xa0 In that case, they can be targeted with radiotherapy to decrease the risk of relapse.\\xa0 This approach has been shown to be effective in achieving cure in adults.\\xa0 It is unlikely that an increase in chemotherapy beyond what was used in this protocol would be tolerated or worth the added toxicity.\\xa0 Indeed, it is unclear whether the 3rd cycle of concurrent cisplatin was beneficial since there was only a trend for improved EFS and the cumulative toxicity is significant.\\xa0 One must be mindful that increases in systemic therapy have been shown to decrease tolerance for head and neck radiotherapy.\\xa0 This can be counterproductive to outcome if there are delays, breaks or failure to complete the course of radiation.

This trial was so successful in its ability to decrease radiation exposure in young patients, that we should be inspired to go further.\\xa0 My thoughts regarding the next trial would be to use PET scans for staging and response assessment and to push the radiotherapy doses lower.\\xa0 This approach is currently being investigated for adult HPV associated head and neck cancer with doses as low as 30 Gy.\\xa0 Perhaps in pediatric (or even EBV positive adult) nasopharynx cancer, 30-36 Gy would be enough for the comprehensive initial fields with boost doses in the range of 50-60 Gy for those who respond favorably to induction chemotherapy.\\xa0 Dose reductions of this magnitude would make major differences in the acute and especially the late toxicities.\\xa0 In addition, modern radiation technologies such as proton therapy allow improved avoidance of normal tissue exposure for these young, curable patients.

In summary, this article provides evidence that response-based radiation dose reduction is possible for pediatric nasopharynx cancer.\\xa0 Even with numerous limitations, the outstanding results of this trial inspire us to continue moving forward in the direction of reducing radiation exposure for these young patients.\\xa0 Long-term follow up is also urged to quantify the expected benefits of these therapeutic changes.

This concludes this JCO Podcast.\\xa0 Thank you for listening.