Small Changes, Big Impact: Excitement and Caution in Dose and Volume Reduction for Nasopharyngeal Carcinoma Radiation Therapy After Induction Chemotherapy.

During the past decade, there has been a shift toward induction chemotherapy (IC) followed by concomitant chemotherapy and radiation therapy (RT) for the treatment of locoregionally advanced nasopharyngeal carcinoma (NPC).1Petit C Lee A Ma J et al.Role of chemotherapy in patients with nasopharynx carcinoma treated with radiotherapy (MAC-NPC): An updated individual patient data network meta-analysis.Lancet Oncol. 2023; 24: 611-623Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar Given the chemo-sensitivity of NPC, the majority of patients will achieve at least a partial response (PR) in the primary tumor and involved lymph nodes; as a result, radiation oncologists have been faced with the question of how to handle postchemotherapy shrinkage in gross tumor volume (GTV) and what doses to prescribe to the various at-risk regions. The long-term outcomes of this noninferiority trial reported by Xiang et al2Xiang L Rong J-F Chen X et al.Reducing target volumes of intensity modulated radiation therapy after induction chemotherapy in locoregionally advanced nasopharyngeal carcinoma: Long-term results of a prospective, Multicenter Randomized Trial.Int J Radiat Oncol Biol Phys. 2023; 117: 914-924Abstract Full Text Full Text PDF Google Scholar and published in this issue of the International Journal of Radiation Oncology • Biology • Physics, provide promising data on the feasibility and benefits of using magnetic resonance–based, post-IC GTV delineation and derivation of clinical target volumes (CTV). Salama et al were the first to address these questions for head and neck cancer in general and recommended using pre-IC primary site and nodal GTVs for RT planning, with post-IC targets corresponding as closely as possible to the original disease tissue in all dimensions.3Salama JK Haddad RI Kies MS et al.Clinical practice guidance for radiotherapy planning after induction chemotherapy in locoregionally advanced head-and-neck cancer.Int J Radiat Oncol Biol Phys. 2009; 75: 725-733Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar They also recommended against modifying radiation doses based on the response to IC, even if a complete response was achieved. These recommendations were subsequently adopted in international guidelines for the delineation of CTV for NPC.4Lee AW Ng WT Pan JJ et al.International guideline for the delineation of the clinical target volumes (CTV) for nasopharyngeal carcinoma.Radiother Oncol. 2018; 126: 25-36Abstract Full Text Full Text PDF PubMed Scopus (172) Google Scholar In fact, the study from Zhang et al using induction gemcitabine and cisplatin, which was practice changing in many centers, used pre-IC volumes.5Zhang Y Chen L Hu G-Q et al.Gemcitabine and cisplatin induction chemotherapy in nasopharyngeal carcinoma.New Eng J Med. 2019; 381: 1124-1135Crossref PubMed Scopus (0) Google Scholar However, there is a radiobiological rationale for prescribing radiation doses based on the tumor's clonogenic density, which may involve a lower dose to residual microscopic disease after regression after IC. Additionally, given the proximity of the tumor to various organs at risk, particularly optic/neurologic tissues and salivary glands, limiting the high-dose region to post-IC targets while lowering the dose to regressed areas could help spare these organs. Several retrospective studies have suggested that reducing radiation dose in response to IC could be a safe approach.6Kong F-F Ni M-S Zhai R-P et al.Local control and failure patterns after intensity-modulated radiotherapy with reduced target volume delineation after induction chemotherapy for patients with T4 nasopharyngeal carcinoma.Transl Oncol. 2022; 16101324Crossref Scopus (4) Google Scholar, 7Xue F Ou D Ou X et al.Long-term results of the phase II dose and volume de-escalation trial for locoregionally advanced nasopharyngeal carcinoma.Oral Oncol. 2022; 134106139Crossref Scopus (3) Google Scholar, 8Zhao C Miao J-J Hua Y-J et al.Locoregional control and mild late toxicity after reducing target volumes and radiation doses in patients with locoregionally advanced nasopharyngeal carcinoma treated with induction chemotherapy (IC) followed by concurrent chemoradiotherapy: 10-year results of a phase 2 study.Int J Radiat Oncol Biol Phys. 2019; 104: 836-844Abstract Full Text Full Text PDF PubMed Google Scholar In this issue, Xiang et al provide further evidence supporting this practice. This was a randomized study conducted in 6 cancer centers in China, involving 212 patients with locally advanced NPC (American Joint Committee on Cancer staging manual, seventh edition, stage III-IVB). The primary endpoint was noninferiority in the 5-year locoregional recurrence-free survival (LRRFS) between target volume (TV) delineations based on the pre-IC and post-IC groups, with a noninferiority margin of 15%. Notably, the IC consisted of only 2 cycles of either cisplatin 75 mg/m2 D1 and 5FU 1000 mg/m2 D1-4 or cisplatin 75 mg/m2 D1 and paclitaxel 175 mg/m2 D1, given every 3 weeks. Regarding the TV delineation of the primary tumor and dose prescription in the post-IC group, 70 Gy in 33 fractions were given to the PTV of the post-IC GTV (ie, without an additional CTV margin) and any involved bone structures before IC; 64 Gy in 33 fractions were given to the PTV1, covering the CTV1, which consisted of an additional margin of 5 to 10 mm from the post-IC GTV, the entire nasopharynx as well as the area of tumor (ie, pre-IC GTV) shrinkage by IC; and a prophylactic dose of 54 Gy in 33 fractions was given to other elective structures, as stated in the article. After a median follow-up of more than 8 years, the primary endpoint of LRRFS was met and exceeded 90% in both groups. Other survival outcomes, such as overall survival, progression-free survival, and distant metastasis-free survival, were similar. Secondary measures, including late toxicity and quality of life, favored the post-IC group, which is not unexpected given the lower radiation dose to organs at risk in this group, as evidenced in their dose statistics analysis. Specifically, there is a significant reduction in grade 2 xerostomia (13%) and hearing loss (17%) in the post-IC group, compared with 26% and 28% in the pre-IC group, respectively. Differences were also observed in cognitive functioning and some symptom scales. Although this study provides valuable evidence for tailoring target delineation and dose prescription according to post-IC tumor extent, there are several issues that should be considered. First, the study used a nonstandard IC regimen of only 2 cycles, and the more common approach is to use 3 cycles; additionally, gemcitabine was not a component of the induction protocol. Therefore, the dose intensity and agents used in this study were not typical. As a result, no patient achieved a complete response and PR was achieved in only approximately 75% of patients; thus, the potential benefit of limiting the dose to 64 Gy to the primary tumor bed for complete responders could not be evaluated. In contrast, Zhang et al found that with 3 cycles of induction gemcitabine and cisplatin, complete response was achieved in 10% and PR in an additional 85%.5Zhang Y Chen L Hu G-Q et al.Gemcitabine and cisplatin induction chemotherapy in nasopharyngeal carcinoma.New Eng J Med. 2019; 381: 1124-1135Crossref PubMed Scopus (0) Google Scholar Second, assessing morphologic and anatomic responses to IC in the skull base infiltrated by the tumor is challenging, leading to a dose of 70 Gy being prescribed to all involved bone structures regardless of the soft tissue tumor response. Perhaps most importantly, the study's sample size estimation was criticized for using a noninferiority margin of 15% based on an assumption that the 5-year LRRFS in both groups would be 91.7%. This means that only a 5-year LRRFS lower than 76.7% in either group would fall outside the noninferiority margin to reject the null hypothesis, such a low LRRFS would be considered unacceptable to most given the devastating consequences of local recurrence of NPC. As a result, the randomized study was relatively small, and the conclusion drawn from it is less robust. Finally, being a multicenter study on treatment planning based on tumor response to IC, a program on RT quality assurance would be a vital feature and should be reported if this has been implemented. Small details regarding RT volumes and planning are critical when considering modifications of approaches for NPC and its effect on tumor control and toxicity. For example, considering tissue that has changed location due to regressing tumor bulk after IC but was never initially involved by disease and is now in a high-dose CTV region, this volume would have been included in the “preinduction” arm in this study from Xiang et al. Arguably, the CTV in such tissue, which is a microscopic disease concept, could be modified and excluded even if one were to use preinduction volumes. Similar nuances could be used in certain air cavities. Modifications of preinduction volumes could potentially be made smaller without employing postinduction volume concepts, thereby reducing the differences seen between pre- and postinduction volumes as described. Different protocols used globally could also affect the generalizability of these findings. For example, some centers add a 3- to 5-mm CTV to GTV and prescribe 70 Gy to a PTV on that CTV volume, with only a larger elective 56 Gy volume beyond that (including 1 cm beyond GTV, whole nasopharynx, as well as all the targeted base of skull elective structures as described in the article). According to this protocol, the 70 Gy volume is similar or slightly larger than described by Xiang et al, but there is no large 64 Gy volume that is 5 to 10 mm beyond GTV and including the whole nasopharynx in all cases. It is challenging to extrapolate results or compare differences in outcomes from pre- versus postinduction volumes when the protocol for defining volumes differs. With different RT and chemotherapy protocols at various institutions, the efficacy and safety of postinduction volumes need to be carefully considered and implemented with caution. However, the concept of covering the shrunken tumor volume in soft tissue that may be seeded with a higher burden of microscopic disease by an intermediate dose of 64 Gy is one that could perhaps be abstracted and applied to centers using postinduction volumes more generally. There are important questions to consider as we move forward with the premise that a lower dose of 64 Gy is safe to treat the microscopic disease that remains after IC. For example, can we go even lower than 64 Gy, and if so, how low can we safely go while still maintaining effective tumor control? For example, the Children's Oncology Group ARAR0331 used response to IC to reduce dose with excellent outcomes.9Rodriguez-Galindo C Krailo MD Krasin MJ et al.Treatment of childhood nasopharyngeal carcinoma with induction chemotherapy and concurrent chemoradiotherapy: Results of the Children's Oncology Group ARAR0331 study.J Clin Oncol. 2019; 37: 3369Crossref PubMed Scopus (32) Google Scholar Of course, results in the pediatric world cannot be generalized to adult NPC, but approaches of different doses depending on the response to IC are an exciting avenue of research as we increasingly move toward IC for many cases. Additionally, determining the optimal agents and number of cycles of IC to maximize tumor response and minimize the high dose region of 70 Gy is an important consideration. Furthermore, functional imaging, biomarkers, or “multi-omic” assessments could offer valuable insights into assessing tumor response,10Ng SP Corry J Ng WT. The Janus face in defining the optimal radiation dose for nasopharyngeal carcinoma.Int J Radiat Oncol Biol Phys. 2022; 113: 114-116Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar including the skull base region. It is worth considering whether the same strategy of dose de-escalation based on IC response could be used in treating human papillomavirus–related oropharyngeal cancer, which is also sensitive to both chemotherapy and RT. Despite these questions, Xiang et al's study provides valuable early data on dose de-escalation based on IC response, which is a promising avenue for future research in treating NPC. Reducing Target Volumes of Intensity Modulated Radiation Therapy After Induction Chemotherapy in Locoregionally Advanced Nasopharyngeal Carcinoma: Long-Term Results of a Prospective, Multicenter, Randomized TrialInternational Journal of Radiation Oncology, Biology, PhysicsVol. 117Issue 4PreviewThe objective of this study was to estimate the long-term survival, late toxicity profile, and quality of life of patients with locoregionally advanced nasopharyngeal carcinoma (NPC) treated with combined induction chemotherapy (IC) and concurrent chemoradiotherapy from a clinical trial focused on reducing the target volume of intensity modulated radiation therapy (IMRT). Full-Text PDF