Magnetic Resonance Imaging Volumetry of Primary Nasopharyngeal Cancer in Patients Treated with Induction Gemcitabine and Cisplatin Followed by Concurrent Cisplatin and Volumetric Modulated Arc Therapy

Introduction The addition of induction chemotherapy (IC) to the standard concurrent chemoradiotherapy (CCRT) is under consideration in locally advanced nasopharyngeal carcinoma (LANPC). To-date, no studies have reported primary gross tumour volume (GTVp) changes using gemcitabine and cisplatin as the IC phase in LANPC. We investigated the timing and magnitude of GTVp response throughout sequential gemcitabine and cisplatin IC and CCRT for LANPC. Toxicity and tumour control probability (TCP) analyses are also presented Methods Ten patients with LANPC underwent sequential IC and CCRT between 2011 and 2015. All patients had magnetic resonance imaging (MRI) at three time points: before IC (MRI0), after IC (MRI1), and three months after CCRT (MRI3). Five of the 10 patients had an additional MRI four to five weeks into CCRT (MRI2). GTVp contours were delineated retrospectively using contrast-enhanced MRIs, and each GTVp underwent secondary review by a neuroradiologist. Acute toxicities were graded retrospectively via chart review based on the National Cancer Institute Common Terminology for Adverse Events version 4.0 (NCI CTCAE v4.0). Results Mean GTVp reduction between MRI0 - MRI1 was from 68 cc to 47 cc and from 47 cc to 9 cc between MRI1 - MRI3. In patients with MRI2, the mean GTVp reduction between MRI1 - MRI2 was from 57 cc to 32 cc. Tumour control probability estimates increased by 0.11 after IC. Patients tolerated the treatment well with one Grade IV toxicity event. Conclusion The observed GTVp response and improved tumor control probability support further investigation into the use of IC in LANPC.


Conclusion
The observed GTVp response and improved tumor control probability support further investigation into the use of IC in LANPC.

Introduction
Locally advanced nasopharyngeal carcinoma (LANPC) is defined by the invasion of a primary gross tumour into adjacent anatomy, including the skull base and/or paranasal sinuses (T3) or intracranial extension and/or involvement of the cranial nerves, hypopharynx, orbit, or extension to infratemporal fossa (T4) [1][2]. The current standard of care for LANPC is cisplatinbased concurrent chemoradiotherapy (CCRT) [3][4][5][6]; however, the feasibility of delivering radical radiotherapy may be complicated by the anatomical proximity of critical organs at risk (OARs) [7].
Based on the limited evidence to support the use of IC, the rationale must be carefully considered when developing a treatment plan. Based on the difficult anatomical location of disease, sequential IC may be used to reduce primary gross tumour volume (GTVp) bulk prior to delivering CCRT [3,5]. There is a paucity of reports on the efficacy of sequential IC and CCRT for reducing GTVp bulk in LANPC. To date, no studies have reported GTVp changes using gemcitabine and cisplatin as an IC phase in LANPC. The primary aim of this work is to describe GTVp changes after IC and assess the potential impact of tumour response on subsequent CCRT. In addition, we follow GTVp during CCRT and three months post-treatment in LANPC using magnetic resonance imaging (MRI) volumetry. Toxicity and tumour control probability (TCP) analyses are also presented

IC and CCRT
IC consisted of cisplatin and gemcitabine given every 21 days for two to three cycles. Cisplatin was administered intravenously 80 mg/m 2 on day 1 of each cycle and gemcitabine 1,250 mg/m 2 was given intravenously on days 1 and 8. During CCRT, cisplatin was given weekly at a dose of 40 mg/m 2 concurrently with radiotherapy. The selection of cisplatin and gemcitabine as an induction regimen was based on Phase II data [13][14][15][16] and the efficacy in the metastatic setting [17]. The evidence suggested a high response rate which was critical for the goal of reducing tumor volume to facilitate radiotherapy delivery.
Pre-IC GTVs were treated with 70 Gy in 35 fractions using volumetric modulated arc therapy (VMAT). If treatment to the pre-IC GTVs was not achievable due to the dose to organs at risk (OARs) exceeding Quantitative Analyses of Normal Tissue Effects in the Clinic (QUANTEC) tolerances, then post-IC GTVs were treated up to 70 Gy, and the pre-IC GTVs received 56 -70 Gy.

Toxicity
Acute toxicities were graded retrospectively via chart review based on the National Cancer Institute Common Terminology for Adverse Events version 4.0 (NCI CTCAE v4.0) [18]. Rates of Grade III/IV toxicity reported from the time of IC to the three-month follow-up MRI were included. The incidence of a gastrostomy tube (G-tube) placement for symptomatic mucositis and/or weight loss > 10% was also recorded.

GTVp delineation
GTVp included the primary tumour, plus involved retropharyngeal lymph nodes visible on diagnostic MRI. GTVp contours were delineated retrospectively using fat-suppressed, gadolinium-enhanced T1-weighted MRIs by one primary observer and reviewed by a second radiation oncologist. Each GTVp underwent a secondary review by a neuroradiologist. GTVp contours are labeled according to the MRI time point. For example, GTVp 0 is delineated on MRI 0 ; GTVp 1 is delineated on MRI 1 , and so on. Contouring was performed using the ARIA™ contouring platform (Varian Medical Systems, Palo Alto, CA).

GTVp response
Absolute volumes of each GTVp were calculated in ARIA. The percent volume tumour response (PVTR) between phases i and j, denoted as PVTR i-j was calculated using equation (1). (1)

TCP calculation
TCP was calculated using equation (2) as described by Lee et al. [14][15][16]. ( where α 0 is the mean value of α and K is the normalization factor for the Gaussian distribution where V i is the volume of GTVp in cc receiving a total dose of D i over n fractions and ρ is the clonogenic cell density. Again, to be consistent with Lee et al., ρ = 10 7 per cc and α/β = 10 were used.
The paired sample t-test was used to compare changes in volume and TCP pre-and post-IC.

Patient characteristics
Patient characteristics are described in Table 1. All patients were Epstein-Barr virus in-situ hybridization positive and had non-keratinizing undifferentiated (World Health Organization (WHO) Type III) nasopharyngeal carcinoma (NPC) on pre-treatment biopsy.

Toxicity
All patients successfully completed IC and CCRT. Overall, three of 10 patients had Grade III acute toxicity throughout treatment ( Table 2). One of 10 required G-tube feeding, and no patients required hospital admission throughout treatment.
GTVp; primary gross tumor volume

Impact of IC on TCP and volume
IC decreased the volume in all patients ( Table 3). Prior to IC, the mean volume was 68.5 cc (median 64.5, range: 22 -106) and after IC, the mean volume was 46.9 cc (median: 40.5, range: 12 -78), p < 0.0001. IC improved TCP in all patients. Prior to IC, the mean TCP was 0.65 (median: 0.72, range: 0.14 -0.89), and after IC, the mean TCP increased to 0.76 (median: 0.84, range: 0.42 -0.90), p = 0.  It is widely accepted that most LANPC tumours shrink in response to IC regimens; however, there is limited data on the timing and magnitude of IC contributions to tumour response. Accurate volumetry is necessary in order to optimize the potential therapeutic benefits of sequential IC and CCRT. In radiotherapy, therapeutic benefit improves by increasing the dosimetric coverage of the clinical target volume and/or decreasing dose received by critical OARS. Hence, the two general strategies to exploit GTVp response during IC include 1) treating the smaller post-IC GTVp, thereby improving the sparing of nearby OARS, or 2) treating the larger pre-IC GTVp, thereby improving the dosimetric coverage of the post-IC CTV. Lee et al. judiciously reported that treatment of the larger pre-IC GTVp is more prudent until further study characterizing the post-IC tumour extent [19]. More recently, a randomized clinical trial reported that treating post-IC GTV led to improved quality of life without reducing local control and survival in LANPC patients [25].
Lee et al. showed that IC with cisplatin and 5-fluorouracil in LANPC patients led, on average, to a 61% reduction in GTVp using MRI volumetry [19]. They calculated that the tumour response to IC improved TCP from 0.83 (pre-IC) to 0.89 (post-IC). The 33% GTVp reduction during IC observed in our study is considerably lower; however, differences are expected due to differing IC regimens, GTVp definitions, and patient populations. We calculated a similar improvement in TCP of +0.11. In the current study, TCP values are consistently lower than those reported by Lee et al. and this may reflect differences in aggressiveness of treatment and/or patient selection. For TCP calculation, we used the identical biological parameters to guide comparisons. Differences in the patient population will influence the accuracy of TCP values reported in our study.
TCP is a metric traditionally used to compare different radiotherapy regimens in terms of their respective probability of achieving tumour eradication. TCP values must be viewed as relative estimates since their calculation is based upon simplified statistical models of malignant clonogenic cells response to irradiation. Furthermore, TCP values do not account for the tumoricidal effects of chemotherapy.
Adaptive re-planning has been proposed in LANPC for patients with GTV reduction throughout treatment. Re-planning partway through treatment using smaller GTVs can enable a more curative dose to be delivered to the GTV while adhering to strict dose limitations to nearby neurologic structures often compromise radiotherapy plans [8,[26][27]. Chen et al. reported improved two-year local control of 88% versus 79% for appropriately selected patients treated with adaptive re-planning compared to patients treated without re-planning [28]. Patients selected for re-planning had worse disease and tumour stage compared to patients who did not, yet they demonstrated a higher rate of local control. Several studies reported that the ideal time point for adaptive re-planning is four to five weeks into CCRT due to OAR movement and GTVp shrinkage [27,29]. Inherent limitations of this study include its small sample size and retrospective nature. In addition, three-month follow-ups may not provide sufficient time to observe the total tumour response or potential local recurrent disease since GTVps could continue to change. Our findings reflect a patient population that is characteristic of endemic NPC since all subjects exhibited non-keratinizing pathology; however, we are unable to correlate Epstein-Barr virus (EBV) status with the GTVp response since EBV serology is not routinely obtained at our center [5]. Finally, we do not have a comparable LANPC patient population with similar MRI datasets who did not undergo IC for comparison, as treatment with IC is standard protocol for patients with T3 and T4 disease treated at our center.
The role of IC in a general NPC population is under investigation. Recently completed and ongoing Phase III trials, however, may provide more insight with modern chemotherapy regimens and radiotherapy techniques. It remains that the overall benefit of IC in LANPC is not fully elucidated, and tumor size and anatomic location may provide better guidance for patient selection.

Conclusions
Our volumetric results support further investigation into the use of IC to reduce GTVp. Larger prospective studies with more frequent MRI evaluation should help to address some of these questions.