Hypofractionated palliative volumetric modulated arc radiotherapy with the Radiation Oncology Study Group 8502 “QUAD shot” regimen for incurable head and neck cancer

Patients with head and neck cancer (HNC) are often ineligible for curative therapy such as surgery and definitive radiotherapy (RT) because of advanced age, poor performance status, extent of the tumor, prior treatment, and comorbidities. Patients with HNC often have symptoms such as pain, hemorrhage, dysphagia, and airway compromise which decrease the quality of life (QOL) [1, 2].

In the 1980s, the Radiation Therapy Oncology Group (RTOG) performed a phase II study of RT, which consisted of 2 days of twice-daily fractionation with a fraction size of 3.7 Gy (14.8 Gy per cycle) repeated at 3 to 6 week intervals for a total of three cycles with an RT dose of 44.4 Gy for pelvic malignancies [3]. Thereafter, this RTOG 8502 “QUAD shot” regimen has been successfully adapted for palliative treatment of HNC. The RTOG 8502 regimen for HNC has been reported to achieve tumor response and palliation in approximate 50 to 85% and 55 to 100% of patients, respectively. Furthermore, toxicity has been reported to be mild, with Grade 3 toxicity present in approximately 0–10% of patients [2, 4‐8]. The current National Comprehensive Cancer Network (NCCN) guidelines recommend the RTOG 8502 regimen using three-dimensional conformal RT (3D-CRT) or intensity-modulated radiotherapy (IMRT) as one of the palliative RT regimens for HNC [9].

Recently, volumetric modulated arc therapy (VMAT) has been introduced to treat HNC [10]. Using this technique, the gantry is rotated while the dose is being delivered, and three parameters (dose rate, field shape, and speed of gantry rotation) can be changed as the beam is rotated [11]. Compared with conventional fixed-field IMRT, VMAT provides similar excellent dose coverage to the target volume with a reduced dose to organs at risk (OAR). Furthermore, the treatment time of VMAT is much shorter than conventional IMRT; the approximate treatment times are 2 to 4 and 10 to 15 min for VMAT and IMRT, respectively [10]. Introduction of VMAT into palliative RT regimen with RTOG 8502 may provide good treatment response with reduced toxicity for patients with HNC. To the best of our knowledge, the treatment results of RTOG 8502 regimen using VMAT has not been evaluated. The purpose of this study was to review a single institutional experience of the RTOG 8502 “QUAD shot” regimen using VMAT for incurable HNC.

RT for incurable HNC has been demonstrated to be an effective palliative modality, even for patients who have received prior RT [2, 14]. Currently, no consensus exists for appropriate palliative RT regimen in HNC. In general, a once-daily hypofractionated RT regimen of 30 Gy/10 fractions is commonly performed as palliative RT regardless of the tumor site; however, this treatment regimen is inappropriate for HNC because of the acute adverse effects. The reported frequency of ≥Grade 3 acute toxicity with this treatment regimen for patients with HNC was > 40% [6]. Other hypofractionated palliative RT regimens have been reported for HNC. Stevens et al. performed palliative RT for 148 patients with newly diagnosed HNC [15]. The median RT dose and fraction number were 50 Gy and 20, respectively; the most frequently used fractionation regimen was a split course designed to deliver a total dose of 50 Gy in 2.5-Gy fractions within 6 weeks, composed of two cycles of 25 Gy in 10 fractions given within 2 weeks, separated by a 2-week break. Overall response was reported in 85 (57%) patients, while 10 (7%) and 8 (5%) patients had unplanned discontinuation and planned RT interruption because of toxicity, respectively. The “Hypo Trial” conducted by Porceddu et al. treated 35 incurable patients with HNC; patients received 30 Gy in five fractions at 2/week, at least 3 days apart, with an additional boost of 6 Gy for small volume disease (≤ 3 cm) in suitable patients [16]. Tumor response was achieved in 28 (80%) patients. Grade 2 and 3 mucositis were reported in 13 (37%) and 9 (26%) patients, respectively, and Grade 2, 3 and 4 dysphagias were reported in 23 (66%), 4 (11%) and 2 (6%) patients, respectively. These RT regimens provide certain palliative response; however, acute adverse effects that may decrease patients’ QOL are still relatively strong. Palliative RT should be considered for relief or prevention of locoregional symptoms; however, severe toxicity should be avoided [9]. Our results suggest that RTOG 8502 regimen using VMAT is one of the strongest candidates of palliative RT regimens with good treatment response and low toxicity.

In earlier studies, RTOG 8502 regimen was performed using a two-dimensional (2D) RT. RT field was typically defined as the gross symptomatic disease plus a 1–2 cm margin based on physical examination [4, 5]. Nowadays, modern diagnostic imaging of MR and FDG/PET-CT, which achieve precise target definition and reduced target volume, has been included in RT planning [12, 17‐19]. Furthermore, the technical development of RT techniques in the last 2 decades, such as 3D-CRT, IMRT, VMAT, ART, and image-guided RT (IGRT) based on CT images, provides an enhanced dose concentration to the target volumes, reduces dose to OARs, and promises precise RT delivery [11, 20‐24]. These sophisticated treatment techniques are of significant value for not only definitive RT but also palliative RT with regard to treatment response and toxicity.

The clinical outcome of RT with RTOG 8502 regimen for patients with head and neck tumors is summarized in Table 4. Paris et al. reported the results of phase I-II study of RTOG 8502 regimen without chemotherapy for incurable HNC in 1992 [4]. They treated 37 patients with 39 lesions with 2D-RT technique using Cobalt 60 or 6 MV photons. The spinal cord dose was limited to 30 Gy by field reduction. Twenty-one (57%) patients completed all three cycles and tumor response was achieved in 30 (77%) of the 39 treated lesions. A decade later, Corry et al. reported the results of phase II study of palliative RT with a similar QUAD shot regimen without chemotherapy for incurable HNC [5]. They performed RT to a maximum of three cycles with a fraction size of 3.5 Gy, which differed slightly from the original RTOG 8502 regimen. Radiation was delivered using 2D-RT and the spinal cord was excluded to limit its dose to 28 Gy in 8 fractions. Sixteen (53%) patients completed all three cycles and 16 (53%) patients achieved a tumor response. Our tumor response results were superior to those achieved with 2D-RT. One of the reasons for this superiority may be that dose coverage for the target volume using VMAT is superior to that of 2D-RT because it is technically difficult to provide uniform distribution to the target volume using 2D-RT while reducing spinal cord dose within the limitation. Recently, Gamez et al. reported treatement results of RTOG 8502 regimen in stage III–IV head and neck tumors [8]. All 21 patients underwent concurrent systemic therapy: 18 (86%) and 3 (14%) patients received carboplatin and cetuximab, respectively. Radiation was delivered using a 3D-CRT in 6 (29%) patients and IMRT in 15 (71%) patients. Sixteen (76%) patients completed all three cycles and 18 (86%) patients achieved a tumor response. Although we did not perform concurrent systemic therapy, our tumor response of VMAT alone was similar to theirs.

The previous reported symptom response and overall response of the RTOG 8502 regimen with or without systemic therapy approximated 55–100% and 65–85%, respectively [4, 5, 7, 8] (Table 4). Our results of symptom response were comparable to these results. Furtheremore, our results of overall response were superior to these results. RTOG 8502 regimen using VMAT provides appropriate treatment response without using systemic therapy: this treament strategy may improve or maintain patient QOL.

The previously reported median OS and PFS of the RTOG 8502 regimen with or without systemic therapy approximated 4–7 months and 3–4 months, respectively [4, 5, 7, 8] (Table 4). Our results were similar with these results. Considering that the prognosis of patients with HNC who undergo non-curative treatment is poor with approximate survival time of 2–4 months [25, 26], palliative RT may contribute to a certin degree of prolonged survival. However, more than half of the patients die within 6 months even if they undergo palliative RT, including RTOG 8502 regimen [4, 5, 7, 8, 15, 16]. Therefore, a smaller number of fractions such as RTOG 8502 regimen is feasible for the palliative RT.

In our series, all patients who received 2 or more treatment cycles achieved overall response. Furthermore, completion of all three treatment cycles is significantly associated with better OS and PFS, which is consistent with previous reports [2, 8]. Treatment with multiple cycles is recommended for better treatment response and/or survival.

The incidence of the Grade 2 and 3 toxicities in patients with HNC treated with RTOG 8502 regimen was reported as approximately 20–40% and 0–10%, respectively [2, 5, 7, 8] (Table 4). Our results of toxicities were much lower than those of previous reports. Furthermore, toxicity was acceptable even in the patients who had received prior RT at the palliative sites. The primary reason for highly reduced toxicity in our patients may be attributed to the use of VMAT, ART, and IGRT. Another reason is that we did not perform concurrent systemic therapy. We recommend the introduction of these sophisticated treatement techniques into palliative RT regimen with RTOG 8502 not only because of their excellent palliative response but because of the highly reduced toxicity.

However, this was a retrospective study based on a relatively small number of patients. The potential for selection bias exists, which may influence the results of the treatment outcomes and analysis. Similarly, we could not evaluate the influence of palliative RT on overall QOL of the patients because our study was retrospective. A prospective trial with a larger cohort should be performed to further evaluate the value of introducing modern sophisticated RT techniques into RTOG 8502 regimen for HNC patients. Further investigations are underway to assess this concern.

The RTOG 8502 “QUAD shot” regimen using VMAT is effective for incurable HNC with highly reduced toxicity. Treatment with multiple cycles is recommended for better treatment response and/or survival.