QUAD SHOT is an ultra-hypofractionated radiotherapy (RT) technique that prescribes 14.0–14.8 Gy over 2 days. Although this technique has already gained some status as an effective palliative treatment for inoperable head and neck cancer (HNC), its application in other situations has not been given much consideration. Herein, we report a case of a 62-year-old woman who received preoperative QUAD SHOT therapy for poorly differentiated parotid carcinoma. In this case, after two courses of QUAD SHOT plus a standard chemotherapy regimen with pembrolizumab, the patient’s inoperable, bulky tumor shrank dramatically and became operable. Best of all, while adequate therapeutic effects were achieved, the patient’s time commitment and physical exertion were limited. RT during this period consisted of only eight fractions over 4 days. According to previous reports, the response rate for QUAD SHOT is sufficiently high, and the rate of serious adverse events is quite low. This case asks the question of whether the indications for QUAD SHOT irradiation can be expanded as one of the preoperative interventions undertaken by HNC surgeons to achieve conversion surgery.

© 2023 The Author(s). Published by S. Karger AG, Basel

Introduction

QUAD SHOT, described by Corry et al. in 2005 [1], is the common name for the RTOG 85-02 regimen for the palliative irradiation schedule developed by Paris et al. in 1993 [2]. It is a simple, 2-day radiotherapy (RT) regimen used for inoperable, advanced head and neck cancer (HNC). One course is 14 Gy in 4 fractions over 2 days. If possible, it is repeated in 3 weeks as a second course. Since one course only takes 2 nights and 3 days, the physical and social burdens of hospitalization and hospital visits are minimized, and the treatment is acceptable to patients with HNCs, many of whom are older individuals. However, there are few reports on its use in combination with surgery. Considering that it was designed as a treatment for advanced, unresectable malignancies, it is naturally regarded only as palliative irradiation.

We report a case in which QUAD SHOT for palliative RT of a bulky parotid carcinoma resulted in a significant reduction in tumor volume and consequently allowed for surgical resection of the primary tumor. Although this treatment was not initially intended for surgical purposes, the patient’s treatment strategy and quality of life were greatly changed due to the successful surgery.

We believe that this case may be the beginning of the introduction of QUAD SHOT as a “preoperative” or “conversion therapy,” and hence, we report its progress. The CARE Checklist has been completed by the authors for this case report, attached as online supplementary material (for all online suppl. material, see www.karger.com/doi/10.1159/000529829).

Case Report

The patient was a 61-year-old woman with no major co-morbidities. She had swelling in her left cheek for 20 years, which was diagnosed as a benign pleomorphic adenoma and followed up only with observation. Just after turning 61 years old, the swelling began to increase rapidly and quickly grew into a giant tumor within a month, despite antibiotic treatment by her general physician. She was hospitalized due to deterioration of her general condition, caused by local inflammation and severe hypercalcemia (Fig. 1a). Computed tomography showed a large primary tumor in the left parotid gland with a maximum diameter of 10 cm, lymph node metastases in the ipsilateral neck, and metastasis in the lower lobe of the right lung (Fig. 2a, d). She was diagnosed with left parotid carcinoma, cT4aN2bM1, stage IVc. The needle biopsy results were negative for various immunostains, and no more insight could be gained other than that it was a poorly differentiated carcinoma. Although resection of the bulky primary lesion was initially envisaged, it was deemed that there was no surgical indication for the following reasons: (i) it was not radical due to the presence of pulmonary metastasis; (ii) the tumor appeared to have invaded the masseter muscle (Fig. 2a), requiring a lengthy reconstructive surgery; and (iii) systemic inflammation caused by infection of the necrotic lesion, worsening of liver function, and low nutritional status (Table 1) made prolonged anesthesia extremely difficult.

Fig. 1.

a Patient’s appearance at the initial visit with marked left buccal swelling. b After the first course of QUAD SHOT and chemotherapy (day 41 after hospitalization, just before the second QUAD SHOT). Tumor necrosis with skin defects was noticeable. c After parotidectomy, followed by reconstruction with femoral skin valve.

Fig. 2.

Upper row: axial CT images of the primary tumor in chronological order. a Pre-treatment; bulky mass including internal necrosis (asterisk) and swollen lymph node (arrow). b After the second course of QUAD SHOT (day 55 after hospitalization), the lymph node metastasis vanished. c Post-parotidectomy. Lower row: axial CT images of lung metastasis. d–f correspond to (a–c), respectively. Tumor volume decreased over time, and the surrounding pneumonia disappeared. CT, computed tomography.

Table 1.

Patient laboratory values at the start of QUAD SHOT and just prior to the surgery

ParametersPre-QUAD SHOTPre-surgeryReferencesWBC count49.8 H4.23.3–8.6 × 103/μLHemoglobin8.3 L9.7 L11.6–14.8 × 106/μLPlatelet count264546 H158–348 × 103/μLC-related protein23.91 H0.640.00–0.14 mg/dLAlbumin2.3 L3.2 L4.1–5.1 × g/dLBlood urea nitrogen7 L128–20 mg/dLCreatinine0.37 L0.39 L0.46–0.79 mg/dLTotal bilirubin0.510.440.40–1.50 mg/dLAST40 H1413–30 U/LALT27 H127–23 U/LLDH650 H170124–222 U/LALP556 H154 H38–113 U/Lγ-GTP509 H–9–32 U/L

Due to poor bleeding control at the biopsy puncture site and the need for early treatment with hemostasis, the first QUAD SHOT of 14 Gy in four fractions twice daily was administered with palliative intent on days 17 and 18 after admission (Fig. 3). From day 20, FP-pembrolizumab (5-fluorouracil 1,000 mg/m2 on days 1–4 and cisplatin 100 mg/m2 plus pembrolizumab 200 mg on day 1) was started as systemic chemotherapy. The main adverse events during this period were grade 3 nausea due to cisplatin and grade 2 buccal mucositis from the RT. As wound hemostasis and improvement of her general condition were observed, the second course of QUAD SHOT was administered on day 45 according to the original schedule. Thereafter, on day 47, FP-pembrolizumab was also administered at the same dose as the first. Adverse effects of the second course included grade 2 nausea and grade 1 diarrhea, which were milder than those of the first course.

Fig. 3.

Irradiated field and dose distribution of the first QUAD SHOT. a CTV, clinical target volume (yellow); PTV, planning target volume (cyan). b Target tumor was enclosed in the 95% area relative to the prescribed dose of 3.5 Gy.

Evaluation computed tomography at the end of two courses showed the disappearance of the lymph node swelling and volume reduction of the lung metastasis (Fig. 2b, e). Since the adhesion of the primary tumor was reduced and a safe margin of resection and reconstruction could be achieved (Fig. 1b), the patient’s treatment plan was promptly changed to resection of the primary lesion. Parotidectomy and reconstruction with a femoral skin valve were completed on day 73 (Fig. 1c).

Intraoperatively, peripheral branches of the facial nerve were identified, with the nerve trunk running through the tumor itself and necrotic tissue from preoperative chemotherapy. Ultimately, the facial nerve was not preserved, considering the preoperative cT4 findings [3, 4], pathological biopsy reports, and the state of incomplete paralysis with a drooping mouth corner.

As mentioned earlier, due to the presence of lung metastases and her poor general condition, the standard operation (modified radical dissection) approach was abandoned. As there were no enlarged lymph nodes in the levels III–IV region originally, only the level II and level V lymph nodes near the tumor were dissected. Plastic surgeons harvested a free anterolateral thigh flap simultaneously with the aim of a shorter operating time and the advantages of quick and flexible placement of the site with good blood flow.

The final pathology results showed carcinoma ex pleomorphic adenoma, 8.5 × 6.0 × 10 cm, pT4aN0. The surgical margin was negative, and no invasion into the masseter muscle was found. The histological efficacy of chemoradiotherapy was determined to be grade 2 as extensive necrosis and a one-third decrease in viable cells were observed.

Though a radical cure remained elusive due to lung metastasis, significant quality-of-life improvement and cosmetic benefits were obtained. The patient’s perioperative course was also excellent. She was discharged from the hospital 18 days after surgery and has since been treated on an outpatient basis and has returned to daily activities. The patient has since continued a fifth course of FP-pembrolizumab chemotherapy, which has further reduced the lung metastasis (Fig. 2c, f).

Discussion

Paris et al. reported the RTOG 85-02 regimen for palliative irradiation of unresectable advanced HNC as having a tumor response rate (partial response + complete response) of 77% [1]. Several subsequent papers reporting response rates in HNC have also shown promising results of 53–86% [1, 2, 5–7] (Table 2), with few reports of grade 3 adverse events. Two studies of QUAD SHOT in combination with chemotherapy in the treatment of HNC and pelvic tumors combined with a paclitaxel-based regimen have been conducted by Carrascosa et al. [6] and with a carboplatin or cetuximab regimen by Gamez et al. [7].

Table 2.

Summary of previous reports of QUAD SHOT for HNCs

AuthorYearNAge (range), yearsChemotherapyRT cycles (N)OutcomeAdverse eventsregimenN123TRCRG2G3QUAD SHOT alone Paris et al. [1]19933765.5 (24–95)None11a2677%28%N/AN/A Corry et al. [2]20053073* (52–88)None691453%11%37%b0% Toya et al. [3]20203481* (54–92)None652385%N/A12%0%QUAD SHOT + chemotherapy Carrascosa et al. [4]20072062.2 (28–85)Paclitaxel19101990%25%10%5%PTX-CDDP1 Gamez et al. [5]20172169.8 (50–89)Carboplatin18051686%24%35%0%Cetuximab3

Since the 2010s, the use of molecular-targeted drugs and immune checkpoint inhibitors has become more common, raising expectations for the long-term survival of patients with advanced cancer [8]. In this situation, we presumed that the QUAD SHOT characteristics, which are expected to shrink tumors with few serious adverse events, might offer new possibilities for conversion surgery from QUAD SHOT as a preoperative treatment.

However, the significance of volume reduction by preoperative RT in the treatment of HNC is not yet well established. In recent phase 2–3 trials reported since the late 2010s, 40–50 Gy in 20–25 fractions of conventional fractionation has been prescribed with or without chemotherapy, with some reports of promising results [9, 10]. Nevertheless, one of the reasons for the lack of popularity of these techniques is that they require a treatment period of 4 to 5 weeks. Compared with conventional RT methods, the introduction of preoperative QUAD SHOT may lead to a major paradigm shift.

We believe that there are four main advantages of introducing preoperative QUAD SHOT. The first is the benefit to the patient in preserving preoperative fitness. Conventional preoperative RT which requires 40–50 Gy, takes a month or longer. Treatment is required daily; therefore, the patient is under heavy time constraints and, depending on geographical circumstances, may require hospitalization for a long period. The QUAD SHOT solves these problems and may also preserve the patient’s strength for postoperative adjuvant therapy. Second, medical oncologists benefit from the associated ease of administration of concomitant chemotherapy. More severe adverse events are likely with concurrent RT and chemotherapy, whether preoperative or postoperative. In HNC treatment, adverse effects of both, such as dermatitis and mucositis, overlap. Nutritional intake is often difficult, and the hematologic toxicity of chemotherapy is exacerbated by a high rate of undernutrition. Otolaryngologists or medical oncologists have traditionally had great difficulty dealing with a two-pronged strategy over weeks to months. In contrast, the QUAD SHOT method permits no or minimal time between the two interventions, simplifying the management of adverse events. This allows physicians to “focus” on their specialty when administering anticancer drugs. Third, QUAD SHOT benefits head and neck surgeons by making it easy to determine when to switch to surgery as there is no direct intervention during the interval time. This is ideal for follow-up and surgery preparation. Additionally, patients who respond quickly can interrupt QUAD SHOT at any time for surgery, before completing three sessions. It allows for scheduling in approximately 1-month increments, facilitating easy decision-making regarding the best timing for surgery. Finally, the radiation oncologist is expected to benefit from the avoidance of late adverse events inherent to RT. In general, treatment with a high single dose tends to cause more damage to normal tissues and more severe late adverse events, even if the total administered dose is lower. QUAD SHOT is bound by the same principle, which is not necessarily true in terms of long-term safety. However, if the irradiated lesion is going to be resected later, late adverse events such as intractable refractory dermatitis or uncontrollable tissue necrosis are not a concern. Rather, the advantage of drastically high-dose irradiation is emphasized by the potential for rapid tumor shrinkage.

However, some ambiguity remains. The three main issues are listed as follows. First, the long-term safety of QUAD SHOT is unknown. While preoperative QUAD SHOT has the advantage of not having to consider late adverse events at the “resection site,” the impact of irradiation on unresected tissue remains unclear. Few studies have reported late adverse events with the original QUAD SHOT designed for patients with a short life expectancy. If successful surgery and long-term survival are achieved with additional treatments such as immune checkpoint inhibitors, the risk that patients will experience unexpected adverse events cannot be ruled out. Second, the pathological types and treatment range that QUAD SHOT is best suited for remain unclear. In our report, we targeted only the tumor itself and the lymph nodes closely associated with it, and there were no skip lesions. However, patients with advanced HNCs generally have multiple lesions on both sides of the neck or, occasionally, skip lesions. Future studies are needed to determine which pathologic type is more responsive, as well as whether irradiation over a wide area is safe and effective. Finally, the statistical superiority of preoperative QUAD SHOT over the conventional fractionation method is still unclear. Despite the reduced treatment duration and ease of complication management, a comparison of efficacy with conventional irradiation is inevitable if preoperative QUAD SHOT is to be introduced in earnest. In this evaluation, a simple comparison of RECIST response rates alone is not very meaningful, and a comparison of the percentage of patients who finally become operable should be made.

In conclusion, we described a case of parotid carcinoma that became resectable after QUAD SHOT at our hospital. Although there are many issues to be addressed regarding the widespread use of preoperative QUAD SHOT, its anticipated benefits are attractive in many aspects of treatment strategies. We look forward to further discussion of preoperative QUAD SHOT for conversion surgery, involving all oncology professionals.

Acknowledgments

The authors thank Editage (www.editage.jp) for their English language editing services.

Statement of Ethics

Written informed consent was obtained from the patient for publication of details of their medical case and any accompanying images. The Central Clinical Research Ethics Committee of our institution determined that our project does not meet the “Common Rule” definition of human subjects’ research and does not require CRB review. The certified review board number is 3200006.

Conflict of Interest Statement

The authors have no conflicts of interest to declare.

Funding Sources

This research did not receive any grants from funding agencies in the public, commercial, or not-for-profit sectors.

Author Contributions

Satoru Takahashi, Masashi Endo, and Katsuyuki Shirai designed this study. Satoru Takahashi, Masashi Endo, Takafumi Nagatomo, Ryutaro Onaga, Hironori Yamaguchi, Rie Yamamoto, and Hiroshi Nishino were involved in patient management. Satoru Takahashi, Masashi Endo, Yukiko Fukuda, Kazunari Ogawa, Michiko Nakamura, Kohei Okada, Masahiro Kawahara, and Keiko Akahane contributed to the analysis of the results. Takeharu Kanazawa, Harushi Mori, and Katsuyuki Shirai supervised the project and approved the final manuscript.

Data Availability Statement

All data supporting the findings of this study have been included in this article. Further inquiries can be directed to the corresponding authors.

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