Pathologic complete response following low-dose radiation for advanced oral cavity cancer in a patient with human immunodeficiency virus

Here we describe one patient with advanced stage oral cavity SCCa who had complete pathologic response following one course, 14 Gy, of the Quad-Shot regimen employed neoadjuvantly while the patient was awaiting surgery. Radiographically, he appeared to have progressed after neoadjuvant therapy, both at the primary site and the regional lymphatics. His cervical adenopathy was considered pathologic based upon likelihood for metastasis, clinical appearance/feel, and pre-treatment PET avidity. Because his advanced primary site would require treatment of regional lymphatics (neck dissection for surgical patients), it was not deemed necessary to biopsy the enlarged nodes at presentation. It is possible that the initial enlargement and radiographic progression of the lymph nodes was due to his underlying HIV disease rather than from his oral tongue cancer. Regardless of the initial status of the neck, a pCR was found at the primary site.

For this patient, consideration has to be given to the potential of spontaneous tumor regression and the additional benefit of HAART in his care. This patient’s HAART regimen consisted of darunavir, dolutegravir, and tenofovir. Spontaneous tumor regression is not a new phenomenon and has been reported in about one in 60,000–100,000 malignancies [11]. Melanoma, renal cell carcinoma, and neuroblastoma are among the most common cancers associated with spontaneous regression, although SCCa has also been reported. The exact cause of tumor regression is not known; there is extensive speculation with one possible explanation being activation of the immune system [12]. The innate immune system is believed to play a role in spontaneous tumor regression, as the phenomenon has been observed following acute infections in which the patient experiences fever due to strong activation of the immune system [13]. Indeed, there are ongoing clinical trials evaluating the QUAD shot regimen in combination with immunotherapy in patients with head and neck cancer, including our own (NCT04373642).

Protease inhibitors are important in HAART therapy for HIV patients. Protease inhibitors, specifically saquinavir and ritonavir, reportedly have antitumor effects through inhibition of 26 s and 20 s proteasome function [14, 15]. The protease inhibitors inhibit the anti-apoptotic NF-KB transcription factor thereby inducing apoptosis. Prostate cancer cells treated with saquinavir show increased sensitivity to chemotherapy and RT [14]. A prospective study of HIV-seropositive women with cervical squamous intra-epithelial lesions (SIL) and on HAART therapy, showed a statistically significant improvement in the prevalence of SIL on Papanicolaou smears as well as on colposcopy [16]. Multiple phase I and phase II clinical trials of the protease inhibitor nelfinavir, chosen for its increased efficacy in preclinical settings, in combination with chemotherapy and RT are ongoing and show encouraging results for multiple types of unresectable solid tumors including liposarcoma, adenocarcinoma of the pancreas, and non-small cell lung carcinoma [17]. Nelfinavir induces apoptosis through inhibition of growth factor receptor activation and Akt signaling [18]. Our patient was on HAART before, during and after RT, including the protease inhibitor darunavir, and this HIV therapy may have contributed to the pCR demonstrated after low-dose RT.

The Quad-Shot regimen has displayed success in the palliative setting for many patients. The Quad-Shot hypofractionated palliative RT regimen was originally devised for advanced pelvic malignancies but has since been adapted for palliation in patients with incurable head and neck cancers [9, 19]. It is thought to be well suited to the head and neck setting, since it delivers a biologically equivalent dose just below the threshold for producing mucositis, and the interval of separation is sufficient for depleted mucosal stem cells to repopulate before the next cycle. The regimen, as designed, consists of 3.5 Gy delivered twice a day for two consecutive days and may be repeated every three or four weeks for a total dose of 42 Gy in three cycles with the goal of adequate palliation while limiting acute and late toxicity [9]. Studies show that with even one cycle of Quad-Shot, patients may achieve approximately 55% palliation, with almost 90% reduction in symptoms with 3 cycles [9, 20, 21]. Additionally, the tumor response rates and decreased toxicity with Quad-Shot are comparable to conventional hypofractionated palliative RT (30 Gy/10 fractions/2 weeks) [22].

Although surgery followed by concurrent RT and/or chemoradiotherapy is the management choice recommended by the NCCN guideline for treating advanced oral tongue squamous cell carcinoma, 5-year survival rates remain low at < 40% [23]. In addition, a preoperative pCR is an independent prognostic factor in advanced SCCa. Kirita et al. reported the long-term prognostic value of achieving pCR in such patients who were treated preoperatively with cisplatin- or carboplatin-based chemotherapy in combination with simultaneous irradiation (target dose 40 Gy), and showed that 10-year progression free survival of patients with pCR was significantly better than that of patients with residual tumor (87.5% vs. 40%) [24].

Although Quad-Shot is reportedly effective for palliation postoperatively or in unresectable disease, no study has evaluated its effectiveness in preoperative tumor control. There are potential advantages to this regimen, as there is a high tolerance with low toxicity, shortened treatment time, and excellent local tumor and symptom control in comparison to other more protracted RT regimens. Although previous reports have described clinical complete responses after the QUAD shot radiation regimen, for example Gamez et al., when combining QUAD shot with radiosensitizing chemotherapy [25], no previous reports have shown a pCR when employing neoadjuvant low-dose RT alone. In a study by Fang et al., patients with unresectable T4b oral cavity SCCa underwent preoperative intensity modulated radiation therapy to a radical dose of 66–76 Gy, with 81.8% of patients showing tumor down-grading and 16.7% achieving pCR. 23 However, the present case indicates that lower doses of RT, namely Quad-Shot, may provide significant tumor response with useful prognostic information at the time of surgery. For this patient, preoperative Quad-Shot also removed the need for high dose adjuvant therapy with or without chemotherapy which would likely have been recommended had surgery been the initial step in treatment. These implications warrant further study of the use of preoperative Quad-Shot for advanced oral cavity SCCa as a window of opportunity intervention when system issues introduce significant delays between diagnosis and treatment initiation (i.e. surgery).

In summary, this is the first reported case of pCR following treatment of advanced oral cavity SCCa with a single cycle of neoadjuvant Quad-Shot palliative RT. Of particular interest in this patient is the potential benefit of HAART in addition to low dose RT preoperatively. HAART along with chemotherapy and radiation has demonstrated promising results in both solid and blood tumors. This report suggests that continued research into HAART as a cancer therapeutic in both HIV and non-HIV patients is warranted.

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