Metronomic therapy using Methotrexate and Celecoxib: A Boon for Oral Cancer patients during COVID-19 Pandemic.

The COVID-19 pandemic has crippled the healthcare system worldwide, with over 35 million cases and 1.04 million deaths by the first week of October. India, with a population of over 1.3 billion, has seen an exponential rise in the number of COVID-19 cases in the past few months, amounting to over 6.6 million cases and 103,600 deaths [1]. The increased need for hospitalization and intensive care in moderate to severe COVID cases has diverted the hospital resources, affecting cancer care in many centers, with the oncologists forced to delay elective surgeries and avoid toxic chemotherapy regimens. Surgery forms the mainstay of management in oral cancer patients and includes complex resections and reconstructions, requiring intensive care in the post-operative period. Given the ongoing pandemic, the risk of COVID-19 infection to patients and health care workers and the risk of morbidity and mortality in patients undergoing surgery has led to several new guidelines during the past few months [2]. Metronomic therapy for Oral Cancer is known to be an effective option to prevent the progression of disease while waiting for surgery [3]. The ease of administration, safety, effectiveness, and a decreased burden on the healthcare resources, led us to opt for metronomic therapy in the present scenario.

The present study includes patients treated with metronomic therapy after the start of lockdown (25th March 2020) because of the COVID-19 pandemic at a tertiary care center in Eastern India. The patient population is part of an ongoing prospective clinical trial (CTRI/2019/09/021263) for which ethical approval was obtained from the Institutional Ethics Committee of All India Institute of Medical Sciences, Bhubaneswar (T/IM-NF/Surg.Onco./18/75). Patients presenting to the out-patient department with locally advanced/unresectable/inoperable oral cavity cancers were explained regarding the disease status, treatment options, prognosis, and resource limitations during the ongoing pandemic. Patients with resectable cancer were counseled for the need for surgery, the pandemic related risks, and to be on the waiting list with an option to take metronomic therapy as a bridge to tide over the COVID pandemic time. Patients with unresectable/inoperable cancer were counseled regarding the prognosis of the disease and the role of chemoradiation and conventional chemotherapy regimens. They were offered metronomic therapy with a palliative intent if not willing for conventional treatment. After informed consent, metronomic therapy started consisted of oral methotrexate 15 mg/m2 once a week and oral celecoxib 200 mg twice daily. The patients were followed every two weeks, either by teleconsultation using video calls or by out-patient visits, to assess the disease status and response to therapy. The response was evaluated using the clinical criteria of the Response Evaluation Criteria in Solid Tumors (RECIST 1.1). The toxicity of the regimen was graded according to the National Cancer Institute (NCI) Common Toxicity Criteria Version 5.

From April 2020 to August 2020, 15 patients, median age 48 years (Range: 33–84 years) with a male to female ratio of 14:1 were included in the study. The median dose of methotrexate used was 25 mg. Compliance with the therapy was 93.3%, with one patient opting for definitive chemoradiation after five weeks of metronomic therapy. No grade 3 or 4 toxicity was reported. Partial response was seen in 9 patients (60%), stable disease in 5 patients (33%), and disease progression in 1 patient (6.7%) [Fig. 1 A-D]. Two patients tested positive for COVID-19 during the follow-up period (13.3%) and were managed with home isolation [Table 1 ]. Due to the inability to provide definitive management, the intention of therapy was to prevent the progression of disease during this period. Of the 15 patients, 11 patients had potentially curable oral cavity cancers, and four patients required palliative therapy. Except for the one patient with advanced unresectable oral cancer who expired, the rest of the patients in the study had either partial response or stable disease. No disease progression was seen.

Fig. 1

A: Patient with carcinoma left alveobuccal region with skin involvement (cT4aN0M0). B: Clinically partial response with metronomic therapy after 18 weeks. C: Patient with carcinoma left buccal mucosa involving angle of the lip (cT4aN0M0). D: Clinically partial response with metronomic therapy after 14 weeks.

Table 1

Case details of patients treated with metronomic therapy during the on-going COVID pandemic.

Case	Age (Yrs)	Gender	Co-morbidity	ECOG	Site of lesion	Presentation	COVID status	TNM stage	Reason for therapy	Days on therapy*	Disease status
1	59	M	Diabetes Mellitus	1	Alveobuccal	Primary	Negative	T4aN0M0 (IVA)	Treatment delay	34	Received Definitive CTRT
2	50	M	None	0	Buccal Mucosa	Primary	Negative	T4aN1M0 (IVA)	Treatment delay	141	Partial Response
3	68	M	None	0	Lip	Primary	Negative	T2N1M0 (III)	Treatment delay	133	Partial Response
4	40	M	None	0	Alveobuccal	Primary	Positive	T4aN0M0 (IVA)	Treatment delay	151	Stable Disease
5	47	M	None	0	Alveobuccal	Primary	Negative	T4aN0M0 (IVA)	Treatment delay	136	Partial Response
6	47	M	None	0	Alveobuccal	Recurrent	Negative	T2N1M0 (III)	Palliation	96	Stable Disease
7	45	M	None	1	Alveobuccal	Primary	Negative	T4aN1M0 (IVA)	Treatment delay	88	Stable Disease
8	35	M	None	1	Alveobuccal	Primary	Negative	T4aN3M0 (IVB)	Palliation	80	Dead
9	69	M	None	1	Alveobuccal	Primary	Negative	T4aN0M0 (IVA)	Treatment delay	112	Partial Response
10	84	M	Hypertension	2	Tongue	Primary	Negative	T2N0M0 (II)	Treatment delay	78	Partial Response
11	60	M	None	1	Alveobuccal	Primary	Negative	T4aN3M0 (IVB)	Palliation	77	Partial Response
12	48	M	None	1	Alveobuccal	Primary	Negative	T4aN2cM0 (IVA)	Treatment delay	64	Partial Response
13	82	F	None	3	Alveobuccal	Primary	Negative	T4aN0M0 (IVA)	Treatment delay	78	Partial Response
14	33	M	None	1	Alveobuccal	Primary	Positive	T4aN2bM0 (IVA)	Palliation	70	Partial Response
15	47	M	None	1	Alveobuccal	Primary	Negative	T3N0M0 (III)	Treatment delay	34	Stable Disease

Days of therapy calculated from the date of start of therapy to last follow-up date.

Several authors have suggested guidelines in the past few months to provide optimal care to cancer patients [4], [5]. Also, oral cancer surgeries are significant aerosol-generating procedures and put the operating team at a significant risk of acquiring the infection. The viral load in asymptomatic patients is similar to symptomatic patients, suggesting the transmission potential of asymptomatic patients [6]. A systematic review has shown the pooled percentage of asymptomatic infection to be 15.6% and presymptomatic infection to be 48.9% [7]. The false-negative rate of RT-PCR for SARS-CoV-2, ranging from 2 to 29%, has added to the woes of identifying asymptomatic cases [8]. For patients undergoing surgery with perioperative SARS-CoV-2 infection, an international cohort study has shown a high rate of pulmonary complications (51.2%) and 30-day-mortality (23.8%) [9].

The challenges during the ongoing COVID pandemic compel us to consider alternate options. Neoadjuvant chemotherapy, considered the foremost option, has not been shown to improve outcomes in resectable oral cavity cancers [10], [11]. The regimens are associated with significant toxicity and low compliance. The present study has brought forward another alternative, metronomic therapy, which is home-based, oral, low cost, and effective in preventing the progression of disease while waiting for surgery. In a retrospective match paired analysis of 32 patients by Pai et al., the use of metronomic methotrexate and celecoxib in the waiting period for surgery led to a decrease in the risk of progression and improved the 2‑year disease‑free survival from 71.6% to 86.5% [3]. In our own experience of 23 patients with locally advanced T4a tumors receiving metronomic therapy for at least eight weeks, disease progression was seen in only three patients (13%) [12]. In the palliative setting, the recently published open-label, randomized, phase III study by Patil et al. showed a significant improvement in overall survival with metronomic therapy (7.5 vs. 6.1 months; p-value 0.026) when compared with intravenous cisplatin [13].

In the present study, we have been successful in avoiding disease progression in resectable disease. In our experience, to manage oral cancers during the ongoing COVID-19 pandemic, metronomic therapy is beneficial. We eagerly await the restoration of health services in the region and provide surgical treatment to resectable patients.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.