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  Table of Contents  
Year : 2013  |  Volume : 50  |  Issue : 2  |  Page : 135-141

Oral metronomic scheduling of anticancer therapy-based treatment compared to existing standard of care in locally advanced oral squamous cell cancers: A matched-pair analysis

1 Department of Surgical Oncology, Tata Memorial Centre, Parel, Mumbai, Maharashtra, India
2 Department of Medical Oncology, Tata Memorial Centre, Parel, Mumbai, Maharashtra, India

Date of Web Publication27-Aug-2013

Correspondence Address:
S D Banavali
Department of Medical Oncology, Tata Memorial Centre, Parel, Mumbai, Maharashtra
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0019-509X.117024

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 » Abstract 

Context: Head and neck cancers in developing countries present with advanced disease, compounded by poor access to tertiary care centers. Aim: We evaluated oral metronomic scheduling of anticancer therapy (MSAT) in advanced operable oral cancers, in conjunction with standard therapy. Settings and Design: This was a retrospective matched-pair analysis carried out in a tertiary referral cancer center. Materials and Methods: Advanced operable oral cancer patients having a waiting period for surgery > 3 weeks were administered MSAT. Patients then underwent standard therapy (surgery +/- adjuvant radiation/chemoradiation) as warranted by the disease, followed by MSAT maintenance therapy. Outcomes of the MSAT group were compared with stage-matched controls with similar waiting periods. Statistical Analysis: Survivals were found using the Kaplan-Meier method and compared between groups using the log rank test. Results: Response was seen in 75% of 32 patients. Two-year disease-free survivals (DFS) in MSAT and control groups were 86.5 and 71.6%, respectively. Two-year DFS in MSAT group who received at least three months of MSAT was 94.6% (P = 0.03). Conclusions: Oral MSAT is an economical, effective, and safe adjuvant therapy for oral cancers. It has the potential for preventing progression of the disease and improving DFS.

Keywords: Chemotherapy, metronomic, oral cancers

How to cite this article:
Pai P S, Vaidya A D, Prabhash K, Banavali S D. Oral metronomic scheduling of anticancer therapy-based treatment compared to existing standard of care in locally advanced oral squamous cell cancers: A matched-pair analysis. Indian J Cancer 2013;50:135-41

How to cite this URL:
Pai P S, Vaidya A D, Prabhash K, Banavali S D. Oral metronomic scheduling of anticancer therapy-based treatment compared to existing standard of care in locally advanced oral squamous cell cancers: A matched-pair analysis. Indian J Cancer [serial online] 2013 [cited 2021 Jun 18];50:135-41. Available from:

 » Introduction Top

Head and neck squamous cell carcinoma (HNSCC) is common in Asian countries. [1] HNSCC is the third most common cancer in India, and the second commonest cancer in Indian males. [2] A large majority of these present in an advanced stage, a problem compounded further by poor access to tertiary cancer centers and increasingly long waiting lists for treatment at these centers. The need of the hour in such a scenario would be to institute a therapy that would prevent progression of the tumor, effect its regression, and ensure that patients remain operable while awaiting surgery, at the same time not delaying surgery by itself. To meet these demands, such chemotherapy would be required to be instituted during the planning of and before the definitive therapy itself which would prevent progression as well as facilitate surgery, prevent recurrence in the time period between the definitive and the adjuvant therapy, and probably be continued as maintenance therapy after the definitive and adjuvant therapies, so as to prevent recurrence or development of new cancers in areas of 'field cancerization'. Such chemotherapy would also be required to be easily deliverable, minimally or totally nontoxic, and economical. This would especially be of importance in low- and middle-income countries (LMICs) like India.

Conventional or maximal tolerated dose (MTD) chemotherapy can cause significant toxicity. Such therapies also necessitate the imposition of rest periods between cycles of therapy, which may cause regrowth of tumor cells and also the growth of selected clones resistant to the therapy. Hence, the therapeutic success obtained during the first cycles of treatment may be diminished. [3] A re-evaluation of 'traditional' high intermittent chemotherapy dose schedules has occurred in recent years following the observation that low doses of chemotherapy given chronically ('metronomic' dosing) can be selectively toxic to proliferating endothelial cells in tumors. [4]

We describe our experience with oral metronomic scheduling of anticancer therapy (MSAT) using methotrexate and celecoxib in locally advanced (stage III and IV) oral cancers started while the patients were awaiting surgery, and continued during the perioperative period and after the adjuvant therapy, and compare the outcomes of these patients with stage-matched controls who underwent treatment as per existing standard of care at the hospital.

 » Materials and Methods Top

This was a retrospective chart analysis of patients with oral cancers in whom MSAT was instituted while awaiting surgery with microvascular free flap reconstruction. The outcomes of these patients were then retrospectively compared with a group of controls who were matched for stage and waiting periods to surgery. Approval was obtained from the Institutional Review Board for this retrospective analysis.

Newly diagnosed patients with HNSCC were given the earliest date for surgery as per the hospital waiting list. Patients who had a waiting period of three weeks or more were referred to medical oncology for MSAT. In no patient, the date of surgery was postponed so as to receive MSAT. The MSAT schedule consisted of oral methotrexate 15 mg/m 2 once a week and oral celecoxib 200 mg twice daily. Once started, the patients went back to their hometown (patients were from all over India) and came back a day prior to the date of surgery. Hematological counts were monitored every 15 days during neoadjuvant chemotherapy (NACT). The MSAT was continued until the day before surgery. Response was assessed clinically on the day prior to surgery, and recorded using the clinical criteria of the World Health Organization (WHO). Complete remission (CR) was defined as the absence of measurable tumor and tumor-related symptoms, partial remission (PR) as a 50% or greater decrease in the sum of the diameters of all measurable lesions, with the appearance of no new lesions and no enlargement of existing lesions, stable disease as response less than PR or progression less than progressive disease, and progressive disease as an increase of 25% or more in the product of the perpendicular diameters of any lesion, or the appearance of any new lesion. Toxicity of MSAT was graded according to the National Cancer Institute (NCI) Common Toxicity Criteria Version 2.

The patients then underwent surgery as warranted by the disease, ensuring wide resection with margins more than 5 mm. MSAT was restarted about a week after surgery. The histopathology was assessed and patients were given adjuvant therapy (radiation or chemoradiation) as per standard practice and as mandated by the histopathology. Methotrexate was discontinued during the period of adjuvant therapy and restarted four weeks after completion of adjuvant therapy with an intention to continue for a total of 18 months [Figure 1].
Figure 1: Scheme of protocol and matched - pair analysis

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For the matched-pair analysis, patients were selected from a database of those who had undergone reconstructive surgery with similar waiting periods but had not received MSAT; this was done so that the waiting period to surgery could be approximated in both the groups. Patients were matched for the T stage and N stage and waiting period. Patients in the control group had also undergone standard surgical interventions as merited by the disease and adjuvant therapy as mandated by histopathology.

Disease-free survival (DFS) was defined as the time period between the initiation of MSAT and the first appearance of a recurrence in cases, and the time period between the date of decision of the tumor board and the first appearance of recurrence in controls. Survival was found using Kaplan-Meier curves, and compared between the two groups using the log rank test.

 » Results Top


Thirty-two patients with oral cancers were started on neoadjuvant MSAT in the period from December 2007 to May 2010. The demographic details of these patients are given in [Table 1].
Table 1: Characteristics of patients according
to the treatment groups

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As the median waiting period to surgery was five weeks (range: 3 to 12 weeks), the median duration of oral MSAT administration before surgery was five weeks.

Response and toxicity

There were no cases of major (grade II to IV) toxicities. No patient developed febrile neutropenia or required admission, blood/platelet transfusions, or supportive care.

Complete response to oral NACT was seen in 2 (6.3%) patients; 22 (68.7%) had partial response, giving a response rate of 75%, whereas 8 (25%) had stable disease. Surgery could be downstaged in six patients. None of the patients developed significant postoperative complications or problems in wound healing.


The median follow-up of the MSAT group was 18 months. During this period, recurrences were seen in four patients. On the other hand, there were nine recurrences in the control group (median follow-up: 19 months). The details are given in [Table 2].
Table 2: Details of recurrences in the two treatment groups

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Compliance to long-term metronomic chemotherapy was varied and is shown in [Table 3]. Of the 27 patients who received at least three months of MSAT following definitive therapy, only one developed recurrence. Five patients failed to follow up with medical oncology after definitive treatment, and thus did not receive any adjuvant MSAT post surgery; of them, three had a recurrence. When the outcomes were compared between those who had continued adjuvant MSAT for at least three months with those who had received no adjuvant MSAT or had received for a period less than three months, there was one recurrence in the former group and three recurrences in the latter group (two-tailed Fisher's exact test, P = 0.03).
Table 3: Relation between compliance to adjuvant metronomic scheduling of anticancer therapy and recurrence

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Matched-pair analysis

Survival in the study group was compared to survival of the control group using a matched-pair analysis. The control group was matched as mentioned previously, and had undergone standard surgery and radiotherapy/chemoradiation in the time period from 2006 to 2008. Using the Kaplan-Meir method, the estimated two-year DFS in the MSAT group and the control group was 86.5 and 71.6%, respectively [Figure 2]. Thus, there was a 14.9% improvement in the estimated two-year DFS (log rank test, P = 0.12). However, when survival was compared for the group who received at least three months of MSAT in the adjuvant setting (n = 27), the estimated two-year DFS in the MSAT group and the control group was 94.6 and 75.4%, respectively, which was statistically significant (log rank test, P = 0.03) [Figure 3].
Figure 2: Comparison of disease - free survivals between the oral metronomic scheduling of anticancer therapy and control groups

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Figure 3: Comparison of disease - free survivals between the patient group receiving at least three months of oral metronomic scheduling of anticancer therapy and the control groups

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 » Discussion Top

In India, HNSCC accounts for 9-10% of the incidence of cancer. [2],[5] Early localized disease is curable by surgery and irradiation. However, two-thirds of the patients in India present with advanced stages of the disease (stages III and IV) [5],[6] in whom the outcome is poorer even with multimodality therapy which includes surgery, radiation, and chemotherapy. Molina et al., sought to determine the importance of race, ethnicity, and socioeconomic status of 20,915 patients with HNSCC in the United States and showed that poor patients, patients who consume alcohol, and those who use tobacco had the worst outcomes. [7] The majority of Indian patients have some or all these poor prognostic factors.

Despite advances in treatment, long-term DFS and overall survival (OS) of patients with advanced disease remains poor. Approximately 40 to 60% develop local recurrences, and 20 to 30% distant metastatic disease. [8] Induction or NACT has become the standard of care in patients with locoregionally advanced HNSCC and has shown high overall response rates including complete responses. [9] However, most studies comparing NACT followed by surgery or radiotherapy with definitive local treatment alone did not detect a survival benefit and the role of NACT remains to be fully validated. [10],[11],[12] Though DCF (DCF: Docetaxel, cisplatin, and fluorouracil) has emerged as the new standard regimen when NACT is indicated, [13] its use has been associated with an increased incidence of stomatitis, diarrhea, neutropenia, and febrile neutropenia (76%), and even toxic deaths (2.3%). [14] Additionally, a substantial number of patients who received DCF chemotherapy did not receive radiation therapy or concurrent chemoradiotherapy as specified in the protocol in both TAX 323 and TAX 324 trials. [9] All these problems are multiplied manifold in patients from LMICs where the majority are from a lower socioeconomic background with poor nutrition. The cost of DCF chemotherapy along with the supportive care required is beyond the reach of many HNSCC patients in LMICs. Patients in LMICs often do not get timely treatment because of the large patient numbers and inadequate infrastructure. There are long waiting lists for surgery as well as for radiation and chemotherapy. It is known that progression of the tumor occurs during this waiting period. [15] To circumvent all these problems, we had to look for alternate means of treatment.

To avoid the problems caused by the traditional chemotherapeutic treatments, several groups began to study a new modality of drug administration that Hanahan called 'metronomic therapy'. [16] This was defined as chronic, equally spaced, and low doses of chemotherapeutic drugs without extended rest periods. The initial researchers demonstrated the antitumor efficacy of some of the most widely used chemotherapeutic drugs administered chronically in low doses as antiangiogenic agents, therefore implying a different cell target. [17],[18] MSAT differs from the hitherto-used chemotherapy in that it targets the cancer milieu or the microenvironment as much as the proliferating cancer cells. This concept stressed the importance of the tumor microenvironment in the proliferation of tumor cells, and the role of angiogenesis in the progression of cancer. Metronomic chemotherapies are now called 'metronomic scheduling of anticancer therapy (MSAT)'. [19] Apart from their antiangiogenic effects, there are two other major effects of MSAT, namely, apoptotic death of cancer cells and immune modulation. [20] This formed our basis for using methotrexate and celecoxib in locally advanced HNSCC.

The use of methotrexate in the neoadjuvant and adjuvant setting in advanced HNSCC has been well documented. However, most of these studies had used the MTD modality. Rentschler et al., randomized patients to either receive or not receive methotrexate in escalating doses. [21] All patients received standard surgery and postoperative radiation therapy. In this study, there was no significant difference in actuarial DFS or OS between the groups. However, Rao et al., effectively targeted the perioperative period. [22] Methotrexate in a dose of 50 mg/m 2 /IV was given on the 3 rd , 10 th , and 17 th postoperative days. At 24 months, the DFS for stage III and IV HNSCC patients in the treated group was 61% as opposed to 37% in the control arm. [22] Schifeling et al., showed that a dose of 15 mg/m 2 of methotrexate saturates HNSCC tumor dihydrofolate reductase and thus dose escalation may have limited value. [23] Thus we chose this dose.

Cyclo-oxygenase-2 (COX-2) expression is upregulated in inflammation, human tumor neovasculature, and in neoplastic cells. [24] It modulates angiogenesis by augmenting the release of angiogenic peptides such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and nitric oxide, [25] and its inhibition results in reduced angiogenesis and downregulation of proangiogenic factors. [26] COX-2 is commonly overexpressed in a variety of premalignant conditions and HNSCC. [27] Celecoxib proved effective for treating HNSCC through the suppression of cell proliferation and the induction of apoptosis in a COX-2- independent manner. [28] COX-2 inhibitors may also be useful in the inhibition and/or prevention of metastasis in patients with HNSCC. [29] Many patients in LMICs are nutritionally deficient. Cachexic patients receiving celecoxib gained weight, experienced increased body mass index (BMI), and demonstrated improved quality of life (QOL). [30] COX-2 inhibitors have been shown to relieve the immunosuppressive effects of tumor cells and improve functions of immune effectors. [31] Celecoxib was shown to inhibit DNA (DNA: Deoxyribonucleic acid) repair and enhance radio response of HNSCC cells. [32] At the same time, overexpression of COX-2 is associated with radio resistance in oral squamous cell carcinoma. [33] This formed the rationale for using celecoxib throughout our MSAT regimen.

To date, the largest and the most number of clinical trials investigating the efficacy of metronomic chemotherapy has been conducted in patients with advanced breast cancer. [20] The results of a phase II trial using neoadjuvant MSAT was published recently. [34] A literature search yielded only one registered ongoing trial assessing MSAT in HNSCC (NCT00855881); this is a prospective trial evaluating the role of maintenance MSAT in treated HNSCC where CR has been achieved. [35]

We studied retrospectively our experience with MSAT which was started in the neoadjuvant setting, and continued into the maintenance phase. The advantage of using methotrexate along with celecoxib in a metronomic scheduling is its economy, easy availability, well-known pharmacodynamic profile, and safety. We found that MSAT was excellently tolerated and was not associated with any serious adverse effects. It had minimal or no toxicity and did not require supportive care. Celecoxib inhibits cell proliferation, induces apoptosis, and augments sensitivity to anticancer drugs in human HNSCC cells and would be useful when used along with other chemotherapeutic agents. [36] This is seen by the excellent response rate of 75% in our patients, which is much better than the response rate noted with single-agent methotrexate used in a higher dose. [37] Additionally, MSAT helped us to continue therapy in the perioperative period, which is not possible using MTD-based chemotherapy. This is an important period during cancer therapy when 'angiogenic switch' can occur affecting the long-term outcome. Data in animal models have shown that survival rates could be significantly improved by giving COX-2-based treatment in this perioperative period. [38] Our data also show that MSAT is safe in this period and does not affect surgery or wound healing.

The usage of MSAT in the maintenance stage is targeted to improve the locoregional control and DFS. When the DFS of the therapy group was retrospectively compared to the control group, we found a 14.9% benefit in expected two-year DFS. This benefit increases to 19.2% if we consider patients who took at least three months of MSAT. This difference was statistically significant. Conceptually, diagnosis and treatment of epithelial cancers should not only be focused on the tumor but also on the field from which it is developed-the concept of 'field cancerization'. [39],[40] This was one of the reasons to continue MSAT for 18 months in patients with advanced HNSCC. There is already some data showing the chemopreventive effect of celecoxib in oral precancers and cancers. [41]

This is a retrospective study with its attendant shortcomings: Response was not uniformly assessed, there was no randomization, and the controls were treated at a slightly earlier point of time. Our results of a 14.9% benefit in two-year DFS maybe because of a short follow-up, small number of patients, and retrospective comparison with matched controls. The effect of MSAT on distant metastasis and OS also could not be studied in this study with a short follow-up and needs further investigation. All these drawbacks make it mandatory for this regimen to stand the test of a prospective randomized controlled trial to validate our results.

The most important advantage of this oral MSAT regimen lies in its economy. We have highlighted this issue previously The monthly cost of this regimen is less than $10 and is an answer to the question raised by Kerr and Midgley, namely, "Can we treat cancer for dollar a day? [42] They have given guidelines for low-income countries; however, the annual direct cost of cancer care in the United States is projected to rise to $173 billion in 2020, and this trend is not sustainable even for a high-income country (HIC) like the United States. [43] Hence, effective low-cost therapies are needed not only for patients in LMICs, but also for those in HICs. The relevance and importance of metronomics in resource-limited countries has recently been highlighted. [44]

 » Conclusion Top

Treatment modifications are necessary in patients with advanced HNSCC to achieve better outcomes. The heavy burden of advanced HNSCC in LMICs like India stretches the limited treatment resources further. In such a scenario, an anticancer therapy schedule that would prevent progression of the disease before definitive management as well as improve long-term outcome is the pressing need of the hour. We used oral metronomic methotrexate and celecoxib in stages III and IV oral cancer patients awaiting reconstructive surgery, and continued the regimen in the post-operative, post-adjuvant stage. This simple, economical schedule was found to have no toxicity and good efficacy. There was better DFS in the cohort of patients where MSAT was continued for at least three months post definitive local treatment. We believe that oral MSAT started in a neoadjuvant mode and continued after adjuvant therapy has the potential for preventing disease progression, and also holds promise for improving long-term outcomes. A further prospective randomized controlled trial using this regimen of MSAT is required to validate these excellent results. Such a trial is currently underway at our institute.

 » References Top

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  [Figure 1], [Figure 2], [Figure 3]

  [Table 1], [Table 2], [Table 3]

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Vanita Noronha,Vijay M. Patil,Amit Joshi,Anuradha Chougule,Shripad Banavali,Kumar Prabhash
Cancer Letters. 2017; 400: 267
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Francesca De Felice,Daniela Musio,Vincenzo Tombolini
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Authors of Document André, N., Pasquier, E.
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