INTRODUCTION Systemic chemotherapy has been used in such


According to the hospital
based cancer registry (HBCR) data, cancers of the head and neck region are the
commonest among male and 6th most common among female cancer patients
attending our hospital1.About 75-80% of these patients present with
stage 3 &4 disease and have less than 33.7% of cure even after radical
treatment2. The scope of salvage of residual or recurrent disease is
limited as many patients are deemed inoperable. Systemic chemotherapy has been
used in such patients but the response rate is low. In addition, the toxicities
of systemic chemotherapy often worsen the distressing symptoms of cancer and
negatively impact the quality of life.

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Metronomic chemotherapy is
an alternative way of delivering chemotherapeutic agents. Instead of giving the
maximum tolerated dose, 1/10th to 1/3rddose is
administered in order to maintain a constant low blood level of the drug. This
form of therapy achieves anti-tumour efficacy with low toxicity and also
targets the tumour endothelial cells. 
Much of the available literature about metronomic chemotherapy comes
from experimental animals clinical trials using a variety of drugs have been
reported in solid tumours in adults and paediatric population. However the use
of metronomic chemotherapy in head and neck cancer is still very limited.  Though some early trials from India have
shown promising results, the initial experience at this institute has shown
that the progression free survival could be significantly improved in patients
with residual and recurrent disease as compared to best supportive care3.

 Most of the patients of head and neck cancer
in this institute come from a rural background with financial constraints. Repeatedvisits
to the hospital for a treatment which is unlikely to cure the disease burdens the
patients and their care givers. In addition management of chemotherapy induced
compounds the “out of pocket” expenditure of these patients. Metronomic
chemotherapy with methotrexate significantly reduces the visits to the hospital
and treatment expenses. If the disease control by metronomic chemotherapy is
comparable to the conventional form, using it in selected patients would reduce
toxicities and economic burden of our patients. 




















Head and neck cancer is
the 6thmost commonly diagnosed cancer worldwide. Epidemiological
studies have estimated the global incidence of all head and neck cancers to be
between 6,00,000 cases per year and the mortality rate between 2,23,000 and 3,00,000
deaths each year4.

The incidence of head and
neck cancers globally is not uniform with a higher incidence in Asia
constituting about 57.5% of global head and neck cancers burden for both sexes5.

Over 2 lakh cases of head
and neck cancer occur each year in India.In Indian males around 30% of all
cancers are head and neck cancers. In females they constitute 11-16% of all

A 5 year (2011 -2015)
consolidated report from hospital based cancer registry(HBCR) at our Regional
cancer centre PGIMER Chandigarh showed that a total of 5284 head and neck
cancers were registered. Head and neck cancers were the most commonly diagnosed
malignancy in males and 6th most commonly diagnosed cancers in
females.Oro-pharyngeal cancer was the most common sub-site to be encountered (1736
cases) among both the sexes1.

Globally,approximately 60
% head and neck cancers are diagnosed in locally advanced stage(III/IV). A
similar proportion of cases(75%)were identified in the patients that present to
us with head and neck cancer. Locally advanced stage precludes surgery as a
treatment option. For the 60% of the patients who present with locally advanced
disease at diagnosis, combined modality therapy is generally recommended. For
patients with un-resectable disease the current standard treatment is
concurrent cisplatin-based chemo-radiation.  However it has been seen that
despite the combination of chemotherapy and radiation therapy the 5-year
survival rates in locally advanced head and neck cancers is still 30-35%2.

The French cooperative
group trial, GORTEC 94-01 compared radiotherapy alone with concurrent
chemo-radiation where carboplatin and 5-FU were given along with 70 Gy of
conventional radiotherapy. Chemo-radiation therapy resulted in significant 5
year loco-regional control (48% vs. 25%;p=0.002), 5 year disease free survival
(27% vs. 15 %;p=0.01) and 5year survival(23 vs.16 %;p=0.05) at the cost of
increases in acute mucositis grade 2 or higher (79% vs. 39%)6.

Wendt et all conducted a
multi-institutional trial where they compared CRT vs. RT alone and found that
CRT doubled the 3-year local control(35% vs 17%;p<0.04) and survival(49% vs 24 %;p <0.03)7. A German muti-center trial compared mitomycin-c(10mg/m2) and 5-FU based concurrent(500mg/m2)chemo-radiation to accelerated radiotherapy and found that 2 year survival (54% vs. 45 %;p=0.0)and local control(61% vs. 45%) were better in combined modality arm8. Another three arm RCT from Vienna compared conventional RT (70Gy) against CHART with or without Mitomycin-C. (V-CHART+MMC vs. V-CHART alone.) V-CHART+MMC arm had better 3year actuarial local control compared to other two arms(48% vs. 32%). Survival was better in V-CHART+ Mitomycin-C(41% vs. 31%)9. MACH-NC- the largest meta-analysis of chemo-radiotherapy in locally advanced head and neck cancers showed that with CRT produced a 6.5% improvement in overall survival and decreased the risk of death by 19%. There was also a 13.5% increase in local control. Thus the cure rate at 5 years after chemo-radiation for locally advanced head and neck cancers was established at 33%2. This meant despite the best available treatment options, 70% of patients either had poor response to CRT and suffered from residual disease or did not have a durable response after CRT leading to local or metastatic recurrence. Majority of patients develop local and/or regional recurrences and distant metastases occur in 20%–30% of patients. The prognosis of patients with recurrent head and neck cancer is very poor. The median survival in most of the cases is 6-12 months depending upon the patient, stage of the disease and disease associated complications and prior treatment complications. A few patients with a loco-regional recurrence can be salvaged by surgery or re-irradiation. However, most patients with recurrent or metastatic (R/M) disease only qualify for palliative treatment. Locally recurrent HNSCC constitute about 50% of the recurrences and surgery is a viable option in these cases. However surgery in recurrent HNSCC requires pristine expertise and in a resource challenged setting like that of ours, it is difficult to get surgeries done because of paucity of onco-surgeons. Recurrent cancers in which the initial treatment was surgical,thepossibility of re-surgery is also bleak because of technical feasibility. Thus a mere 15 % of locally recurrent cases qualify for surgery as an option. Re-irradiation in loco-regionally recurrent HNSCC is being practiced in increasing numbers of late because of the advent of conformal radiation. However many factors preclude its routine use. In our patients especially who were initially treated by radical chemo-radiation, majority of them receive Radiation therapy by conventional open field technique. Thus the tolerance doses of organs at risk like the spinal cord are already exceeded. Also the time period elapsed between treatment completion and recurrence usually precludes the use of re-irradiation as a routine modality10. Treatment options for these candidates who don't qualify for local treatment i.e. salvage surgery or re-irradiation include supportive care only,cytotoxic therapy viz. single-agent chemotherapy, combination chemotherapy, targeted therapies either alone or in combination with cytotoxic agents and metronomic chemotherapy. Treatment choice usually is decided by factors such as performance status (PS), co-morbidity, prior treatment, symptoms, patient preference and logistics. Goals of treatments in these circumstances are mainly symptom control and prevention of new cancer-related symptoms, and if assessable, objective tumour response (OR), disease stabilization (SD) or both combined (disease control; DC) and in addition prolongation of overall survival (OS) and progression-free survival (PFS). Conventional chemotherapy regimens consists of drug administrations in cycles near or at the maximum tolerated dose, followed by a long drug free period to permit the patient to recover from acute toxicities. Historically Single agent methotrexate has been most frequently investigated as a palliative chemotherapy option in the form of a weekly intravenous regimen. Apart from being cost effective, it is easy to administer thus reducing hospital admission and exhaustionof resources. A weekly dose of 40–60mg/m2 of methotrexate were considered standard therapy withvariable response rate recorded between 3.9–25%.Overall survival reported with MTX was around 6Months11-14. Combination chemotherapy was compared to single agent chemotherapy in recurrent/metastatic head and neck cancer. Cisplatin and 5-fluorouracil as single agents or in combination were compared. The overall response rate to the combination (32%) was superior to that of CP (17%) or 5-FU (13%) (P = .035). Response was associated with good performance status (PS) but not with primary site, site of recurrence, histology, prior irradiation, or relative dose intensity. There was no significant difference in median survival (5.7 months) among the groups15. Although taxanes have considerable activity in recurrent or metastatic head and neck squamous cell carcinoma, no randomized studies performed in the palliative setting have demonstrated a significantimprovement in overall survival13. In a phase III trial 218 patients within recurrent or metastatic head and neck squamous cell carcinoma were randomized to either cisplatin-5 Fluorouracil or cisplatin–paclitaxel. There was no significant difference in overall survival, response rate or toxicity16. The use ofcetuximab in combination with cisplatin and 5-fluorouracilled to an improvement in overall survival with respect tothe cisplatin and 5-fluorouracil combination.                      In a phase III trial, the addition of cetuximab was shown to improve median survival from 7.4 to 10.1 months and median progression-free survival from 3.3 to 5.6 months with significant acceptable toxicities in recurrent or metastatic head and neck cancer17. Subsequently combination chemotherapy with or without targeted therapy is the recommended treatment for recurrent head and neck squamous cell carcinoma. However, there is always an impending risk of debilitating toxicities like stomatitis, diarrhoea, febrile neutropenia, and even death associated with conventional chemotherapy in recurrent HNSCC patients who already suffer from a multitude of nutritional, immunological physical& mental deficiencies. While tolerance to chemotherapy is one aspect that precludes the use of combination chemotherapy in recurrent head and neck squamous cell carcinomas, the cost of chemotherapy, targeted therapy along with supportive care is beyond the reach of many HNSSC patients in developing countries like India is another factor that needs to be taken into consideration before initiating treatment. Amidst confusion regarding the appropriate treatment approach for patients of recurrent head and neck cancer, a different form of chemotherapy found its place in the treatment options. It is called metronomic chemotherapy. The term "metronomic" derives from the musical device "metronome" that produces regular and metrical ticks that represent a regular aural pulse. In the same way, metronomic chemotherapy is the regular administration of CHT that results in a constant low blood level of the drug. Metronomic chemotherapy doesn't refer to the mechanism of action of the antineoplastic drug, but it reflects the frequent administration of low doses (1/10th–1/3rd of the maximum tolerated dose MTD) of drugs, at shorter intervals without interruption. It represents a different philosophy from the conventional CHT administration that is based on the MTD, the highest dose of a treatment with acceptable toxicity able to kill as many tumour cells as possible. Metronomic chemotherapy exerts its anti-cancer activity by inhibiting tumor angiogenesis, stimulating anticancer immune responseand inducing tumor dormancy.Angiogenesis, the growth of new blood vessels, is associated to tumor growth and metastasis. Due to the faster cell proliferation, as well as the presence of immature endothelial cells in the basement membrane of new vessel walls and the lack of both innervation and collateral supply, the vascular endothelium is an attractive vulnerable element in the tumor18.  Thus drugs that inhibit angiogenesis process represent a strategy for stopping cancer, especially by affecting the regrowth of intra-tumoral vascular endothelial cells. At the beginning, metronomic efficacy was exclusively relied on its anti-angiogenesis mechanism and several angiogenesis inhibitors or anti-angiogenesis drugs were developed and investigated. The vascular endothelial growth factor (VEGF) was probably the most important angiogenesis stimulator and was believed to play a key role in the neovascularization of human tumors. It has been suggested that both tumor cellsand their supporting endothelial cells represent the main target site19. Preclinical studies of experimental cancer conducted in vitro and in vivo demonstrated anti-angiogenic effect of metronomic chemotherapy 20-21. Browder et al. showed that cyclophosphamide based MC provided sustained apoptosis of endothelial cells, resulting in eradication of Lewis lung carcinoma and L1210 leukemia20. Klement et al. revealed that low doses of vinblastine in association with anti-VEGF resulted in full regressions of large established tumors, without increasing toxicity 21.                At metronomic doses, immunomodulation has been shown to be another mechanism of anti-cancer effect. The activation of both innate and adaptive immune system is mediated by some drugs, including taxanes andcyclophosphamide. It has been demonstrated that metronomic chemotherapy selectively induced reduction of circulating regulatory Tcells and subsequent reduction of their inhibitory functions on antigen-specific immune response22. Induction of tumor dormancy is nowadays considered a potential mechanism of metronomic chemotherapy. Dormancy is defined as apause in cancer progression. There are three mechanisms of cancer dormancy including angiogenic dormancy (inability of tumor cells to recruit blood vessels), cellular dormancy (tumor cells in G0-G1 arrest) and immune-surveillance (prevent residual tumor cells expansion)23. Therefore, by inhibiting angiogenesis and controlling immune system, MC can promote tumor dormancy. Thus the metronomic chemotherapy has a "Cytostatic" anti-cancer effect when compared to conventional chemotherapy which has cytotoxicity as major mechanism of action. By reducing the time between administrations, the purpose is to prevent regrowth of tumour cells and minimise the possibility of chemotherapy resistance. Despite the paucity of clinical experience with metronomic chemotherapy in recurrent head and neck cancer, the results from a few available trials is encouraging. A study from Tata memorial hospital Mumbai by Patil et al. showed that oral metronomic chemotherapy may be a more appropriate treatment method in terms of safety in patients with metastatic, relapsed or inoperable HNSCC. In this study, they randomized a total of 110 patients to oral metronomic chemotherapy (n=57) who received daily celecoxib 200 mg × 2 and weekly methotrexate 15 mg/m2 versus platinum-based chemotherapy (n=53)  cisplatinum 75 mg/m2 given 3 weekly. Overall survival, as well as progression free survival were significantly increased in metronomic chemotherapyarm compared to chemotherapy arm (101 versus 66 days,p = 0.014 and 249 versus 152 days, p = 0.02, respectively)24. A study from Madras medical college evaluated the efficacy and toxicity of oral metronomic celecoxib and methotrexate in 30 patients of recurrent head and neck squamous cell carcinoma.The combination of weekly oral methotrexate 5 mg twice daily for 2 days/week and oral celecoxib 200mg twice daily was offered as metronomic chemotherapy. At the end offour months, 60% had stable disease (SD), 10% had partial response(PR), and 30% had progressivedisease(PD). The clinical benefit rate (PR+SD) was 70%. The estimated median time to progression was 8 weeks. The pain control was achieved in about 80% of patients. Only 1 patient had Grade III mucosal toxicity, 11 patients had Grade I/II mucosal toxicity and 18 patients had no mucosal toxicity.Mean QOL scores were improved with this metronomic chemotherapy. The authors concluded that metronomic chemotherapy was well tolerated and provided good symptom control25 Mateen et al enrolled 72 patients of recurrent head and neck cancer  and prescribed oral methotrexate 2.5 mg twice in a week and capecitabine 500mg twice a day for atleast 6 months. Two year progression free survival and overall survival were 18 and 40% respectively26. Geetha M et al showed that addition of erlotinib to metronomic chemotherapy leads to improvement in progression free survival (PFS) and overall survival in recurrent head and neck cancers.Oralmethotrexate (15 mg/m2/week), oral celecoxib (200 mg twice daily) and erlotinib (150 mg once daily)were administered till the progression of the disease or till intolerable side effects. Complete remission was seen in 2 patients, partialremission in 7 patients, stable disease in 4 patients, and progressive disease in 2 patients. The medianestimated PFS was 148 days (95% confidence interval 95.47–200.52 days).Grade 3–4 toxicity was seen in 6 patients (40%)27. Another study by Shobhana et al demonstrated in patients with inoperable and recurrent head and neck squamous cell carcinoma cases where oral methotrexate, oral erlotinib and celecoxib were administered and the primary end point was PFS and OS. After follow up of 6 months.12 patients had good clinical response. Progression free survival was 7.8 months. Grade 3 rash was seen in 3 patients27. Data from an unpublished study from the Department of Radiotherapy RCC, PGIMER suggested that metronomic chemotherapy when compared with best supportive care showed improvement in median progression free survival. Metronomic chemotherapy was well tolerated with only 25 % grade II mucositis in patients receiving it. It also led to decrease in analgesic usage signifying symptom control was better with metronomic chemotherapy. Although the data on metronomic chemotherapy in recurrent head and neck cancer is encouraging, there is severe dearth of randomised trials and sufficient sample sizes to draw conclusions regarding optimisation of drugs, doses and combinations to achieve the best possible results. Moreover, the picture of recurrent head and neck cancers in a setting like that of ours has not been evaluated in previous studies. Majority of patients with recurrent head and neck cancers in our institutes come from rural and low socio-economic strata who cannot afford chemotherapy and supportive care.The proposed study aims at evaluating if a cost effective metronomic chemotherapy with oral methotrexate can compare to the established standard of care of combination chemotherapy in terms of tolerance, efficacy and symptom control, which would lead to its adoption as an established treatment option in a subset of patients who are unable to tolerate or afford chemotherapy.


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