CONCOMITANT CHEMORADIATION IN HEAD AND NECK CANCER: ROLE OF 5-FU ANALOGS.

Concomitant chemoradiation in head and neck cancers: Role of 5-FU analogs.

Mittal Kailash¹, Dhull Anil Kumar², Atri Rajeev², Dhankhar Rakesh², Kaushal Vivek²

¹Assistant Professor, Department of Radiotherapy, UPRIMS&R, Saifai, Etawah (U.P.)

²Department of Radiotherapy, Regional Cancer Center, PGIMS, Rohtak.

Abstract: Head and neck cancer forms the major chunk of cancer patients in developing country like India. About 2/3^rd of the patients present in locally advanced stage in which the cure rates are low. Concomitant chemoradiation with platinum compounds is the standard treatment for such patients as it offers organ and function preservation with better quality of life. MACH-NC update (2009) shows that concomitant chemoradiation provides an absolute survival benefit of 6.5% at 5 years. Many chemotherapeutic agents including 5-FU, taxanes and biologically targeted therapy have been investigated in an effort to maximize the locoregional and survival in locally advanced head and neck cancer. Oral chemotherapeutic agent gives the ease of self medication on daily basis without the need for hospital admission and intravenous infusion. Theoretically daily administration of oral chemotherapy agent mimics the continous infusion of a parenteral agent. Since infusional 5-FU along with Radical RT has achieved a complete response rate of 68% for 5-FU arm versus 56% for placebo arm (p=0.04) with the overall median survival of 33 months for 5-FU versus 25 months for placebo arm, Capecitabine (analog of 5-FU) in low doses have been used in concomitant setting for locally advanced head and neck cancer. Overall response rate observed has been 33-89% with manageable toxicity and near total patient compliance. The maximally tolerated dose to be given daily during radiation therapy is 500 mg/m² b.i.d. Lower dose doses of 250-350 mg/m² have also been used in concomitant with lesser toxicity and greater tolerability.

Keywords:

Head & Neck Cancers, Concomitant-Chemoradiation, 5-Folorouracil, Capcetabine.

Introduction

Head and neck cancers are among the ten most frequent cancers in the world with an annual incidence of about 643,000 new cases and mortality of about 350,000 cases.¹ They account for one-fourth of male and one-tenth of female cancers in India.² The age adjusted incidence for cancers of the oral cavity, oropharynx, nasopharynx, hypopharynx and larynx in India ranges from 15.4 to 110.6 per 1, 00,000 males and 2 to 51.2 per 1, 00,000 females.² Head and neck cancers account for 33% of all cancers seen in Department of Radiotherapy, Pt. B.D. Sharma Post Graduate Institute of Medical Sciences, Rohtak.³

Head and neck squamous cell carcinoma comprises mainly squamous cell carcinomas of mucous membrane of upper aero digestive tract. Significant risk factors for head and neck cancer include tobacco (whether smoked, chewed, or inhaled as snuff), alcohol and dietary factors, with strong evidence that alcohol and tobacco consumption are synergistic.^{4, 5}

The manifestations vary according to stage and primary site of tumor. Dysphagia, odynophagia, otalgia, hoarseness of voice, mucosal ulceration, decreased tongue mobility, nasal obstruction; epistaxis, cranial nerve neuropathies and cervical lymphadenopathy are common presenting complaints. The late stages of all head and neck cancers have easily detectable signs and symptoms, including trismus, formation of fistulae, ocular symptoms, airway obstruction and ankyloglossia.⁵

The majority of head and neck cancer patients (about 60%) are diagnosed having locally advanced disease.⁶ Lymph node involvement may be present in up to 15%-75% cases.⁷ Because of high incidence of advanced disease at presentation and local failure rates of 50%-60%, the management of head and neck cancer is a challenging proposition.⁶ Single modality definitive therapy either radical Radiation Therapy (RT) or Surgery is the preferred treatment option for patients with T1 and T2 head and neck cancer. Radical RT affords good potential for organ preservation without compromise in clinical outcome. For locally advanced head and neck cancer combined modality treatment with combination of Surgery, RT and chemotherapy is employed.⁷

Role of Chemotherapy

Attempts to improve survival rates increases the toxicity of treatment or both, have led to investigational therapies, including the addition of chemotherapy to surgery or radiation therapy since the advent of chemotherapeutic agents. Drugs like platinum compounds, fluorouracil, hydroxyurea, methotrexate, gemcitabine, taxanes, vinorelbine and recently biologically targeted therapy (eg. Cetuximab) etc. have been used concomitantly with radiation therapy to increase the local control and survival in head and neck cancer patients.⁵

Three major goals have been pursued with the experimental addition of chemotherapy to standard surgery and radiation therapy, i.e. to increase the overall rates of survival and to decrease the morbidity of standard therapy and minimize the need for radical surgery (organ preservation). There are three general approaches to the addition of chemotherapy.⁵

The first involves the use of induction (neo-adjuvant) chemotherapy, in which a specific number of chemotherapy cycles are given before standard local and regional therapy is instituted. Neo adjuvant chemotherapy with docetaxel, cisplatin and 5-FU has shown a significant improvement in survival in head and neck cancer.⁸ The second approach involves the use of adjuvant chemotherapy in an attempt to eradicate the microscopic lesions presumed to remain after surgery, radiation therapy, or both approaches. The third approach involves the use of concomitant chemotherapy and radiation therapy in an attempt to eradicate systemic microscopic disease while simultaneously enhancing the cytotoxicity of radiation against macroscopic disease in the head and neck with better chances of organ preservation. This is the most widely used approach now a days.⁵

Concomitant Chemoradiation

Concomitant chemotherapy and radiation therapy offers the opportunity for direct interaction of both modalities. It is postulated that cells with intrinsic or acquired resistance to radiation will be sensitive to radiation in the presence of chemotherapy by synchronization through cell cycle, amplification of free radical induced damage, inhibition of repair of radiation induced sub lethal damage and potentially lethal damage.⁹

Clinically, two types of schedules of concomitant chemotherapy and radiation therapy have been investigated.

In the first approach multiple agents are given at higher doses and in more intensive schedules. As a result, toxicity is further increased, requiring regularly scheduled interruptions of radiation therapy. The second adds single-agent chemotherapy at a low or moderate dose to standard radiation therapy. Several studies have reported an increase in disease-free survival, local control and overall survival with manageable toxicities.⁶

MACH-NC Analysis

Evidence is accumulating from clinical trials that concomitant chemo radiation is more effective than radiotherapy alone or sequential chemo radiotherapy in many tumor types. The updated IPD meta-analysis of chemotherapy in head and neck cancer (MACH-NC) showed a more pronounced benefit of the concomitant chemotherapy as compared to induction chemotherapy with the absolute survival benefit of 6.5% at 5 years.¹⁰ During the past two decades, a large number of laboratory and clinical studies have been conducted to search for more effective radio sensitizers. Capecitabine has also been evaluated as a potent radio enhancer among the newer cytotoxic agents.^5,11

General Principles of Concurrent Chemoradiation

Concurrent chemo radiotherapy attempts to capitalize on the tumor-radiosensitizing properties of chemotherapy or novel agents, in addition to potentially delivering active agents that function systemically. However, sensitizing effects are not tumor specific and affect adjacent normal tissues within the radiation field. Concurrent chemo radiotherapy trials have consistently reported an increased incidence of acute grade 3 and 4 toxic effects, with mucositis and dermatitis being the most prominent. Multiple highly effective chemo radiotherapy treatment platforms exist but unfortunately, the optimum timing, dosing and choice of systemic agents, in addition to radiation schedule, are controversial.¹¹

Mohit et al (2007) estimated the radio therapeutic dose equivalence of chemo-radiotherapy in head and neck cancer. Results showed that 1% increase in BED yields a 1.1% increase in LRC. The mean BED of standard fractionated chemo-radiotherapy was 71Gy (10.8Gy contributed by chemotherapy). The mean BED of modified fractionated chemo-radiotherapy was 76Gy, 10.4Gy contributed by chemotherapy). Thus it was concluded that chemotherapy increases BED by approximately 10Gy in standard and modified fractionated radiotherapy, equivalent to a dose escalation of 12Gy in 2Gy daily or 1.2Gy twice daily. Such an escalation could not be safely achieved by increasing radiation dose alone.¹²

Single Agent Concurrent Chemoradiation

Synchronous treatment is completed more quickly than alternating treatment. It is therefore preferable from a theoretical standpoint in terms of addressing the issue of accelerated repopulation, albeit at the expense of increased acute side effects. Many agents have been used synchronously with RT in head and neck cancer viz. Bleomycin, Methotrexate, Cisplatin, Carboplatin, 5-FU, taxanes, cetuximab etc.⁶

Cisplatin

Cisplatin is a potent radio sensitizer and the drug most commonly used for chemo radiotherapy in HNC. Currently, the most widely used standard regimen is 100 mg/m² cisplatin every 3 weeks, combined with ~70 Gy radiation delivered in 1.8–2.0 Gy daily fractions. This regimen causes severe toxic effects, such as nephrotoxic, ototoxic and neurotoxic effects, nausea and vomiting, as well as severe mucositis.^{5, 11}

Carboplatin

Data for single-agent carboplatin-based chemo radiotherapy are limited. One HNC trial comparing cisplatin with carboplatin demonstrated similar efficacy and survival. The side effects of carboplatin are more favorable than those seen with cisplatin-based chemo radiotherapy because few nephrotoxic or neurotoxic effects arise. In conclusion, single-agent carboplatin-based chemo radiotherapy has a favorable toxicity profile for patients with HNC.¹¹

5-Fluorouracil

The agent 5-fluorouracil (5-FU) has activity in HNC and, theoretically, is of particular interest because of its activity during the radio resistant S-phase of the cell cycle. Indeed, its radiosensitizing properties are well established and the drug is commonly used for chemo radiotherapy in several diseases. 5-fluorouracil is well tolerated if infused daily for several consecutive days at doses of 250–1,200 mg/m², depending on the respective regimen. Three randomized trials that compared radiation with single-agent 5-FU chemo radiotherapy have shown a survival benefit or trends for a benefit of the combined regimen.¹³

Common side effects of 5-FU-based chemo radiotherapy include mucositis, hand–foot syndrome, and diarrhea. The side effects of this type of chemo radiotherapy were more manageable than those arising with cisplatin therapy, with grade 3 or 4 mucositis being reported in 31.8% of patients. Most regimens today use 5-FU in combination with cisplatin or hydroxyurea, with or without paclitaxel. Potential alternatives to infusional 5-FU are the derivatives capecitabine and tegafur–uracil (UFT), which have a protracted metabolism. Early trials show feasibility and potential activity.¹⁴

Taxanes

Taxanes are potent radio sensitizers in locally advanced HNSCC. A response rate of 65% and 2-year survival of 46% were reported with concurrent paclitaxel and radiotherapy when administered at weekly doses of up to 40 mg/m². Mucositis and leukopenia were reported, but the toxic effects were high.¹¹

Concurrent Cetuximab and Radiotherapy

Concomitant chemoradiation with cetuximab (EGFR inhibitor) has shown a marked increase in median survival, from 29.3 months to 49 months, was seen when radiation was combined with cetuximab. The 3-year survival was 45% for radiation alone and 55% for those receiving the combination therapy. Overall, the regimen was well tolerated, with similar rates of toxicity compared with radiation alone.¹⁵

 Multi-agent based concurrent chemo radiation

5-Fluorouracil and Cisplatin

The combining of several drugs during chemo radiotherapy offers improved radio sensitization of tumor cells and can increase systemic activity, but these effects might be at the expense of increased frequency of toxic effects. In a trial by Brizel et al, 116 patients with HNSCC (53% of whom had unresectable tumors) were randomized to receive hyper fractionated radiotherapy alone or a bolus dose of cisplatin and infusional 5-FU with once-daily radiation. Chemo radiotherapy was associated with a significantly improved 3-year loco regional control rate compared with radiotherapy alone (70% versus 44%), and a trend towards improved 3-year survival was noted (55% versus 34%, P = 0.07).⁶

Paclitaxel and Cisplatin

Several multiagent chemo radiotherapy regimens were compared in the RTOG 97-03 multicenter, randomized, phase II trial. Patients received cisplatin and paclitaxel chemo radiotherapy, cisplatin and 5-FU chemo radiotherapy or 5-FU and hydroxyurea chemo radiotherapy (FHX). This trial demonstrated equivalent 2-year overall survival for cisplatin and paclitaxel chemo radiotherapy and the FHX regimen (66.6% and 69.4%), with both of these regimens being superior to cisplatin and 5-FU chemo radiotherapy (57.4%).^{5, 6, 11}

Cetuximab and Cisplatin

A small study, reported by Pfister et al. assessed cetuximab and cisplatin-based chemo radiotherapy in 22 patients with loco regionally advanced disease; the results showed excellent 3-year overall survival of 76%. This study was closed early, however, because of unexpected toxicity in five patients and 100% mucositis (grade 3 & 4), which included two deaths.¹⁶

Carboplatin plus 5-fluorouracil

Two European trials examined the use of carboplatin and 5-FU-based chemo radiotherapy in locally advanced head and neck cancer. The group receiving the combined regimen had significantly higher 3-year survival than those receiving radiation alone (51% versus 31%) and an improved locoregional control rate (66% versus 42%). Carboplatin-based chemo radiotherapy is better tolerated than cisplatin-containing regimens. Acute radiation-related toxic effects are common, but manageable (grade 3 or 4: mucositis 68%, dermatitis 30%, neutropenia 18%). Carboplatin and 5-FU chemo radiotherapy can be used as an alternative to cisplatin therapy.^{5, 6, 11}

Single agent versus multi-agent based chemoradiation

The meta-analysis of chemotherapy on head and neck cancer (MACH-NC) by Pignon et al, suggested a possible survival benefit 6.5% at 5 years for multidrug-based chemo radiotherapy, although the heterogeneity of the examined regimens makes interpretation difficult. Furthermore, the beneficial effects of cisplatin in this meta-analysis superseded this effect, and single-agent cisplatin-based chemo radiotherapy was statistically similar to cisplatin and 5-FU combination therapy.¹⁰ Single-agent cisplatin-based therapy, therefore, continues to be a viable standard.^{5, 6}

Oral Chemotherapy in Head and Neck Cancer

Clinical experience with oral administration of chemotherapy in head and neck cancer patients is limited. Nevertheless, given the anatomic location of the disease, its risk factors, and epidemiology, it is clear that some special considerations apply to this patient population. Most of the head and neck cancer patients receive radical RT on OPD basis. Oral chemotherapeutic agent gives them the ease of self medication on daily basis without the need for hospital admission and intravenous infusion. Theoretically daily administration of oral chemotherapy agent mimics the continous infusion of a parenteral agent. Futhermore, a good radiosensitiser must be able to be given orally.⁹

Table-1 enumerates oral chemotherapy agents that have been studied in head and neck cancer patients. Of these, hydroxyurea is approved by the US Food and Drug Administration for use as a radiation sensitizer. Most other agents have been studied either less frequently or not at all in concomitant setting.¹⁷

Table-1

Orally administered chemotherapy agents in head and neck cancer

There are some worth mentioning studies that have evaluated the role of oral chemotherapy agents along with radiation therapy.

5-FU, Hydroxyurea, and Concomitant Radiotherapy

At the University of Chicago, a regimen consisting of infusional 5-FU with oral hydroxyurea and concomitant radiation therapy (FHX) have been used. This regimen was based on the observed single-agent activity of both chemotherapy agents, the possibility of a synergistic interaction between hydroxyurea and 5-FU based on the intracellular depletion of dUMP leading to enhanced binding of 5-FdUMP to its target enzyme, thymidylate synthase, and the possibility of radiation enhancement by both drugs. Highly encouraging locoregional and distant control and overall survival rates were achieved.¹⁸

Eniluracil, 5-FU, and Radiotherapy

A phase I study of eniluracil 20 mg administered every 12 hours × 14 doses with escalating doses of 5-FU administered twice daily × 10 doses and concurrent, twice-daily radiotherapy (150 cGy/fraction) for 5 consecutive days was conducted. This 5-day chemoradiotherapy regimen was repeated every other week until completion of radiotherapy (usually 5 cycles or 75 Gy). Evaluation suggested that systemic myelosuppression rather than radiation enhancement was dose-limiting. This combination of 5-FU and eniluracil was also evaluated in patients with recurrent or metastatic disease (without concurrent radiotherapy) in a phase II study conducted by the National Cancer Institute of Canada.¹⁷

Oral Etoposide

Intravenously administered etoposide has been shown to be minimally active in head and neck cancer. Therefore, oral etoposide has been studied, albeit infrequently. One group of investigators reported on 16 extensively previously treated patients who were administered oral etoposide 100 mg/m²×5 every 3 weeks; no response activity was observed.¹⁷

Oral Analogs of 5-FU

5-Fluorouracil (5-FU) is the fluorinated analog of uracil which was first synthesized in 1957. It belongs to the antimetabolite family and is a chemotherapeutic agent with activity against a variety of solid tumours, including head and neck, breast, prostate, pancreatic, liver, genitourinary and gastrointestinal tract carcinomas. When combined with radiation therapy, improved local control and survival rates have been reported in a variety of malignancies, compared to radiotherapy alone.¹⁹

This drug has a complex molecular activity, interfering with DNA synthesis and mRNA translation. Thymidine phosphorylase transforms 5-FU to 5-fluorodeoxyuridine (5FdUrd), which binds to thymidilate synthase and to tetrahydrofolate, forming a stable complex and thus preventing the formation of thymidine from thymine. DNA synthesis is blocked, leading to cell death. Moreover, through the enzymatic activity of thymidine kinase, the 5FdUrd can be metabolized into fluorouridinemono- and triphosphate (FdUMP and FdUTP), which is directly inserted into the DNA, leading to pathological DNA structures. The mRNA polymerase can also use FdUTP for mRNA formation, leading to blockage of the mRNA translation.²⁰

Due to the fact that 5-FU has an unpredictable gastrointestinal absorption and rapid degradation, it must be administered intravenously. 5-FU concentrations in plasma depend on drug dosage as well as the rate of administration, because it displays saturable pharmacokinetics. In colorectal cancer patients, it was found that protracted infusion of 5 to 28 days increased the response rate (RR) from 14% (achieved with bolus infusions) to 22%.^11,19,20

Nevertheless, continuous-infusion of 5-FU has been complicated by hospital and/or home health

costs, infection risk of IV devices, and overall patient burden. To overcome these disadvantages, still preserving the benefits of continuous-infusion, oral pro-drugs of FU were developed.

The first oral 5-FU prodrug, namely Ftorafur (Tegafur), was developed in 1967 and a Phase I study in patients with gastrointestinal carcinomas showed palliative benefits. Nevertheless, further development of that product in the United States was limited due to neurologic toxicities. UFT, a combination of tegafur and uracil, an inhibitor of the primary enzyme responsible for FU degradation to central nervous system active metabolites, is also used clinically. Another oral pro-drug that takes advantage of a different metabolic pathway to form 5-FU, is doxifluridine (5'-FdUrd; 5'-deoxy-5-fluorouridine). The enzyme thymidine phosphorylase is necessary to convert this pro-drug to its active form. Higher levels of this enzyme are expressed in tumour tissues and the intestinal tract, which is responsible for dose limiting toxicity evidenced by diarrhea.^19,20

Capecitabine is a carbonate derivative of 5'-DFUR that is absorbed through the intestine in pro-drug form. Three activation steps are necessary to metabolize capecitabine to its active form FU

Capecitabine is absorbed through the intestine and converted to 5'-deoxy-S-fluorocytidine (5'-DFCR) by carboxylesterase and then to 5'-deoxy-S-fluorouridine (5'-DFUR) by cytidine deaminase (Cyt D), both steps taking place in the liver. Finally, thymidine phosphorylase(TP) converts S'-DFUR to the active drug, FU. This occurs in both tumor and normal tissues; however, the enzyme is found at higher concentrations in most tumor tissue compared with normal healthy tissue. This theoretically allows a selective activation of the drug and low systemic toxicity.^19,20

UFT

UFT (tegafur and uracil) has also been studied in head and neck cancer. Tanaka et al reported on 43 previously treated patients with recurrent head and neck cancer. The overall response rate was 38% with a partial response rate of 19% and complete response rate of 19%. Additional trials have evaluated UFT in combination with cisplatin or carboplatin. In a study involving 36 previously untreated head and neck cancer patients, Gonzalez-Baron reported an overall response rate of 94% (22% complete response rate) for the combination of cisplatin and tegafur. The combination of carboplatin and tegafur resulted in an objective response rate of 62% (33% CR) in 22 patients. Additional studies evaluating the combination of carboplatin, tegafur, leucovorin, and cisplatin with UFT have also been reported.^19,20

UFT as Radiation Sensitizer

UFT has also been evaluated as a radiation sensitizer. Fifty-two patients with larynx cancer were treated with this combination. Improved disease-free and overall survival was reported as compared with a historical control group of 113 patients treated by the same investigators.

Capecitabine

N4-pentyloxycarbonyl-5′-deoxy-5-fluorocytidine, more commonly called Capecitabine is a cytotoxic agent that is administered orally and is activated preferentially in tumors. This carbamate of fluoropyrimidine was synthesized in the 1990s by Japanese researchers as an oral formulation designed to circumvent the unacceptable toxicity of 5′d5-FUrd.²¹

Capecitabine is available as 150 mg and 500 mg tablets. After oral administration, Capecitabine crosses the gastrointestinal barrier intact and is rapidly and almost completely absorbed, thus, diarrhea does not occur with its use. It is subsequently converted into 5-FU in a three-stage mechanism involving several enzymes. In the first step, it is metabolized into 5′-deoxy- 5-fluorocytidine (5′-dFCR) by hepatic carboxylesterase. 5′-dFCR is then deaminated into 5′d5-FUrd by cytidine deaminase, mainly localized in liver and tumor tissues. Finally, 5′d5-FUrd is transformed into 5-FU under the action of thymidine phosphorylase (TP), an enzyme with higher activity in tumor than in normal tissues. Higher levels of 5-FU are thus produced within tumors with minimal exposure of healthy tissue to 5-FU. After oral administration of capecitabine 5-FU concentrations in the colorectal resections were on average 3.2 times greater than in the normal bowel and 21 times greater than in plasma.²¹

Capecitabine has been used effectively in various malignancies as colorectal carcinoma, metastatic breast cancer, pancreatic cancer, esophageal cancer and even in head and neck cancer. It was approved by FDA for use in colorectal cancer in 1998. The drug has been used concomitantly with radiation therapy in doses varying from 250 mg/m², 300mg/m², 350mg/m², 450mg/m² to as high as 2500mg/m² given twice daily.^19,22-25

Higher the dose of capecitabine, given concomitantly with radiation therapy, more is the toxicity. Lower and intermediate dose schedules have shown better tumor control with minimal toxicity.^22-25 The drug is to be used with caution and dose modification in hepatic impairment, renal insufficiency, lactation and in pregnancy. The prominent side effects are nausea, vomiting, stomatitis, diarrhea, hand-foot syndrome, allergic reactions and bone marrow suppression. Much of its side effects are dose related and occur frequently with higher dose as shown in Table-2.¹⁹ Capecitabine has shown efficacy in head and neck cancer akin to 5-FU.

Table-2

Incidence of Adverse Effects of Capecitabine

(When given in a dose of 2500mg/m²)

Efficacy of Capecitabine in Head and neck cancer

Rich et al in a article “Four decades of continuing innovation with fluorouracil: current and future approaches to fluorouracil chemoradiation therapy” states that, 5- FU chemoradiation maximizes local control and, for some tumor sites (such as head and neck, pancreatic, biliary, cervical, esophageal, and gastric cancers), improves survival rates. Moreover, 5-FU chemoradiation results in improved organ preservation with excellent functional outcome in several anatomic sites including head and neck cancer. He stresses the introduction of oral prodrug analogs will likely further improve the results of 5-FU therapy in several organ systems, such as the rectum, head and neck, and esophagus.¹⁴

Browman et al used infusional 5-FU in concomitant setting in stage III & IV head and neck cancer with curative intent. He delivered 66 Gy of radiation therapy in 2-Gy fractions once daily 5 days per week. In the experimental arm infusional 5-FU 1.2 gm/sq.m/day was given as 72-hour infusion in first and the third week of radiation. The complete response rate was 68% for 5-FU arm and 56% for placebo arm (p=0.04). The overall median survival was 33 months for 5-FU and 25 months for placebo arm. Toxicity was greater in study arm but did not interfere with the radiation therapy delivery. Hence, Capecitabine which is a prodrug of 5-FU also offers the prospect of use in concomitant setting as single agent. It has the advantage of being given orally no infusion required no hospital admission for infusion. It is given daily which is radiobiologically a better radiosensitising technique than interval chemotherapy.¹³

Kim JG et al evaluated the efficacy and safety of concurrent chemoradiation with capecitabine and cisplatin in patients with locally advanced squamous cell carcinoma of the head and neck. In total, 37 patients with stage III or IV head and neck squamous cell carcinoma patients were enrolled in the study. The chemotherapy consisted of two cycles of intravenous cisplatin of 80 mg/m² on day 1 and oral capecitabine 825 mg/m² twice daily from day 1 to day 14 at 3-week intervals. The radiotherapy (1.8-2.0 Gy, 1 fraction/day to a total dose of 70-70.2 Gy) was delivered to the primary tumor site and neck. After the chemoradiation, 29 complete responses (78.4%) and 6 partial responses (16.2%) were confirmed. At a median follow-up duration of 19.8 months, the estimated overall survival and progression-free survival rate at 2-year was 76.8 and 57.9%, respectively. Concurrent chemoradiation with capecitabine and cisplatin was found to be well tolerated and effective in patients with locally advanced head and neck squamous cell carcinoma.²²

Dose-limiting toxicity (DLT), efficacy and maximum tolerated dose (MTD) of capecitabine with concurrent radiotherapy was evaluated in 30 patients with node-positive stage II nasopharyngeal cancer by Guo et al. Capecitabine was administered orally on day 1 of radiotherapy by an intermittent schedule (14 days treatment; 7-day rest, in doses varying from 500- 1250 mg/m², bid. Radiotherapy of 68 - 72 Gy in 34 - 36 fractions was delivered to the nasopharynx and 64 - 70 Gy in 32 - 35 fractions to the node-positive area. Complete response (CR) 12 (42.9%), partial response (PR) 13 (46.4%), the overall response rate (CR + PR) was 89.3%. The complete response rates of the node-positive area and of the nasopharynx were 50% (14/28) and 46.4% (13/28) respectively. No DLT was observed at the dosage group of 500 mg/m² and 750 mg/m². Three of 9 patients experienced DLT at 1000 mg/m² with grade III stomatitis; 4/6 at 1250 mg/m² experienced DLT with grade III stomatitis, 4/6 with grade III diarrhea, 1/6 with grade IV febrile neutropenia and 1/6 with grade III thrombocytopenia. The study concluded that a dose of 750 mg/m² of capecitabine might be recommended for combination with radiotherapy. This regimen is tolerable and valid for nasopharyngeal carcinoma.²³

Pivot et al conducted a study in patients with locally recurrent or metastatic head and neck carcinoma. The treatment plan included cisplatin on day 1 every 21 days, followed by capecitabine twice daily from day 2 to day 15, with a 1-week rest period. Twenty-one patients were included. Dose (mg/m²) increments for cisplatin and capecitabine (bid), respectively, were as follows: level 1, 80 and 1000 (three patients); level 2, 100 and 1000 (12 patients); and level 3, 100 and 1125 (five patients). Objective response was obtained in 33% (seven patients- three complete responses and four partial responses), recommending doses of level 2 with cisplatin 100 mg/m² on day 1 and capecitabine 1000 mg/m² bid on days 1-14, every 28 days for further studies.²⁴

Sykes et al conducted a phase I non-randomized dose finding study in patients with advanced squamous cell carcinoma of the head and neck. Capecitabine was given twice daily, 7 days a week at a dose starting at 350 mg/m² bid. Radiotherapy using a beam directed technique was prescribed to 55 Gy in 20 fractions over 4 weeks. A total of 24 patients were treated. Radiotherapy was completed without delay in all cases. There was no systemic drug related toxicity. The maximally tolerated dose he recommended for use in concomitant setting is 500 mg/m² b.i.d. Thus, capecitabine offers the prospect of an orally administered drug for use synchronously with radiation therapy, which is well tolerated.²⁵

Conclusion

Head and neck cancer forms the major chunk of cancer patients in developing country like India. About 2/3^rd of the patients present in locally advanced stage in which the cure rates are low. Concomitant chemoradiation with platinum compounds is the standard treatment for such patients as it offers organ and function preservation with better quality of life. MACH-NC update (2009) shows that concomitant chemoradiation provides an absolute survival benefit of 6.5% at 5 years. Many chemotherapeutic agents including 5-FU, taxanes and biologically targeted therapy have been investigated in an effort to maximize the locoregional and survival in locally advanced head and neck cancer. Oral chemotherapeutic agent gives the ease of self medication on daily basis without the need for hospital admission and intravenous infusion. Theoretically daily administration of oral chemotherapy agent mimics the continous infusion of a parenteral agent. Since infusional 5-FU along with Radical RT has achieved a complete response rate of 68% for 5-FU arm versus 56% for placebo arm (p=0.04) with the overall median survival of 33 months for 5-FU versus 25 months for placebo arm, Capecitabine (analog of 5-FU) in low doses have been used in concomitant setting for locally advanced head and neck cancer. Overall response rate observed has been 33-89% with manageable toxicity and near total patient compliance. The maximally tolerated dose to be given daily during radiation therapy is 500 mg/m² b.i.d. Lower dose doses of 250-350 mg/m² have also been used in concomitant with lesser toxicity and greater tolerability.

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