Study
Trial design
Sample size (HNSCC/oral cavity)
Regimen
RR/PFS/TTP/TTF/DOR
OS
Schornagel et al. (1995) [5]
Phase III randomized trial for first-line chemotherapy treatment
131/43 (33 %)
Edatrexate 70 mg/m2 weekly (reduced from 80 mg/m2 due to toxicity)
RR 21 %a
DOR: 6.1 monthsa
No OS difference
133/43 (32 %)
Methotrexate 40 mg/m2 weekly
RR 16 %a
DOR: 6.4 monthsa
Degardin et al. (1998) [6]
Phase II single-arm trial for first-line chemotherapy treatment
63/12 (19 %)
Vinorelbine 30 mg/m2 weekly
RR 16 %
DOR: 19 weeks
32 weeks
Testolin et al. (1994) [7]
Phase II single-arm trial for pretreated patient
15/1 (6.6 %)
Vinorelbine 20 mg/m2 weekly
RR 6 %
Unknown
Degardin. et al. (1996) [8]
Phase II single-arm trial for first-line chemotherapy treatment
Unknown/40
Oxaliplatin 130 mg/m2 every 3 weeks
RR 6 % (previously treated)
DOR: 3 months (previously treated)
RR 13 % (untreated)
DOR: 2 months (untreated)
5 months
Murphy et al. (2001) [9]
Phase II single-arm (two dose cohorts) trial for first-line chemotherapy treatment
33/7 (21.2 %)
Irinotecan 125 mg/m2 weekly ×4 every 6 weeks (19 patients)
RR 26.3 %
RR 14.2 %
30.2 % (1 year)
Irinotecan 75 mg/m2 weekly ×2 every 3 weeks (14 patients)
Pivot et al. (2001) [10]
Phase II single-arm trial for first-line chemotherapy treatment
34/Unknown
Pemetrexed 500 mg/m2 every 21 days
RR 26.5 %
TTF: 3.9 months
6.4 months
Martinez-Trufero et al. (2010) [11]
Phase II single-arm trial for pretreated patient (no more than one previous systemic chemotherapy)
40/Unknown
Capecitabine 1250 mg/m2 bid 1–14 every 21 days
RR 24.2 %
TTP: 4.8 months
7.3 months
Catimel. et al. (1994) [12]
Phase II single-arm trial including both first-line and pretreated patient
54/Unknown
Gemcitabine 800 mg/m2 (or 1250 mg/m2) weekly, 3 weeks on 1 week off
RR 13 %
Unknown
5.2.1 Platinum Agents
Both cisplatin (cis-diamminedichloroplatinum(II)) and carboplatin (cis-diammine(1,1-cyclobutanedicarboxylato)platinum(II)) are platinum(II) complexes with two ammonia groups in the cis position. While cisplatin has two chloride “leaving” groups, carboplatin possesses a cyclobutane moiety. Although surgery with positive margin is a strong predictor of local recurrence, negative margin does not confer lack of disease relapse. Over 50 % of oral cavity cancers despite negative margin develop disease recurrence either locoregionally or at distant sites. Disease recurrence is often an indicator of incurability (Table 5.2).
Table 5.2
Selected platinum agent-based chemotherapy studies
|
Study
|
Trial design
|
Sample size (HNSCC/oral cavity)
|
Regimen
|
RR/PFS
|
OS
|
|---|---|---|---|---|---|
|
Liverpool Head and Neck Oncology Group (1990) [13]
|
Phase III randomized trial for first-line chemotherapy treatment
|
200/48
|
Cisplatin (100 mg/m2) every 28 days
|
RR 21.5 %a
|
Single-agent cisplatin superior to single MTX alone, no significant difference among arms of cisplatin single agent or combination
|
|
Methotrexate (40 mg/m2) every 14 days
|
|||||
|
Cisplatin (100 mg/m2) and 5-FU (1 g/m2 × 4) every 28 days
|
|||||
|
Cisplatin (100 mg/m2) and methotrexate (40 mg/m2) every 28 days
|
|||||
|
Forastiere et al. (1992) [14]
|
Phase III randomized trial for first-line chemotherapy treatment
|
277/unknown
|
Cisplatin (100 mg/m2) and 5-FU (1 g/m2 × 4) every 21 days
|
RR 32 %b
DOR 4.2 months
|
6.6 monthsa
|
|
Carboplatin (300 mg/m2) and 5-FU (1 g/m2 × 4) every 28 days
|
RR 21 %
PFS 5.1 months
|
5.0 monthsa
|
|||
|
Methotrexate (40 mg/m2) every 7 days
|
RR 10 %
PFS 4.1 months
|
5.6 monthsa
|
|||
|
Jacobs et al. (1992) [15]
|
Phase III randomized trial for first-line chemotherapy treatment
|
249/104
|
Cisplatin (100 mg/m2) and 5-FU (1 g/m2 × 4) every 21 days
|
RR 32 %a
TTP <2.5 monthsa
RR 17 %
RR 13 %
|
5.7 month (no difference among arms)
|
|
Cisplatin (100 mg/m2) every 21 days
|
|||||
|
5-FU (1 g/m2 × 4) every 21 days
|
|||||
|
Phase III randomized trial for first-line chemotherapy treatment
|
CABO (methotrexate (40 mg/m2) days 1 and 15, bleomycin (10 mg) and vincristine (2 mg) days 1, 8, and 15, cisplatin (50 mg/m2) day 4, every 21 days)
|
RR 34 %a PFS 19 weeks
|
|||
|
Clavel et al. (1994) [16]
|
356/140
|
cisplatin (100 mg/m2) and 5-FU (1 g/m2 × 4) every 21 days
|
RR 31 %
PFS 17 weeks
|
29 weeks for the entire group, no difference among arms
|
|
|
cisplatin (50 mg/m2) days 1 and 8, every 28 days
|
RR 15 %
PFS 12 weeks
|
||||
|
Gibson et al. (2005) [17]
|
Phase III randomized trial including both first-line and pretreated patient
|
104/18
|
Cisplatin (100 mg/m2) and 5-FU (1 g/m2 × 4) every 21 days
|
RR 27 %a
|
8.7 monthsa
|
|
Cisplatin (75 mg/m2) and paclitaxel (175 mg/m2 over 3 h) every 21 days
|
RR 26 %a
|
8.1 monthsa
|
Siddik has described the mechansism of action and resistance for cisplatin [18]. Cisplatin is first activated through a series of spontaneous equation reactions through which the cis-chloro ligands of cisplatin are replaced with water molecules [19]. The activated cisplatin then binds DNA and forms primarily intrastrand DNA adducts between adjacent guanines or a guanine and an adenine [19–21], which subsequently activates several signal transduction pathways, including those involving ATR, p53, p73, and MAPK, and eventually results in the activation of apoptosis [21]. Cisplatin has been the cornerstone of treatment for head and neck cancer. Carboplatin shares a similar mechanism of action as cisplatin. Carboplatin is generally less emetogenic, nephrotoxic, and neurotoxic but more myelosuppression than cisplatin [22].
In vitro studies using cisplatin-resistant cell lines have suggested the mechanism of resistance is multifactorial [23]. Any intracellular changes that interrupt the complex process of the cytotoxic effect of cisplatin, starting from the initial drug entry into cells to the final stages of apoptosis, will lead to drug resistance. These could occur through the reduction in drug accumulation due to either impaired influx through the cell membrane or enhanced efflux, inactivation of cisplatin by thiol-containing compounds, notably glutathione and metallothioneins, increased DNA adduct repair, and finally the inhibition of apoptotic activation induced by DNA damages. In HNSCC, a copper efflux transporter involved in the uptake of cisplatin, ATP7B, was found to contribute to the acquisition of cisplatin resistance in human oral squamous cell lines [24], and amplification of glutathione S-transferase π (GST-π) was suggested to be associated with cisplatin resistance and poor clinical outcomes in head and neck cancer patients treated with cisplatin-based therapy [25]. Of note, cisplatin-resistant tumors are fully cross-resistant to the platinum analogue carboplatin [26].
5.2.2 Taxanes
The taxanes are important newer class of anticancer agents that have showed activities in HNSCC. Initially derived from the bark of the scarce Pacific yew, paclitaxel can now be produced by partial synthesis from a precursor, 10-deacetylbaccatin III, derived from the needles of more abundant yew species [27, 28]. Docetaxel, an analogue of paclitaxel, is also derived semisynthetically from 10-deacetylbaccatin III [29]. Classically they bind to β-tubulin in microtubules, causing the formation of unusually stable microtubules and results in mitotic arrest [30–42], which further triggers the mitotic spindle checkpoint and results in apoptosis [42]. The main shared toxicities of paclitaxel and docetaxel are neutropenia and peripheral neuropathy. Hypersensitivity reactions to the polyoxyethylated castor oil vehicle of paclitaxel may occur during infusion. Transient sinus bradycardia can occur in patients receiving paclitaxel. Docetaxel may induce fluid retention, palmar-plantar erythrodysesthesia, and onychodystrophy. Less neurotoxicity but more stomatitis is associated with docetaxel than paclitaxel [43].
The intrinsic or acquired resistance to taxanes is often a multifactorial process, with the most common mechanism being through multidrug resistance (MDR) conferred by the expression of P-glycoprotein (Pgp), which is responsible for extruding taxanes across plasma membrane and the blood–brain barrier and/or associated coexpressed resistance mechanisms [44]. Additionally, altered metabolism of the drug, alterations in tubulin, and aberrant signal transduction pathways and/or cell death pathways can all contribute to the resistance as demonstrated by in vitro studies [24]. The feasibility of combining various Pgp inhibitors and taxanes were investigated extensively in multiple phase I clinical studies [27]. Inhibition of Pgp by tariquidar (XR9576) was detected in circulating mononuclear cells in patients with lung, ovarian, and cervical cancer [28]. However, whether Pgp inhibition can actually increase concentrations of anticancer agents in tumor tissue in the clinical setting remains to be demonstrated.
5.2.3 5-FU
5-FU is an analogue of the naturally occurring pyrimidine uracil. Upon entering the cells, it is converted to several active metabolites including fluorodeoxyuridine monophosphate (FdUMP), fluorodeoxyuridine triphosphate (FdUTP), and fluorouridine triphosphate (FUTP). The 5-FU cytotoxicities are executed through misincorporation of fluoronucleotides into RNA and DNA and inhibition of the nucleotide synthetic enzyme thymidylate synthase (TS) [45]. 5-FU is often administered as continuous infusion in HNSCC regimens. The common toxicities associated with 5-FU are diarrhea, mucositis, myelosuppression, and hand-foot syndrome [43].
Resistance to fluoropyrimidines is also a multifactorial event. Increased expression of TS; mutations in TS protein associated with reduced binding affinity to FdUMP; decreased levels of substrate for thymidylate synthase reaction; decreased corporation of 5-FU into RNA and DNA; decreased expression of mismatch repair enzymes, such as hMLH1 and hMSH2; increased DNA repair enzymes, uracil glycosylase and dUTPase; increased salvage of physiologic nucleotides including thymidine; and increased expression of the catabolic enzyme dihydropyrimidine dehydrogenase (DPD) are all associated with fluoropyrimidine resistance. Arsenic trioxide (ATO), an agent that inhibits TS protein and gene expression in vitro, significantly decreased TS gene expression in PBMC of all treated patients and the tumor tissue of half of the patients who underwent biopsy in a phase I study in colorectal cancer patients [31].
5.2.4 MTX
MTX enters cells through an active carrier transport mechanism or endocytic pathway. Inside cells, MTX is polyglutamylated and retained in the cells. MTX or its polyglutamylated form binds tightly to dihydrofolate reductase (DHFR) and inhibits the formation of tetrahydrofolate (THF). THF is required for thymidine biosynthesis. Additionally, polyglutamylated MTX also inhibits purine synthesis [46]. The main toxicities of MTX are myelosuppression and gastrointestinal toxicity [43].
Decreased carrier-mediated transport of MTX, increased expression or decreased binding affinity for MTX of DHFR and/or TS, decreased antifolate polyglutamylation through either decreased FPGS expression or increased expression of catabolic enzyme γ-glutamyl hydrolase, and expansion of intracellular THF cofactor pools are all involved in inherent and acquired resistance to MTX [47].
5.2.5 Cetuximab
Cetuximab is a human–murine chimeric immunoglobulin G1 (IgG1) monoclonal antibody that is directed against the human EGF receptor (EGFR). It competitively binds to the extracellular domain of the human EGFR. Cetuximab blocks binding of endogenous EGFR ligands, resulting in inhibition of the function of the receptor. Additionally, it induces downregulation of EGFR via internalization of EGFR and targets cytotoxic immune effector cells to EGFR-expressing tumor cells through antibody-dependent cell-mediated cytotoxicity [35].
Despite the clinical benefits observed with EGFR-targeted therapies, there are no validated biomarkers of response to cetuximab in HNSCC. The very high frequency of EGFR expression and low incidence of K-RAS exon 12/13 and EGFR tyrosine kinase domain mutations in HNSCC limit their utility in predicting response to cetuximab [36]. However, as observed in colorectal, non-small cell lung cancer, and pancreatic cancer, the presence and/or intensity of acneiform skin rash have been consistently associated with overall survival improvement in HNSCC [37].
5.3 The Role of Chemotherapy in Definitive Management
5.3.1 Chemotherapy with Concomitant Radiation as Adjuvant Therapy
5.3.1.1 Evidence
Surgery is the main modality of treatment of oral cavity cancer [48]. However, when the disease is locally advanced, the risk of relapse after surgery alone is high and additional treatment is usually indicated. Radiation therapy can eradicate micrometastases, decrease recurrence, and improve survival when offered postoperatively in patients with high-risk disease [49, 50]. The addition of concurrent chemotherapy can augment the effect of radiation, but it is often associated with increased toxicities. Therefore identifying the patients who will derive a significant survival benefit from this approach is crucial. The combined data from two randomized studies, EORTC 22931 and RTOG 9501, defined the risk factors associated with poor outcome that can be overcome by the addition of concomitant chemotherapy to radiation therapy and established the proper criteria for postoperative concurrent chemoradiation [51–53].
|
Hazard ratio for overall survival
|
Primary end point
|
Definition of high risk
|
Percentage of patients with primary in oral cavity (%)
|
Study
|
|---|---|---|---|---|
|
OS was better with combined treatment. p = 0.02 by the log-rank test; hazard ratio for death, 0.70; 95 % confidence interval, 0.52–0.95
|
Progression-free survival
|
Presence of tumor at the surgical section margins (at 5 mm or less), extracapsular extension (ECE) of nodal disease, clinical involvement of lymph nodes at levels 4 or 5 from carcinomas arising in the oral cavity or oropharynx, stage of pT3 or pT4 with any N except T3N0 of the larynx, N 2 or N3, perineural disease, and vascular embolism
|
26
|
EORTC
|
|
Overall survival was not significant (hazard ratio for death, 0.84; 95 % confidence interval, 0.65–1.09; p = 0.19)
|
Locoregional disease control
|
Presence of tumor at the surgical section margins, ECE, and involvement of two or more lymph nodes
|
27
|
RTOG
|
Both studies demonstrated a significant improvement in locoregional control and disease-free or progression-free survival with combined modality therapy. However, the EORTC study showed a significant overall survival improvement, while the RTOG did not. A combined analysis of these two studies identified only ECE or positive margin as the most significant poor prognostic factors, and the addition of cisplatin to radiation improve all aspects of outcome including locoregional control, disease-free/progression-free survival, or overall survival in patients with those two risk factors. These studies provided the base for the risk-adapted strategies in postoperative adjuvant therapy and established ECE and positive margin as the indications for adding concomitant systemic chemotherapy to adjuvant radiation [51].
5.3.1.2 Recommended Regimen
Both EORTC 22931 and RTOG 9501 studies compared the addition of three planned cycles of concomitant cisplatin at 100 mg/m2 every 3 weeks to radiotherapy (60–66 Gy, over 6–6.5 weeks, standard fractionation) with the same radiotherapy alone in patients with high-risk features of oral cavity, oropharynx, larynx, or hypopharynx cancers. Hence concomitant cisplatin at 100 mg/m2 every 3 weeks to radiotherapy on D1, D22, and D43 is the regimen of choice [52, 53]. Other variants of cisplatin dose like weekly administration and daily administration have been studied. It seems that weekly administered cisplatin is better tolerated than 3 weekly cisplatin. In addition patients unfit for weekly cisplatin have shown to have better tolerance to weekly cisplatin [54, 55, 56, 57].
5.3.1.3 Applicability in Oral Cancers
As more than 1/4th of patients in both studies were having oral cavity primary. These results seem applicable at this site.
5.3.1.4 Future Studies
As there is lack of studies dealing with oral cancers alone in this situation, Tata Memorial Hospital, Mumbai, has recently concluded a study called OCAT (oral cancer adjuvant treatment). This study of nearly 900 odd patients will further clarify the adjuvant treatment in oral cancers.
5.3.2 Chemotherapy with Concomitant Radiation as Primary Curative Management in Unresectable Disease
5.3.2.1 Evidence
Although primary surgical management has been widely accepted as the standard approach in treating locally advanced oral cavity cancers, in patients with surgically unresectable disease or patients who are medically inoperable, definitive radiotherapy can be offered as an alternative. When compared with radiation therapy alone, the addition of concurrent chemotherapy to radiation has been shown to be consistently associated with improved survival in patients with locally advanced HNSCC in randomized studies, and meta-analyses, therefore, should be offered to patients with locally advanced disease who are able to tolerate this approach [2, 58–61].
In an intergroup trial reported by Adelstein et al., 271 (oral cavity: 36) patients with unresectable locally advanced head and neck cancer were randomized to one of three arms: radiotherapy alone (70 Gy), concurrent cisplatin (100 mg/m2 days 1, 22, and 43) and radiotherapy (70 Gy), or concurrent cisplatin and 5-fluorouracil (every 4 weeks) with split-course radiotherapy (radiotherapy to 30 Gy, evaluation for surgical respectability, then 30–40 Gy additional radiotherapy if unresectable or complete response). With a median follow-up of 41 months, concurrent cisplatin and radiotherapy without a planned treatment break led to a statistically significant survival benefit comparing with radiation alone (37 % vs. 23 % p = .014) without changing the rate of distant metastases, although more treatment-related toxicities were observed in the concurrent chemotherapy and radiotherapy arms [56].
In the meta-analysis of chemotherapy in head and neck cancer (MACH-NC) of 87 trials, Pignon et al. compared locoregional treatment with or without chemotherapy. The study showed that the addition of chemotherapy to radiotherapy yielded an improvement in survival, with an overall absolute benefit of 4 % at 5 years. There was no significant benefit of adjuvant or neoadjuvant chemotherapy observed; however, a significant benefit of concomitant chemotherapy (absolute benefit at 2 and 5 years of 8 %) was detected [60, 61]. The update of MACH-NC further demonstrated that the benefit of concomitant chemotherapy appears to be similar irrespective of whether the radiotherapy was given conventionally or using altered fractionation. The study also concluded that multi-agent chemotherapy did not provide a significant benefit over single-agent cisplatin in the concurrent setting, although the effect of chemotherapy was significantly higher (p = 0.006) with platinum than other mono-chemotherapy agents, and the magnitude of the benefit of concomitant chemotherapy is less in older patients [2].
In another meta-analysis comparing radiotherapy versus chemoradiation, Budach et al. adopted more strict criteria to exclude the trials using outdated chemotherapy agents or suboptimal radiation schedules. The study also intended to compare different radiation dose and fractionation schedules and chemotherapy regimens used in the chemoradiation trials. A large survival benefit of 12.0 months was observed in favor of concomitant chemoradiation irrespective of whether the radiation was delivered by conventionally fractionated, hyperfractionated, or accelerated schedules [62].
5.3.2.2 Recommended Regimen
On the basis of MACH-NC, single-agent cisplatin seems to be the modality of choice. The dose of cisplatin commonly used is same as the adjuvant CTRT.
In addition to cytotoxic chemotherapy, cetuximab, a monoclonal antibody against the epidermal growth factor receptor, is also associated with improvement in the local regional control (24.4 months vs. 14.9 p = 0.005) and median overall survival (49 months vs. 29.3 p = 0.03) when given with radiation concomitantly as reported by Bonner et al.]. Of note, oral cavity cancer patients were excluded from the study [63].
5.3.2.3 Applicability in Oral Cancers
These results seem to be completely applicable in oral cancers. The trial of Adelstein et al. had only 13 % of patients with oral cancers but MACH-NC analysis had more than 2000 patients of oral cancers included. Further the comprehensive site-specific analysis clearly shows that 5-year absolute benefits associated with the concomitant chemotherapy were 8.9 % in oral cavity cancers.
5.3.3 Chemotherapy as Induction Therapy in Resectable Disease
5.3.3.1 Evidence
Adding induction chemotherapy to standard surgery has also been tested extensively, but has not been proven to be effective in improving survival. In a randomized prospective study focused on oral cavity cancer reported by Licitra et al., patients with a resectable, stage T2–T4 (>3 cm), N0–N2, M0 disease were randomized to surgery with or without induction chemotherapy. Although a high response rate (clinical complete response rate 27 %) was achieved after three cycles of cisplatin and fluorouracil induction treatment, no significant difference in overall survival was detected, and a 55 % 5-year overall survival was observed in both arms. Nevertheless, the patients in the chemotherapy arm needed less segmental mandibulectomy (31 % vs. 52 % in the control group) and postoperative radiotherapy (33 % v 46 %). Since both procedures are associated with poor quality of life, the observation raised the question whether this approach can facilitate organ and function preservation and improvement of posttreatment quality of life [64, 65]. Similar findings of inability of TPF (triple drug) induction chemotherapy to improve survival in resectable oral cancers were published by Zhong et al. In addition NACT would identify a subset of patients who had pathological CR who had very good outcomes. In Licitra et al. publication, patients with either a pathologic complete response or with minimal residual disease had a 5-year disease-free survival rate of 85 % versus 49 % of cases with evident persistent disease (p = .001) [64].
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