Induction chemotherapy for oral cavity cancer patients: Current status and future perspectives

Oral Oncology xxx (2015) xxx–xxx

Contents lists available at ScienceDirect

Oral Oncology journal homepage: www.elsevier.com/locate/oraloncology

Review

Induction chemotherapy for oral cavity cancer patients: Current status and future perspectives Gustavo Nader Marta a,⇑, William N. William Jr. b, Olavo Feher c, André Lopes Carvalho d, Luiz Paulo Kowalski e a

Department of Radiation Oncology, Hospital Sírio-Libanês and Instituto do Câncer do Estado de São Paulo (ICESP), Faculdade de Medicina da Universidade de São Paulo, Brazil Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M.D. Anderson Cancer Center, USA Department of Medical Oncology, Hospital Sírio-Libanês and Instituto do Câncer do Estado de São Paulo (ICESP), Faculdade de Medicina da Universidade de São Paulo, Brazil d Department of Head and Neck Cancer, Hospital do Câncer de Barretos, Fundação Pio XII, Brazil e Department of Head and Neck Surgery and Otorhinolaryngology, A.C. Camargo Cancer Center, Brazil b c

a r t i c l e

i n f o

Article history: Received 7 August 2015 Received in revised form 5 October 2015 Accepted 13 October 2015 Available online xxxx Keywords: Oral cavity Neoplasms Treatment Induction chemotherapy Surgery Radiotherapy

s u m m a r y There is a lack of data from phase III randomized studies to support an ideal approach for locally advanced oral cavity cancer patients. In general, surgery, radiotherapy and chemotherapy are valid treatment options, and combined approach is usually indicated given poor clinical outcomes with single modality therapy. The aim of this study is to review the current status and future perspectives of induction chemotherapy for locally advanced oral cavity cancer patients. Ó 2015 Elsevier Ltd. All rights reserved.

Introduction Global yearly estimates for new oral cavity cancer cases are 263,000, with 127,000 expected deaths related to disease [1]. Most patients have locally advanced disease at the time of diagnoses and tumor presentation is often characterized by local invasion and lymph node involvement [2]. Performance status, patient age and preferences, and tumor features (stage, primary site, operable status) are usually taken into account when designing treatment plans. Extensive data from phase III randomized studies to support an ideal approach for locally advanced oral cavity cancers patients are lacking. Treatment strategies are established based on head and neck clinical trials that mostly included a small proportion of patients with oral cavity cancer. In general, surgery, radiotherapy and chemotherapy [3–5] are valid treatment options. Combined approach is usually

⇑ Corresponding author at: Department of Radiation Oncology, Hospital SírioLibanês, Rua Dona Adma Jafet 91. Sao Paulo, SP 01308-050, Brazil. Tel.: +55 11 33945367; fax: +55 11 31550983. E-mail addresses: [email protected] (G.N. Marta), [email protected] (W.N. William Jr.), [email protected] (O. Feher), [email protected] (A.L. Carvalho), [email protected] (L.P. Kowalski).

indicated given poor clinical outcomes with single modality therapy [6]. Systemic therapy is often integrated into the treatment of head and neck cancer patients. The MACH-NC Collaborative Group meta-analysis recognized concurrent chemoradiation as a standard of care for management of locally advanced head and neck cancer. Concurrent chemoradiation therapy was associated with a statistically significant improvement in overall survival compared to radiation therapy alone (hazard ratio of death: 0.81 [0.78–0.86]). In contrast, induction chemotherapy was associated with a marginal, not statistically significant improvement in survival (hazard ratio of death: 0.96 [0.90–1.02]). Differences in patterns of failure were observed in patients exposed to concomitant chemotherapy and induction chemotherapy strategies: concurrent treatment primarily improved locoregional recurrence and survival; induction treatment improved the rate of distant metastases, with no impact on locoregional control. Nonetheless, the improvements in distant metastases rates were not enough to translate into better overall survival. While these data are not sufficient to support induction chemotherapy as a standard treatment approach, they indicates that some patients may derive benefit from induction approach, especially as locoregional control is optimized and distant metastases become an important cause of death [7].

http://dx.doi.org/10.1016/j.oraloncology.2015.10.009 1368-8375/Ó 2015 Elsevier Ltd. All rights reserved.

Please cite this article in press as: Marta GN et al. Induction chemotherapy for oral cavity cancer patients: Current status and future perspectives. Oral Oncol (2015), http://dx.doi.org/10.1016/j.oraloncology.2015.10.009

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In addition to decreasing the risk of distant metastases, the rationale for induction chemotherapy includes: primary tumor reduction (which could be associated with less toxicities related to subsequent surgery and/or radiotherapy) and the opportunity to evaluate for tumor response and possible adjustments of subsequent therapy as appropriate (a strategy better evaluated so far in laryngeal HNSCC) [8]. As we continue to identify differences in etiology (including contributions of viral infections and tobacco), molecular pathology, prognosis and treatment options within and between the multiple HNSCC subsites, it is important to ascertain the role of each therapeutic modality according to the primary site of the disease. Therefore, the aim of this study is to review the current status and future perspectives of induction chemotherapy specifically for locally advanced oral cavity cancer patients. Induction chemotherapy in non-surgical treatment protocols Primary surgery followed by adjuvant treatment is considered the standard of care for locally advanced oral cavity cancer patients. However, non-surgical treatment might be an alternative option in some patients [9]. Induction chemotherapy (two versus three drugs) followed by (chemo) radiotherapy studies Several studies have assessed the role of induction chemotherapy (two versus three drugs) followed by radiotherapy with or without concurrent chemotherapy for non-surgical management of the patients with locally advanced head and neck cancers. Hitt et al randomized 382 untreated stage III or IVA-B patients to receive three cycles of induction chemotherapy with cisplatin and fluorouracil (PF) or paclitaxel, cisplatin, and fluorouracil (PCF). After induction, patients with a partial (more than 80% reduction of the primary disease) or complete response received chemoradiotherapy (cisplatin – days 1, 22, and 43 – concomitantly with conventional radiotherapy). Complete response rates after induction chemotherapy were significantly higher in the PCF arm (33% PCF versus 14% PF; p < 0.001). No difference in overall survival was observed (43 months PCF versus 37 months PF; p = 0.06) but the median time to treatment relapse was 20 months in the PCF group compared to 12 months in the PF group (p = 0.006). The subset analysis of unresectable patients showed superior outcomes in favor of the PCF arm (overall survival was 36 months in the PCF arm versus 26 months in the PF arm; p = 0.04). In regards to acute toxicity during induction chemotherapy, the PF arm had significantly more mucositis grade 2–4 than the PCF arm (53% PCF versus 16% PF; p < 0.01), whilst alopecia was more frequent in PCF group (10% PCF versus 2% PF; p < 0.01).No other differences in toxicities were seen between the groups [10]. Posner et al. (TAX 324 Study Group) studied 501 patients with stage III or IVA-B tumors (unresectable disease or patients candidates for organ preservation) who received induction chemotherapy (three cycles given every three weeks) with PF or docetaxel, cisplatin and fluorouracil (TPF) followed by chemoradiotherapy (weekly carboplatin concomitantly with radiotherapy). The estimated three-year overall survival was significantly higher in the TPF group (62% TPF versus 48% PF; p = 0.006) as well as the median overall survival (71 months TPF versus 30 months PF; p = 0.006). No differences in distant metastases rates were observed between the two groups. Some adverse events during induction chemotherapy were more frequent in the TPF arm [neutropenia grade 3 or 4 (p < 0.001); febril neutropenia (p = 0.04)] [11]. The update of this study with 5 years of follow up data showed persistent benefits in progression-free survival and overall survival for the TPF group [39].

Likewise, Vermonken et al. (EORTC 24971/TAX 323 Study Group) randomized 358 patients stage III or IV with unresectable disease to receive induction chemotherapy with TPF or PF (four cycles every 3 weeks) followed by radiotherapy. Progression-free survival was significantly higher in the TPF group (11.0 months TPF versus 8.2 months PF; p = 0.007). A decrease in the risk of death was also lower in the TPF arm (overall survival rates at 3 years: 37% TPF compared to 26% PF; p = 0.02). The PF group had more grade 3 or 4 hearing loss, nausea, vomiting, stomatitis, and thrombocytopenia while the TPF group had more grade 3 or 4 neutropenia and leukopenia [12]. After 5 years of follow up, the benefits in progression-free survival and overall survival for TPF group were sustained [13]. A recent meta-analysis of randomized clinical trials in head and neck cancers compared induction chemotherapy with PF or docetaxel/paclitaxel plus PF. The result of this study demonstrated that the use of a three-drug induction chemotherapy regimen resulted in significantly lower locoregional relapses, distant failures, and deaths compared to a two-drug induction regimen [14]. Nonetheless, the majority of relapses occurred at the primary site or in the neck, illustrating the need to develop better strategies for improved locoregional control, particularly for high risk patients. While TAX 323 and TAX 324 showed improved survival for the triple drug arm, and led to the approval of docetaxel by regulatory agencies worldwide for use as part of an induction regimen in locally advanced HNSCC, induction chemotherapy has not been accepted as a standard of care for most patients in routine clinical practice. In both studies, an arm of upfront concurrent chemoradiation was not included. Moreover, the definitive local therapy utilized consisted of either radiation therapy alone (in TAX 323), or concurrent carboplatin and radiation therapy (in TAX 324). These two modalities could be considered an attenuated approach, which may not confer optimal locoregional control. As such, it is unclear whether the benefits in locoregional control and survival observed in the TPF arms would be sustained in the setting of more intense concurrent chemoradiation therapy with cisplatin-based regimens. Additionally, the survival benefits of TAX 323 and TAX 324 may not be applicable to patients who receive surgery as part of their definitive local therapy, given potential differences in locoregional control of surgical versus non-surgical approaches, especially in patients with oral cavity cancers, for which surgical resection is usually recommended as the preferred treatment modality, Table 1 summarizes the characteristics and results of the aforementioned clinical trials (Pointreau et al. [15] included hypopharynx and larynx cancer patients only). It is important to highlight the small percentage of oral cavity cancer patients that were included in these studies. Considering all trials, oral cavity cancer corresponded to only 12.7% of total cases (Graphic 1), raising the question whether the findings are applicable to this particular patient population and underscoring the need for oral cavityspecific induction clinical trials. Induction chemotherapy followed by chemoradiotherapy versus chemoradiotherapy studies In this section, we summarize the results of clinical trials evaluating induction chemotherapy followed by concurrent chemoradiotherapy versus concurrent chemoradiotherapy upfront for management of patients with locally advanced head and neck cancers. Haddad et al. (PARADIGM study) assessed 145 head and neck patients who received TPF induction chemotherapy followed by chemoradiotherapy or concurrent chemoradiotherapy (ChemoRT) upfront. Three-year overall survival was 78% in ChemoRT arm versus 73% TPF plus ChemoRT arm (p = 0.77). Equally, progression-free

Please cite this article in press as: Marta GN et al. Induction chemotherapy for oral cavity cancer patients: Current status and future perspectives. Oral Oncol (2015), http://dx.doi.org/10.1016/j.oraloncology.2015.10.009

22.9 (5 years) 13.5 (5 years) 27.5 (5 years) 18.6 (5 years) 8.5 165 358

Note: IC = Induction chemotherapy; PF = cisplatin, fluorouracil; TPF = docetaxel, cisplatin, fluorouracil; RT = radiotherapy; Chemo = chemotherapy.

6.6 TPF followed by RT PF followed by RT Stage III or IV disease and no distant metastases 63 25

Stage III or IV cancer (no distant metastases) and tumors considered to be unresectable or were candidates for organ preservation 71 90 76 264 501

Posner et al. [11]/ Lorch et al (2011) Vermorken et al. [12]/Vermorken et al. [13]

105

45.5 (5 years) 34.4 (5 years) 42.0 (5 years) 17.0 15.0

52.0 (5 years)

– – 132 382 Hitt et al. [10]

84

116

50

Untreated stage III or IV cancer

PF followed by concurrent ChemoRT (cisplatin) PF followed by concurrent ChemoRT (carboplatin)

Paclitaxel, cisplatin, fluorouracil followed by concurrent ChemoRT (cisplatin) TPF followed by concurrent ChemoRT (carboplatin)

53.6 (2 years) 33.0 14.0

66.5 (2 years)

Arm 2 Arm 1 Arm 1 Arm 2 Arm 1

Arm 2

Overall survival (%) Outcomes Intervation Eligibility criteria Oral cavity Larynx Hypopharynx/ pharynx Oropharynx

Tumor site (n)

Patients (n) Study

Table 1 Induction chemotherapy (two versus three drugs) followed by (chemo)radiotherapy studies.

Arm 1

Arm 2

Complete response after IC (%)

Progression-free survival (%)

G.N. Marta et al. / Oral Oncology xxx (2015) xxx–xxx

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survival was not different between the treatment groups. Induction chemotherapy patients had more febrile neutropenia (23% versus 1%) as well as more serious adverse events than ChemoRT group (52 versus 22) [16]. Cohen et al. (DeCIDE trial) studied 285 N2 or N3 locally advanced squamous cell carcinoma of the head and neck patients who were randomized to TPF induction chemotherapy followed by concurrent chemoradiotherapy (docetaxel, fluorouracil, and hydroxyurea) or upfront concurrent chemoradiotherapy (same regimen). No differences in overall survival, recurrence-free survival, and distant failure free survival between the groups were seen. During induction chemotherapy, myelosuppresion was the most common adverse event (grade P3 neutropenia: 11%; grade P3 absolute neutrophil count: 36%; grade 2 hemoglobin: 26%) and approximately 30% of the patients developed grade P2 mucositis. Serious adverse events were observed more frequently in the induction chemotherapy group (47% versus 28%; p = 0.002) and there were four deaths related to induction chemotherapy toxicity [17]. Both PARADIGM [16] and DeCIDE [17] trials were incapable of accruing to their original target sample size, raising the question whether these studies were appropriately powered to detect modest, yet clinically meaningful, benefits of induction chemotherapy as regards to overall survival. Hitt et al. compared two different induction chemotherapy regimens (tree cycles of TPF or PF) followed by concurrent chemoradiotherapy (cisplatin-based) versus concurrent chemoradiotherapy alone. Four hundred thirty-nine patients were included and no differences in overall survival, progression-free survival and time-to-treatment failure were observed in the three groups. During induction chemotherapy, febrile neutropenia (grade 3–4) was more common in the TPF arm (17% TPF versus 1.9% PF), as well as grade 3–4 leukopenia (15.7% TPF versus 3.9% PF). Thirteen patients died due to treatment toxicity (7 in TPF arm; 4 in PF arm; 2 in ChemoRT) [18]. The GSTTC Italian Study Group reported the results of a multicenter 2  2 factorial study involving 415 patients with locally advanced head and neck cancer. Patients were randomized to four different treatment groups: Group G1: concurrent chemoradiotherapy (two cycles of cisplatin/5-fluorouracil concomitant with radiotherapy); Group G2: concurrent cetuximab and radiotherapy; Group G3: induction chemotherapy (3 cycles of TPF) followed by concurrent chemoradiotherapy (same regime); Group G4: induction chemotherapy (3 cycles of TPF) followed by concurrent cetuximab and radiotherapy. After a median follow-up of 41.3 months, induction chemotherapy was associated with improvement of 3-year progression free survival (46.8% versus 36.7% – HR: 0.73; 95%CI 0.57–0.94; p = 0.015) and 3-year overall survival (57.6% versus 45.7% – HR:0.72; 95%CI 0.55–0.96; p = 0.025). Induction

Graphic 1. Included oral cavity cancer patients in induction chemotherapy (two versus three drugs) followed by (chemo)radiotherapy studies.

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Study

Patients (n)

Tumor site (n) Oropharynx

Pharynx

Larynx

Oral cavity

Eligibility criteria

Haddad et al. [16]

145

80

15

24

26

Cohen et al. [17]

273

159

–

37

39

Hitt et al. [18]

439

187

78

81

93

Ghi et al. [19]

415

234

97

82

Other

38

2

Intervation

Overall survival

Arm 1

Arm 2

Arm 3

Arm 4

Arm 1

Arm 2

Arm 3

Arm 4

Unresectable or low surgical curability (advanced tumor stage 3 or 4 or regional-node stage 2 or 3, except T1N2), or candidates for organ preservation Untreated nonmetastatic N2 or N3

Concurrent ChemoRT (cisplatin)

–

–

78% (3 years)

73% (3 years)

–

–

–

–

31% (Mortality rates)

28% (Mortality rates)

–

–

Untreated,unresectable, nonmetastatic stage III or IV patients

Concurrent ChemoRT (cisplatin)

TPF followed by concurrent ChemoRT (docetaxel or carboplatin) TPF followed by concurrent ChemoRT (docetaxel, 5-FU, HYD) PF followed by concurrent ChemoRT (cisplatin)

27.2 months

26.6 months

26.6 months

Concurrent ChemoRT (cisplatin/ 5-FU)

TPF followed by concurrent ChemoRT (cisplatin) TPF followed by concurent CET and RT

27.0 months

Unresectable, stage III–IV, ECOG PS 0–1 patients

TPF followed by concurrent ChemoRT (cisplatin) TPF followed by concurrent ChemoRT (cisplatin/ 5-FU)

Concurrent ChemoRT (docetaxel, 5-FU, HYD)

Concurent CET and RT

45.7% (3 years)

57.6% (3 years)

Note: IC = Induction chemotherapy; PF = cisplatin, fluorouracil; TPF = docetaxel, cisplatin, fluorouracil; ChemoRT = chemoradiotherapy; RT = radiotherapy; HYD = hydroxyurea; 5-FU = 5-fluorouracil; CET = cetuximab.

G.N. Marta et al. / Oral Oncology xxx (2015) xxx–xxx

Please cite this article in press as: Marta GN et al. Induction chemotherapy for oral cavity cancer patients: Current status and future perspectives. Oral Oncol (2015), http://dx.doi.org/10.1016/j.oraloncology.2015.10.009

Table 2 Induction chemotherapy followed by chemoradiotherapy versus chemoradiotherapy studies.

G.N. Marta et al. / Oral Oncology xxx (2015) xxx–xxx

Graphic 2. Included oral cavity cancer patients in induction chemotherapy followed by chemoradiotherapy versus chemoradiotherapy studies.

chemotherapy did not compromise the ability to deliver concomitant treatment. In both induction and concomitant groups, around 30% of patients needed to interrupt radiotherapy for more than three consecutive days. The 2  2 factorial study design, and the frequent radiation treatment interruptions in both the induction and non-induction arms are limitations of this study may not allow us to readily adopt induction chemotherapy into clinical routine [19]. Table 2 summarizes the characteristics and results of clinical trials. Again, it is important to highlight that the percentage of oral cavity cancer patients included in the studies was small. Considering all trials, oral cavity cancer corresponds to only 18.8% of the total patients (Graphic 2).

Induction chemotherapy in surgical treatment protocols for oral cavity cancers Surgical resection is considered one of the most important treatment modalities for oral cavity cancer since prospective and retrospective data demonstrate significant increase in survival among surgically treated patients. Currently, it is largely acceptable that non-surgical protocols should be limited for unresectable and/or inoperable patients [20,21]. Two published phase III randomized trials evaluated the role of induction chemotherapy followed by surgery with or without postoperative radiotherapy exclusively in patients with advanced oral cavity cancers. Licitra et al. assessed 195 patients who received induction chemotherapy (three cycles of PF) followed by surgery versus surgery alone. High-risk patients [positive resection margins, extracapsular nodal spread, nodal disease (N2 or N3), vascular invasion, or perineural invasion] underwent adjuvant radiotherapy (postoperative radiotherapy was delivered in 46 patients in the control group versus 33 patients in the induction chemotherapy group). No differences in 5-year overall survival, local–regional relapse and distant relapse were demonstrated. Patients that did not receive induction chemotherapy had more frequent mandible resections than the group that did not receive induction chemotherapy (31% versus 52%). During induction chemotherapy, 37% of patients had severe toxicity (grade 3–4) and three deaths related to treatment were documented [22]. An update of this study with a median follow-up of 11.5 years showed similar results in regards to clinical outcomes [23]. Zhong et al. randomized 256 patients to receive two cycles of TPF induction chemotherapy followed by surgery or surgery alone. In both arms, all patients underwent postoperative radiotherapy. The median follow-up was 30 months and no differences in overall

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survival, disease-free survival and locoregional recurrence were observed in the groups. Patients that had a favorable pathologic response or a clinical response after induction chemotherapy had better clinical outcomes (locoregional control, distant control and overall survival). Most patients had grade 1–2 adverse events during induction chemotherapy. Grade 3 events such as hematologic toxicity, febrile neutropenia and diarrhea were low and occurred in 6.6%, 1.6%, 0.8% of the patients, respectively. No grade 4 toxicity was reported [24]. The meta-analysis of these studies demonstrated that induction chemotherapy when prescribed before surgery did not improve clinical outcomes (loco-regional recurrence, disease-free survival and overall survival) in patients with oral cavity cancer. An analysis of individual data from 84 patients with cN2 showed statistically significant overall survival benefit in favor of induction chemotherapy group, with no differences in other endpoints (loco-regional control and disease-free survival). These results must be cautiously interpreted due to the small number patients with cN2 evaluated as well as due to the limit number of events associated with the measured clinical outcomes [25].

Discussion For patients with advanced oral cavity cancers, surgery frequently involves mandibulectomy that is often related to substantial functional damage, probably negatively impacting the quality of life. Moreover, postoperative radiotherapy can contribute to adverse functional concerns and it is also associated with increased risk of ischemic stroke [26]. Hence, a less aggressive local management may make it possible to take clinical benefits for the oral cavity cancer patients. In this context, the inclusion of induction chemotherapy in the treatment strategy could be applicable, especially for patients with locally advanced disease. Regarding induction chemotherapy in non-surgical treatment protocols, the first published studies assessed the role of induction chemotherapy (two versus three drugs) followed by (chemo)radiotherapy for locally advanced head and neck cancer. The results of these studies [10–12], which were confirmed by a meta-analysis, showed that the best induction chemotherapy approach should involve three drugs (taxane plus PF). In other words, patients who undergo taxane plus PF induction chemotherapy have better overall survival than patients that receive PF induction chemotherapy. In addition, it is important to mention that no initial trials did directly compare induction chemotherapy with a specific arm of concurrent chemoradiotherapy upfront [7]. Afterwards, three studies [16,18,27] assessed the role of induction chemotherapy followed by concurrent chemoradiotherapy and compared to concurrent chemoradiotherapy alone for locally advanced head and neck cancer. Induction chemotherapy was not related to overall survival benefits. Even for N2/N3 patients only (DeCIDE trial) [27], who are more likely to develop distant metastasis, induction chemotherapy did not improve survival and locoregional recurrence. Nevertheless, a statistically significant difference in favor of induction chemotherapy strategy was seen as regards to incidence of distant recurrence in patients that did not have prior locoregional recurrence (p = 0.043). Thus, perhaps patients with higher risk of distant metastases may benefit from induction, if they achieve adequate locoregional control. The N2/N3 selection of DeCIDE trial is not very useful if a lot of oropharynx and Human papillomavirus (HPV) positive patients were included, for which the staging system does not work very well [28]. Only one unpublished study (Italian Study) [19] demonstrated that induction chemotherapy significantly improved overall sur-

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Table 3 Induction chemotherapy followed by surgery or surgery alone with or without postoperative radiotherapy studies. Study

Licitra et al. [22]/Bossi et al. [23] Zhong et al. [24]

Patients (n)

195

256

Eligibility criteria

Intervation

Outcomes

Arm 1

Resectable, stage T2-T4, N0-N2, M0, previously untreated oral cavity squamous cell carcinoma III or IVA locally advanced resectable oral squamous cell carcinoma

Arm 2

PF followed by surgery and postoperative RT for highrisk patients TPF followed by radical surgery and postoperative RT

Surgery and postoperative RT for high-risk patients Radical surgery and postoperative RT

Complete response after IC (%)

Overall survival (%)

Arm 1

Arm 2

Arm 1

Arm 2

27.0

–

46.5 (10 years)

37.7 (10 years)

8.1

–

68.8 (2 years)

68.2 (2 years)

Note: IC = Induction chemotherapy; PF = cisplatin, fluorouracil; TPF = docetaxel, cisplatin, fluorouracil; RT = radiotherapy.

vival, and further analysis on this study as regards to patterns of failure and HPV status are eagerly awaited to adequately place it in context with the current knowledge on management of locally advanced HNSCC. Apart from chemotherapy seeming to be unable to improve survival, there is an underrepresented population of oral cavity cancer patients in induction chemotherapy non-surgical treatment protocols studies (Graphics 1 and 2). This fact emphasizes that this specific subset of patients was not robustly assessed. Regarding induction chemotherapy in surgical treatment protocols, just two small trials [22–24] evaluated oral cavity cancer only and they did not support the use of induction chemotherapy before surgery with or without postoperative radiotherapy. Again, no overall survival benefit was observed in induction chemotherapy group (Table 3). Although both trials fail to demonstrate a survival improvement, there could be a subset of patients who may benefit from induction chemotherapy strategy. Zhong et al. [24] showed in exploratory analysis that cN2 patients had a survival benefit after TPF induction. Other advantages described in the Italian study [22,23] are the reduction of the number of patients that needed to receive mandibulectomy and postoperative radiotherapy indicating that induction chemotherapy could be used as a conductor for less aggressive local management for oral cavity cancer patients. Based on available studies, induction chemotherapy should not be routinely used for the treatment of locally advanced oral cavity cancer. However, the role of induction chemotherapy is still an issue that needs to be better understood, particularly for the subset of oral cavity cancer patients. Upcoming studies must focus on the recognizable genomic characterization of head and neck cancer [29] and biomarker features associated with response to induction chemotherapy especially for patients with oral cavity cancer. Thus, it will be possible to completely exploit the role of induction chemotherapy regimens and offer them to chemosensitive patients in order to avoid unnecessary treatment costs and toxicities in unresponsive ones. Evaluation of biomolecular markers such as p53 gene mutations can be one strategy since there is some evidence correlating them with lower response to induction chemotherapy. The loss of transactivation activities of p53 mutant proteins might be associated with a significant low pathologic complete remission rate and suboptimal response to cisplatin-based induction chemotherapy [30,31]. Other biomarkers can also be validated as promising predictive factors of treatment response and may support new future induction chemotherapy studies [32–34]. Yang et al. assessed immunohistochemical staining for growth differentiation factor 15 (GDF15)

in pretreatment biopsy samplings of most patients that were included in Zhong trial [24]. Patients with positive lymph nodes and low GDF15 expression benefitted from induction chemotherapy in terms of distant metastasis-free survival (p = 0.039) and overall survival (p = 0.039). Better locoregional recurrence-free survival (p = 0.035), distant metastasis-free survival (p = 0.009), disease-free survival (p = 0.011) and overall survival (p = 0.019) were observed in patients with negative lymph nodes and high GDF15 expression who received induction chemotherapy. They also found that overexpression of GDF15 was significantly correlated to migration, invasion, promoted cell proliferation and colony formation through decreased phosphorylation of ERK1/2 and AKT [35]. The same group using the same patients’ data evaluated the role of Cyclin D1 and Annexin A1 expressions as predictive for benefit from induction chemotherapy. When compared with the group treated with surgery upfront, patients with high Cyclin D1 expression and nodal stage cN2 who underwent induction chemotherapy had significantly superior distant metastasis-free survival (p = 0.025) and overall survival (p = 0.025). Likewise, patients with low Annexin A1 expression and poorly or moderate differentiated cancer benefited from induction chemotherapy strategy measured by clinical outcomes (distant metastasis-free survival [p = 0.048]; overall survival [p = 0.078]) [36,37]. Assessing pretherapy biopsy specimens of 265 TAX 324 patients, correlations between tumor markers expression and survival were performed. Higher expression of beta tubulin II is intensely related to worse outcome in locally advanced head and neck tumor patients who received induction chemotherapy pointing that low expression of beta tubulin II might help to select patients most likely to experience benefit from induction chemotherapy approach [34]. Another important approach that should be strongly considered is immunotherapy for head and neck cancer. Several tumors are correlated to insufficiencies in the human immune system that can be linked to the initiation and development of carcinogenesis. Many effects such as higher tumor associated macrophages, higher immunosuppressive regulatory T cells, lower absolute lymphocyte counts, down-regulation of tumor leukocyte antigen expression, damaged natural killer (NK) activity and poor antigen-presenting function have been recognized in patients with head and neck cancer [38]. Future studies may involve immunotherapeutic strategies in combination with other classical treatments to get better clinical outcomes. Conflict of interest None declared.

Please cite this article in press as: Marta GN et al. Induction chemotherapy for oral cavity cancer patients: Current status and future perspectives. Oral Oncol (2015), http://dx.doi.org/10.1016/j.oraloncology.2015.10.009

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Please cite this article in press as: Marta GN et al. Induction chemotherapy for oral cavity cancer patients: Current status and future perspectives. Oral Oncol (2015), http://dx.doi.org/10.1016/j.oraloncology.2015.10.009