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Induction chemotherapy prior to surgery with or without postoperative radiotherapy for oral cavity cancer patients: Systematic review and meta-analysis
European Journal of Cancer (2015) xxx, xxx– xxx
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Induction chemotherapy prior to surgery with or without postoperative radiotherapy for oral cavity cancer patients: Systematic review and meta-analysis Gustavo N. Marta a,⇑, Rachel Riera b, Paolo Bossi c, Lai-ping Zhong d, Lisa Licitra c, Cristiane R. Macedo e, Gilberto de Castro Junior f, Andre´ L. Carvalho g, William N. William Jr. h, Luis Paulo Kowalski i a
Department of Radiation Oncology, Hospital Sı´rio-Libaneˆs and Instituto do Caˆncer do Estado de Sa˜o Paulo – Faculdade de Medicina da Universidade de Sa˜o Paulo, Sa˜o Paulo, Brazil b Brazilian Cochrane Center and Discipline of Emergency Medicine and Evidence–Based Medicine Universidade Federal de Sa˜o Paulo – Escola Paulista de Medicina (UNIFESP–PM), Sa˜o Paulo, Brazil c Head and Neck Cancer Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy d Department of Oral & Maxillofacial-Head & Neck Oncology, Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, China e Brazilian Cochrane Center and Post Graduation Program of Internal Medicine Universidade Federal de Sa˜o Paulo (UNIFESP), Sa˜o Paulo, Brazil f Department of Clinical Oncology, Hospital Sı´rio-Libaneˆs and Instituto do Caˆncer do Estado de Sa˜o Paulo – Faculdade de Medicina da Universidade de Sa˜o Paulo, Sa˜o Paulo, Brazil g Department of Head and Neck Cancer, Hospital do Caˆncer de Barretos – Fundac¸a˜o Pio XII, Sa˜o Paulo, Brazil h Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, USA i Department of Head and Neck Surgery and Otorhinolaryngology, AC. Camargo Cancer Center, Sa˜o Paulo, Brazil Received 6 August 2015; accepted 12 August 2015
KEYWORDS Oral cavity Neoplasms Induction chemotherapy Surgery Radiotherapy
Abstract Background: Locoregionally advanced oral cavity cancers are aggressive tumours with high risk of relapse after definitive treatment. This study was performed to assess the effectiveness and safety of induction chemotherapy prior to surgery for untreated oral cavity cancer patients. Material and methods: Only prospective phase III randomised studies comparing induction chemotherapy followed by surgery with or without postoperative radiotherapy (Chemo
⇑
Corresponding author at: Hospital Sı´rio-Libaneˆs – Department of Radiation Oncology, Rua Dona Adma Jafet 91, Sao Paulo-SP 01308-050, Brazil. Tel.: +55 11 31550558; fax: +55 11 31550983. E-mail addresses: [email protected] (G.N. Marta), [email protected] (R. Riera), [email protected] (P. Bossi), [email protected] (L.-p. Zhong), [email protected] (L. Licitra), [email protected] (C.R. Macedo), [email protected] (G. de Castro Junior), [email protected] (A.L. Carvalho), [email protected] (W.N. William Jr.), [email protected] (L.P. Kowalski). http://dx.doi.org/10.1016/j.ejca.2015.08.007 0959-8049/Ó 2015 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Marta G.N. et al., Induction chemotherapy prior to surgery with or without postoperative radiotherapy for oral cavity cancer patients: Systematic review and meta-analysis, Eur J Cancer (2015), http://dx.doi.org/10.1016/j.ejca.2015.08.007
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Prognosis Survival Treatment
Group) compared with surgery with or without postoperative radiotherapy (Control Group) were eligible. Two of the authors independently selected and assessed the studies regarding eligibility criteria and risk of bias. Results: Two studies were selected. A total of 451 patients were randomly assigned to Chemo Group (n = 226) versus Control Group (n = 225). Most patients had tumours at clinical stages III/IV (89.1%). Both trials were classified as having low risk of bias. No significant overall benefit in favour of induction chemotherapy was found regarding loco-regional recurrence, disease-free survival and overall survival. A subgroup analysis of individual data from cN2 patients showed statistically significant overall survival benefit in favour of induction chemotherapy. The included studies did not directly compare toxicity between the groups and no statistical analysis was performed regarding safety outcomes. Conclusions: Based on the available studies, induction chemotherapy when administered before surgery with curative intent did not improve clinical outcomes in locoregionally advanced oral cavity cancer patients. Clinically assessed N2 patients might benefit from induction chemotherapy. Ó 2015 Elsevier Ltd. All rights reserved.
1. Introduction Squamous cell carcinoma is the most common cancer that occurs in the oral cavity, with an estimated 300,000 new cases worldwide each year [1–3]. Locoregionally advanced oral cavity cancers are aggressive tumours with elevated probabilities of relapse after definitive treatment with surgery or radiotherapy (RT). Therefore, a multimodal approach combining surgery and postoperative radiotherapy or chemoradiotherapy has been proposed [4]. There are insufficient reports from phase III prospective randomised clinical studies to show an ideal approach for patients with locally advanced oral cavity malignancies. Guidelines and treatment options are based upon studies that included a majority of patients with primary cancers at other head and neck sites and also retrospective data. In general, the primary therapy for locally advanced oral cavity squamous cell carcinoma (SCC) usually involves surgery followed by radiotherapy and chemotherapy (in the setting of high-risk pathological features such as positive resection margins, and extracapsular nodal spread). Upfront chemoradiation is an option for patients who decline surgery, have unresectable tumour and/or are medically inoperable [5]. Nevertheless, overall survival and tumour control are disappointing, because approximately 50% of the patients will die after 5 years from diagnosis, due to local and/or systemic recurrences [6]. Although improvement in surgical techniques and use of adjuvant treatments have been observed, the 5-year survival rate has not improved considerably in recent years, persisting at 55% [7,8]. New treatment strategies for locally advanced oral cavity SCC have been tested, including preoperative chemotherapy. Induction chemotherapy might reduce tumour burden, ameliorate tumour-related symptoms
and improve surgical results. Moreover, induction chemotherapy could treat micrometastatic disease early on, potentially leading to improved overall clinical outcomes [9]. This study was performed to assess the effectiveness and safety of induction chemotherapy prior to surgery for untreated oral cavity SCC patients. 2. Materials and methods 2.1. Study design This was a systematic review carried out in accordance with The Cochrane Collaboration Handbook of Interventions Systematic Reviews [10]. The manuscript was arranged using the PRISMA Statement as reporting guidance [11]. 2.2. Criteria for considering studies for this review We included trials that assessed any induction chemotherapy strategy followed by surgery with or without postoperative radiotherapy compared with surgery with or without postoperative radiotherapy. Only randomised controlled trials were considered. Cluster or crossover designs were excluded. Oral cavity SCC patients (any age) who had not received prior treatment were eligible. The main outcome measures were overall survival (OS), local control (LC) and toxicity as assessed at any time point after the interventions. At least one of these three outcomes should have been assessed and reported in the trial to be included in the present analysis. 2.3. Search methods for identifying studies The electronic search was conducted with no language, publication year or publication status
Please cite this article in press as: Marta G.N. et al., Induction chemotherapy prior to surgery with or without postoperative radiotherapy for oral cavity cancer patients: Systematic review and meta-analysis, Eur J Cancer (2015), http://dx.doi.org/10.1016/j.ejca.2015.08.007
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restrictions. We searched the following databases: Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2014, Issue 10), MEDLINE via Ovid (1966 to January 2015), EMBASE via Elsevier (1980 to January 2015) and LILACS via Biblioteca Virtual em Sau´de (1982 to January 2015). We also screened the reference lists of relevant studies. In addition, we performed a search for ongoing and/or unpublished trials on The US National Institutes of Health Ongoing Trials Register (www.clinicaltrials. gov). 2.4. Selection of studies The abstracts of retrieved studies were assessed and selected by two reviewers (independently) considering their probability to be included. After that, the full text of selected studies was evaluated regarding their eligibility criteria by two reviewers (GNM and RR). Disagreements between them were solved by a third reviewer (LPK). 2.5. Methodological quality assessment The risk of bias of the included studies was assessed in accordance with the Cochrane Handbook for Systematic Reviews of Interventions [10] and was carried out by two reviewers (GNM and RR) independently. When necessary, a third reviewer (LPK) solved disagreements. The studies were considered to have high, unclear or low risk of bias according to an assessment of the following items: generation of allocation sequences, allocation concealment, blinding of participants and personnel (performance bias), blinding of outcome assessment (detection bias), incomplete data addressed, presence of biases in reports and other sources of bias that might influence the study’s validity.
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2.7. Assessment of heterogeneity When appropriate, heterogeneity was assessed using the chi-squared (Chi2) statistic (p value less than 0.1). We also used the I2 statistic to assess the variation across studies due to heterogeneity rather than chance. I2 values greater than 50% were considered substantial heterogeneity [10]. 3. Results 3.1. Study selection and characteristics of the included studies The flowchart of the retrieved studies and the characteristics of included studies are presented in Fig. 1 and Table 1, respectively. Three papers, reporting two studies fulfilled the eligibility criteria (Bossi et al. [12], Licitra et al. [13], Zhong et al. [14]). 451 patients were randomly assigned to induction chemotherapy followed by surgery with or without radiotherapy (n = 226), versus surgery with or without radiotherapy (n = 225). Most of the patients were male (75.8%); tumours at clinical stages III/IV comprised 89.1% of the patients.
Total citations n = 4397
Excluded n =4295
2.6. Measures of treatment effect Dichotomous outcomes were summarised as risk ratios (RRs) and continuous outcomes as mean differences (MD). The size effect of the intervention for timeto-event outcomes was calculated by the pooled hazard ratio (HR), followed by the confidence interval (CI) of 95%, from the Peto’s method of fixed effect. The HR calculation was performed after imputation of the derivative of expected events (O–E) and log-rank variance (V) for each included study. For determining O–E, the Z-Score for two-tailed p-value was calculated based on relative risk of each study. A confidence interval of 95% was assumed for all analysis. When the data were not available for HR calculation, RR was used instead. For the meta-analysis, the fixed model effect was used, except when substantial heterogeneity was found. In this case, random effect was applied.
Selected for full text reading n = 102
Excluded n =99
Included studies n = 2 (3 publications) Fig. 1. Flowchart of the process of study selection.
Please cite this article in press as: Marta G.N. et al., Induction chemotherapy prior to surgery with or without postoperative radiotherapy for oral cavity cancer patients: Systematic review and meta-analysis, Eur J Cancer (2015), http://dx.doi.org/10.1016/j.ejca.2015.08.007
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Table 1 Characteristics of included studies.
Total (n) Chemotherapy arm Control arm Sex n – (%) Male Female Mean age (years) Chemotherapy arm Control arm Tumour site n – (%) Tongue Floor of mouth Gingiva Retromolar trigone Palate Buccal Staging system
Bossi et al./Licitra et al.
Zhong et al.
195 98
256 128
97
128
163 (83.6%) 32 (16.4%)
179 (69.9%) 77 (30.1%)
55
55
55
56
84 56 26 29
(43.1%) (28.8%) (13.3%) (14.8%)
113 (44.1%) 30 (11.7%) 40 (15.7%) 10 (3.9%)
0 0 UICC TNM classification of malignant tumours 4th edition (1987)
18 (7.0%) 45 (17.6%) UICC TNM classification of malignant tumours 6th edition (2002)
T stage n – (%) T1 – T2 80 (41%) T3 77 (39.5%) T4 38 (19.5%) N stage n – (%) N0 111 (56.9%) N1 52 (26.7%) N2 32 (16.4%) Stage grouping n – (%) II 49 (25.1%) III 86 (44.1%) IV 60 (30.8%) Eligibility criteria Biopsy-proven, resectable, stage T2–T4, N0–N2, M0, previously untreated oral cavity squamous cell carcinoma Intervention – Cisplatin 100 mg/m2 and fluorouracil 1000 mg/m2, given as a 120-h infusion, for three cycles every 21 days followed by surgery (chemotherapy arm). Patients received the third chemotherapy cycle only if a partial response was observed – Surgery alone In both arms, postoperative radiotherapy (45–65 Gy) was reserved to high-risk patients, and surgery was modulated depending on the tumour’s closeness to the mandible Outcomes Overall survival, loco-regional relapse, distant metastasis, complete pathological response, complete clinical response, adverse events, mortality
3.2. Methodological quality of studies The methodological quality of the included studies, assessed independently by two observers, is presented in Supplementary Material 1 and 2. Overall, and in accordance with the Cochrane risk of bias table [10], both studies were classified as having a low-risk of bias. 3.3. Results for effectiveness outcomes 3.3.1. Loco-regional relapse Data regarding loco-regional relapse were available in both studies. Meta-analysis of two trials did not show
9 (3.5%) 57 (22.2%) 149 (58.2%) 41 (16.1%) 110 (43%) 94 (36.7%) 52 (20.3%) – 177 (69.1%) 79 (30.9%) III or IVA locally advanced resectable oral squamous cell carcinoma – Two cycles of TPF induction chemotherapy (docetaxel 75 mg/m2 on day 1, cisplatin 75 mg/m2 on day 1 and fluorouracil 750 mg/m2 on days 1–5) followed by radical surgery and postoperative radiotherapy (54–66 Gy) – Up-front radical surgery and postoperative radiotherapy
Overall survival, local control, safety
significant benefit in the induction chemotherapy group compared to the control group (2-year loco-regional relapse/heterogeneity: Chi2 = 0.14, df = 1 (p = 0.71); I2 = 0%; test for overall effect: Z = 0.13 [p = 0.90]). (Fig. 2). 3.3.2. Disease-free survival Fig. 3 shows data regarding disease-free survival. A non-significant increase in disease-free survival favouring the chemotherapy group was observed (2-year disease-free survival/ heterogeneity: Chi2 = 0.64, df = 1 (p = 0.42); I2 = 0%; test for overall effect: Z = 0.52 [p = 0.60]).
Please cite this article in press as: Marta G.N. et al., Induction chemotherapy prior to surgery with or without postoperative radiotherapy for oral cavity cancer patients: Systematic review and meta-analysis, Eur J Cancer (2015), http://dx.doi.org/10.1016/j.ejca.2015.08.007
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3.3.3. Overall survival Meta-analysis of two studies did not demonstrate a significant benefit in the induction chemotherapy group versus the control group (2-year overall survival/heterogeneity: Chi2 = 0.08, df = 1 (p = 0.78); I2 = 0%; test for overall effect: Z = 0.07 [p = 0.94]). (Fig. 4).
3.3.5. Results for safety outcomes Included studies did not directly compare toxicity and quality of life rates between the groups, and no statistical analysis was performed regarding safety outcomes. The toxicities were reported by Common Terminology Criteria for Adverse Events (version 3.0) [14] and World Health Organisation Classification [12,13]. Licitra et al. [13]/Bossi et al. [12] demonstrated 37% severe toxicity (grade 3 or 4) and three deaths related to induction chemotherapy. Zhong et al. [14] did not observe any grade IV adverse events and no chemotherapy related deaths occurred (Supplementary Material 3). Long term toxicities are reported in Bossi et al. [12].
3.3.4. cN2 subgroup analysis A subgroup analysis of individual data from cN2 patients was performed. In total, 84 patients were cN2. Meta-analysis of two studies did not demonstrate a significant benefit in the induction chemotherapy group versus control group as regards to loco-regional relapse (2-year loco-regional relapse/heterogeneity: Chi2 = 0.01, df = 1 [p = 0.90]; I2 = 0%; test for overall effect: Z = 1.54 [p = 0.12]) – Fig. 5 – and disease-free survival (2-year disease-free survival/heterogeneity: Chi2 = 0.01, df = 1 [p = 0.90]; I2 = 0%; test for overall effect: Z = 1.54 [p = 0.12]) – Fig. 6. However, statistically significant overall survival benefit in favour of induction chemotherapy was observed (2-year overall survival/ heterogeneity: Chi2 = 0.05, df = 1 [p = 0.82]; I2 = 0%; test for overall effect: Z = 2 [p = 0.04]) – Fig. 7. Chemotherapy Study or Subgroup
Events
5
4. Discussion Standard management for advanced oral cavity SCC comprises a multidisciplinary approach including surgery and postoperative radiotherapy associated or not with chemotherapy. Despite technical improvements in the involved therapeutic modalities [15–17], long-term overall survival and tumour control are still unsatisfactory [8,9].
Control
Risk Ratio
Total Events Total Weight
Risk Ratio M-H, Fixed, 95% CI
M-H, Fixed, 95% CI
1.1.1 2-years Bossi 2014 - Licitra 2003
25
98
27
97
41.0%
Zhong 2013
40
128
39
128
59.0%
1.03 [0.71, 1.48]
225 100.0%
0.98 [0.74, 1.31]
226
Subtotal (95% CI) Total events
0.92 [0.58, 1.46]
66
65
Heterogeneity: Chi² = 0.14, df = 1 (P = 0.71); I² = 0% Test for overall effect: Z = 0.13 (P = 0.90)
0.01
0.1
1
Favours Chemotherapy
10
100
Favours Control
Test for subgroup differences: Not applicable
Fig. 2. Forest plot of comparison: Chemotherapy Control (no chemotherapy). Outcome: loco-regional relapses.
Chemotherapy Study or Subgroup
Events
Control
Risk Ratio
Total Events Total Weight
Risk Ratio
M-H, Fixed, 95% CI
M-H, Fixed, 95% CI
4.1.1 2-years Bossi 2014 - Licitra 2003
63
98
56
97
41.0%
Zhong 2013
80
128
81
128
59.0%
0.99 [0.82, 1.19]
225 100.0%
1.04 [0.90, 1.20]
Subtotal (95% CI) Total events
226 143
1.11 [0.89, 1.39]
137
Heterogeneity: Chi² = 0.64, df = 1 (P = 0.42); I² = 0% Test for overall effect: Z = 0.52 (P = 0.60)
0.1 0.2
0.5
1
2
5
10
Favours control Favours chemotheray
Fig. 3. Forest plot of comparison: Chemotherapy Control (no chemotherapy). Outcome: disease-free survival.
Please cite this article in press as: Marta G.N. et al., Induction chemotherapy prior to surgery with or without postoperative radiotherapy for oral cavity cancer patients: Systematic review and meta-analysis, Eur J Cancer (2015), http://dx.doi.org/10.1016/j.ejca.2015.08.007
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Chemotherapy Study or Subgroup
Events
Control
Risk Ratio
Total Events Total Weight
Risk Ratio
M-H, Fixed, 95% CI
M-H, Fixed, 95% CI
3.1.1 2-years Bossi 2014 - Licitra 2003
66
98
67
Zhong 2013 Subtotal (95% CI)
88
128 226
87
Total events
154
43.6%
0.98 [0.80, 1.18]
128 56.4% 225 100.0%
97
1.01 [0.86, 1.19] 1.00 [0.88, 1.13]
154
Heterogeneity: Chi² = 0.08, df = 1 (P = 0.78); I² = 0% Test for overall effect: Z = 0.07 (P = 0.94)
0.01
0.1 1 10 100 Favours control Favours chemotherapy
Fig. 4. Forest plot of comparison: Chemotherapy Control (no chemotherapy). Outcome: overall survival.
Control Chemotherapy Study or Subgroup Bossi 2014 /Licitra 2003 Zhong 2013
log[Hazard Ratio]
Hazard Ratio
Total Weight
Hazard Ratio
IV, Fixed, 95% CI
SE
Total
-0.3366 2.1307
16
16
-0.596 0.3891
25
27
96.8%
0.55 [0.26, 1.18]
41
43 100.0%
0.56 [0.26, 1.18]
Total (95% CI)
IV, Fixed, 95% CI
3.2% 0.71 [0.01, 46.50]
Heterogeneity: Chi² = 0.01, df = 1 (P = 0.90); I² = 0% 0.002 Test for overall effect: Z = 1.54 (P = 0.12)
0.1
1
Favours Chemotherapy
10
500
Favours Control
Fig. 5. Forest plot of comparison: Chemotherapy Control (no chemotherapy). Outcome: loco-regional relapses for cN2 patients.
Control Chemotherapy Study or Subgroup
log[Hazard Ratio]
Hazard Ratio
Hazard Ratio
SE
Total
Bossi 2014 /Licitra 2003
-0.337 2.1401
16
16
Zhong 2013
-0.596 0.3891
25
27
96.8%
0.55 [0.26, 1.18]
41
43 100.0%
0.56 [0.26, 1.18]
Total (95% CI)
Total Weight
IV, Fixed, 95% CI
IV, Fixed, 95% CI
3.2% 0.71 [0.01, 47.35]
Heterogeneity: Chi² = 0.01, df = 1 (P = 0.91); I² = 0% 0.001 Test for overall effect: Z = 1.54 (P = 0.12)
0.1
Favours Chemotherapy
1
10
1000
Favours Control
Fig. 6. Forest plot of comparison: Chemotherapy Control (no chemotherapy). Outcome: disease-free survival for cN2 patients.
The use of chemotherapy in advanced head and neck SCC has shown a significant advantage in terms of overall survival, when delivered concurrently with radiotherapy [18]. Nonetheless, the role of induction chemotherapy strategy in head and neck SCC has been extensively discussed, with conflicting results [19]. Induction chemotherapy, as a treatment before surgery and/or radiotherapy, is an attractive strategy. However, the only reported prospective trial on this subject included only patients with hypopharyngeal carcinoma. Beauvellain et al. [19,20] had shown significant improvement on survival rates of patients submitted to neoadjuvant chemotherapy prior to surgery, and postoperative radiotherapy, when compared to surgery and radiotherapy.
In oral cavity cancer patients, surgical practices might result in significant functional impairment and can deeply and negatively impact on patients’ quality of life. Likewise, radiotherapy can contribute with disparaging functional consequences, especially in postoperative context. Hence, a less aggressive local approach could result in an increased clinical advantage in oral cavity cancer patients. This, in theory, could support the inclusion of induction chemotherapy in the treatment approach. This would be in line with current organpreserving protocols developed in other head and neck tumours. There are five prospective randomised trials that compared two induction chemotherapy schemes – two-drug (cisplatin plus fluorouracil) versus three-drug (taxane
Please cite this article in press as: Marta G.N. et al., Induction chemotherapy prior to surgery with or without postoperative radiotherapy for oral cavity cancer patients: Systematic review and meta-analysis, Eur J Cancer (2015), http://dx.doi.org/10.1016/j.ejca.2015.08.007
G.N. Marta et al. / European Journal of Cancer xxx (2015) xxx–xxx
Control Chemotherapy Study or Subgroup
log[Hazard Ratio]
Hazard Ratio
Hazard Ratio
SE
Total
Bossi 2014 /Licitra 2003
-0.2514 2.6458
16
16
Zhong 2013
-0.8723 0.4327
25
27
97.4%
0.42 [0.18, 0.98]
41
43 100.0%
0.42 [0.18, 0.98]
Total (95% CI)
Total Weight
7
IV, Fixed, 95% CI
IV, Fixed, 95% CI
2.6% 0.78 [0.00, 138.97]
Heterogeneity: Chi² = 0.05, df = 1 (P = 0.82); I² = 0% 0.001 Test for overall effect: Z = 2.00 (P = 0.04)
0.1
Favours Chemotherapy
1
10
1000
Favours Control
Fig. 7. Forest plot of comparison: Chemotherapy Control (no chemotherapy). Outcome: overall survival for cN2 patients.
(docetaxel or paclitaxel), cisplatin, and fluorouracil)) followed by concurrent radiochemotherapy in patients with head and neck cancer. The meta-analysis of these studies showed that three-drug was related to significant decreases of progression, locoregional recurrence and distant relapse compared with two-drug supporting a usual agreement that the three-drug regimen is more active [21]. However, it remained unproven whether this promising induction protocol followed by chemoradiation was more effective than chemoradiation alone for advanced head and neck cancer. Afterwards, some studies assessed the issue of whether induction chemotherapy previous to concurrent chemoradiation could potentially derive a significant clinical benefit in comparison to concurrent cisplatin-based chemoradiation alone. No overall survival benefit was seen in the induction chemotherapy group [22–24]. It should be noted that all the above-mentioned studies comprised only low proportions of patients with oral cavity cancer and the protocols did not evaluate surgery as first-line therapy. Our meta-analysis included trials in patients with oral SCC only where surgery represented the main treatment strategy. Two studies were found and we evaluated whether preoperative chemotherapy with or without adjuvant radiotherapy could improve clinical outcomes. In one study, 195 patients were randomly allocated to induction of two-drug chemotherapy (cisplatin plus fluorouracil) followed by surgery or up-front radical surgery. Only high-risk patients underwent adjuvant radiotherapy (positive surgical margins and/or extracapsular tumour spread and/or more than three metastatic cervical lymph nodes and/or invasion of soft tissues of the face) [12,13]. In the second study, 256 patients were randomly allocated to induction of three-drug chemotherapy (docetaxel, cisplatin and 5-fluorouracil) followed by surgery or up-front radical surgery. All patients received postoperative radiotherapy [14]. Forest plots of comparison of the two groups did not show any difference in loco-regional relapse, disease-free survival and overall survival based upon 2 years follow-up. Furthermore, after 5-year and 10-year follow up, Bossi et al. [12] demonstrated similar result (Figs. 2–4). Subgroup analysis of cN2 patients demonstrated statistically significant benefit in overall survival in favour
of the induction chemotherapy group, with no differences in other endpoints (loco-regional control and disease-free survival). These results should be interpreted with caution due to the small number of patients with cN2 analysed and also due to the small number of events related to the assessed clinical outcomes. However, these findings are hypothesis generating and assist in the selection of patients for future studies. Interestingly, in both trials, the authors broke down the survival curve according to response to chemotherapy, for exploratory purposes. Patients with pathologic complete response had a better outcome suggesting the presence among head and neck SCC of highly chemosensitive tumours. Nevertheless, study designs do not allow concluding that this favourable outcome is due to chemotherapy. In this scenario, designing trials with selection of cN2 tumours and/or with favourable molecular profile deserve future attention as a way to maximise induction chemotherapy efficacy. No statistical analysis was performed as regards toxicity in this meta-analysis. Licitra et al. [13] showed that more than a third of all patients developed grade 3 or 4 toxicity. Additionally, three deaths associated with two-drug induction chemotherapy were seen. These findings highlight the need of intensive supportive care in patients undergoing chemotherapy and the possibility of harmful and also fatal effects related to the induction approach. One of the main limitations of this meta-analysis is related to the included studies and not to the systematic review itself. Although all studies were classified as having low-risk bias, there were only two included trials. Another limitation is the different protocol treatments used to included studies (induction chemotherapy with two-drug or three-drug; patients without high-risk pathological features did not receive postoperative radiotherapy in the Licitra et al. [13]/ Bossi et al. [12] study). Nevertheless, the results are very similar independent of the used treatment protocol. Induction chemotherapy strategy may offer clinical benefits in patients with some disease features. The subgroup analysis of Zhong et al. study [14] demonstrated a benefit from induction chemotherapy in patients with cN2 disease, who appeared to have improved distant
Please cite this article in press as: Marta G.N. et al., Induction chemotherapy prior to surgery with or without postoperative radiotherapy for oral cavity cancer patients: Systematic review and meta-analysis, Eur J Cancer (2015), http://dx.doi.org/10.1016/j.ejca.2015.08.007
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metastasis-free survival and overall survival. Moreover, Licitra et al. [13] showed that primary chemotherapy seemed to be involved in reducing the quantity of patients who required mandibulectomy and/or radiotherapy. Thus, upcoming clinical trials should focus on the association of biomarkers predictive of response to induction chemotherapy strategy to assess the function of neoadjuvant therapies in chemosensitive patients that could result in better clinical outcomes. In conclusion, the present meta-analysis gives a higher level of evidence in an effort to obtain a better understanding of induction chemotherapy in patients with oral cavity cancer. Based on available studies, induction chemotherapy when administered before surgery with curative intent did not improve clinical outcomes in locoregionally advanced oral cavity cancers patients overall, but there may be a survival benefit from induction chemotherapy in the cN2 subgroup. This effect, however, needs to be further validated in prospective trials. Conflict of interest statement None. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10. 1016/j.ejca.2015.08.007. References [1] Petersen PE. The World Oral Health Report 2003: continuous improvement of oral health in the 21st century–the approach of the WHO Global Oral Health Programme. Community Dent Oral Epidemiol 2003;31(Suppl. 1):3–23. [2] Kademani D. Oral cancer. Mayo Clin Proc 2007;82:878–87. [3] Torre LA, Bray F, Siegel RL, et al. Global cancer statistics, 2012. CA Cancer J Clin 2015;65:87–108. [4] Bessell A, Glenny AM, Furness S, et al. Interventions for the treatment of oral and oropharyngeal cancers: surgical treatment. Cochrane Database Syst Rev 2011:CD006205. [5] Genden EM, Ferlito A, Silver CE, et al. Contemporary management of cancer of the oral cavity. Eur Arch Otorhinolaryngol 2010;267:1001–17. [6] Pulte D, Brenner H. Changes in survival in head and neck cancers in the late 20th and early 21st century: a period analysis. Oncologist 2010;15:994–1001. [7] Neville BW, Day TA. Oral cancer and precancerous lesions. CA Cancer J Clin 2002;52:195–215. [8] Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin 2005;55:74–108. [9] Hanna GJ, Haddad RI, Lorch JH. Induction chemotherapy for locoregionally advanced head and neck cancer: past, present, future? Oncologist 2013;18:288–93.
[10] Higgins JPT, Green S, editors. Cochrane Handbook for Systematic Reviews of Interventions: Version 5.0.2 [updated September 2011]. The Cochrane Collaboration; 2008. [11] Liberati A, Altman DG, Tetzlaff J, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ 2009;339:b2700. [12] Bossi P, Lo Vullo S, Guzzo M, et al. Preoperative chemotherapy in advanced resectable OCSCC: long-term results of a randomized phase III trial. Ann Oncol 2014;25:462–6. [13] Licitra L, Grandi C, Guzzo M, et al. Primary chemotherapy in resectable oral cavity squamous cell cancer: a randomized controlled trial. J Clin Oncol 2003;21:327–33. [14] Zhong LP, Zhang CP, Ren GX, et al. Randomized phase III trial of induction chemotherapy with docetaxel, cisplatin, and fluorouracil followed by surgery versus up-front surgery in locally advanced resectable oral squamous cell carcinoma. J Clin Oncol 2013;31:744–51. [15] Marta GN, Silva V, de Andrade Carvalho H, et al. Intensitymodulated radiation therapy for head and neck cancer: systematic review and meta-analysis. Radiother Oncol 2014;110:9–15. [16] Fabregas JC, Loaiza-Bonilla A, Talebi TN, et al. Concurrent chemoradiotherapy versus induction chemotherapy followed by chemoradiotherapy (sequential approach) in the management of head and neck cancer. Expert Rev Anticancer Ther 2013;13:1065–72. [17] Lee HS, Kim WS, Hong HJ, et al. Robot-assisted Supraomohyoid neck dissection via a modified face-lift or retroauricular approach in early-stage cN0 squamous cell carcinoma of the oral cavity: a comparative study with conventional technique. Ann Surg Oncol 2012;19:3871–8. [18] Pignon JP, le Maitre A, Maillard E, et al. Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): an update on 93 randomised trials and 17,346 patients. Radiother Oncol 2009;92:4–14. [19] Denaro N, Russi EG, Adamo V, Merlano MC. State-of-the-art and emerging treatment options in the management of head and neck cancer: news from 2013. Oncology 2014;86:212–29. [20] Beauvillain C, Mahe M, Bourdin S, et al. Final results of a randomized trial comparing chemotherapy plus radiotherapy with chemotherapy plus surgery plus radiotherapy in locally advanced resectable hypopharyngeal carcinomas. Laryngoscope 1997;107:648–53. [21] Blanchard P, Bourhis J, Lacas B, et al. Taxane-cisplatinfluorouracil as induction chemotherapy in locally advanced head and neck cancers: an individual patient data meta-analysis of the meta-analysis of chemotherapy in head and neck cancer group. J Clin Oncol 2013;31:2854–60. [22] Hitt R, Grau JJ, Lopez-Pousa A, et al. A randomized phase III trial comparing induction chemotherapy followed by chemoradiotherapy versus chemoradiotherapy alone as treatment of unresectable head and neck cancer. Ann Oncol 2014;25:216–25. [23] Haddad R, O’Neill A, Rabinowits G, et al. Induction chemotherapy followed by concurrent chemoradiotherapy (sequential chemoradiotherapy) versus concurrent chemoradiotherapy alone in locally advanced head and neck cancer (PARADIGM): a randomised phase 3 trial. Lancet Oncol 2013;14:257–64. [24] Cohen EE, Karrison TG, Kocherginsky M, et al. Phase III randomized trial of induction chemotherapy in patients with N2 or N3 locally advanced head and neck cancer. J Clin Oncol 2014;32:2735–43.
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Induction chemotherapy prior to surgery with or without postoperative radiotherapy for oral cavity cancer patients: Systematic review and meta-analysis Gustavo N. Marta a,⇑, Rachel Riera b, Paolo Bossi c, Lai-ping Zhong d, Lisa Licitra c, Cristiane R. Macedo e, Gilberto de Castro Junior f, Andre´ L. Carvalho g, William N. William Jr. h, Luis Paulo Kowalski i a
Department of Radiation Oncology, Hospital Sı´rio-Libaneˆs and Instituto do Caˆncer do Estado de Sa˜o Paulo – Faculdade de Medicina da Universidade de Sa˜o Paulo, Sa˜o Paulo, Brazil b Brazilian Cochrane Center and Discipline of Emergency Medicine and Evidence–Based Medicine Universidade Federal de Sa˜o Paulo – Escola Paulista de Medicina (UNIFESP–PM), Sa˜o Paulo, Brazil c Head and Neck Cancer Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy d Department of Oral & Maxillofacial-Head & Neck Oncology, Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, China e Brazilian Cochrane Center and Post Graduation Program of Internal Medicine Universidade Federal de Sa˜o Paulo (UNIFESP), Sa˜o Paulo, Brazil f Department of Clinical Oncology, Hospital Sı´rio-Libaneˆs and Instituto do Caˆncer do Estado de Sa˜o Paulo – Faculdade de Medicina da Universidade de Sa˜o Paulo, Sa˜o Paulo, Brazil g Department of Head and Neck Cancer, Hospital do Caˆncer de Barretos – Fundac¸a˜o Pio XII, Sa˜o Paulo, Brazil h Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, USA i Department of Head and Neck Surgery and Otorhinolaryngology, AC. Camargo Cancer Center, Sa˜o Paulo, Brazil Received 6 August 2015; accepted 12 August 2015
KEYWORDS Oral cavity Neoplasms Induction chemotherapy Surgery Radiotherapy
Abstract Background: Locoregionally advanced oral cavity cancers are aggressive tumours with high risk of relapse after definitive treatment. This study was performed to assess the effectiveness and safety of induction chemotherapy prior to surgery for untreated oral cavity cancer patients. Material and methods: Only prospective phase III randomised studies comparing induction chemotherapy followed by surgery with or without postoperative radiotherapy (Chemo
⇑
Corresponding author at: Hospital Sı´rio-Libaneˆs – Department of Radiation Oncology, Rua Dona Adma Jafet 91, Sao Paulo-SP 01308-050, Brazil. Tel.: +55 11 31550558; fax: +55 11 31550983. E-mail addresses: [email protected] (G.N. Marta), [email protected] (R. Riera), [email protected] (P. Bossi), [email protected] (L.-p. Zhong), [email protected] (L. Licitra), [email protected] (C.R. Macedo), [email protected] (G. de Castro Junior), [email protected] (A.L. Carvalho), [email protected] (W.N. William Jr.), [email protected] (L.P. Kowalski). http://dx.doi.org/10.1016/j.ejca.2015.08.007 0959-8049/Ó 2015 Elsevier Ltd. All rights reserved.
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Prognosis Survival Treatment
Group) compared with surgery with or without postoperative radiotherapy (Control Group) were eligible. Two of the authors independently selected and assessed the studies regarding eligibility criteria and risk of bias. Results: Two studies were selected. A total of 451 patients were randomly assigned to Chemo Group (n = 226) versus Control Group (n = 225). Most patients had tumours at clinical stages III/IV (89.1%). Both trials were classified as having low risk of bias. No significant overall benefit in favour of induction chemotherapy was found regarding loco-regional recurrence, disease-free survival and overall survival. A subgroup analysis of individual data from cN2 patients showed statistically significant overall survival benefit in favour of induction chemotherapy. The included studies did not directly compare toxicity between the groups and no statistical analysis was performed regarding safety outcomes. Conclusions: Based on the available studies, induction chemotherapy when administered before surgery with curative intent did not improve clinical outcomes in locoregionally advanced oral cavity cancer patients. Clinically assessed N2 patients might benefit from induction chemotherapy. Ó 2015 Elsevier Ltd. All rights reserved.
1. Introduction Squamous cell carcinoma is the most common cancer that occurs in the oral cavity, with an estimated 300,000 new cases worldwide each year [1–3]. Locoregionally advanced oral cavity cancers are aggressive tumours with elevated probabilities of relapse after definitive treatment with surgery or radiotherapy (RT). Therefore, a multimodal approach combining surgery and postoperative radiotherapy or chemoradiotherapy has been proposed [4]. There are insufficient reports from phase III prospective randomised clinical studies to show an ideal approach for patients with locally advanced oral cavity malignancies. Guidelines and treatment options are based upon studies that included a majority of patients with primary cancers at other head and neck sites and also retrospective data. In general, the primary therapy for locally advanced oral cavity squamous cell carcinoma (SCC) usually involves surgery followed by radiotherapy and chemotherapy (in the setting of high-risk pathological features such as positive resection margins, and extracapsular nodal spread). Upfront chemoradiation is an option for patients who decline surgery, have unresectable tumour and/or are medically inoperable [5]. Nevertheless, overall survival and tumour control are disappointing, because approximately 50% of the patients will die after 5 years from diagnosis, due to local and/or systemic recurrences [6]. Although improvement in surgical techniques and use of adjuvant treatments have been observed, the 5-year survival rate has not improved considerably in recent years, persisting at 55% [7,8]. New treatment strategies for locally advanced oral cavity SCC have been tested, including preoperative chemotherapy. Induction chemotherapy might reduce tumour burden, ameliorate tumour-related symptoms
and improve surgical results. Moreover, induction chemotherapy could treat micrometastatic disease early on, potentially leading to improved overall clinical outcomes [9]. This study was performed to assess the effectiveness and safety of induction chemotherapy prior to surgery for untreated oral cavity SCC patients. 2. Materials and methods 2.1. Study design This was a systematic review carried out in accordance with The Cochrane Collaboration Handbook of Interventions Systematic Reviews [10]. The manuscript was arranged using the PRISMA Statement as reporting guidance [11]. 2.2. Criteria for considering studies for this review We included trials that assessed any induction chemotherapy strategy followed by surgery with or without postoperative radiotherapy compared with surgery with or without postoperative radiotherapy. Only randomised controlled trials were considered. Cluster or crossover designs were excluded. Oral cavity SCC patients (any age) who had not received prior treatment were eligible. The main outcome measures were overall survival (OS), local control (LC) and toxicity as assessed at any time point after the interventions. At least one of these three outcomes should have been assessed and reported in the trial to be included in the present analysis. 2.3. Search methods for identifying studies The electronic search was conducted with no language, publication year or publication status
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restrictions. We searched the following databases: Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2014, Issue 10), MEDLINE via Ovid (1966 to January 2015), EMBASE via Elsevier (1980 to January 2015) and LILACS via Biblioteca Virtual em Sau´de (1982 to January 2015). We also screened the reference lists of relevant studies. In addition, we performed a search for ongoing and/or unpublished trials on The US National Institutes of Health Ongoing Trials Register (www.clinicaltrials. gov). 2.4. Selection of studies The abstracts of retrieved studies were assessed and selected by two reviewers (independently) considering their probability to be included. After that, the full text of selected studies was evaluated regarding their eligibility criteria by two reviewers (GNM and RR). Disagreements between them were solved by a third reviewer (LPK). 2.5. Methodological quality assessment The risk of bias of the included studies was assessed in accordance with the Cochrane Handbook for Systematic Reviews of Interventions [10] and was carried out by two reviewers (GNM and RR) independently. When necessary, a third reviewer (LPK) solved disagreements. The studies were considered to have high, unclear or low risk of bias according to an assessment of the following items: generation of allocation sequences, allocation concealment, blinding of participants and personnel (performance bias), blinding of outcome assessment (detection bias), incomplete data addressed, presence of biases in reports and other sources of bias that might influence the study’s validity.
3
2.7. Assessment of heterogeneity When appropriate, heterogeneity was assessed using the chi-squared (Chi2) statistic (p value less than 0.1). We also used the I2 statistic to assess the variation across studies due to heterogeneity rather than chance. I2 values greater than 50% were considered substantial heterogeneity [10]. 3. Results 3.1. Study selection and characteristics of the included studies The flowchart of the retrieved studies and the characteristics of included studies are presented in Fig. 1 and Table 1, respectively. Three papers, reporting two studies fulfilled the eligibility criteria (Bossi et al. [12], Licitra et al. [13], Zhong et al. [14]). 451 patients were randomly assigned to induction chemotherapy followed by surgery with or without radiotherapy (n = 226), versus surgery with or without radiotherapy (n = 225). Most of the patients were male (75.8%); tumours at clinical stages III/IV comprised 89.1% of the patients.
Total citations n = 4397
Excluded n =4295
2.6. Measures of treatment effect Dichotomous outcomes were summarised as risk ratios (RRs) and continuous outcomes as mean differences (MD). The size effect of the intervention for timeto-event outcomes was calculated by the pooled hazard ratio (HR), followed by the confidence interval (CI) of 95%, from the Peto’s method of fixed effect. The HR calculation was performed after imputation of the derivative of expected events (O–E) and log-rank variance (V) for each included study. For determining O–E, the Z-Score for two-tailed p-value was calculated based on relative risk of each study. A confidence interval of 95% was assumed for all analysis. When the data were not available for HR calculation, RR was used instead. For the meta-analysis, the fixed model effect was used, except when substantial heterogeneity was found. In this case, random effect was applied.
Selected for full text reading n = 102
Excluded n =99
Included studies n = 2 (3 publications) Fig. 1. Flowchart of the process of study selection.
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Table 1 Characteristics of included studies.
Total (n) Chemotherapy arm Control arm Sex n – (%) Male Female Mean age (years) Chemotherapy arm Control arm Tumour site n – (%) Tongue Floor of mouth Gingiva Retromolar trigone Palate Buccal Staging system
Bossi et al./Licitra et al.
Zhong et al.
195 98
256 128
97
128
163 (83.6%) 32 (16.4%)
179 (69.9%) 77 (30.1%)
55
55
55
56
84 56 26 29
(43.1%) (28.8%) (13.3%) (14.8%)
113 (44.1%) 30 (11.7%) 40 (15.7%) 10 (3.9%)
0 0 UICC TNM classification of malignant tumours 4th edition (1987)
18 (7.0%) 45 (17.6%) UICC TNM classification of malignant tumours 6th edition (2002)
T stage n – (%) T1 – T2 80 (41%) T3 77 (39.5%) T4 38 (19.5%) N stage n – (%) N0 111 (56.9%) N1 52 (26.7%) N2 32 (16.4%) Stage grouping n – (%) II 49 (25.1%) III 86 (44.1%) IV 60 (30.8%) Eligibility criteria Biopsy-proven, resectable, stage T2–T4, N0–N2, M0, previously untreated oral cavity squamous cell carcinoma Intervention – Cisplatin 100 mg/m2 and fluorouracil 1000 mg/m2, given as a 120-h infusion, for three cycles every 21 days followed by surgery (chemotherapy arm). Patients received the third chemotherapy cycle only if a partial response was observed – Surgery alone In both arms, postoperative radiotherapy (45–65 Gy) was reserved to high-risk patients, and surgery was modulated depending on the tumour’s closeness to the mandible Outcomes Overall survival, loco-regional relapse, distant metastasis, complete pathological response, complete clinical response, adverse events, mortality
3.2. Methodological quality of studies The methodological quality of the included studies, assessed independently by two observers, is presented in Supplementary Material 1 and 2. Overall, and in accordance with the Cochrane risk of bias table [10], both studies were classified as having a low-risk of bias. 3.3. Results for effectiveness outcomes 3.3.1. Loco-regional relapse Data regarding loco-regional relapse were available in both studies. Meta-analysis of two trials did not show
9 (3.5%) 57 (22.2%) 149 (58.2%) 41 (16.1%) 110 (43%) 94 (36.7%) 52 (20.3%) – 177 (69.1%) 79 (30.9%) III or IVA locally advanced resectable oral squamous cell carcinoma – Two cycles of TPF induction chemotherapy (docetaxel 75 mg/m2 on day 1, cisplatin 75 mg/m2 on day 1 and fluorouracil 750 mg/m2 on days 1–5) followed by radical surgery and postoperative radiotherapy (54–66 Gy) – Up-front radical surgery and postoperative radiotherapy
Overall survival, local control, safety
significant benefit in the induction chemotherapy group compared to the control group (2-year loco-regional relapse/heterogeneity: Chi2 = 0.14, df = 1 (p = 0.71); I2 = 0%; test for overall effect: Z = 0.13 [p = 0.90]). (Fig. 2). 3.3.2. Disease-free survival Fig. 3 shows data regarding disease-free survival. A non-significant increase in disease-free survival favouring the chemotherapy group was observed (2-year disease-free survival/ heterogeneity: Chi2 = 0.64, df = 1 (p = 0.42); I2 = 0%; test for overall effect: Z = 0.52 [p = 0.60]).
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3.3.3. Overall survival Meta-analysis of two studies did not demonstrate a significant benefit in the induction chemotherapy group versus the control group (2-year overall survival/heterogeneity: Chi2 = 0.08, df = 1 (p = 0.78); I2 = 0%; test for overall effect: Z = 0.07 [p = 0.94]). (Fig. 4).
3.3.5. Results for safety outcomes Included studies did not directly compare toxicity and quality of life rates between the groups, and no statistical analysis was performed regarding safety outcomes. The toxicities were reported by Common Terminology Criteria for Adverse Events (version 3.0) [14] and World Health Organisation Classification [12,13]. Licitra et al. [13]/Bossi et al. [12] demonstrated 37% severe toxicity (grade 3 or 4) and three deaths related to induction chemotherapy. Zhong et al. [14] did not observe any grade IV adverse events and no chemotherapy related deaths occurred (Supplementary Material 3). Long term toxicities are reported in Bossi et al. [12].
3.3.4. cN2 subgroup analysis A subgroup analysis of individual data from cN2 patients was performed. In total, 84 patients were cN2. Meta-analysis of two studies did not demonstrate a significant benefit in the induction chemotherapy group versus control group as regards to loco-regional relapse (2-year loco-regional relapse/heterogeneity: Chi2 = 0.01, df = 1 [p = 0.90]; I2 = 0%; test for overall effect: Z = 1.54 [p = 0.12]) – Fig. 5 – and disease-free survival (2-year disease-free survival/heterogeneity: Chi2 = 0.01, df = 1 [p = 0.90]; I2 = 0%; test for overall effect: Z = 1.54 [p = 0.12]) – Fig. 6. However, statistically significant overall survival benefit in favour of induction chemotherapy was observed (2-year overall survival/ heterogeneity: Chi2 = 0.05, df = 1 [p = 0.82]; I2 = 0%; test for overall effect: Z = 2 [p = 0.04]) – Fig. 7. Chemotherapy Study or Subgroup
Events
5
4. Discussion Standard management for advanced oral cavity SCC comprises a multidisciplinary approach including surgery and postoperative radiotherapy associated or not with chemotherapy. Despite technical improvements in the involved therapeutic modalities [15–17], long-term overall survival and tumour control are still unsatisfactory [8,9].
Control
Risk Ratio
Total Events Total Weight
Risk Ratio M-H, Fixed, 95% CI
M-H, Fixed, 95% CI
1.1.1 2-years Bossi 2014 - Licitra 2003
25
98
27
97
41.0%
Zhong 2013
40
128
39
128
59.0%
1.03 [0.71, 1.48]
225 100.0%
0.98 [0.74, 1.31]
226
Subtotal (95% CI) Total events
0.92 [0.58, 1.46]
66
65
Heterogeneity: Chi² = 0.14, df = 1 (P = 0.71); I² = 0% Test for overall effect: Z = 0.13 (P = 0.90)
0.01
0.1
1
Favours Chemotherapy
10
100
Favours Control
Test for subgroup differences: Not applicable
Fig. 2. Forest plot of comparison: Chemotherapy Control (no chemotherapy). Outcome: loco-regional relapses.
Chemotherapy Study or Subgroup
Events
Control
Risk Ratio
Total Events Total Weight
Risk Ratio
M-H, Fixed, 95% CI
M-H, Fixed, 95% CI
4.1.1 2-years Bossi 2014 - Licitra 2003
63
98
56
97
41.0%
Zhong 2013
80
128
81
128
59.0%
0.99 [0.82, 1.19]
225 100.0%
1.04 [0.90, 1.20]
Subtotal (95% CI) Total events
226 143
1.11 [0.89, 1.39]
137
Heterogeneity: Chi² = 0.64, df = 1 (P = 0.42); I² = 0% Test for overall effect: Z = 0.52 (P = 0.60)
0.1 0.2
0.5
1
2
5
10
Favours control Favours chemotheray
Fig. 3. Forest plot of comparison: Chemotherapy Control (no chemotherapy). Outcome: disease-free survival.
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Chemotherapy Study or Subgroup
Events
Control
Risk Ratio
Total Events Total Weight
Risk Ratio
M-H, Fixed, 95% CI
M-H, Fixed, 95% CI
3.1.1 2-years Bossi 2014 - Licitra 2003
66
98
67
Zhong 2013 Subtotal (95% CI)
88
128 226
87
Total events
154
43.6%
0.98 [0.80, 1.18]
128 56.4% 225 100.0%
97
1.01 [0.86, 1.19] 1.00 [0.88, 1.13]
154
Heterogeneity: Chi² = 0.08, df = 1 (P = 0.78); I² = 0% Test for overall effect: Z = 0.07 (P = 0.94)
0.01
0.1 1 10 100 Favours control Favours chemotherapy
Fig. 4. Forest plot of comparison: Chemotherapy Control (no chemotherapy). Outcome: overall survival.
Control Chemotherapy Study or Subgroup Bossi 2014 /Licitra 2003 Zhong 2013
log[Hazard Ratio]
Hazard Ratio
Total Weight
Hazard Ratio
IV, Fixed, 95% CI
SE
Total
-0.3366 2.1307
16
16
-0.596 0.3891
25
27
96.8%
0.55 [0.26, 1.18]
41
43 100.0%
0.56 [0.26, 1.18]
Total (95% CI)
IV, Fixed, 95% CI
3.2% 0.71 [0.01, 46.50]
Heterogeneity: Chi² = 0.01, df = 1 (P = 0.90); I² = 0% 0.002 Test for overall effect: Z = 1.54 (P = 0.12)
0.1
1
Favours Chemotherapy
10
500
Favours Control
Fig. 5. Forest plot of comparison: Chemotherapy Control (no chemotherapy). Outcome: loco-regional relapses for cN2 patients.
Control Chemotherapy Study or Subgroup
log[Hazard Ratio]
Hazard Ratio
Hazard Ratio
SE
Total
Bossi 2014 /Licitra 2003
-0.337 2.1401
16
16
Zhong 2013
-0.596 0.3891
25
27
96.8%
0.55 [0.26, 1.18]
41
43 100.0%
0.56 [0.26, 1.18]
Total (95% CI)
Total Weight
IV, Fixed, 95% CI
IV, Fixed, 95% CI
3.2% 0.71 [0.01, 47.35]
Heterogeneity: Chi² = 0.01, df = 1 (P = 0.91); I² = 0% 0.001 Test for overall effect: Z = 1.54 (P = 0.12)
0.1
Favours Chemotherapy
1
10
1000
Favours Control
Fig. 6. Forest plot of comparison: Chemotherapy Control (no chemotherapy). Outcome: disease-free survival for cN2 patients.
The use of chemotherapy in advanced head and neck SCC has shown a significant advantage in terms of overall survival, when delivered concurrently with radiotherapy [18]. Nonetheless, the role of induction chemotherapy strategy in head and neck SCC has been extensively discussed, with conflicting results [19]. Induction chemotherapy, as a treatment before surgery and/or radiotherapy, is an attractive strategy. However, the only reported prospective trial on this subject included only patients with hypopharyngeal carcinoma. Beauvellain et al. [19,20] had shown significant improvement on survival rates of patients submitted to neoadjuvant chemotherapy prior to surgery, and postoperative radiotherapy, when compared to surgery and radiotherapy.
In oral cavity cancer patients, surgical practices might result in significant functional impairment and can deeply and negatively impact on patients’ quality of life. Likewise, radiotherapy can contribute with disparaging functional consequences, especially in postoperative context. Hence, a less aggressive local approach could result in an increased clinical advantage in oral cavity cancer patients. This, in theory, could support the inclusion of induction chemotherapy in the treatment approach. This would be in line with current organpreserving protocols developed in other head and neck tumours. There are five prospective randomised trials that compared two induction chemotherapy schemes – two-drug (cisplatin plus fluorouracil) versus three-drug (taxane
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Control Chemotherapy Study or Subgroup
log[Hazard Ratio]
Hazard Ratio
Hazard Ratio
SE
Total
Bossi 2014 /Licitra 2003
-0.2514 2.6458
16
16
Zhong 2013
-0.8723 0.4327
25
27
97.4%
0.42 [0.18, 0.98]
41
43 100.0%
0.42 [0.18, 0.98]
Total (95% CI)
Total Weight
7
IV, Fixed, 95% CI
IV, Fixed, 95% CI
2.6% 0.78 [0.00, 138.97]
Heterogeneity: Chi² = 0.05, df = 1 (P = 0.82); I² = 0% 0.001 Test for overall effect: Z = 2.00 (P = 0.04)
0.1
Favours Chemotherapy
1
10
1000
Favours Control
Fig. 7. Forest plot of comparison: Chemotherapy Control (no chemotherapy). Outcome: overall survival for cN2 patients.
(docetaxel or paclitaxel), cisplatin, and fluorouracil)) followed by concurrent radiochemotherapy in patients with head and neck cancer. The meta-analysis of these studies showed that three-drug was related to significant decreases of progression, locoregional recurrence and distant relapse compared with two-drug supporting a usual agreement that the three-drug regimen is more active [21]. However, it remained unproven whether this promising induction protocol followed by chemoradiation was more effective than chemoradiation alone for advanced head and neck cancer. Afterwards, some studies assessed the issue of whether induction chemotherapy previous to concurrent chemoradiation could potentially derive a significant clinical benefit in comparison to concurrent cisplatin-based chemoradiation alone. No overall survival benefit was seen in the induction chemotherapy group [22–24]. It should be noted that all the above-mentioned studies comprised only low proportions of patients with oral cavity cancer and the protocols did not evaluate surgery as first-line therapy. Our meta-analysis included trials in patients with oral SCC only where surgery represented the main treatment strategy. Two studies were found and we evaluated whether preoperative chemotherapy with or without adjuvant radiotherapy could improve clinical outcomes. In one study, 195 patients were randomly allocated to induction of two-drug chemotherapy (cisplatin plus fluorouracil) followed by surgery or up-front radical surgery. Only high-risk patients underwent adjuvant radiotherapy (positive surgical margins and/or extracapsular tumour spread and/or more than three metastatic cervical lymph nodes and/or invasion of soft tissues of the face) [12,13]. In the second study, 256 patients were randomly allocated to induction of three-drug chemotherapy (docetaxel, cisplatin and 5-fluorouracil) followed by surgery or up-front radical surgery. All patients received postoperative radiotherapy [14]. Forest plots of comparison of the two groups did not show any difference in loco-regional relapse, disease-free survival and overall survival based upon 2 years follow-up. Furthermore, after 5-year and 10-year follow up, Bossi et al. [12] demonstrated similar result (Figs. 2–4). Subgroup analysis of cN2 patients demonstrated statistically significant benefit in overall survival in favour
of the induction chemotherapy group, with no differences in other endpoints (loco-regional control and disease-free survival). These results should be interpreted with caution due to the small number of patients with cN2 analysed and also due to the small number of events related to the assessed clinical outcomes. However, these findings are hypothesis generating and assist in the selection of patients for future studies. Interestingly, in both trials, the authors broke down the survival curve according to response to chemotherapy, for exploratory purposes. Patients with pathologic complete response had a better outcome suggesting the presence among head and neck SCC of highly chemosensitive tumours. Nevertheless, study designs do not allow concluding that this favourable outcome is due to chemotherapy. In this scenario, designing trials with selection of cN2 tumours and/or with favourable molecular profile deserve future attention as a way to maximise induction chemotherapy efficacy. No statistical analysis was performed as regards toxicity in this meta-analysis. Licitra et al. [13] showed that more than a third of all patients developed grade 3 or 4 toxicity. Additionally, three deaths associated with two-drug induction chemotherapy were seen. These findings highlight the need of intensive supportive care in patients undergoing chemotherapy and the possibility of harmful and also fatal effects related to the induction approach. One of the main limitations of this meta-analysis is related to the included studies and not to the systematic review itself. Although all studies were classified as having low-risk bias, there were only two included trials. Another limitation is the different protocol treatments used to included studies (induction chemotherapy with two-drug or three-drug; patients without high-risk pathological features did not receive postoperative radiotherapy in the Licitra et al. [13]/ Bossi et al. [12] study). Nevertheless, the results are very similar independent of the used treatment protocol. Induction chemotherapy strategy may offer clinical benefits in patients with some disease features. The subgroup analysis of Zhong et al. study [14] demonstrated a benefit from induction chemotherapy in patients with cN2 disease, who appeared to have improved distant
Please cite this article in press as: Marta G.N. et al., Induction chemotherapy prior to surgery with or without postoperative radiotherapy for oral cavity cancer patients: Systematic review and meta-analysis, Eur J Cancer (2015), http://dx.doi.org/10.1016/j.ejca.2015.08.007
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metastasis-free survival and overall survival. Moreover, Licitra et al. [13] showed that primary chemotherapy seemed to be involved in reducing the quantity of patients who required mandibulectomy and/or radiotherapy. Thus, upcoming clinical trials should focus on the association of biomarkers predictive of response to induction chemotherapy strategy to assess the function of neoadjuvant therapies in chemosensitive patients that could result in better clinical outcomes. In conclusion, the present meta-analysis gives a higher level of evidence in an effort to obtain a better understanding of induction chemotherapy in patients with oral cavity cancer. Based on available studies, induction chemotherapy when administered before surgery with curative intent did not improve clinical outcomes in locoregionally advanced oral cavity cancers patients overall, but there may be a survival benefit from induction chemotherapy in the cN2 subgroup. This effect, however, needs to be further validated in prospective trials. Conflict of interest statement None. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10. 1016/j.ejca.2015.08.007. References [1] Petersen PE. The World Oral Health Report 2003: continuous improvement of oral health in the 21st century–the approach of the WHO Global Oral Health Programme. Community Dent Oral Epidemiol 2003;31(Suppl. 1):3–23. [2] Kademani D. Oral cancer. Mayo Clin Proc 2007;82:878–87. [3] Torre LA, Bray F, Siegel RL, et al. Global cancer statistics, 2012. CA Cancer J Clin 2015;65:87–108. [4] Bessell A, Glenny AM, Furness S, et al. Interventions for the treatment of oral and oropharyngeal cancers: surgical treatment. Cochrane Database Syst Rev 2011:CD006205. [5] Genden EM, Ferlito A, Silver CE, et al. Contemporary management of cancer of the oral cavity. Eur Arch Otorhinolaryngol 2010;267:1001–17. [6] Pulte D, Brenner H. Changes in survival in head and neck cancers in the late 20th and early 21st century: a period analysis. Oncologist 2010;15:994–1001. [7] Neville BW, Day TA. Oral cancer and precancerous lesions. CA Cancer J Clin 2002;52:195–215. [8] Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin 2005;55:74–108. [9] Hanna GJ, Haddad RI, Lorch JH. Induction chemotherapy for locoregionally advanced head and neck cancer: past, present, future? Oncologist 2013;18:288–93.
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Please cite this article in press as: Marta G.N. et al., Induction chemotherapy prior to surgery with or without postoperative radiotherapy for oral cavity cancer patients: Systematic review and meta-analysis, Eur J Cancer (2015), http://dx.doi.org/10.1016/j.ejca.2015.08.007