REVIEW URRENT C OPINION
Is there still a role for induction chemotherapy in locally advanced head and neck cancer? Milena P. Mak a,b and Bonnie S. Glisson a
Purpose of review Despite decades of research, the role of induction chemotherapy (ICT) in the treatment of locally advanced head and neck squamous cell carcinoma remains controversial. When nonsurgical approaches are preferred, chemoradiation (CRT) is the standard of care. However, ICT continues to be investigated, as it can cytoreduce tumors, improve radiotherapy feasibility and tolerability, select patients for organ preservation with radiation, and decrease the risk of distant metastasis. Recent findings Herein, we review the recent randomized trials that investigated the role of taxanes in ICT, compared with surgery or CRT alone. A metaanalysis of older trials comparing taxane-containing ICT to cisplatin and 5-fluorouracil is discussed. In addition, long-term results from Radiation Therapy Oncology Group 91-11, a three-arm trial of larynx preservation approaches, are discussed, as well as a recent trial of sequential CRT for larynx preservation. As in previous randomized trials, no survival benefit for ICT was demonstrated. However, two studies showed a reduced risk of distant metastasis in advanced nodal stage patients. As regards larynx preservation, ICT followed by radiation alone in responders to chemotherapy remains an effective option. Summary ICT is still controversial and in general, should remain investigational. An exception may be its use in a larynx preservation approach, albeit with a lower crude larynx preservation rate compared with CRT. The results of recent trials provide rationale and support hypothesis generation for future research, which should focus on subsets of patients most likely to benefit, for example, high nodal stage. It will be critical to study human papillomavirus (HPV)-associated oropharynx cancer separately or, at least, stratify by HPV status given its influence on prognosis and attendant implications for statistical design. Keywords chemoradiation, head and neck cancer, induction chemotherapy
INTRODUCTION In 2009, a large metaanalysis [Meta-analysis of chemotherapy in head and neck cancer (MACH_NC)] established concurrent platinum-based chemoradiation (CRT) as a standard of care for locally advanced head and neck squamous cell carcinoma (LAHNSCC) based on an 8.6% absolute increase in cancer-specific survival at 5 years, with hazard ratio, 0.81; 95% confidence interval (CI), 0.78–0.86, when compared with locoregional treatment without chemotherapy. However, despite concurrent treatment with its attendant high rates of severe acute toxicity, median survival rates were less than 50% at 3 years. This same analysis showed that ICT, predominantly with cisplatin and 5-fluorouracil, was associated with a reduced risk of distant metastasis, hazard ratio, 0.73; 95% CI, 0.61–0.88, although there was only a trend to a survival benefit with ICT (2.4% at
5 years, hazard ratio, 0.96; 95% CI, 0.90–1.02; P ¼ 0.18). The survival benefit of CRT is primarily attributed to improved locoregional control, with less impact on distant metastasis compared with ICT (hazard ratio, 0.88; 95% CI, 0.77–1) [1]. These findings, combined with the relatively poor survival
a Department of Thoracic/Head and Neck Medical Oncology, The University of Texas, MD Anderson Cancer Center, Houston, Texas, USA and b Medical Oncology, Instituto do Cancer do Estado de Sao Paulo, Faculdade de Medicina da Universidade de Sao Paulo, Sao Paulo, Brazil
Correspondence to Milena P. Mak, MD, Medical Oncology, Instituto do Cancer do Estado de Sao Paulo, Faculdade de Medicina da Universidade de Sao Paulo, Av. Dr Arnaldo, 251 5th floor, CEP 01246-000 Sao Paulo, SP, Brazil. Tel: +55 11 3893 2686; fax: +55 11 3083 1746; e-mail: [email protected] Curr Opin Oncol 2014, 26:247–251 DOI:10.1097/CCO.0000000000000073
1040-8746 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
www.co-oncology.com
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Head and neck
KEY POINTS ICT may have a role in decreasing the risk of distant metastasis in patients with high nodal stage LAHNSCC: its use in that setting remains investigational. Taxane-based ICT and definitive radiation therapy remain a treatment option for larynx and hypopharynx preservation. CRT results in higher larynx preservation rates compared with radiation therapy alone and ICT followed by radiation therapy. Using response to ICT to deintensify CRT in the setting of HPV-related oropharynx cancer remains investigational. Molecular correlates of chemotherapy/radiation therapy sensitivity and of local vs. distant recurrence risk may inform patient selection in future trials.
with CRT provided rationale for further investigation of ICT.
INDUCTION CHEMOTHERAPY IN THE SETTING OF LARYNX PRESERVATION On the basis of the results of two large randomized trials for patients with squamous cancer of the larynx and hypopharynx, respectively, ICT with cisplatin and 5-fluorouracil followed by definitive radiation for responding patients was viewed as the standard of care for larynx preservation through the 1990s. Given the efficacy of CRT, the Radiation Therapy Oncology Group 91-11 (RTOG 91-11) study randomized patients to a control arm of ICT with cisplatin and 5-fluorouracil followed by radiation therapy vs. experimental arms of cisplatin-based CRT or radiation therapy alone. The initial results of this trial published in 2003 showed that both the CRT and ICT arms had better laryngectomy-free survival (primary endpoint), compared with radiation therapy alone. There was no difference in overall survival among the three groups, presumably due to surgical salvage for locoregional recurrence. The CRT arm compared favorably in terms of larynx preservation rate and local control compared with the ICT arm (hazard ratio, 0.58; 95% CI, 0.37– 0.89; P ¼ 0.005) and the radiation therapy arm (hazard ratio, 0.46; 95% CI, 0.30–0.71; P < 0.001), albeit at the expense of significant toxicity [2,3 ]. The 5 and 10-year outcomes for RTOG 91-11, published in March 2013, continued to confirm the original findings of superior laryngectomy-free survival for both chemotherapy arms as well as higher larynx preservation rates for CRT. Most notable, however, was an excess of nonlarynx cancer-related deaths in the CRT arm, compared with ICT and &&
248
www.co-oncology.com
radiation therapy, (31, 21, and 17%, respectively), that was associated with a separation in the survival curves. This difference, however, was not statistically significant (hazard ratio, 1.25; 95% CI 0.98– 1.61; P ¼ 0.08), occurred without documented increased late effects in the CRT arm, and remains unexplained [3 ]. Nevertheless, the absolute 11% difference in 10-year survival rates favoring the ICT arm cannot be ignored and suggests that ICT followed by radiation therapy remains an effective option that might be preferred over CRT in selected patients. In 2007, two studies addressing the addition of docetaxel to cisplatin and 5-fluorouracil (TPF), compared with cisplatin and 5-fluorouracil alone followed by radiation or radiation with carboplatin, showed increased response rates and overall survival benefit for TPF [4,5], triggering evaluation of this more effective ICT regimen in larynx preservation. In the Groupe d’Oncologie Radiothe´rapie Teˆte Et Cou (GORTEC) 2000–2001, which compared TPF with cisplatin and 5-fluorouracil ICT, higher response rate (80 vs. 59%, P ¼ 0.002), treatment compliance (62.7 vs. 32%, P < 0.001), and 3-year larynx preservation (70.3 vs. 57.5%, P ¼ 0.03) were yielded with TPF. There was no difference in 3-year overall survival (OS) (60% in both arms) [6]. Building on the results of GORTEC 2000–2001, the Radiotherapy With Cisplatin Versus Radiotherapy With Cetuximab After Induction Chemotherapy for Larynx Preservation (TREMPLIN) randomized phase II trial was designed to address the optimal sequential CRT arm for larynx preservation, following TPF ICT. After TPF, responders were randomized to either cisplatin-based CRT or bioradiotherapy (BRT) with cetuximab with the intent to improve larynx preservation rates by 10% compared with those with TPF and radiation therapy (70%). A total of 153 patients eligible for total laryngectomy were included in this trial. The majority of patients (74%) were able to receive the planned three cycles of TPF, however, there were four deaths during ICT, two from toxicity. Similarly to other studies, a 23.5% rate of grade 3 and 4 toxicity occurred, mostly hematological (neutropenia and febrile neutropenia) and renal. The 126 responders by clinical, radiological, and endoscopic evaluation were randomized to CRT or BRT, which yielded equally high 3-month larynx preservation rates (95 and 93%, respectively) and comparable 18-month survival (92 and 89%, respectively) [7 ]. Because these data included only the randomized patients, they are inflated, and the authors correctly concluded that neither arm was promising enough to pursue further evaluation. These investigators continue to endorse ICT with TPF followed by &&
&
Volume 26 Number 3 May 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Induction chemotherapy for head and neck cancer Mak and Glisson
definitive radiation therapy as the standard of care for larynx preservation in managing advanced T-stage larynx and hypopharynx cancer. A pivotal question not addressed by the TREMPLIN trial is the optimal treatment of patients who do not have response to ICT. The authors reported a dropout rate of 24%, representing predominantly patients who did not respond to ICT and were offered total laryngectomy, which was performed in 69% of patients [7 ]. Although resection is the standard of care, the role of CRT in this setting may warrant investigation. In the RTOG 9111 trial, of the 24 nonresponders after two cycles of cisplatin and 5-fluorouracil ICT, seven proceeded to total laryngectomy and 11 were treated with additional CT or radiation therapy, all achieving complete response [2]. Only one patient in this group required laryngectomy. &
INDUCTION CHEMOTHERAPY VS. CHEMORADIATION IN LOCALLY ADVANCED HEAD AND NECK SQUAMOUS CELL CARCINOMA Although taxane-based ICT led to improved survival compared with cisplatin and 5-fluorouracil in LAHNSCC patients, its efficacy compared with standard CRT was not studied in TAX 323 or 324. In the 2012 American Society of Clinical Oncology annual meeting, two randomized phase III trials designed to answer that question were presented. Only one of these, PARADIGM, has been published in final form. Both are reviewed herein because of the importance of their findings in informing future research with ICT. The PARADIGM trial included 145 unresectable stage III and IV head and neck squamous cell carcinoma patients. Patients were randomized to either ICT with TPF followed by CRT or concurrent highdose cisplatin for two cycles with accelerated radiotherapy. In the ICT arm, docetaxel was given during CRT if there was inadequate response to ICT. Alternatively, carboplatin as in TAX 324, was given to patients with clear response. Sample size was originally targeted at 330 patients to detect a 40% decrease in the hazard of death, with 80% power to detect a survival rate increase from 55% in the CRT arm to 70% in the sequential CRT arm. However, because of slow accrual, the study was halted, limiting the power of the study and interpretation of its results. All 145 patients had WHO performance status 0 or 1, and the majority had stage IV disease (86%) and oropharynx primary site (55%). Human papillomavirus (HPV) status was not assessed, as accrual occurred from 2002 to 2004. Seven patients in the ICT arm (10%) were unable to receive CRT, and one
patient died during ICT. There was no difference in 3-year OS between the two groups, 78% in the CRT arm and 73% in the ICT arm (hazard ratio, 1.09; 95% CI, 0.59–2.03; P ¼ 0.77). Notably, these outcomes are markedly superior to earlier trials with either ICT or CRT. Disease failure patterns were similar in both groups. There was higher hematological toxicity in the ICT arm, with 23% grade 3 or 4 febrile neutropenia compared with 1% in patients who underwent CRT [8 ]. As previous data had demonstrated that ICT could decrease the rate of distant metastasis [1], in the Docetaxel Based Chemoradiotherapy Plus or Minus Induction Chemotherapy to Decrease Events in Head and Neck Cancer (DeCIDE) trial, only patients considered at highest risk of distant failure (N2/N3) were included. From 2004 to 2009, patients were randomized to two cycles of TPF followed by CRT with DFHX (docetaxel 25 mg/m2 d1, 5-fluorouracil 600 mg/m2 d1–d5, and hydroxyurea and radiation with 150 cGy twice daily d1–d5 every 2 weeks for four cycles) or the same CRT regimen. In order to detect a 35% (hazard ratio 1.6) reduction in the risk of death in the sequential arm, an original sample size of 400 patients was planned; assuming an increase in 3-year OS from 50% in the CRT arm to 65% in the sequential treatment. Because of slow accrual, sample size was reestimated, targeted hazard ratio was increased to 2.0, and after the inclusion of 280 patients, the study was closed. The most frequent primary site was oropharynx (58%) and, as in PARADIGM, HPV status was not assessed prospectively. A 7% dropout rate was seen in the ICT arm. Both arms had similar OS rates at 3 years with 75% in the ICT arm and 73% in the CRT arm (hazard ratio, 0.92; 95% CI, 0.59–1.42; P ¼ 0.70). Again, these outcomes are superior to older trials. There were significantly fewer distant failures in the ICT arm (10 vs. 19%, hazard ratio, 0.46 95% CI 0.23–0.92; P ¼ 0.025). In an unplanned subset analysis, a statistically significant difference in distance recurrence without locoregional recurrence was found in favor of the ICT arm (P ¼ 0.043). There was a trend to survival benefit for 96 patients with N2c and N3 tumors (P ¼ 0.19) [9 ]. The results are notable given these patients received only two cycles of ICT. Both DeCIDE and PARADIGM were unable to accrue to their original target and are thus, underpowered. Further complicating interpretation is the improved outcome of both control arms compared with the estimated survival rates (50 and 55%, respectively). This likely reflects the impact of HPV-related oropharynx cancers in both arms, although contributions from an improvement in supportive care and radiation planning/technique
1040-8746 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
&&
&
www.co-oncology.com
249
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Head and neck
are also possible. As in many trials with ICT, a small subset of patients experienced toxicity during ICT, which compromised their ability to complete or initiate curative CRT. This emphasizes the need for careful patient selection and aggressive supportive care. Although ICT did not result in an overall survival benefit compared with CRT in either trial, neither study can be viewed as definitive on this point given the statistical issues. The trend to survival benefit for patients with N2c/N3 disease from DeCIDE warrants further investigation.
PREOPERATIVE CHEMOTHERAPY Surgical treatment is the preferred option for the management of oral cavity squamous cell carcinoma (OSCC). The addition of postoperative radiation or CRT in patients at high risk of recurrence has improved outcomes; however, survival rates at 5 years remain only 50–60% [10,11]. A previous phase III study evaluating preoperative cisplatin and 5-fluorouracil in locally advanced OSCC patients failed to demonstrate any survival advantage, with 5-year OS of 55% in both arms [12]. To evaluate the more effective TPF regimen in this setting, 256 patients with locally advanced OSCC who were candidates for curative resection were randomized to either two cycles of TPF followed by surgery or surgery alone in a phase III trial from China. Postoperative radiation therapy consisted of 54–60 Gy and 66 Gy in patients whose tumors had high-risk features. The response rate after ICT was 81% assessed by Response Evaluation Criteria In Solid Tumors. Pathologic complete response was observed in 12% of specimens from the ICT arm. However, at 2 years, there was no difference in OS between the treatment arms (68 and 69%, for ICT and surgery arms, respectively). The rate of distant metastasis also did not differ (5% ICT and 9% surgery). The rate of grade 3 hematological toxicity was only 7%, and there was no increase in perioperative morbidity in the ICTtreated patients. An exploratory subset analysis demonstrated a distant metastasis-free survival and overall survival benefit for patients with N2c disease on the ICT arm, (hazard ratio, 0.418; 95% CI, 0.179–0.974; P ¼ 0.043). In the ICT overall population, better outcomes were seen in patients who experienced favorable pathologic response (
Is there still a role for induction chemotherapy in locally advanced head and neck cancer? Milena P. Mak a,b and Bonnie S. Glisson a
Purpose of review Despite decades of research, the role of induction chemotherapy (ICT) in the treatment of locally advanced head and neck squamous cell carcinoma remains controversial. When nonsurgical approaches are preferred, chemoradiation (CRT) is the standard of care. However, ICT continues to be investigated, as it can cytoreduce tumors, improve radiotherapy feasibility and tolerability, select patients for organ preservation with radiation, and decrease the risk of distant metastasis. Recent findings Herein, we review the recent randomized trials that investigated the role of taxanes in ICT, compared with surgery or CRT alone. A metaanalysis of older trials comparing taxane-containing ICT to cisplatin and 5-fluorouracil is discussed. In addition, long-term results from Radiation Therapy Oncology Group 91-11, a three-arm trial of larynx preservation approaches, are discussed, as well as a recent trial of sequential CRT for larynx preservation. As in previous randomized trials, no survival benefit for ICT was demonstrated. However, two studies showed a reduced risk of distant metastasis in advanced nodal stage patients. As regards larynx preservation, ICT followed by radiation alone in responders to chemotherapy remains an effective option. Summary ICT is still controversial and in general, should remain investigational. An exception may be its use in a larynx preservation approach, albeit with a lower crude larynx preservation rate compared with CRT. The results of recent trials provide rationale and support hypothesis generation for future research, which should focus on subsets of patients most likely to benefit, for example, high nodal stage. It will be critical to study human papillomavirus (HPV)-associated oropharynx cancer separately or, at least, stratify by HPV status given its influence on prognosis and attendant implications for statistical design. Keywords chemoradiation, head and neck cancer, induction chemotherapy
INTRODUCTION In 2009, a large metaanalysis [Meta-analysis of chemotherapy in head and neck cancer (MACH_NC)] established concurrent platinum-based chemoradiation (CRT) as a standard of care for locally advanced head and neck squamous cell carcinoma (LAHNSCC) based on an 8.6% absolute increase in cancer-specific survival at 5 years, with hazard ratio, 0.81; 95% confidence interval (CI), 0.78–0.86, when compared with locoregional treatment without chemotherapy. However, despite concurrent treatment with its attendant high rates of severe acute toxicity, median survival rates were less than 50% at 3 years. This same analysis showed that ICT, predominantly with cisplatin and 5-fluorouracil, was associated with a reduced risk of distant metastasis, hazard ratio, 0.73; 95% CI, 0.61–0.88, although there was only a trend to a survival benefit with ICT (2.4% at
5 years, hazard ratio, 0.96; 95% CI, 0.90–1.02; P ¼ 0.18). The survival benefit of CRT is primarily attributed to improved locoregional control, with less impact on distant metastasis compared with ICT (hazard ratio, 0.88; 95% CI, 0.77–1) [1]. These findings, combined with the relatively poor survival
a Department of Thoracic/Head and Neck Medical Oncology, The University of Texas, MD Anderson Cancer Center, Houston, Texas, USA and b Medical Oncology, Instituto do Cancer do Estado de Sao Paulo, Faculdade de Medicina da Universidade de Sao Paulo, Sao Paulo, Brazil
Correspondence to Milena P. Mak, MD, Medical Oncology, Instituto do Cancer do Estado de Sao Paulo, Faculdade de Medicina da Universidade de Sao Paulo, Av. Dr Arnaldo, 251 5th floor, CEP 01246-000 Sao Paulo, SP, Brazil. Tel: +55 11 3893 2686; fax: +55 11 3083 1746; e-mail: [email protected] Curr Opin Oncol 2014, 26:247–251 DOI:10.1097/CCO.0000000000000073
1040-8746 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
www.co-oncology.com
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Head and neck
KEY POINTS ICT may have a role in decreasing the risk of distant metastasis in patients with high nodal stage LAHNSCC: its use in that setting remains investigational. Taxane-based ICT and definitive radiation therapy remain a treatment option for larynx and hypopharynx preservation. CRT results in higher larynx preservation rates compared with radiation therapy alone and ICT followed by radiation therapy. Using response to ICT to deintensify CRT in the setting of HPV-related oropharynx cancer remains investigational. Molecular correlates of chemotherapy/radiation therapy sensitivity and of local vs. distant recurrence risk may inform patient selection in future trials.
with CRT provided rationale for further investigation of ICT.
INDUCTION CHEMOTHERAPY IN THE SETTING OF LARYNX PRESERVATION On the basis of the results of two large randomized trials for patients with squamous cancer of the larynx and hypopharynx, respectively, ICT with cisplatin and 5-fluorouracil followed by definitive radiation for responding patients was viewed as the standard of care for larynx preservation through the 1990s. Given the efficacy of CRT, the Radiation Therapy Oncology Group 91-11 (RTOG 91-11) study randomized patients to a control arm of ICT with cisplatin and 5-fluorouracil followed by radiation therapy vs. experimental arms of cisplatin-based CRT or radiation therapy alone. The initial results of this trial published in 2003 showed that both the CRT and ICT arms had better laryngectomy-free survival (primary endpoint), compared with radiation therapy alone. There was no difference in overall survival among the three groups, presumably due to surgical salvage for locoregional recurrence. The CRT arm compared favorably in terms of larynx preservation rate and local control compared with the ICT arm (hazard ratio, 0.58; 95% CI, 0.37– 0.89; P ¼ 0.005) and the radiation therapy arm (hazard ratio, 0.46; 95% CI, 0.30–0.71; P < 0.001), albeit at the expense of significant toxicity [2,3 ]. The 5 and 10-year outcomes for RTOG 91-11, published in March 2013, continued to confirm the original findings of superior laryngectomy-free survival for both chemotherapy arms as well as higher larynx preservation rates for CRT. Most notable, however, was an excess of nonlarynx cancer-related deaths in the CRT arm, compared with ICT and &&
248
www.co-oncology.com
radiation therapy, (31, 21, and 17%, respectively), that was associated with a separation in the survival curves. This difference, however, was not statistically significant (hazard ratio, 1.25; 95% CI 0.98– 1.61; P ¼ 0.08), occurred without documented increased late effects in the CRT arm, and remains unexplained [3 ]. Nevertheless, the absolute 11% difference in 10-year survival rates favoring the ICT arm cannot be ignored and suggests that ICT followed by radiation therapy remains an effective option that might be preferred over CRT in selected patients. In 2007, two studies addressing the addition of docetaxel to cisplatin and 5-fluorouracil (TPF), compared with cisplatin and 5-fluorouracil alone followed by radiation or radiation with carboplatin, showed increased response rates and overall survival benefit for TPF [4,5], triggering evaluation of this more effective ICT regimen in larynx preservation. In the Groupe d’Oncologie Radiothe´rapie Teˆte Et Cou (GORTEC) 2000–2001, which compared TPF with cisplatin and 5-fluorouracil ICT, higher response rate (80 vs. 59%, P ¼ 0.002), treatment compliance (62.7 vs. 32%, P < 0.001), and 3-year larynx preservation (70.3 vs. 57.5%, P ¼ 0.03) were yielded with TPF. There was no difference in 3-year overall survival (OS) (60% in both arms) [6]. Building on the results of GORTEC 2000–2001, the Radiotherapy With Cisplatin Versus Radiotherapy With Cetuximab After Induction Chemotherapy for Larynx Preservation (TREMPLIN) randomized phase II trial was designed to address the optimal sequential CRT arm for larynx preservation, following TPF ICT. After TPF, responders were randomized to either cisplatin-based CRT or bioradiotherapy (BRT) with cetuximab with the intent to improve larynx preservation rates by 10% compared with those with TPF and radiation therapy (70%). A total of 153 patients eligible for total laryngectomy were included in this trial. The majority of patients (74%) were able to receive the planned three cycles of TPF, however, there were four deaths during ICT, two from toxicity. Similarly to other studies, a 23.5% rate of grade 3 and 4 toxicity occurred, mostly hematological (neutropenia and febrile neutropenia) and renal. The 126 responders by clinical, radiological, and endoscopic evaluation were randomized to CRT or BRT, which yielded equally high 3-month larynx preservation rates (95 and 93%, respectively) and comparable 18-month survival (92 and 89%, respectively) [7 ]. Because these data included only the randomized patients, they are inflated, and the authors correctly concluded that neither arm was promising enough to pursue further evaluation. These investigators continue to endorse ICT with TPF followed by &&
&
Volume 26 Number 3 May 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Induction chemotherapy for head and neck cancer Mak and Glisson
definitive radiation therapy as the standard of care for larynx preservation in managing advanced T-stage larynx and hypopharynx cancer. A pivotal question not addressed by the TREMPLIN trial is the optimal treatment of patients who do not have response to ICT. The authors reported a dropout rate of 24%, representing predominantly patients who did not respond to ICT and were offered total laryngectomy, which was performed in 69% of patients [7 ]. Although resection is the standard of care, the role of CRT in this setting may warrant investigation. In the RTOG 9111 trial, of the 24 nonresponders after two cycles of cisplatin and 5-fluorouracil ICT, seven proceeded to total laryngectomy and 11 were treated with additional CT or radiation therapy, all achieving complete response [2]. Only one patient in this group required laryngectomy. &
INDUCTION CHEMOTHERAPY VS. CHEMORADIATION IN LOCALLY ADVANCED HEAD AND NECK SQUAMOUS CELL CARCINOMA Although taxane-based ICT led to improved survival compared with cisplatin and 5-fluorouracil in LAHNSCC patients, its efficacy compared with standard CRT was not studied in TAX 323 or 324. In the 2012 American Society of Clinical Oncology annual meeting, two randomized phase III trials designed to answer that question were presented. Only one of these, PARADIGM, has been published in final form. Both are reviewed herein because of the importance of their findings in informing future research with ICT. The PARADIGM trial included 145 unresectable stage III and IV head and neck squamous cell carcinoma patients. Patients were randomized to either ICT with TPF followed by CRT or concurrent highdose cisplatin for two cycles with accelerated radiotherapy. In the ICT arm, docetaxel was given during CRT if there was inadequate response to ICT. Alternatively, carboplatin as in TAX 324, was given to patients with clear response. Sample size was originally targeted at 330 patients to detect a 40% decrease in the hazard of death, with 80% power to detect a survival rate increase from 55% in the CRT arm to 70% in the sequential CRT arm. However, because of slow accrual, the study was halted, limiting the power of the study and interpretation of its results. All 145 patients had WHO performance status 0 or 1, and the majority had stage IV disease (86%) and oropharynx primary site (55%). Human papillomavirus (HPV) status was not assessed, as accrual occurred from 2002 to 2004. Seven patients in the ICT arm (10%) were unable to receive CRT, and one
patient died during ICT. There was no difference in 3-year OS between the two groups, 78% in the CRT arm and 73% in the ICT arm (hazard ratio, 1.09; 95% CI, 0.59–2.03; P ¼ 0.77). Notably, these outcomes are markedly superior to earlier trials with either ICT or CRT. Disease failure patterns were similar in both groups. There was higher hematological toxicity in the ICT arm, with 23% grade 3 or 4 febrile neutropenia compared with 1% in patients who underwent CRT [8 ]. As previous data had demonstrated that ICT could decrease the rate of distant metastasis [1], in the Docetaxel Based Chemoradiotherapy Plus or Minus Induction Chemotherapy to Decrease Events in Head and Neck Cancer (DeCIDE) trial, only patients considered at highest risk of distant failure (N2/N3) were included. From 2004 to 2009, patients were randomized to two cycles of TPF followed by CRT with DFHX (docetaxel 25 mg/m2 d1, 5-fluorouracil 600 mg/m2 d1–d5, and hydroxyurea and radiation with 150 cGy twice daily d1–d5 every 2 weeks for four cycles) or the same CRT regimen. In order to detect a 35% (hazard ratio 1.6) reduction in the risk of death in the sequential arm, an original sample size of 400 patients was planned; assuming an increase in 3-year OS from 50% in the CRT arm to 65% in the sequential treatment. Because of slow accrual, sample size was reestimated, targeted hazard ratio was increased to 2.0, and after the inclusion of 280 patients, the study was closed. The most frequent primary site was oropharynx (58%) and, as in PARADIGM, HPV status was not assessed prospectively. A 7% dropout rate was seen in the ICT arm. Both arms had similar OS rates at 3 years with 75% in the ICT arm and 73% in the CRT arm (hazard ratio, 0.92; 95% CI, 0.59–1.42; P ¼ 0.70). Again, these outcomes are superior to older trials. There were significantly fewer distant failures in the ICT arm (10 vs. 19%, hazard ratio, 0.46 95% CI 0.23–0.92; P ¼ 0.025). In an unplanned subset analysis, a statistically significant difference in distance recurrence without locoregional recurrence was found in favor of the ICT arm (P ¼ 0.043). There was a trend to survival benefit for 96 patients with N2c and N3 tumors (P ¼ 0.19) [9 ]. The results are notable given these patients received only two cycles of ICT. Both DeCIDE and PARADIGM were unable to accrue to their original target and are thus, underpowered. Further complicating interpretation is the improved outcome of both control arms compared with the estimated survival rates (50 and 55%, respectively). This likely reflects the impact of HPV-related oropharynx cancers in both arms, although contributions from an improvement in supportive care and radiation planning/technique
1040-8746 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
&&
&
www.co-oncology.com
249
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Head and neck
are also possible. As in many trials with ICT, a small subset of patients experienced toxicity during ICT, which compromised their ability to complete or initiate curative CRT. This emphasizes the need for careful patient selection and aggressive supportive care. Although ICT did not result in an overall survival benefit compared with CRT in either trial, neither study can be viewed as definitive on this point given the statistical issues. The trend to survival benefit for patients with N2c/N3 disease from DeCIDE warrants further investigation.
PREOPERATIVE CHEMOTHERAPY Surgical treatment is the preferred option for the management of oral cavity squamous cell carcinoma (OSCC). The addition of postoperative radiation or CRT in patients at high risk of recurrence has improved outcomes; however, survival rates at 5 years remain only 50–60% [10,11]. A previous phase III study evaluating preoperative cisplatin and 5-fluorouracil in locally advanced OSCC patients failed to demonstrate any survival advantage, with 5-year OS of 55% in both arms [12]. To evaluate the more effective TPF regimen in this setting, 256 patients with locally advanced OSCC who were candidates for curative resection were randomized to either two cycles of TPF followed by surgery or surgery alone in a phase III trial from China. Postoperative radiation therapy consisted of 54–60 Gy and 66 Gy in patients whose tumors had high-risk features. The response rate after ICT was 81% assessed by Response Evaluation Criteria In Solid Tumors. Pathologic complete response was observed in 12% of specimens from the ICT arm. However, at 2 years, there was no difference in OS between the treatment arms (68 and 69%, for ICT and surgery arms, respectively). The rate of distant metastasis also did not differ (5% ICT and 9% surgery). The rate of grade 3 hematological toxicity was only 7%, and there was no increase in perioperative morbidity in the ICTtreated patients. An exploratory subset analysis demonstrated a distant metastasis-free survival and overall survival benefit for patients with N2c disease on the ICT arm, (hazard ratio, 0.418; 95% CI, 0.179–0.974; P ¼ 0.043). In the ICT overall population, better outcomes were seen in patients who experienced favorable pathologic response (
![[Induction chemotherapy in locally advanced head and neck cancer? Yes].](/assets/img/hold.png)
