For patients with locally or regionally advanced SCC, much effort has been directed toward improvements in primary management with the addition of chemotherapy to surgery, radiotherapy, or both. Toward this end, three general strategies have been undertaken: (1) induction, also known as neoadjuvant therapy, with chemotherapy given before surgery or radiation; (2) concomitant chemoradiation, with chemotherapy given simultaneously with radiation to enhance its effect; and (3) adjuvant therapy, where chemotherapy is given after surgery or radiation in an effort to decrease microscopic metastatic disease burden.
Induction chemotherapy has been investigated as an approach to improve outcomes in terms of overall survival and tumor control in patients with stage III/IV disease undergoing definitive local therapy. Theoretical advantages to this approach include reducing the risk of distant disease recurrence, enhancing organ preservation, improving response to definitive radiotherapy by reducing tumor bulk, and modification of subsequent local therapy to response.
This approach was first investigated in the 1970s after the cisplatin and 5-FU regimen proved to be highly active in metastatic disease. Trials over the next three decades investigated the role of chemotherapy added to local therapy in locally advanced disease. In the 2009 meta-analysis that established concomitant chemoradiation as a standard of care for nonsurgical management of stage III/IV SCC, direct comparisons of concomitant chemoradiation and induction chemotherapy indicated that although concomitant chemoradiation was superior to induction chemotherapy followed by radiation for local control and survival, induction chemotherapy was more effective at decreasing distant failure (42). This conclusion lent credence to contemporaneous trials investigating induction chemotherapy followed by chemoradiation.
Following demonstration of the activity of taxanes in head and neck cancer, a series of trials investigated the combination of three-drug regimens with a platinum, taxane, and 5-FU. In 2007, two multicenter phase III trials, the European TAX 323 (43) and the North American TAX 324 (44), demonstrated the superiority of induction TPF (docetaxel, cisplatin, 5-FU) over PF (cisplatin, 5-FU). In TAX 323, a total of 358 patients with untreated, unresectable, and locally advanced tumors were randomized to receive either docetaxel 75 mg/m2, cisplatin 75 mg/m2, and 5-FU 750 mg/m2/d for 5 days (TPF) or cisplatin 100 mg/m2 and 5-FU 1,000 mg/m2/d for 5 days (PF), followed by radiotherapy alone. The primary end point, median progression-free survival, was 11.0 months in the TPF group and 8.2 months in the PF group (hazard ratio [HR], 0.72; P = .007), and median overall survival was 18.8 months versus 14.5 months. The TAX 324 trial also compared TPF to PF, but in that study, the doses in the TPF arm were docetaxel 75 mg/m2, cisplatin 100 mg/m2, and 5-FU 1,000 mg/m2/d for 4 days. Both induction regimens were followed by concomitant chemoradiotherapy with weekly carboplatin area under the curve (AUC) of 1.5. The median overall survival was 71 months in the TPF group and 30 months in the PF group (P = .006). Notably, there was better locoregional control in the TPF group than in the PF group (P = .04). Rates of neutropenia and febrile neutropenia were significantly higher in the TPF group in both studies.
These two phase III trials led to US Food and Drug Administration (FDA) approval of induction chemotherapy TPF for patients with locally advanced HNSCC in 2007. Despite the impressive results of TAX 324, the value of adding induction chemotherapy to chemoradiation remained an unanswered question given the lack of definitive randomized trials comparing this approach to upfront chemoradiation. A randomized phase II trial by Paccagnella et al of induction TPF followed by chemoradiation versus chemoradiation alone reported a higher radiologic clinical response and a trend toward improved progression-free survival and overall survival (45).
Two recent phase III trials, PARADIGM (46) and DeCIDE (47), were designed to test the hypothesis that induction chemotherapy followed by chemoradiation would confer a survival benefit over chemoradiation alone. These studies failed to meet their accrual targets and were therefore underpowered. The PARADIGM trial enrolled previously untreated patients with SCC of the oral cavity, oropharynx, hypopharynx, or larynx, patients with tumors deemed to be either unresectable or of low surgical curability on the basis of T stage (T3 or T4) and/or nodal status (N2 or N3), or patients who were candidates for organ preservation. The concomitant chemoradiation alone control group received cisplatin 100 mg/m2 on days 1 and 22, and radiotherapy was given as an accelerated concomitant boost over 6 weeks for a total of 72 Gy in 1.8-/1.5-Gy fractions. Induction TPF was given as per TAX 324, and subsequent chemoradiation was adapted to response. Partial and complete responders received weekly carboplatin at AUC 1.5 for 7 weeks and 70 Gy of radiotherapy over 7 weeks in 2-Gy fractions. Patients who responded poorly were treated with an intensified regimen of weekly docetaxel 20 mg/m2 for 4 weeks and 6 weeks of radiation to 72 Gy. The trial was powered to detect an improvement in 3-year survival from 55% in the control group (based on historical controls) to 70% in the induction group. However, due to slow accrual, the trial closed with 145 patients enrolled, less than half of the planned enrollment. Overall 3-year survival was 73% (95% confidence interval [CI], 60%-82%) in the induction TPF followed by chemoradiation group versus 78% in the chemoradiation alone group (46).
The DeCIDE trial (47) randomized patients with N2/3 M0 disease to either two cycles of induction TPF followed by chemoradiation or chemoradiation alone. Chemoradiation was given as DFHX (docetaxel, 5-FU, and hydroxyurea) with concurrent twice-daily radiotherapy or IMRT. Radiation doses were adaptive, with 74 to 75 Gy given to gross disease, 54 Gy to high-risk microscopic disease, and 39 Gy to low-risk microscopic disease. This study was similarly powered to detect an improvement in 3-year survival from 50% in the control group to 65% in the induction group. However, this trial also failed to accrue well, enrolling 280 patients versus the planned 400 patients. There were no statistically significant differences in overall survival (HR, 0.91; 95% CI, 0.59-1.41) or relapse-free survival. In competing risk analysis, there was a statistically significant reduction in risk of distant relapse without locoregional recurrence in the induction arm (P = .043).
Given that both studies failed to show survival benefit, but were ultimately underpowered to do so, the role of induction chemotherapy remains controversial. Importantly, in both studies, the 3-year overall survival rate of 70% to 78% in the chemoradiation alone arm was significantly higher than the historical control of 50% to 55% used in the pretreatment power calculations. This improvement in survival is likely multifactorial—a result of improved supportive care, technical advances in radiotherapy, and a shift in the biology of the disease the incidence as smoking-induced cancers declines and HPV-associated HNSCCs increases. Although the PARADIGM trial did not test for HPV, in DeCIDE, the HPV-positive rate of the 31% of patients tested was over 80%, and HPV-associated disease is known to have higher survival rates.
The Gruppo di Studio Tumori della Testa e del Collo (GSTCC) trial presented by Ghi and colleagues at the 2014 American Society of Clinical Oncology (ASCO) annual meeting, but not yet published, is a 2 × 2 factorial design of induction TPF versus no induction followed by chemoradiation with either cetuximab or PF in 415 patients. This trial showed a survival benefit of 53.7 months in the induction arm versus 30.3 months in the upfront chemoradiation arm (HR, 0.72; 95% CI, 0.55-0.96; P = .025) and additionally showed a reduction in distant metastases. The difference in outcomes observed in this trial versus the DeCIDE and PARADIGM trials is likely due to different patient populations and inclusion criteria.
Induction chemotherapy may also have value as a component of a sequential approach in which chemotherapy is followed by radiotherapy as a single modality in select locally advanced patients, thus sparing some of the toxicity of concomitant chemoradiation. In our center, a phase II trial with 47 patients investigated the efficacy of combining cetuximab with paclitaxel and carboplatin in a 6-week induction regimen followed by risk-based local therapy (radiation, concomitant chemoradiotherapy, or surgery) based on tumor stage and site at diagnosis. Inclusion criteria were stage IV M0 with nodal staging of N2b/c/N3. Of note, local therapy was determined at diagnosis and was not adapted to response. After induction chemotherapy, 9 patients (19%) achieved a clinically complete response, and 36 patients (77%) achieved a partial response. Local therapy consisted of concomitant chemoradiotherapy in 23 patients, radiotherapy alone in 23 patients, and surgery in 1 patient. The 3-year progression-free survival and overall survival rates were 87% and 91%, respectively (48). A recent update to this trial reported a 5-year overall survival rate of 89% and very favorable long-term speech and swallow functions (49). This strategy is undergoing further testing. At the ASCO 2014 annual meeting, Cmelak et al (50) presented preliminary results of E2399. Patients with locally advanced HPV-positive disease responding to induction chemotherapy with paclitaxel, cisplatin, and cetuximab were effectively treated with a reduced-dose cetuximab-IMRT regimen, 54 Gy, if they achieved a clinical complete response to the induction chemotherapy. An early outcomes analysis showed 84% progression-free-survival and 95% overall survival at 2 years.
Concomitant Radiotherapy and Chemotherapy
In patients with locally advanced but M0 disease, the strategy of concomitant radiotherapy and chemotherapy has led to improved local and regional tumor control compared to radiotherapy alone (42). Synergy between chemotherapy and radiation is based on several mechanisms, including (1) inhibition of DNA repair; (2) redistribution of cells to sensitive phases of the cell cycle; and (3) promoting oxygenation of anoxic tissues. The net effect is to improve cellular cytotoxicity (51,52,53). However, combined therapy also enhances acute mucocutaneous toxicity, which may prompt subsequent dose reductions and treatment interruptions in radiotherapy. Thus, in combining these two treatment modalities, it is essential that toxicity not preclude the delivery of therapy in an effective schedule to avoid compromise of efficacy.
In a landmark phase II trial in 1987, the RTOG administered cisplatin (100 mg/m2) every 3 weeks to 124 patients with locally advanced unresectable head and neck cancer (54). Sixty percent of patients completed the combined treatment per protocol, and 69% of all patients achieved a complete response. A comparison to RTOG patients treated with radiotherapy alone suggested improvement in survival time for the combined treatment.
The use of concomitant combination chemotherapy and radiation has long been under intense study (55). Meta-analysis (42) of prospective clinical trials demonstrates an enhancement of local tumor control and improvement of survival with combined therapy over radiation treatment alone, and chemoradiation is the standard of care in locally advanced non-surgical disease.
Combining several drugs with radiation will enhance acute toxicity, which may be severe. Therefore, investigators have piloted trials designed with split-course radiation to allow for healthy tissue recovery. Most of these studies have been limited to patients with stage III or IV locally advanced SCC, with local control and improved survival time as the primary objectives. These regimens alternate chemotherapy and radiotherapy or use split-course radiotherapy to maximize tumor cell kill and minimize tissue toxicity. However, protracted radiation treatment times may result in decreased local control rates because of accelerated repopulation of cancer stem cells (56,57). The strategy of alternating non–cross-resistant agents may potentially eliminate not only tumor cell repopulation but also primary drug resistance.
Brizel et al (58) compared a hyperfractionated radiotherapy arm to total dose of 75 Gy versus concomitant PF and hyperfractionated radiation to 70 Gy followed by two cycles of adjuvant chemotherapy. There was a statistically significant improvement in local disease control and a strong trend toward improved overall survival for the combined-modality arm. In this trial, neck dissection was recommended in patients with N2/3 disease. Clayman et al (59) have reviewed the MDACC experience, examining the indication for neck dissection in this patient population. Their report suggests that neck dissections are required only when there is radiographic evidence of residual disease 6 to 8 weeks following the completion of definitive chemoradiation. Wendt et al (60) reported a statistically significant 3-year survival advantage after the concomitant use of cisplatin, 5-FU, and leucovorin with split-course radiotherapy versus radiotherapy given as a single therapeutic modality. Calais et al (61) compared a more standard once-daily fractionation radiation schedule with the same radiotherapy and concomitant carboplatin and 5-FU, demonstrating a statistically significant advantage in locoregional tumor control and overall survival at 3 years. Jeremic et al (62) also investigated the value of adding cisplatin given daily to a hyperfractionated radiation therapy program versus the same radiation schedule given alone in patients with locally advanced HNSCC. In this report, locoregional and distant disease control and overall survival were improved at 5 years. Adelstein et al (63) compared standard daily radiotherapy with two schedules of concomitant chemoradiotherapy in a large intergroup study. The addition of high-dose cisplatin to conventional single daily dose radiotherapy improved survival from 23% to 37% at 3 years. The clearest benefit in these studies was an improvement in locoregional control, which translated into a survival advantage. Acute toxicity was increased, especially mucositis and hematologic effects, but there was no obvious escalation of long-term sequelae. However, this may need further investigation. In aggregate, overall 3-year survival exceeded 50% in these experimental programs, underscoring the potential therapeutic efficacy of concomitant chemotherapy and radiation in patients with advanced head and neck cancers.
Cetuximab, a monoclonal antibody, is approved for use in combination with radiation in previously untreated patients. In a landmark study, patients with locoregionally advanced head and neck cancer were randomly assigned to receive either high-dose radiotherapy alone (213 patients) or high-dose radiotherapy plus weekly cetuximab (211 patients) at an initial dose of 400 mg/m2 of body surface area, followed by 250 mg/m2 weekly for the duration of radiotherapy (64). The primary end point, median duration of locoregional control, was 24.4 months among patients treated with cetuximab plus radiotherapy and 14.9 months among patients given radiotherapy alone (HR, 0.68; P = .005). The median duration of overall survival was 49.0 months among patients treated with combined therapy and 29.3 months among patients treated with radiotherapy alone (HR for death, 0.74; P = .03). However, the rates of distant metastases at 1 and 2 years were similar in both groups. With the exception of acneiform rash and infusion reactions, the incidence of grade 3 or greater toxic effects, including mucositis, did not differ significantly between the two groups.
Cetuximab plus radiotherapy is directly compared to chemoradiation for patients with HPV-associated oropharyngeal cancer in a phase III randomized trial (RTOG 1016), but results from this trial are not yet available. This trial represents the recent trend in investigational treatment strategies undertaken by clinical trial cooperative groups that have focused on treatment “de-intensification” for selected patients (namely those with HPV-associated oropharyngeal cancer), with the goals of maintaining or improving established cure rates but reducing treatment-related toxicity.
There has been a series of trials investigating the use of EGFR antibodies with chemoradiation. The phase III RTOG 0522 trial randomized 940 patients to high-dose cisplatin-based chemoradiotherapy with or without cetuximab (65). The combined biochemoradiotherapy failed to meet the primary end point of improving progression-free survival, with a 3-year rate of 61.2% versus 58.9% with cetuximab, and demonstrated a trend toward worse locoregional control. This trend was likely the result of significantly increased toxicities that led to radiation interruptions in 26.9% of patients. There was also a significant difference in treatment-related deaths (10 vs 3; P = .05). The CONCERT-1 and -2 trials have further explored bioradiotherapy with panitumumab (Table 19-4) (66,67), showing no overall survival or local disease control advantage after matching chemoradiotherapy with the addition of the antibody.
Table 19-4EGFR-Based Bioradiotherapy With Panitumumab ||Download (.pdf) Table 19-4 EGFR-Based Bioradiotherapy With Panitumumab
| ||No. ||2-Year LRC (%) |
|CONCERT-1 || || |
| CT-RT ||63 ||68 |
| CT-RT + P ||87 ||61 |
|CONCERT-2 || || |
| CT-RT ||61 ||61 |
| P-RT ||90 ||51 |
The aggregate results of these trials indicate that improved disease-free and overall survival times have been obtained for patients with locally advanced HNSCC using concomitant chemotherapy and radiotherapy rather than radiotherapy as a single treatment modality. Combination chemotherapy with radiotherapy may increase response but causes increased toxicity. Well-designed clinical trials are still needed to determine optimal chemotherapy and radiotherapy schedules.
Adjuvant chemotherapy is indicated in patients at high risk of recurrence after surgical resection, generally defined as having narrow or involved margins at the primary site, multiple nodal metastases, or extracapsular spread (Table 19-5) (68,69,70).
Table 19-5Postoperative Chemoradiation: Randomized Trials ||Download (.pdf) Table 19-5 Postoperative Chemoradiation: Randomized Trials
|Study ||Eligibility ||Experimental Arms ||Outcome |
|Bachaud et al (68), 1996 ||Nodal ECS ||RT + weekly cisplatin (n = 39) ||DFS (P < .02) and OS (P < .01) better |
|RTOG 9501 (69), 2004 ||Multiple nodal metastases, ECS, or positive margins ||RT + cisplatin days 1, 22, 43 (n = 228) ||2-y LRC (82% vs 72%; P = .01) + PFS (P = .04) better |
|EORTC 22931 (70), 2004 ||Stage III/IV ||RT + cisplatin days 1, 22, 43 (n = 167) ||PFS (P = .04) + OS (P = .02) better |
Two large phase III studies, RTOG 9501 (69) and EORTC 22931 (70), tested cisplatin-based concomitant chemoradiotherapy in the adjuvant setting. Although with some variations between the studies, patients with high-risk features (positive margin, extracapsular spread, lymphovascular invasion, perineural invasion, and multiple positive lymph nodes) were randomly assigned to receive either radiotherapy alone or radiotherapy plus cisplatin at 100 mg/m2 every 3 weeks for three cycles. In RTOG 9501, concomitant chemoradiotherapy significantly reduced the risk of locoregional recurrence compared with radiotherapy alone (HR for local or regional recurrence, 0.61; P = .01). However, no survival benefit was observed. In addition, the incidence of grade 3 or greater adverse effects was 34% in the radiotherapy group and 77% in the combined-therapy group (P < .001). In EORTC 22931, both the progression-free survival (HR, 0.75; P = .04) and overall survival (HR, 0.70; P = .02) rates were significantly higher in the combined-therapy group than in the radiotherapy group. Severe acute adverse effects were more frequent after combined therapy (41%) than in the radiotherapy group (21%).
More recently, based on the benefit of cetuximab bioradiotherapy in the definitive setting and the additive benefit of cetuximab to chemotherapy in the metastatic setting (71), RTOG 0234 explored the incorporation of cetuximab into adjuvant chemoradiation (72). This phase II trial compared two biochemoradiotherapy regimens to historical high-dose cisplatin-based chemoradiotherapy in RTOG 9501 with the intent to select a regimen for further testing against standard high-dose cisplatin-based chemoradiotherapy in a phase III trial. Both docetaxel (15 mg/m2)/radiation/cetuximab and weekly cisplatin (30 mg/m2)/radiation/cetuximab outperformed the historical control with 2-year overall survival rates of 79% and 69% and 2-year disease-free survival rates of 66% and 57%, respectively (HR, 0.69 for the docetaxel arm vs control, P = .01; and HR, 0.76 for the cisplatin arm vs control, P = .05). Grade 3 or 4 myelosuppression was observed in 28% of patients in the cisplatin arm and 14% of patients in the docetaxel arm, and mucositis was observed in 56% and 54% of patients, respectively. Although these results are promising, as has been noted previously, comparison with historical controls is problematic given the shifting epidemiology from smoking-related cancer to better prognosis HPV-related cancers, which has likely contributed to the improvements in survival rates of the control arms seen in the recent induction trials (46,47). RTOG 1216 is an ongoing phase II/III trial of surgery and postoperative radiation delivered with concurrent cisplatin versus docetaxel versus docetaxel and cetuximab for high-risk HNSCC.
Although adjuvant concomitant chemoradiotherapy has been demonstrated to be more effective than radiotherapy, there is significant associated toxicity. The two risk factors most associated with benefit from concomitant chemoradiotherapy are extracapsular extension and positive surgical margins (73).