A phase 2 trial of induction nab-paclitaxel and cetuximab given with cisplatin and 5-fluorouracil followed by concurrent cisplatin and radiation for locally advanced squamous cell carcinoma of the head and neck†‡
We recognize the contributions by Jose Iglesias, MD; Rick Hippert; Bruce Haughey, MBBS; Jason Diaz, MD; Randall Paniello, MD; Eric Hallowell; and Nancy Gregory.
Poster presentations were made at the American Society of Clinical Oncology annual meetings of 2010 and 2011.
Complete response (CR) at the primary tumor site as assessed by clinical examination following induction chemotherapy with PF (cisplatin and 5-fluorouracil [5-FU]) is a favorable predictive factor for overall survival and disease control in patients with locally advanced squamous cell carcinoma of the head and neck. In most series, the rate of CR at the primary site after induction PF was 20% to 30%. This study evaluated the efficacy and feasibility of induction nab-paclitaxel and cetuximab given with PF (ACPF) followed by definitive chemoradiation (CRT) in a phase 2 trial.
Patients with squamous cell carcinoma of the head and neck were treated with ACPF (nab-paclitaxel 100 mg/m2/week; cetuximab 250 mg/m2/week; cisplatin 75 mg/m2 on day 1; 5-FU 750 mg/m2/day on days 1 through 3) every 21 days for 3 cycles followed by CRT (cisplatin 100 mg/m2 on days 1, 22, and 43 of radiation therapy [RT]). CR at the primary tumor site after 2 cycles of ACPF was the primary endpoint.
Thirty patients were enrolled, of which 22 (73%) had large (T3/T4) primary tumors. The CR rate at the primary tumor site after 2 cycles of ACPF was 53% and the overall response rate was 100%. Twenty-nine (96%) patients completed 3 cycles of ACPF, 26 (90%) completed definitive RT per protocol, and 22 of the 27 evaluable patients (81%) received > 2 of the 3 planned doses of cisplatin with RT. The estimated 2-year overall and progression-free survival rates were 84% and 65%, respectively.
Squamous cell carcinoma of the head and neck (HNSCC) afflicts more than 500,000 patients annually worldwide.1 Most patients present with locally advanced disease and are often treated with definitive radiation therapy (RT). Chemotherapy given concurrently with RT (CRT) improved local-regional disease control and overall survival (OS) compared with RT alone but had minimal impact on the rate of distant metastases.2 Randomized trials of induction chemotherapy demonstrated a reduction in distant failure rates, but only 2 trials showed an improvement in OS.3, 4 Recently, superior OS was observed with the addition of either docetaxel or cremophor-based paclitaxel to induction PF (cisplatin and 5-fluorouracil [5-FU]) in patients subsequently treated with definitive RT5 or CRT.6, 7 However, recurrent disease remains the primary cause for treatment failure following induction chemotherapy and definitive CRT.
Complete response (CR) at the primary site following induction PF correlated with improved OS and disease control after definitive RT.8, 9 In most series, the rate of CR at the primary site after induction PF was 20% to 30%.4, 9 Two strategies to improve CR rates at the primary site following induction chemotherapy include the use of novel taxanes and the addition of epidermal growth factor receptor inhibitors. Increased intratumoral paclitaxel accumulation and antitumor activity occurred with nanoparticle albumin-bound paclitaxel (nab-paclitaxel; Celgene Corporation, Summit, NJ) compared with cremophor-based paclitaxel in nude mice bearing several human tumor xenografts.10
In breast cancer, nab-paclitaxel resulted in higher tumor response rates in comparison with cremophor-based paclitaxel,11 which may be due to the high tumor expression of SPARC (secreted protein acidic and rich in cysteine). SPARC plays a role in albumin receptor–mediated endothelial transport.12 SPARC expression is common in tumor and stromal cells of HNSCC but not in adjacent normal oral mucosa,13 and correlated with tumor response to nab-paclitaxel in patients with HNSCC.14 More specifically, the concept is that high tumor expression of SPARC reflects tumor cells that have high rates of albumin receptor–mediated endocytosis, and they respond better to albumin-bound chemotherapeutic agents because they accumulate more albumin in the tumor cells. Inhibition of epidermal growth factor receptor by cetuximab reduces proliferation and induces apoptosis of HNSCC cell lines, and enhances the activity of cisplatin in xenograft models.15 The addition of cetuximab to PF increased tumor response rates and OS in patients with metastatic HNSCC, and had an acceptable safety profile.16
We hypothesized that a novel induction regimen of weekly nab-paclitaxel and cetuximab given with every 3-week PF (ACPF) would result in a high favorable tumor response rate in patients with locally advanced HNSCC who are subsequently treated with definitive CRT. The primary efficacy endpoint was CR rate at the primary tumor site after 2 cycles of induction chemotherapy as assessed by clinical examinations, because this endpoint represents a surrogate marker of improved disease control after definitive RT.8, 9 We also sought to determine whether this novel regimen would be associated with an acceptable toxicity profile and whether it would adversely affect delivery of definitive CRT.
MATERIALS AND METHODS
Eligible patients were 18 years of age or older with untreated HNSCC of stages III and IVa/b (T1 excluded) originating in the oropharynx, larynx, and oral cavity.17 Other criteria included adequate performance status (Eastern Cooperative Oncology Group status of 0 to 2) and vital organ function. Exclusion criteria included peripheral sensory neuropathy (PSN) of grade 2 or higher. The Washington University Human Research Protection Office approved the protocol, and all study participants signed informed consent. This clinical trial was registered at ClinicalTrials.gov under identifier NCT00736944.
Induction therapy consisted of every 3-week cycles of intravenous (IV) nab-paclitaxel 100 mg/m2 weekly on days 1, 8, and 15, cetuximab 400 mg/m2 day 1 and 250 mg/m2 weekly subsequently, cisplatin 75 mg/m2 on day 1 and 5-FU 750 mg/m2 continuous infusion daily on days 1-3 (ACPF) (Fig. 1). After 2 cycles of ACPF, patients underwent an assessment of tumor response at the primary site by clinical examination (laryngoscopy in office or operating room) by experienced oncologic surgeons, using categorical outcomes commonly employed by others with slight modifications:8, 18 CR, defined as complete resolution of lesion or near CR, with minimal residual mucosal abnormality; partial response (PR), defined as 50% to 94% decrease; stable disease (SD), defined as 0% to 49% decrease; and progressive disease (PD), defined as any increase. Patients with favorable (ie, CR, near CR, PR) tumor response at the primary site by clinical examination then received a third cycle of ACPF before definitive CRT, whereas patients with an unfavorable (ie, SD, PD) tumor response at the primary site by clinical examination proceeded directly to definitive CRT.
Definitive CRT began within 22 to 56 days after the initiation of cycle 3 of ACPF. Intensity-modulated radiation therapy was administered once daily, 5 days weekly. The total dose of RT to gross disease was 7000 cGy in 35 fractions of 200 cGy each over 7 weeks, and areas at risk for microscopic disease in the ipsilateral and contralateral neck received 5600 cGy. A dose of 6300 cGy in 35 fractions was allowed to areas considered intermediate risk at physician discretion. Patients with serum creatinine < 2.0 mg/dL were scheduled to receive cisplatin 100 mg/m2 on days 1, 22, and 43 of RT. Patients who failed to meet this criteria and had no serious hypersensitivity reaction with prior cetuximab, received cetuximab (400 mg/m2 IV loading dose 1 week before RT then 250 mg/m2 weekly × 7 doses) as a single agent concurrent with RT. Patients who failed to meet criteria for either cisplatin or cetuximab received RT alone.
Baseline assessments included history and physical examination, laryngoscopy, computed tomography (CT) of the neck, and body [18F]fluorodeoxyglucose positron emission tomography/CT (FDG-PET/CT). Assessments of patient symptoms and adverse events (AEs) were performed weekly during ACPF, every 3 weeks during and 4 to 6 weeks after RT using National Cancer Institute Common Toxicity Criteria (NCI-CTC), version 3.0. After 2 cycles of ACPF and 10 to 12 weeks after RT, patients underwent assessment of tumor response by clinical examination, CT of the neck, and FDG-PET/CT. Response Evaluation Criteria In Solid Tumors (RECIST), version 1.0 was used to determine anatomic tumor response by CT.19 Subsequently, patients were assessed for tumor response with physical examination and laryngoscopy every 3 months and CT of the neck and chest performed at 6, 12, 20, 28, and 36 months following RT. Patient comorbidities were quantified using the 27-item Adult Comorbidity Evaluation (ACE-27) index.20
SPARC expression was assessed by immunohistochemistry (IHC) performed on pretreatment formalin-fixed, paraffin-embedded primary tumor specimens using 4-μm sections. IHC was performed by hand using a commercially available monoclonal antibody for SPARC (osteonectin; clone 15G12; Vector Laboratories; dilution 1:50; antigen retrieval consisting of proteinase K digestion; 30-minute room temperature incubation with primary antibody followed by a 30-minute room temperature incubation with secondary). A known SPARC-expressing HNSCC was used as a positive control. Samples were analyzed semiquantitatively by the study pathologist (J.L., Jr.) reviewing 10 high-power fields with scoring of tumor cells for extent of staining in quartiles as: 0 = no staining; 1+ = 0% to 24% staining; 2+ = 25% to 49% staining; 3+ = 50% to 74% staining; 4+ = 75% to 100% staining. Samples were also analyzed semiqualitatively for staining intensity of tumor cells as: negative = none; 1+ = weak; 2+ = moderate; 3+ = strong. Similar analyses were performed on the peritumoral stromal fibroblasts.
For all patients with oropharyngeal primaries, IHC was performed for p16 as described.21 Slides were reviewed by the study pathologist and scored in a binary fashion as positive (staining in > 50% of tumor cells) versus negative (no staining or staining in <50% of tumor cells).
Tumor Response and Survival
The primary objective was to determine the CR rate (defined as a composite of CR and near CR) at the primary tumor site using clinical examinations following 2 cycles of ACPF. We hypothesized that the CR rate at the primary tumor site would be at least similar to our historical experience with docetaxel, PF, and cetuximab (TPF+Cet): 50% in T2, 20% in T3, and 0% in T4 disease.22 Given a sample size of 30 patients (10 in each T-classification stratum), the overall proportion with CR at the primary tumor site was estimated within 19%, as the 95% confidence interval for 7 of 30 patients (9.9%, 42.3%).
OS (time from diagnosis to death or to last follow-up alive) and progression-free survival (PFS, time from diagnosis to death due to disease progression, to disease progression or to last follow-up alive) were estimated by the Kaplan-Meier method.23 RT delivery (number of fractions, elapsed days, and total dose) and chemotherapy administration (number of planned doses administered, total dose/m2) were determined and summarized for the group by descriptive statistics.
Safety Analysis and Planned Stopping Rule
The type and grade of each AE were documented in a frequency distribution for the whole group. An interim safety analysis was performed after the first 10 patients to confirm that the rate of grade 3 or 4 AEs during ACPF did not exceed the predetermined maximum allowable frequency of 35%.
Patient Characteristics and SPARC Expression
Thirty patients were enrolled (Table 1). Most patients were older than 50 years and were smokers. Significant comorbidities ranging from moderate to severe (ACE-27 indices scores of 2 or 3) were present in 63% of patients. Most patients had large (T3,T4) primary tumors (74%) and bulky (> N2b) nodal disease in the neck (80%). Twenty-two patients (73%) had oropharyngeal cancers, of which 17 of 21 (81%) tested were positive for p16, a surrogate marker for the human papilloma virus (HPV).
Table 1. Patient and Tumor Characteristics
Age, y (mean)
ECOG performance status
ACE comorbidity index
N0 and N1
SPARC expression was assessed by IHC staining on 28 patients (Table 2). The proportion of cells staining for SPARC and the staining intensity of SPARC expression were greater in the stromal cells compared with that of the tumor cells. Stromal fibroblast staining for SPARC was present in all 28 evaluable cases (100%), whereas tumor cell staining was present in 10 of 28 evaluable cases (35.7%).
Abbreviations: IHC, immunohistochemistry; SPARC, secreted protein acidic and rich in cysteine.
Proportion of cells positive in 10 high-power fields
Intensity of cell staining
Overall positive staining
Primary Tumor Site Response to ACPF
After 2 cycles of ACPF, the composite CR rate at the primary tumor site as assessed by clinical examination was 53.3% (CR was 40% [12 patients]; near CR was 13.3% [4 patients]), whereas the rate of PR was 46.7% (14 patients). On univariate analysis, variables associated with attaining a CR at the primary tumor site following 2 cycles of ACPF included fewer packs per day smoked and absence of SPARC staining in the tumor (Table 3).
Table 3. Variables Associated With Primary Tumor Site Response to 2 Cycles of ACPF
Primary Tumor Site Response
Fisher's exact test; *** Kruskal-Wallis test.
Abbreviations: ACPF, nab-paclitaxel, cetuximab, cisplatin, 5-fluorouracil; SPARC, secreted protein acidic and rich in cysteine.
The tumor response rates at neck nodal sites after 2 cycles of ACPF based on clinical examinations were 61% CR (11 patients) and 39% PR (7 patients). Twelve patients were not evaluable because of initial absence of nodal disease on clinical examination. On univariate analysis, the only variable associated with attaining a CR at the neck nodal sites following 2 cycles of ACPF was absence of smoking history (CR in 3 of 3 nonsmokers versus 8 of 15 smokers, P = .049). Table 4 summarizes and correlates the tumor response rates at the primary site and at the neck nodes after 2 cycles of ACPF based on clinical examination, CT, and FDG-PET/CT scans.
Table 4. Tumor Response at Primary and Neck Nodal Sites as Assessed by Clinical Examination, CT, and FDG-PET/CT Following 2 Cycles of ACPF
Thirty patients completed 2 cycles, and 29 of the patients completed 3 cycles of ACPF, and 28 patients underwent definitive radiation-based therapy per protocol. One patient died after cycle 2 of ACPF due to treatment-related mortality (TRM), and 1 was removed from study following ACPF due to noncompliance but was treated with definitive CRT.
During ACPF, the proportion of planned doses of nab-paclitaxel, cisplatin, cetuximab, and 5-FU administered were 92%, 97%, 87%, and 99%, respectively. During definitive RT, 26 patients received cisplatin, 1 received cetuximab, 1 received RT alone, and 1 received cisplatin off protocol. Twenty-six of the 29 evaluable patients (90%) completed the planned 35 fractions of RT, whereas 2 elected to stop RT early and 1 received RT off protocol. The median (range) elapsed days and dose of RT administered were 50 (8-69) and 70 Gy (14-72 Gy), respectively. The proportions of the 27 evaluable patients given 3, 2, 1, or 0 doses of cisplatin during RT were 48% (13), 33% (9), 15% (4), and 4% (1), respectively. Across the planned sequential therapy with ACPF and CRT, the median (range) cumulative dose of cisplatin delivered was 425 mg/m2 (150-525 mg/m2).
Adverse Events During ACPF
Table 5 summarizes the grade 3 or 4 AEs related to ACPF. The proportion of the 30 patients who experienced maximum grade 3, 4, or 5 AEs were 33% (10), 3% (1), and 3% (1), respectively. Some patients experienced more than 1 AE of grade 3 or higher. Most grade 3 AEs that occurred, such as acneiform rash, asymptomatic neutropenia, fatigue, and mucositis were manageable. One patient experienced a grade 4 hypersensitivity reaction due to cetuximab. The single grade 5 AE was a neutropenia-related pneumonia. The safety analysis demonstrated that the incidence of grade 3 or 4 AEs in the first 10 patients was 30%, which lies within the predetermined acceptable range (<35%).
Table 5. Grade 3 or 4 Adverse Events That Occurred During ACPF
During ACPF (N = 30)
3 to 5 combined
One patient expired during ACPF due to pneumonia (grade 5) in association with grade 4 neutropenia.
Nineteen (63%) patients developed (grade 1 to 3) PSN (12 with grade 1, 6 with grade 2, 1 with grade 3): 6 during ACPF, 2 during CRT, and 11 after CRT. At last follow-up, only 5 patients still complained of PSN. Twenty patients (67%) required placement of a gastrostomy tube. Three (14%) of the 21 patients who had reached the 1 year posttreatment follow-up had a gastrostomy tube in place.
In this intent-to-treat analysis, 24 (80%) patients were alive and disease-free, 3 (10%) were alive with disease, 1 (3%) died due to disease, 1 (3%) died due to intercurrent illness (acute-on-chronic hepatitis C), and 1 (3%) died due to TRM. Sites of failure included local-regional (3 patients) or distant (1 patient) locations. The median (range) follow-up of the patients was 25 months (2-39 months). OS and PFS are depicted in Figure 2. The estimated 2-year OS for the whole group was 84%, and for the oropharynx and laryngeal cancer subsites were 80% and 86%, respectively. The estimated 2-year PFS for the whole group was 65%, and for the oropharynx and laryngeal cancer subsites were 62% and 64%, respectively.
Surgical Treatment Following Definitive Therapy
One patient underwent a neck dissection for a residual neck mass, and 4 underwent biopsies of the primary tumor site to evaluate indeterminate residual mucosal abnormalities. All showed no evidence of malignancy.
CR at the primary tumor site as assessed by clinical examination following induction chemotherapy with PF is a favorable predictive factor for OS and disease control in patients with HNSCC who were subsequently treated with definitive RT.8, 9 In this study, we observed a high CR rate (53%) at the primary tumor site following 2 cycles of ACPF. These data compare favorably to the likelihood of achieving a CR at the primary site as assessed by clinical examination with induction PF: 21% in laryngeal HNSCC,18 20% in oropharyngeal carcinoma,4 and 33% in oral cavity carcinoma.24 Large primary tumors are associated with a low rate of CR after induction PF.25 In our study, 37% of patients had T4 tumors compared with < 16% of patients in these trials with induction PF.
Reported CR rates at the primary site with other induction regimens that included a taxane and/or cetuximab have been variable, but were generally lower than comparably staged patients in our ACPF trial. In our historical experience with TPF+Cet, the CR rate at the primary site by clinical examination was only 14% overall (T2 = 50%;T3 = 20%;T4 = 0%).22 Higher rates of CR were reported with a similar TPF+Cet regimen.26, 27 Rates of CR at the primary site with TPF varied from 8% to 40%.28, 29 Cremophor-based paclitaxel added to PF increased the CR rate at the primary site from 33% to 49%.7 A high rate of CR (70%) at the primary site was reported with weekly paclitaxel, cetuximab, and carboplatin, but most patients had T1 or T2 tumors.30
Our patient population was enriched in HPV-related oropharyngeal SCC (56%), which could have affected the primary endpoint because such tumors are more chemosensitive.31 However, p16 status did not significantly associate with achieving a CR at the primary tumor site following 2 cycles of ACPF. This may have occurred because most patients had additional adverse characteristics such as smoking history (90% of patients) and large (T3,4) primary tumors (73% of patients) that offset the favorable predictive effect of HPV status on primary tumor site response to induction chemotherapy.32
Most patients in this study had significant comorbidities (63%), were smokers, and were older. In this context, the treatment delivery of induction ACPF and of definitive CRT was very good. Nearly all patients (96%) completed 3 cycles of ACPF, with the proportion of planned doses of each drug administered being 87% to 99%. Of the 29 evaluable patients, 26 (90%) completed the planned 35 fractions of definitive RT per protocol, and 81% received >2 of the 3 planned doses of cisplatin concurrently. In comparison, delivery of >2 of 3 planned doses of cisplatin concurrent with definitive RT was reported to be 74% following induction PF33 and 43% to 66% following induction TPF.34, 35
The frequency and distribution of AEs during ACPF were expected for induction chemotherapy administered to patients with locally advanced HNSCC. Overall, 12 (40%) patients experienced grade 3 or higher AEs, of which 1 (3%) resulted in a TRM. However, several of the grade 3 or 4 AEs (rash, neutropenia, and fatigue) were manageable and did not result in serious sequelae. For comparison, reported rates of grade 3 or higher AEs during induction TPF were 27% to 85%,35, 36 during induction docetaxel, cisplatin, and cetuximab was 77%26 and during weekly paclitaxel, carboplatin, and cetuximab was 45%.30
Consistent with prior reports, we found SPARC expression to be common in tissue specimens obtained from patients with HNSCC.13 In contrast to a prior study, we observed an inverse relationship between SPARC expression in tumor cells and primary tumor site response to ACPF.14 The reason for these disparate findings is unclear. SPARC expression has been shown to correlate with worse prognosis, so perhaps this overcomes the relationship with increased accumulation of tumor cell nab-paclitaxel.
The 2-year OS and PFS for our patients treated with ACPF followed by definitive CRT were 84% and 65%, respectively. These outcomes compare favorably to other reports using induction regimens of taxane and platinum with or without cetuximab.6, 7, 26, 30, 35-37 Our data are limited by the median follow-up and the heterogeneity in tumor characteristics.
In conclusion, the novel induction regimen of ACPF was feasible and resulted in a high CR rate (53%) at the primary tumor site even in large (T3,4) primary tumors. ACPF did not adversely affect delivery of definitive CRT. The 2-year survival outcomes with ACPF followed by definitive CRT were favorable and warrant further investigation.
This research project was supported in part by the Celgene Corporation and by the Biostatistics Core and Imaging and Response Assessment Core of the Alvin J. Siteman Cancer Center.
CONFLICT OF INTEREST DISCLOSURE
Dr Thorstad has received honoraria from Bristol-Myers Squibb. The other authors made no disclosure. Dr Adkins has received honoraria from Eli Lilly and research funding from Celgene.