A randomized phase 2 study was performed to investigate the efficacy/toxicity of combining concomitant boost radiation and weekly carboplatin/paclitaxel with or without amifostine in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN).
Patients with newly diagnosed, locally advanced stage III or IV SCCHN received 4 weekly doses of carboplatin (area under the curve, 1.5) and paclitaxel (45 mg/m2) concurrently with concomitant boost radiation consisting of 72 grays in 42 fractions over 6 weeks (every day for 18 days, twice a day for 12 days) (grading determined according to the TNM staging system). All patients were randomized to subcutaneous daily amifostine at a dose of 500 mg (Arm A) or no amifostine (Arm B). Toxicity data were collected weekly, and saliva collection was performed with and without citric acid stimulation. To evaluate the correlation between serum cytokine levels and the severity of oral mucositis, we evaluated a subset (13 patients in Arm A and 11 patients in Arm B) of subjects at baseline and then on alternate weeks.
Fifty-eight patients were enrolled, 29 in each arm. The majority of patients were men (90%), had stage IV disease (82%), and had the oropharynx as the primary tumor site (60%). Major toxicities encountered were similar in both arms and included grade 3 (as determined by Common Terminology Criteria for Adverse Events, version 3.0) mucositis (75% in Arm A and 70% in Arm B) and grade 2 xerostomia (41% in both arms). The median number of amifostine doses delivered was 28, with skin toxicity (grade 3 in 11 patients) as the limiting factor. Saliva production showed no difference between the arms. The median follow-up was 34 months, and only 5 failures had been encountered (2 local and 3 distant) at the time of last follow-up, with an overall survival rate of 89%. Neck dissection was performed in 25 patients; 5 patients demonstrated persistent disease and 4 patients were alive without disease recurrence at the time of last follow-up. The median time to percutaneous endoscopic gastrostomy removal was 9.6 months in Arm A and 10.4 months in Arm B. Only 1 patient remained percutaneous endoscopic gastrostomy–dependent at the time of last follow-up. A correlation was noted between levels of selected cytokines and mucositis severity, in which higher levels of proinflammatory cytokines (tumor necrosis factor, interleukin [IL]-1, and IL-6) and lower levels of anti-inflammatory cytokines (IL-13) were noted. No changes in C-reactive protein levels were noted.
Patients with locally advanced head and neck cancer are frequently treated with concurrent chemoradiotherapy.1 Recent meta-analyses have confirmed the advantage of concurrent chemoradiotherapy in patients with newly diagnosed squamous cell carcinoma of the head and neck (SCCHN), compared with the use of radiotherapy alone.2 The most commonly used regimen is every-3-week bolus cisplatin, although many weekly schedules are also used. When considering treatment with radiotherapy alone, there is a local control benefit from concomitant boost or hyperfractionated radiotherapy compared with once-daily radiation.3 For both the addition of chemotherapy and the use of concomitant boost, the cost of the increased efficacy is increased toxicity.3 The side effects of radiation-based treatment can be divided into 2 categories: 1) acute side effects, which include xerostomia, mucositis, skin toxicity, and dysphagia; and 2) long-term complications, which include dysphagia with percutaneous endoscopic gastrostomy dependency, xerostomia, and hypothyroidism. Xerostomia, mucositis, and chronic dysphagia are the most troublesome side effects to the patients. Permanent percutaneous endoscopic gastrostomy dependence is markedly increased in chemoradiotherapy protocols when compared with the use of radiotherapy alone. This is observed in programs using once–a–day radiotherapy, as well as altered fractionation regimens combined with chemotherapy treatments.4 Esophageal dysfunction and stenosis may result from fibrosis, which can be aggravated by disuse associated with acute mucositis and xerostomia. Amifostine reduces the incidence of postoperative moderate to severe xerostomia5 and is approved by the US Food and Drug Administration for this indication. However, a course of amifostine requires daily intravenous access with a specialized nurse in a monitored setting to treat side effects such as acute hypotension and nausea/vomiting.
Weekly carboplatin and paclitaxel have been evaluated with daily radiotherapy with good results,6 but to our knowledge the use of altered fractionation radiotherapy using the concomitant boost approach with carboplatin and paclitaxel has not been tested to date.
In addition to its intravenous use, the subcutaneous (sc) delivery of amifostine has been studied in patients with head and neck cancer treated with standard radiotherapy and is associated with an improved toxicity profile and ease of administration.7, 8 In this study, we used sc amifostine with carboplatin/paclitaxel/concomitant boost chemoradiotherapy in a randomized phase 2 format.
MATERIALS AND METHODS
The objectives of the current study were: 1) to assess the locoregional control, overall survival, and progression-free survival (PFS) of a chemoradiotherapy regimen comprised of concomitant boost radiation with carboplatin/paclitaxel in patients with head and neck cancer; 2) to assess the efficacy of sc amifostine in reducing toxicity when added to this chemoradiotherapy regimen; 3) to assess toxicity of the combination by frequent assessment with formal swallowing evaluations; and 4) to measure cytokine levels and assess their relation with mucositis grades.
Traditional chemoradiotherapy results in a 1-year locoregional control rate of 60%; a rate of 80% was considered to constitute evidence that the experimental regimen demonstrated promise. We considered the experimental chemoradiation regimen to be worthy of further study if 29 patients on either arm were in locoregional control at 1 year. Although the same locoregional control rate was projected for both arms, they were evaluated independently to account for possible differences in dose intensity resulting from the differential treatment of toxicity. Given this design, the study was expected to have a 91% probability of finding the treatment to be effective if the true locoregional control rate was 80%, and a 7% probability of finding the treatment effective if the true locoregional control rate was 60%. If exactly 29 of 40 patients were in locoregional control at 1 year, the 90% exact binomial confidence interval on the response rate would be 59% to 84%.
All eligible, randomized patients who received at least 1 dose of radiotherapy were included in the analysis. Patients who withdrew without an assessment of outcome were considered to be unevaluable and were included in the denominator when calculating proportions. Forty-five patients will be randomized to each arm, of whom 40 are assumed to meet criteria for inclusion.
The rates of grade 2 and 3 xerostomia and grades 3 and 4 mucositis were collected and compared between the 2 arms. The median duration of percutaneous endoscopic gastrostomy dependence for adequate nutrition with and without amifostine was also assessed. Serial video swallowing tests were also performed.
The study was designed as a randomized phase 2 trial. All patients received concomitant boost radiation with 4 weekly doses of carboplatin/paclitaxel. Patients were randomized between daily sc amifostine (Arm A) or no amifostine (Arm B). The study was performed across Dana-Farber Cancer Institute and 3 of its affiliated institutions.
This clinical trial was approved by the Dana-Farber Cancer Institute/Harvard Cancer Center Institutional Review Board (IRB). All patients signed an IRB-approved informed consent. The randomization process was centralized and managed through the Dana-Farber Cancer Institute protocol office.
Patients with stage III or IV, previously untreated, locally advanced SCCHN were eligible for participation (grading determined according to the TNM staging system). Primary tumor sites allowed included oral cavity, oropharynx, larynx, hypopharynx, and unknown primary tumor. Additional eligibility criteria included measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) guidelines; an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1; and normal hematologic, renal, and liver function. Exclusion criteria included grade ≥2 peripheral neuropathy (as determined by Common Terminology Criteria for Adverse Events, version 3.0), other serious comorbid illness, and involuntary weight loss of >20% of body weight in the 3 months preceding study entry.
Baseline evaluations included history, physical examination, hematology and chemistry profiles, computed tomography (CT) or magnetic resonance imaging (MRI) of the neck, chest radiography, and triple endoscopy or its equivalent. Baseline positron emission tomography (PET)/CT scans were allowed, but not required. Dental evaluation was required, and placement of a percutaneous endoscopic gastrostomy feeding tube was recommended to all patients before the initiation of therapy or within the first 3 weeks. Weekly toxicity assessments using Common Terminology Criteria for Adverse Events were used during chemoradiotherapy. The worst grade of toxicity encountered is reported. After completion of treatment, toxicity assessments were performed every 4 weeks.
Saliva collection was performed to assess hyposalivation as a manifestation of xerostomia. Stimulated (after citric acid) and unstimulated saliva were collected over a mandated timed 6-minute period at Weeks 12, 24, and 52 after radiotherapy. Subjects were asked to spit their saliva into the collection tube for a total of 6 minutes, which was timed by the stopwatch. At the end of 6 minutes, the collection tube was immediately sealed and weighed using a calibrated scale with an accuracy of 0.001 g.
Patients received swallowing therapy and nutrition consultation to encourage oral intake throughout treatment. Video swallow studies were conducted at the start of radiotherapy and approximately 8, 12, 24, and 52 weeks after chemoradiotherapy. The occurrence of penetration and aspiration, degree of pharyngeal residue, and incidence of upper esophageal narrowing was assessed and used as measures of the progression of dysphagia.
Clinical and radiographic evaluation of response was performed between Week 8 and Week 10 after the last day of radiotherapy and included physical examination, CT or MRI of the neck, and PET/CT if performed at baseline. The decision to perform a neck dissection after the completion of treatment was made based on clinical and radiographic response.
Patients received carboplatin (area under the curve, 1.5) and paclitaxel at a dose of 45 mg/m2. Both drugs were given weekly for the first 4 weeks of radiotherapy. They were planned for delivery such that at least 3 fractions of radiation will follow the chemotherapy each week. Chemotherapy was thus given on Monday, Tuesday, or even Wednesday, provided that it was given before radiotherapy. No chemotherapy was given during the last 2 weeks of radiation when patients were receiving only twice–daily radiotherapy. Patients randomized to Arm A received daily subcutaneous amifostine injections of 500 mg, 30 to 60 minutes before each daily radiation treatment. During twice-daily radiotherapy, the injection was only given before the morning radiation dose. All patients had a feeding tube placed before or within the first 3 weeks of radiotherapy. Patients were given hydration via their feeding tube or through oral hydration before receiving the dose of amifostine.
Patients were enrolled in this study as upfront treatment or after induction chemotherapy, at the discretion of the treating physician.
Radiotherapy was given 5 days a week using a concomitant boost schedule. The initial target volume encompassing the macroscopic and subclinical disease sites was delivered at 1.8 grays (Gy) per fraction to a dose of 54 Gy/30 fractions. From the 19th treatment day, patients received radiotherapy twice daily for 12 treatment days to a total of 30 treatment days over 6 weeks. The second daily fraction was 1.5 Gy delivered to a boost volume consisting of macroscopic disease plus 1 cm, to 1.5-cm margins. There was a minimum 6-hour interfraction interval. Overall, the primary and involved lymph nodes received 72 Gy in 42 fractions over 6 weeks. Regional, but uninvolved, lymph nodes received 5400 centigrays (cGy) in 30 fractions, and the lower neck received 5040 cGy, all at 180 cGy/fraction. The field arrangement was a standard 3-field technique using 2 lateral and an anterior low neck photon field. Electrons were used for the posterior neck after cord tolerance was reached. The patients with an unknown primary tumor were treated with 54 Gy to potential primary sites. The use of intensity-modulated radiotherapy (IMRT) was not allowed.
Serum for cytokine analysis was collected in serum separator tubes at baseline and then on alternate weeks (Weeks 2, 4, 6, and 8) during treatment and at 8 weeks after the completion of therapy. Mucositis grades were collected at the time of cytokine collection. Samples were centrifuged at 2500 revolutions per minute for 10 minutes at 4°C; and the serum was collected, labeled, and stored at −70°C until analysis.
Cytokine levels (tumor necrosis factor [TNF]-α, interleukin [IL]-1β, IL-6, and IL-13) were determined using enzyme–amplified sensitivity immunoassays (EASIA; Biosource International, Camarillo, Calif) as delineated by the manufacturer in 96-well microtiter plates precoated with monoclonal antibodies. Each plate had antibodies specific for the cytokine to be evaluated. After incubation and binding, the serum was removed, and the wells were washed. Secondary antibodies conjugated with horseradish peroxidase (HRP) were added, allowed to incubate, and then removed. HRP chromogen was added, and cytokine concentrations were determined by measuring absorbance of the colored product of the HRP reaction. Cytokine concentrations were determined using a standard cytokine curve. The concentration of C-reactive protein (CRP) was determined using a spectrophotometric technique in which a CRP reagent was added to serum samples to form turbid antigen-antibody complexes. The protein concentration was measured according to turbidity at 340 nanometers (nm).
A total of 58 patients were enrolled between May 2003 and April 2006. Table 1 shows patient characteristics. The study was stopped before the completion of planned accrual because IMRT was becoming the de facto standard technique in treating head and neck cancer. Most patients enrolled were men, and the oropharynx was the predominant primary site (62% and 58%, respectively, for Arms A and B). The vast majority of patients had stage IV locally advanced disease (86% for Arm A and 80% for Arm B). The TNM distribution for both arms is shown in Table 2. Induction chemotherapy was used in 27 of 58 patients overall, with docetaxel, cisplatin, and 5-fluorouracil being the predominant regimen used. Sixteen patients in Arm A and 11 in Arm B underwent induction chemotherapy. All patients with N3 disease (5 of 5) and the majority of the patients with N2 disease (20 of 32) underwent induction chemotherapy.
Table 1. Baseline Patient Characteristics
Arm A, n = 29
Arm B, n = 29
ECOG indicates Eastern Cooperative Oncology Group; TPF, docetaxel, cisplatin, and 5-fluorouracil; PF, cisplatin and 5-fluorouracil.
Median age, y
ECOG performance status
Primary tumor site (%)
Table 2. TNM Staging
The average number of amifostine doses delivered per patient was 25 (median, 28 doses). The main reason for withholding amifostine was skin toxicity, including both local irritation at the injection site and generalized rash. Grade 2 (n = 13 patients) and 3 (n = 12 patients) skin toxicities were encountered in the 29 patients who received amifostine. The median number of carboplatin/paclitaxel infusions was 4 weeks of the 4 weeks intended. Radiation breaks were infrequent. In fact, the median duration of radiotherapy calculated from Day 1 of radiation until the end of therapy was similar in both treatment arms (43 days for both Arms A and B).
The median follow-up was 34 months, and the minimum follow-up was 26 months. Five failures had occurred in total, 2 in Arm A and 3 in Arm B. The 5 failures (all in patients with stage IV disease) were distributed as follows: 4 in the oropharynx and 1 in the larynx, 3 of 5 with distant metastasis only, 1 of 5 with both local and distant recurrence, and 1 of 5 with local recurrence. Of these 5 failures, 3 had induction chemotherapy (T2N3, T4N3, and T4N2C, all with oropharynx primary tumors), and 2 did not (T3N2B-oropharynx − and T2N2B-larynx−). One patient died without evidence of disease progression from a cardiac event 4 years after the completion of therapy. The overall survival rate for the entire group was 89% (95% confidence interval [95% CI], 80-98 %), with no differences noted between Arms A and B. The 3-year PFS rate was 90% (95% CI, 82-98%). The 3-year locoregional control rate was 96% (95% CI, 88-100%), also with no differences noted between the treatment arms (Figs. 1A and 1B, 2A and 2B, and 3A and 3B).
Neck dissection was performed on those patients who had clinical and/or radiographic evidence of disease at a minimum of 8 weeks after completing chemoradiotherapy. Neck dissection was performed in 25 patients in total (14 in Arm A and 11 in Arm B). Of these 25 neck dissections performed, persistent disease was detected in 5 of 25 of patients (2 with N3 disease, 2 with N2b disease, and 1 with N2c disease), 1 of 5 patients died of disease progression, and 4 of 5 patients were alive without disease recurrence.
For the endpoint of xerostomia, we were not able to demonstrate that amifostine had a positive effect, and there was no differences detected between the arms in terms of xerostomia, with 41% of patients reporting xerostomia of grade ≥2. Saliva collection before and after citric acid stimulation was undertaken in an effort to measure salivary flow. No difference was observed between the 2 treatment arms. Mucositis rates were also similar between arms, with 75% and 70% of patients developing grade 3 mucositis by the end of the treatment. Only 1 patient developed grade 4 mucositis (Arm B). Percutaneous endoscopic gastrostomy dependency measured from the time of percutaneous endoscopic gastrostomy insertion to removal was high at 9.6 months and 10.4 months, respectively, for Arms A and B. At the time of last follow–up, only 1 patient still had a feeding tube in place.
At baseline, 23% of the patients reviewed penetrated, 6% aspirated, and 26% had pharyngeal residue. Patients on both arms of the study had a steady decline in swallowing function from onset until 24 weeks after radiotherapy. Penetration, aspiration, and pharyngeal residue were consistently noted throughout the study period at Weeks 8, 12, 24, and 52 on both arms of the study, with no difference noted between Arms A and B. Narrowing in the upper esophagus occurred in 38% of these patients, but only 31% required dilations. The remaining patients with esophageal narrowing were able to advance their diet and have their feeding tubes removed without dilations.
Table 3 is a summary of the findings with regard to mean cytokine levels in relation to the grade of oral mucositis. We analyzed the correlation between serum pro-inflammatory and anti-inflammatory cytokine levels as a function of mucositis severity. Levels of TNF-α, IL-1β, and IL-6 were found to be elevated in the sera of patients at times of mucositis compared with when mucositis was not noted. However, levels of IL-13, an anti-inflammatory cytokine, were only found to be reduced at times when mucositis scores were severe (grade 3). A very marginal and insignificant increase in soluble TNF receptor-1 was observed in the sera of patients with mucositis. CRP levels were not associated with mucosal injury.
Table 3. Mean Cytokine Concentration by OM Grade
Cytokine Concentration, pg/mL
OM indicates oral mucositis; CRP, C-reactive protein; TNF, tumor necrosis factor; IL, interleukin; s-TNF-R1, soluble TNF receptor-1.
The treatment of head and neck cancer continues to evolve. Concurrent chemoradiotherapy and sequential chemoradiotherapy are often used in patients with locally advanced disease.1 The regimens most frequently used are platinum based, with bolus cisplatin and weekly carboplatin/paclitaxel commonly used with radiotherapy. Concomitant boost radiation has been shown to increase locoregional control, compared with standard fractionated radiotherapy.3, 4, 9 In this randomized phase 2 study, we evaluated a new regimen combining carboplatin/paclitaxel with concomitant boost radiation. This regimen proved to be highly effective in those patients with stage III and IV disease, with only 5 failures of 58 patients noted with a minimum 2 years of follow-up.
The results of the current study are quite encouraging, with an overall survival rate of 89% reported. This compares quite favorably with other regimens used in this disease. Tsao et al recently reported a phase 1 of 2 study with 52 patients enrolled using a fairly similar regimen of weekly platinum/taxane (cisplatin/docetaxel) for 4 weeks along with a concomitant boost regimen.10 They reported a 2-year PFS rate and overall survival rate of 61% and 65%, respectively, with a percutaneous endoscopic gastrostomy dependency rate in surviving patients of 17%. Radiation Therapy Oncology Group (RTOG) 99-14, a phase 2 study with 65 patients enrolled, used a bolus cisplatin × 2 approach every 21 days with concomitant boost radiotherapy. The overall survival rate was 71%, with a percutaneous endoscopic gastrostomy dependency rate of 29% noted in surviving patients.4 Staar et al have previously reported that 51% of their surviving patients were percutaneous endoscopic gastrostomy dependent when concurrent altered fractionation radiation and chemotherapy was used.11 They also reported a percutaneous endoscopic gastrostomy dependence in the radiotherapy–alone arm of 25%. The rate of percutaneous endoscopic gastrostomy dependency was very low in the current study, with only 1 patient still requiring a percutaneous endoscopic gastrostomy at the time of last follow–up. However, the time to percutaneous endoscopic gastrostomy removal was relatively high for both treatment arms, likely reflecting the acute effects of such an intensive regimen. Our rate was much lower, likely reflecting a combination of improved radiation technique along with an early intervention in terms of swallowing consultation, with a speech and swallow therapist available and aggressive swallowing management and exercises performed throughout the treatment and afterward. This early intervention is crucial in preserving long-term swallowing function.12, 13
We also randomized patients to treatment with sc amifostine in an effort to detect an effect on xerostomia and mucositis. Amifostine has been used intravenously in patients with head and neck cancer and is approved by the US Food and Drug Administration in the postoperative setting. Its use has been limited in the upfront, definitive setting, mainly because of concern regarding toxicity, the need for intravenous infusion, and associated logistics. Recently, it was shown that amifostine can be safely administered subcutaneously with a better toxicity profile14 and without the need for extensive monitoring. Early data were promising in terms of limiting mucositis and xerostomia7, 8 in the patients treated for SCCHN. Indeed, in a recently reported phase 2 study, 54 patients received amifostine sc at a dose of 500 mg concurrently with postoperative radiotherapy. No chemotherapy was used in this study, and radiation was administered once a day. The incidence of grade ≥2 acute xerostomia was 56%, and the incidence of grade ≥2 late xerostomia at 1 year was 45%. The incidence of acute xerostomia was lower than reported previously, with no amifostine administered in a controlled study, and rates of acute xerostomia were similar between the sc and intravenous amifostine treatments in the 2 studies. The authors concluded that sc amifostine provided a well-tolerated yet simpler alternative to intravenous amifostine for reducing acute xerostomia in patients with head and neck cancer.7
In a study by Koukourakis et al,8 60 patients with thoracic tumors, 40 with head and neck tumors, and 40 with pelvic tumors who were undergoing radical radiotherapy were enrolled in a randomized phase 2 trial to assess the feasibility, tolerance, and cytoprotective efficacy of amifostine administered subcutaneously. A flat dose of amifostine–500 mg–was administered subcutaneously before each radiotherapy fraction. A significant reduction in pharyngeal, esophageal, and rectal mucositis was noted in the amifostine arm (P < .04). The delays in radiotherapy because of grade 3 mucositis were significantly longer in the group of patients treated without amifostine (P < .04). Amifostine was found to significantly reduce the incidence of acute perineal skin and bladder toxicity (P < .0006). The authors concluded that the sc administration of amifostine is well tolerated, effectively reduces radiotherapy's early toxicity, and prevents delays in radiotherapy in a group of patients treated with radiation alone.
It is possible that the increased toxicity of a combination of 2 drugs and concomitant boost radiation is such that a benefit from amifostine was not demonstrated in the current study, especially when a taxane-based chemotherapy regimen was used. It is not clear at this stage whether concomitant boost radiation will emerge as the optimal schedule with which to deliver radiation concurrently with chemotherapy when treating patients with head and neck cancer. The RTOG 0129 study has been completed and will hopefully answer this question. Patients in this study were randomized to receive cisplatin × 3 with standard once–daily radiotherapy (2.0 Gy per fraction) or cisplatin × 2 and concomitant boost radiation (1.8/1.5 Gy per fraction).
This study was initiated before the widespread use of IMRT for the treatment of head and neck cancer. As IMRT became more available and its use more standard in the treatment of patients with head and neck cancer, it became difficult to enroll patients in the current study, and a decision was made to close the study at a total of 58 enrolled patients. This unfortunately is not uncommon in medicine because newer drugs and technologies evolve. It is unlikely, however, that the endpoints of xerostomia and mucositis would have changed or become positive in favor of amifostine had the study reached its planned accrual of 80 patients, given the trends observed in both treatment arms.
The increased use of IMRT and the development of other newer radiation technologies have resulted in a significant improvement in salivary flow in patients with head and neck cancer.15, 16 It does appear that chronic toxicity is decreased with these modalities, specifically chronic xerostomia. This is fairly significant and hopefully will translate into a better quality of life for patients. In addition, the use of newer targeted agents such as the epidermal growth factor receptor inhibitors might result in a better toxicity profile17 of the combined regimens used in this disease. Whether amifostine might give added benefit in this situation remains an open question.
The cytokine data analysis indicated an increased level of TNF-α with increasing oral mucositis grade. Recent studies have suggested an important role of TNF-α in the pathogenesis of intestinal mucositis induced by chemotherapy.18 The administration of anti-TNF appears to reverse mucosal inflammation via down-regulated proinflammatory cytokines, particularly IL-23 and IL-17, and decreased leukocyte infiltration in the bowel.19
In conclusion, 4 weekly doses of carboplatin/paclitaxel concurrently with concomitant boost radiation was found to be quite effective in patients with locally advanced head and neck cancer, demonstrating an excellent overall survival and an acceptable toxicity profile. The use of amifostine with this regimen did not appear to result in an improvement in salivary function, mucositis, or swallowing function.