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Annals of Oncology Advance Access originally published online on June 6, 2008
Annals of Oncology 2008 19(10):1787-1794; doi:10.1093/annonc/mdn364
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© The Author 2008. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org

head and neck cancer

Induction chemotherapy and concurrent chemoradiotherapy for locoregionally advanced head and neck cancer: a multi-institutional phase II trial investigating three radiotherapy dose levels

J. K. Salama1,3, K. M. Stenson3,5, E. O. Kistner4, B. B. Mittal6, A. Argiris9, M. E. Witt1, F. Rosen8, B. E. Brockstein7, E. E. W. Cohen2,3, D. J. Haraf1,3 and E. E. Vokes1,2,3,*

1 Department of Radiation and Cellular Oncology
2 Section of Hematology/Oncology, Department of Medicine
3 The Cancer Research Center
4 Biostatistics Laboratory, Department of Health Studies
5 Section of Otolaryngology Head and Neck Surgery, Department of Surgery, University of Chicago, Chicago, IL
6 Feinberg School of Medicine, Northwestern University, Chicago, IL
7 Feinberg School of Medicine, Evanston Northwestern Healthcare, Northwestern University, Evanston, IL
8 John H. Stroger, Jr. Hospital of Cook County, Chicago, IL
9 University of Pittsburgh Medical Center, Pittsburgh, PA

* Correspondence to: Dr E. E. Vokes, University of Chicago, 5841 S. Maryland Avenue, MC 2115, Chicago, IL 60637, USA. Tel: +1-773-702-3002; Fax: +1-773-702-3002; E-mail: evokes{at}medicine.bsd.uchicago.edu


   Abstract
Top
 Abstract
introduction
 patients and methods
 results
 discussion
 funding
 Acknowledgements
 References
 
Background: We hypothesized induction chemotherapy (IndCT) would improve distant control (DC) without compromising locoregional control (LRC) for locoregionally advanced head and neck cancer patients. Additionally, we systematically lowered radiotherapy (RT) doses attempting to maintain LRC while decreasing toxicity.

Patients and methods: Stages III–IV (M0) locoregionally advanced head and neck cancer patients received carboplatin/paclitaxel (Taxol) IndCT followed by four or five cycles consisting of 5 days of paclitaxel, fluorouracil, hydroxyurea, and BID RT followed by a nine day break. RT dose to gross disease (high risk), intermediate, and low-risk volumes were reduced from cohort A (n = 68): 75, 60, and 45 Gy; to cohort B (n = 64): 75, 54, and 39 Gy; then cohort C (n = 90): 72, 51, and 36 Gy.

Results: A total of 222 patients accrued from November 1998 to September 2002. Median follow-up is 56 months. In all, 93/96/76% achieved a complete response to concurrent chemoradiotherapy (CRT) in cohort A/B/C. Three- and 5-year overall survivals (OSs) are 68% and 62%, respectively. Five-year LRC and DC are 91% and 87%, respectively. Response to IndCT predicted for OS, LRC, and time to progression (TTP). Cohort C patients had similar OS (P = 0.95), LRC, and DC, but worse (TTP) (P = 0.027).

Conclusions: IndCT before CRT reduces distant progression while maintaining high LRC. The cohort B schedule provides the best therapeutic ratio. A randomized trial investigating IndCT before CRT has been initiated.

Key words: chemoradiotherapy, induction chemotherapy, locoregionally advanced head and neck cancer


   introduction
Top
 Abstract
 introduction
patients and methods
 results
 discussion
 funding
 Acknowledgements
 References
 
Prior investigations from our group have focused on using the radiation sensitizers 5-fluorouracil (5-FU), hydroxyurea (HU), and radiotherapy (RT) every other week (FHX) as a base regimen for locoregionally advanced head and neck cancer treatment [1]. Initially, we investigated induction chemotherapy (IndCT) followed by FHX and reported high survival rates, but locoregional recurrence (LRR) continued to predominate [2]. Subsequently, we investigated improving locoregional control (LRC) by intensifying FHX by adding novel agents [3, 4] and hyperfractionating RT [5]. These trials demonstrated that concurrent multiagent chemotherapy and hyperfractionated RT reversed the traditional relapse pattern, with distant relapses (DRs) occurring more frequently than LRR [4].

On the basis of these investigations, we hypothesized that IndCT before hyperfractionated FHX would decrease DR while maintaining high LRC. We chose carboplatin and paclitaxel as a well-tolerated nonmucositis-inducing IndCT regimen. The first report of this trial validated this hypothesis with high LRC and low DR, but grades 3-4 mucositis and dermatitis were significant [6]. Therefore, we attempted to decrease CRT toxicity by decreasing RT doses in two subsequent cohorts. In the second cohort, we reduced radiation dose to areas at risk for microscopic disease in IndCT responders. Again, high locoregional and distant control (DC) rates were seen with decreased dermatitis [7]. In the final cohort, IndCT responders had further radiation dose reduction, both to areas of microscopic disease and gross disease. In this analysis, we provide a final report of the two goals of the study: testing the hypothesis that IndCT could be delivered safely and effectively improving DC before intensive chemoradiotherapy. Additionally, we tested the hypothesis that sequential RT dose reductions in this setting would maintain high LRC rates while decreasing acute toxicity rates.


   patients and methods
Top
 Abstract
 introduction
 patients and methods
results
 discussion
 funding
 Acknowledgements
 References
 
Cohort A accrued from November 1998 to January 2000, cohort B from January 2000 to January 2001 and cohort C from February 2001 to September 2002. Eligible patients had pathologically proven squamous cell or poorly differentiated head and neck carcinoma. All patients had stage IV disease except for stage III tongue base or hypopharyngeal primaries. Patients were evaluated by medical, radiation, and surgical oncologists and had performance status (PS) of zero to two. Pretherapy evaluation included history and physical, panendoscopy, and radiographic assessment of the primary tumor, neck, and chest. All patients underwent dental, swallowing, and quality-of-life evaluation. Patients could not have received prior chemotherapy or RT. Organ-preserving surgery (diagnostic modified neck dissection, simple small primary excision, or resection of airway-threatening tumors) was allowed. Glossectomies or laryngectomies were not allowed. Tracheostomies were placed at surgeons’ discretion. Gastrostomy tubes were not routinely placed before therapy. Patients signed institutional review board approved informed consent before therapy.

induction chemotherapy
Figure 1 illustrates the protocol schema. Before CRT, patients received IndCT. Cohorts A and B received 6 weekly paclitaxel (Taxol Bristol-Myers Squibb, New York, USA) (135 mg/m2 over 3 h) and carboplatin [area under the curve (AUC) = 2 over 30 min] cycles. Cohort C IndCT dosing schedule was changed to paclitaxel 100 mg/m2 (days 1, 8, and 15) and carboplatin AUC = 6 (day 1) every 4 weeks for two cycles as data emerged that this schedule resulted in higher response rates in non-small-cell lung cancer [8].


Figure 1
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  		Figure 1. Concurrent chemoradiotherapy treatment schema.

 
concurrent chemotherapy
Patients underwent four or five CRT cycles on the basis of the extent of preprotocol surgery. Each 14-day cycle consisted of 5 days of 500 mg hydroxyurea by mouth (HU PO) every 12 h for 6 days the evening before the first fraction of RT, 600 mg/m2/day continuous infusion 5-FU on days 1–5, and 100 mg/m2 paclitaxel over 1 h on day 1 followed by 9 days without any chemotherapy or RT.

radiotherapy
Patients underwent computed tomography-based treatment planning where risk defined volumes were contoured. The gross tumor volume (GTV) included all known gross disease detected on physical or radiographic examination both at the primary and neck before IndCT. Planning target volume 1 (PTV1) included the GTV plus a 1.5 cm expansion. PTV2 included PTV1 plus the first echelon of uninvolved lymph nodes, and PTV 3 included PTV2 plus the second uninvolved lymph node echelon. Volumes were modified to avoid spinal cord overlap or extension beyond the skin. Sequential plans were created for PTV1, PTV2, and PTV3. Radiation doses were prescribed to a PTV minimum. A RT plan was considered acceptable if the PTV was encompassed by the 95% isodose line, and <1% of the PTV received >110% of the prescription dose.

RT was delivered b.i.d. with 1.5-Gy fractions using 6 MV photons. Patients received a single 2-Gy fraction for mechanical failure or holiday. In cohort A, PTV1 received 75 Gy, PTV2 received 60 Gy, and PTV3 received 45 Gy. In cohort B, patients who had a complete response (CR) or partial response (PR) to IndCT maintained the same dose to regions of gross disease, but radiation doses to PTV2 and PTV3 were reduced to 54 and 39 Gy, respectively. In cohort C, IndCT responders had radiation doses to PTV2 and PTV3 reduced to 51 and 36 Gy, respectively, and PTV1 dose was reduced from 75 to 72 Gy. During cohort A, most patients were treated with conventional two-dimensional or three-dimensional conformal RT. As intensity-modulated radiotherapy (IMRT) became available, it was increasingly utilized.

assessment of response
We evaluated response after IndCT and again after CRT. Clinical response was evaluated by physical examination including examination under anesthesia. Clinical CR was defined as the absence of gross disease. Clinical PR was defined as ≥50% reduction in gross disease, stable disease (SD) was defined as no change in gross disease, and progressive disease (PD) was defined as gross disease enlargement. Radiographic response criteria were on the basis of the bidimensional tumor measurements. Best response was defined as the best response clinically or radiographically. Patients with ≥N2 disease were recommended to undergo post-therapy selective neck dissection. Salvage surgery was recommended for residual disease after chemoradiotherapy. Surgery at the primary was omitted for patients with a CR confirmed by post-therapy physical examination, radiographic imaging, and/or negative biopsy.

statistical evaluation
The primary end points were to evaluate the response rate, patterns of failure, time to progression (TTP), and overall survival (OS) of IndCT followed by five cycles of TFHX. OS, progression-free survival, TTP, time to local progression (LRC), and time to distant progression were computed using Kaplan–Meier [9] estimates. TTP (local, distant, or cumulative) was defined as the interval from the initiation of protocol therapy to locoregional or distant progression. Patients who died were censored and were not counted as having an event. Log-rank tests were conducted to test for equality between survival curves. Patients who progressed or died during induction, those with nonmeasurable disease, and those not evaluated at the end of IndCT were excluded from the response to induction survival analysis. The landmark approach was followed for these analyses [10]. Cox proportional hazards models [11] of LRC, DC, and OS were conducted using a backwards selection approach including predictors at the {alpha} = 0.05 level. For time to local–regional and distant failure, patients who died before recurrence were censored at the time of death. Variables considered in the model include age, sex, race, PS, tumor stage, nodal stage (>2a), neck dissection, PTV1 dose (Gy), patient cohort, and CR and PR to IndCT. Cochran–Armitage trend tests were conducted to test whether the proportions of subjects with gastrostomy tubes, tracheotomies, and grades 3–4 toxic effects increased or decreased across the three cohorts. For this report, patients were followed until 31 January 2007.


   results
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 Abstract
 introduction
 patients and methods
 results
discussion
 funding
 Acknowledgements
 References
 
The median follow-up for all patients is 56 months (cohort A: 76 months, cohort B: 62 months, cohort C: 53 months). Patients characteristics (n = 222) are shown in Table 1 and tumor characteristics shown in Table 2. Eleven had stage III disease; the remainder were stage IV. Oropharyngeal primaries were the most common (44.6%) followed by supraglottic larynx (16.7%), oral cavity (11.3%), and hypopharynx (10.4%). Fifteen patients with oropharyngeal primaries did not smoke and had minimal alcohol consumption. Sixty-three percent were white and 34.2% were black. Before treatment, 174 patients (78.4%) underwent biopsy only, 27 (12.2%) underwent limited neck dissection, six (2.7%) underwent organ-preserving surgery most often tonsillectomy as part of an unknown primary evaluation, and 15 (6.8%) underwent both organ-preserving surgery and neck dissection.


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  		Table 1. Patient and tumor characteristics for all cohorts

 

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  		Table 2. TN stage for all cohorts

 
toxic effects of and response to IndCT
Eighty percent of patients received >80% of the planned carboplatin dose and 78.4% received >80% of planned paclitaxel. Fifty-six percent experienced grades 3–4 toxicity during IndCT. The most common IndCT toxic effects were grades 3–4 neutropenia (41%), and grades 3–4 leukopenia (22%).

One hundred eighty-three patients were assessable for IndCT response as 25 patients did not have measurable disease, and 14 were not reevaluated following IndCT. Of assessable patients, 85.8% (n = 157) responded to IndCT. Response to IndCT (CR or PR) did not vary between cohorts (cohort A: 85%, cohort B: 76%, and cohort C: 75%). An equivalent percentage (15%) of cohorts B and C patients had SD following IndCT.

delivery, response, and toxic effects of concurrent CRT
Radiation was delivered per protocol. The median doses to PTV3, PTV2, and PTV1 were 45 Gy (mean ± standard deviation: 44.04 ± 5.44), 60 Gy (56.44 ± 6.12), 73 Gy (70.68 ± 6.63); 39 Gy (38.98 ± 2.41), 54 Gy (53.12 ± 3.11), and 74 Gy (71.32 ± 5.73); and 36.25 Gy (36.96 ± 2.28), 51 Gy (50.93 ± 3.70), 72 Gy (69.04 ± 7.66); for cohorts A, B, and C respectively. Thirty-eight percent were treated with IMRT (cohort A: 15%, cohort B: 20%, and cohort C: 69%). Concurrent chemotherapy was delivered per protocol with 90%, 89%, and 96% of patients received >80% of the planned paclitaxel, HU, and 5-FU doses.

Acute toxic effects are shown in Table 3. Ninety-one percent experienced grades 3–4 toxicity during CRT; the most common being mucositis (71%). There was no significant difference in worst mucositis between the cohorts despite reduced radiation doses (cohort A: 76%, cohort B: 76%, and cohort C: 66%; P = 0.1478). Statistically significant decreased grades 3–4 dermatitis were demonstrated with decreasing RT doses (cohort A: 61%, cohort B: 45%, and cohort C: 30%, P = 0.0001). A trend for decreased rates of dermatitis was seen in patients treated with IMRT over those treated with conventional therapy (P = 0.061).


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  		Table 3. Acute toxicity during induction chemotherapy and concurrent chemoradiotherapy

 
response to concurrent chemoradiotherapy
The CR rate following chemoradiotherapy was 87% for all patients. The CR rate for cohort C (76%) was significantly lower than in cohort A (93%) or cohort B (96%) (P = 0.0021). Nineteen patients (11%) achieved a PR following CRT; 79% of these patients were treated on cohort C of the trial. Two patients (1%) progressed during CRT.

locoregional and DC
All three cohorts exhibited high LRC (Figure 2). Three- and 5-year estimated LRCs for all patients were 91% [95% confidence interval (CI) 85% to 94%] (cohort A: 92%, cohort B: 97%, and cohort C: 85%). There was no statistical difference in LRC between the cohorts. Few patients failed distantly. The estimated 3- and 5-year DCs for all patients were 89% (95% CI 84% to 93%) and 87% (95% CI 81% to 91%), respectively. No significant differences in DC could be detected between the cohorts, with 5-year DC being 90% (95% CI 79% to 96%), 88% (95% CI 74% to 94%), and 83% (95% CI 73% to 90%); P = (0.38) for cohorts A, B, and C, respectively. Salvage surgery at the primary was carried out in only six patients (2.7%).


Figure 2
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  		Figure 2. Time to locoregional progression, distant progression, and combined time to progression.

 
time to progression
Cohort C patients had significantly worse TTP (P = 0.027) with 5-year estimates being 80% (95% CI 68% to 88%), 82% (95% CI 69% to 90%), and 66% (95% CI 55% to 75%) for cohorts A, B, and C, respectively.

overall survival
For all patients, the estimated 3- and 5-year OSs were 68%(95% CI 62% to 74%) and 62% (95% CI 55% to 68%), respectively. No significant differences in survival could be detected between the three cohorts with 5-year OS being 66% (95% CI 53% to 76%), 59% (95% CI 45% to 70%), and 61% (95% CI 49% to 71%) for cohorts A, B, and C, respectively (P = 0.95) as shown in Figure 3.


Figure 3
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  		Figure 3. Overall survival by cohort and the entire population.

 
neck control
Seventy-four patients (44%) with ≥N2 disease underwent adjuvant neck dissection. Residual cancer in neck dissection specimens was seen in 4.7% (one of 21) of cohort A, 13.6% (three of 22) of cohort B, and 35% (11 of 31) of cohort C (P = 0.13). No difference in locoregional (P = 0.41) or distant progression (P = 0.21) could be detected between patients who underwent neck dissection and those that did not.

speech and swallowing toxicity
Before treatment, 26% (n = 58; 31% cohort A, 30% cohort B, 20% cohort C) of patients had gastrostomy tubes placed. During the course of treatment, an additional 36% required gastrostomy tubes. At last follow-up, 23% who had not failed locally still had a gastrostomy tube. There was a trend for lower gastrostomy tube placement rates with lower RT doses (26% cohort A, 22% cohort B, 14% cohort C; P = 0.08).

Furthermore, 24% had tracheostomies placed before protocol treatment. Two patients had tracheostomies placed during treatment. At last follow-up, excluding patients who failed locoregionally, 19% had a tracheostomy in place. There was a statistically significant trend for lower tracheostomy rates across the three cohorts (26% cohort A, 14% cohort B, and 11% cohort C; P = 0.0098).

prognostic significance of response to IndCT
Patients with a PR or CR to IndCT had improved survival (P < 0.0001, as shown in Figure 4), TTP (P = 0.0001), LRC (P = 0.0129), and DC than patients with SD or PD (P < 0.0001). There was no difference in any end point between patients who achieved a CR or PR. These improvements were evident whether response was clinical, radiographical, or best response. TTP analyses were duplicated excluding IndCT progressers. Patients with an IndCT CR or PR had significantly improved LRC (P = 0.0095), DC (P = 0.0036), and improved TTP (P = 0.0043) compared with those with SD.


Figure 4
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  		Figure 4. Overall survival estimated by best response to induction chemotherapy.

 
multivariate analysis
On multivariate analysis for LRC, PS = 2 [hazard ratio (HR) 7.66, 95% CI 1.49–39.45, P = 0.0150] and African-American race (HR 3.70, 95% CI 1.36–10.09, P = 0.0106) were significantly associated with worse LRC. African-American patients experienced worse DC (p = 0.0414). Patients with IndCT CR or PR experienced better DC (HR 0.17, 95% CI 0.06–0.51, P = 0.0016 and HR 0.21, 95% CI 0.08–0.54, P = 0.0011). Similarly, induction CR or PR (HR 0.42, 95% CI 0.22–0.82, P = 0.0103 and HR 0.37, 95% CI 0.20–0.68, P = 0.0014) and higher PTV1 radiation dose (HR 0.95, 95% CI 0.92–0.98, P = 0.001) were associated with improved OS. Finally, PS of one or two (HR 2.55, 95% CI 1.47–4.45, P = 0.0009 and HR 4.46, 95% CI 1.73–11.52, P = 0.0020) was associated with worse OS.


   discussion
Top
 Abstract
 introduction
 patients and methods
 results
 discussion
funding
 Acknowledgements
 References
 
This study's primary goal was to investigate the effects on relapse patterns by adding IndCT to an intensive CRT regimen. This large series demonstrated equivalent and favorable times to local and distant progression at 91% and 87%, respectively. Our hypothesis, that IndCT could improve DC without compromising LRC, is supported by these results. Similar results were reported when carboplatin/paclitaxel induction followed by concurrent paclitaxel and 70 Gy RT demonstrated equivalent 3-year LRC (82%) and 3-year DC (81%) [12]. Ongoing randomized trials investigating IndCT before CRT demonstrated significantly improved response rates [13, 14] and improved TTP [14] in patients receiving IndCT. Recently reported trials suggest that IndCT with docetaxel, 5-FU, and cisplatin before CRT improves TTP, response rate, laryngeal preservation, and OS when compared with cisplatin and 5-FU [15–17].

Our data and others indicate that IndCT response may predict outcome after CRT [18]. Previously shown for IndCT before RT alone, this is also true for IndCT before CRT, which was not previously established. As shown in Figure 2, patients with a PR or CR to IndCT had improved OS, TTP, LRC, and DC. This correlates with studies demonstrating that patients achieving a pathologic CR to IndCT had a significantly lower risk of dying of disease compared with those who did not have a CR (3% versus 25%) [19]. Although patient outcomes following SD to IndCT were worse than those achieving a PR or CR, 71.4%. This suggests that patients without PD during IndCT could be managed with an initial organ-preserving approach reserving surgery for salvage.

Mucositis and dermatitis were severe in all cohorts. However, as shown in Table 2, cohort C patients had significantly lower acute grades 3–4 dermatitis. Furthermore, persistent tracheostomies and gastrostomy tubes were less frequent in cohort C. While reduction in acute and chronic toxic effects could be attributed to lower RT doses in cohort C, the integration of IMRT, with skin sparing effects and the potential to spare pharyngeal musculature, may also have contributed.

RT doses currently employed during CRT are largely empirically derived from tumor control and normal tissue toxicity probabilities of patients treated with RT alone. By sequentially reducing RT doses on the basis of IndCT response, to areas of gross disease as well as high and intermediate risk volumes in the setting of concurrent chemotherapy, we hypothesized that radiation-induced toxic effects would decrease, maintaining high LRC rates. Only a large randomized trial could definitively answer whether reduced efficacy is seen with lower RT doses. Our data indicate that the first radiation dose reduction to areas at risk for microscopic disease (PTV2–3) remained effective, but further dose reduction to these and to areas of gross disease (PTV1), as in cohort C, resulted in significantly worse TTP (P = 0.027), CR rate (P = 0.0021), and increased positive neck dissection specimen rate in regions of known gross disease [20]. Although IndCT administration changed in cohort C, CR, PR, and SD rates to IndCT were similar to cohort B and therefore are unlikely to explain the differences in progression or survival. Within the context of the TFHX CRT platform, it appears that we have identified a dose–response relationship. Therefore, we have applied the cohort B treatment schedule to our ongoing trials.

When compared with other large series of locoregionally advanced head and neck cancer patients treated with an organ-preserving approach [21–24], the OS of our series is comparable being >60% at 5 years. Our results must be considered in the context that they were obtained in a multi-institutional setting and not at a single tertiary referral center. Additionally, we included patients with extensive organ dysfunction, bone involvement, and cartilage invasion, excluded from other large series. While some believe these patients will have worse control and functional outcomes with CRT, recent reports from our and other institutions demonstrate these patients have high rates of functional organ preservation with CRT [18, 25].

In conclusion, we have demonstrated that carboplatin and paclitaxel IndCT before CRT can be delivered safely and effectively. Response to IndCT predicts for long-term control and survival. These results are the basis of an ongoing randomized trial testing the utility of IndCT before CRT.


   funding
Top
 Abstract
 introduction
 patients and methods
 results
 discussion
 funding
Acknowledgements
 References
 
Bristol-Myers Squibb; University of Chicago Cancer Research Center; the Francis Lederer Foundation; the Vlada and Robert Svendsen Foundation.


   Acknowledgements
Top
 Abstract
 introduction
 patients and methods
 results
 discussion
 funding
 Acknowledgements
References
 
For help in protocol design and patient care: Merrill S. Kies, David Gustin, Theodore Karrison, Mike Yao, and Louis Portugal.

Received for publication February 22, 2008. Revision received April 21, 2008. Accepted for publication April 22, 2008.


   References
Top
 Abstract
 introduction
 patients and methods
 results
 discussion
 funding
 Acknowledgements
 References
 
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18. Urba S, Wolf G, Eisbruch A, et al. Single-cycle induction chemotherapy selects patients with advanced laryngeal cancer for combined chemoradiation: a new treatment paradigm. J Clin Oncol (2006) 24:593–598.[Abstract/Free Full Text]

19. Haddad R, Tishler R, Wirth L, et al. Rate of pathologic complete responses to docetaxel, cisplatin, and fluorouracil induction chemotherapy in patients with squamous cell carcinoma of the head and neck. Arch Otolaryngol Head Neck Surg (2006) 132:678–681.[Abstract/Free Full Text]

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