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Figure 1.
Time to progression for 45 patients. The dotted lines represent the (pointwise) 95% confidence intervals (CIs). The 1-year, 3-year, and 5-year progression-free survival percentages were 88.9% (95% CI, 75.3%-95.2%), 82.2% (95% CI, 67.6%-90.7%), and 80% (95% CI, 65.1%-89.1%), respectively.

Time to progression for 45 patients. The dotted lines represent the (pointwise) 95% confidence intervals (CIs). The 1-year, 3-year, and 5-year progression-free survival percentages were 88.9% (95% CI, 75.3%-95.2%), 82.2% (95% CI, 67.6%-90.7%), and 80% (95% CI, 65.1%-89.1%), respectively.

Figure 2.
Overall survival for progression for 45 patients. The dotted lines represent the (pointwise) 95% confidence intervals (CIs). The 1-year, 3-year, and 5-year overall survival percentages were 97.8% (95% CI, 85.3%-99.7%), 88.9% (95% CI, 75.3%-95.2%), and 81.3% (95% CI, 63.7%-90.9%), respectively.

Overall survival for progression for 45 patients. The dotted lines represent the (pointwise) 95% confidence intervals (CIs). The 1-year, 3-year, and 5-year overall survival percentages were 97.8% (95% CI, 85.3%-99.7%), 88.9% (95% CI, 75.3%-95.2%), and 81.3% (95% CI, 63.7%-90.9%), respectively.

Table 1. 
Dosage Modification of Bioadjuvant Therapy
Dosage Modification of Bioadjuvant Therapy
Table 2. 
Patterns of Failure in Original Report and Current Report*
Patterns of Failure in Original Report and Current Report*
1.
Jemal  AMurray  TSamuels  AGhafoor  AWard  EThun  MJ Cancer statistics, 2003. CA Cancer J Clin 2003;535- 26
PubMedArticle
2.
Lotan  RXu  XCLippman  SM  et al.  Suppression of retinoic acid receptor-β in premalignant oral lesions and its up-regulation by isotretinoin. N Engl J Med 1995;3321405- 1410
PubMedArticle
3.
Hong  WKEndicott  JItri  LM  et al.  13-cis-Retinoic acid in the treatment of oral leukoplakia. N Engl J Med 1986;3151501- 1505
PubMedArticle
4.
Lippman  SMBatsakis  JGToth  BB  et al.  Comparison of low-dose isotretinoin with beta carotene to prevent oral carcinogenesis. N Engl J Med 1993;32815- 20
PubMedArticle
5.
Chiesa  FTradati  NMaruzza  M  et al.  Prevention of local relapses and new localisations of oral leukoplakias with the synthetic retinoid fenretinide (4-HPR): preliminary results. Eur J Cancer B Oral Oncol 1992;28B97- 102
PubMedArticle
6.
Hong  WKLippman  SMItri  LM  et al.  Prevention of second primary tumors with isotretinoin in squamous-cell carcinoma of the head and neck. N Engl J Med 1990;323795- 801
PubMedArticle
7.
Benner  SEPajak  TFLippman  SMEarley  CHong  WK Prevention of second primary tumors with isotretinoin in patients with squamous cell carcinoma of the head and neck: long-term follow up. J Natl Cancer Inst 1994;86140- 141
PubMedArticle
8.
Bolla  MLefur  RTon Van  J  et al.  Prevention of second primary tumors with etretinide in squamous cell carcinoma of the oral cavity and oropharynx: results of a multicenter double-blind randomized study. Eur J Cancer 1994;30A767- 772
PubMedArticle
9.
Khuri  FRLee  JJLippman  SM  et al Isotretinoin effects on head and neck cancer recurrence and second primary tumors.  In: Proceedings from the American Society of Clinical Oncology; May 31–June 3, 2003; Chicago, Ill. Abstract 359
10.
Shin  DMKhuri  FRMurphy  B  et al.  Combined interferon-alfa, 13-cis-retinoic acid and alpha-tocopherol in locally advanced head and neck squamous cell carcinoma: novel bioadjuvant phase II trial. J Clin Oncol 2001;193010- 3017
PubMed
11.
Forastiere  AKoch  WTrotti  ASidransky  D Head and neck cancer. N Engl J Med 2001;3451890- 1900
PubMedArticle
12.
Schantz  SPHarrison  LBForastiere  AA Tumors of the nasal cavity and paranasal sinuses, nasopharynx, oral cavity and oropharynx.  In: DeVita  JR, Hellman  S, Rosenberg  SA, eds.Cancer: Principles and Practice of Oncology. 5th ed. Philadelphia, Pa: JB Lippincott Co; 1997:741-782
13.
Tupchong  LScott  CBBlitzer  PH  et al.  Randomized study of preoperative versus postoperative radiation therapy in advanced head and neck carcinoma: long-term follow up of RTOG study 73-03. Int J Radiat Oncol Biol Phys 1991;2021- 28
PubMedArticle
14.
Cooper  JSPajak  TFRubin  P  et al.  Second malignancies in patients who have head and neck cancer incidence, effects on survival and implications based on the RTOG experience. Int J Radiat Oncol Biol Phys 1989;17449- 456
PubMedArticle
15.
Licciardello  JTSpitz  MRHong  WK Multiple primary cancer in patients with cancer of the head and neck: second cancer of the head and neck, esophagus and lung. Int J Radiat Oncol Biol Phys 1989;17467- 476
PubMedArticle
16.
Tepperman  BSFitzpatrick  PJ Second respiratory and upper digestive tract cancer after oral cancer. Lancet 1981;2547- 549
PubMedArticle
17.
Smith  MAParkinson  DRCheson  BD  et al.  Retinoids in cancer therapy. J Clin Oncol 1992;10839- 864
PubMed
18.
Pinto  HLoprinzi  CKardinal  CAdams  GPandya  K Phase III trial of low-dose 13-cis-retinoic acid for prevention of second primary cancers in stage I/II head and neck cancer: an Eastern Cooperative Oncology Group study.  In: Proceedings from the American Society of Clinical Oncology; May 12-15, 2001; San Francisco, Calif. Abstract 886
19.
DeLaney  TFAfridi  NTaghian  AG  et al.  13-cis-Retinoic acid with alpha 2a-interferon enhances radiation cytotoxicity in head and neck squamous cell carcinoma in vitro. Cancer Res 1996;562277- 2280
PubMed
20.
Toma  SMonteghirfo  STasso  P  et al.  Antiproliferative and synergistic effect of interferon alpha-2a, retinoids and their association in established human cancer cell lines. Cancer Lett 1994;82209- 216
PubMedArticle
21.
Lingen  MWPolverini  PJBouck  NP Retinoic acid and interferon alpha act synergistically as antiangiogenic and antitumor agents against human head and neck squamous cell carcinoma. Cancer Res 1998;585551- 5558
PubMed
22.
Shin  DMWang  ZKFong  CLi  MMyers  E Biochemopreventive combination (13-cis-retinoic acid, interferon-α2a and α-tocopherol) may have synergistic effect over single-agents or 2-drug combinations in vitro culture of squamous cell carcinoma of the head and neck cells [abstract]. Proc Am Assoc Cancer Res200243311a . Abstract 1546
23.
Papadimitrakopoulou  VAClayman  GLShin  DM  et al.  Biochemoprevention for dysplastic lesions of the upper aerodigestive tract. Arch Otolaryngol Head Neck Surg 1999;1251083- 1089
PubMedArticle
Original Article
April 2005

Phase 2 Bioadjuvant Study of Interferon Alfa-2a, Isotretinoin, and Vitamin E in Locally Advanced Squamous Cell Carcinoma of the Head and NeckLong-term Follow-up

Arch Otolaryngol Head Neck Surg. 2005;131(4):304-307. doi:10.1001/archotol.131.4.304
Abstract

Objective  To evaluate the long-term effects of the combination of isotretinoin, interferon alfa-2a, and vitamin E in locally advanced squamous cell carcinoma of the head and neck.

Design  Phase 2 prospective study.

Setting  Tertiary care academic medical centers.

Patients  Forty-five patients entered this study. All patients had stage III or IV squamous cell carcinoma of the head and neck and had been treated with surgical resection, radiation, or both. All patients were then treated with bioadjuvant chemopreventive treatment for 12 months. We previously reported a 24-month median follow-up of this phase 2 trial of the combination of isotretinoin, interferon alfa-2a, and vitamin E as bioadjuvant therapy after definitive local therapy. In that study, all 45 patients completed treatment, but 1 patient was excluded from analysis of recurrence and development of second primary tumors.

Main Outcome Measure  Longer-term (49.4-month median) follow-up.

Results  Among the 45 patients treated under the protocol, only 7 patients (16%) had died. Nine (20%) of 45 patients experienced progressive disease. Only 1 second primary tumor (acute promyelocytic leukemia) occurred during follow-up, and no aerodigestive second primary tumors occurred among the 45 patients. The 5-year progression-free survival and overall survival percentages were 80% (95% confidence interval, 65.1%-89.1%) and 81.3% (95% confidence interval, 63.7%-90.9%), respectively. These results are significantly better than the historical 5-year overall survival for advanced squamous cell carcinoma of the head and neck (approximately 40%).

Conclusion  The bioadjuvant combination is highly effective in preventing recurrence and second primary tumors, and its role as standard therapy in advanced squamous cell carcinoma of the head and neck is being investigated in a randomized phase 3 study.

Squamous cell carcinoma of the head and neck (SCCHN) accounts for approximately 3% of all malignancies, with an estimated 40 000 new cases and 11 000 deaths annually in the United States.1 Despite advanced curative therapy for SCCHN, the outcome of such treatment is poor. Preventive strategies are clearly desirable.

Retinoids, including vitamin A and its synthetic derivatives, have been extensively studied during the past 2 decades.2 A landmark trial by Hong et al3 showed that a high dose of isotretinoin was active against oral leukoplakia, although the toxicity was significant. In a subsequent study reported on by Lippman et al,4 patients with oral leukoplakia were initially treated with isotretinoin at a high dose and randomized to a lower dose of isotretinoin or beta carotene, and the patients treated with the lower dose of isotretinoin had a better response than those treated with beta carotene. Chiesa et al5 studied the synthetic retinoid fenretinide in patients with oral leukoplakia treated surgically. In their 1-year study, 3 (8%) of 39 patients in the treated group vs 12 (29%) of 41 who received no intervention were found to have local relapse or new lesions. The role of retinoids in the adjuvant setting in SCCHN has been studied. A phase 3 study randomized patients with stage I to IV SCCHN to either 50 to 100 mg/m2 of isotretinoin daily for 1 year or placebo.6 Although there were no significant differences between the 2 groups in the number of locoregional or distant recurrences of the primary cancers, the treatment groups had significantly fewer second primary tumors (SPTs). In short-term follow-up, the rate of SPTs was significantly lower in the treated group; however, in long-term follow-up, the SPT rates became much less significant, compared with the initial report.7 In a similar study conducted by Bolla et al,8 there was no difference in SPT rates for local or distant recurrence. Khuri et al9 recently reported data from an intergroup, placebo-controlled, double-blind study evaluating the efficacy of low-dose isotretinoin (30 mg/d) in prevention of SPTs in patients with stage I or II SCCHN. Since 1991, 1190 patients were randomized to receive 30 mg of isotretinoin daily or placebo for 3 years. There were no differences in SPT rates between the 2 groups, and a transient protective effect of isotretinoin on recurrence was lost after cessation of treatment. Therefore, single-agent retinoid therapy does not appear to have any impact on the prevention of SPTs or recurrence in SCCHN.

METHODS

We previously reported on a phase 2 study demonstrating activity and tolerability of the combination of isotretinoin, interferon alfa-2a, and vitamin E as bioadjuvant therapy after definitive local therapy.10 In the original report, a total of 45 patients with locally advanced (stages III and IV) SCCHN were treated for 12 months with isotretinoin, 50 mg/m2 orally daily; interferon alfa-2a, 3 × 106 IU/m2 in subcutaneous injections 3 times per week; and vitamin E, 1200 IU orally daily, with dose modifications (Table 1). Toxic effects were manageable, the most frequent being fatigue, influenzalike symptoms, mild to moderate hematologic side effects, and mucocutaneous toxic effects, as well as hypertriglyceridemia. There was only 1 case of a grade 4 toxic effect (infection) (see detailed information in Shin et al10). Overall, 84% (38/45) of enrolled patients completed the full 12-month course of treatment.

Length of survival was assessable for all patients. One patient was excluded from analyses of recurrence and SPT development because the patient already had recurrent disease at the time of study entry. At a median of 24 months of follow-up, 4 (9%) of 44 patients had regional recurrences and 2 patients (5%) had local plus distant recurrences. No SPT of the aerodigestive tract was observed in a 24-month follow-up, but 1 case of acute promyelocytic leukemia occurred. The overall 1- and 2-year survival percentages were 93% and 91%, respectively, while the 1-year and 2-year disease-free survival percentages were 91% and 84%, respectively.

RESULTS

The Kaplan-Meier plot of the survival curve for the time to progression is depicted in Figure 1. At a median follow-up of 49.4 months, only 9 (20%) of 44 patients experienced progressive disease, 3 since the last report (Table 2). Two patients had local recurrences, and 1 had local and distant relapse. The progression-free survival percentages at 1 year, 3 years, and 5 years were 88.9% (95% confidence interval [CI], 75.3%-95.2%), 82.2% (95% CI, 67.6%-90.7%), and 80% (95% CI, 65.1%-89.1%), respectively. The current Kaplan-Meier survival curve is shown in Figure 2. Seven (15.6%) of the 45 patients died. The median follow-up among the 38 surviving patients was 49.4 months. The median overall survival had not yet been reached. The overall survival percentages at 1 year, 3 years, and 5 years were 97.8% (95% CI, 85.3%-99.7%), 88.9% (95% CI, 75.3%-95.2%), and 81.3% (95% CI, 63.7%-90.9%), respectively.

Only 1 SPT, a case of acute promyelocytic leukemia, was observed in the whole cohort, including observation from the longer follow-up. No SPT of the aerodigestive tract was observed. No other SPT was seen since the last follow-up.

COMMENT

Results of this extended follow-up for the bioadjuvant therapy in locally advanced SCCHN are highly encouraging. If these results are confirmed in phase 3 randomized trials, this therapy could benefit a large number of patients, since approximately two thirds of patients with SCCHN have developed locally advanced disease at diagnosis.11 Furthermore, most patients in advanced stages have a poor prognosis, with historical long-term survival around 30%.12 The 5-year survival percentage in our patient cohort was far superior, at more than 80%. Also, there were no further recurrences after 2 years of follow-up, while historically no plateau in recurrence rates has been evident until at least 4 or 5 years of follow-up.13 However, the current results should be interpreted cautiously, since the patients who entered this phase 2 study were a relatively select group (ie, relatively young; median age, 52 years), were highly motivated, and had disease controlled up to 24 weeks from the definitive treatment. Nevertheless, these data suggest that the bioadjuvant therapy may offer a long-term effect in regard to prevention of recurrence, which is quite exciting, especially considering that there is no established role for adjuvant chemotherapy in high-risk SCCHN.

A second important finding in this study was the low incidence of SPTs. One large series14 reported the incidence of SPTs at 3 years, 5 years, and 8 years as 10%, 15%, and 23%, respectively. Other authors15,16 have reported the rate of SPT risk to range from 3% to 7% per year. In our cohort of stage III and IV SCCHN, there were no cases of SPT of the aerodigestive tract, despite the high-risk nature of our population of patients. There was only 1 case of acute promyelocytic leukemia, which is not known to be related to SCCHN.

We demonstrated that bioadjuvant therapy (isotretinoin, interferon alfa-2a, and vitamin E) might have a significant role in preventing SPTs and in decreasing the risk of recurrence in advanced SCCHN. The outcome with this combination might represent an advance in comparison with single-agent retinoids. Synthetic and natural retinoids are able to reverse established leukoplakia, with responses as high as 100%.17 High-dose, single-agent isotretinoin significantly reduces the risk of SPTs compared with placebo in SCCHN.6 However, no effect on the risk of local or distant recurrences of initial cancer was observed with this regimen. Most recently, 2 randomized placebo-controlled clinical trials were reported in the literature evaluating the role of low-dose single-agent isotretinoin in the prevention of SPTs in patients with stage I or II SCCHN.9,18 Neither of these studies showed a decrease in the incidence of SPT in patients treated with low-dose isotretinoin.

The improvement in the outcome observed in our study might be explained by the synergy among interferon alfa-2a, retinoids, and vitamin E. The combination of retinoids and interferon is known to enhance radiation-induced cytotoxicity,19 synergistically inhibit cell growth,16 and promote neovascularization20,21 in SCCHN. Vitamin E was later added to our regimen because it decreases isotretinoin toxicity and also may have chemopreventive activity. The improved efficacy observed with combination bioadjuvant therapy compared with single-agent retinoids or retinoids plus interferon was mechanistically demonstrated in preclinical models. In our recent study, the 3-drug combination (isotretinoin, interferon alfa-2a, and vitamin E) was more effective in growth inhibition of SCCHN cells than the single agents alone or 2-drug combinations (ie, interferon alfa-2a plus isotretinoin). This is due to increased S-phase arrest, decreased number of cells at G2 /M phase, increased apoptosis, and up-regulation of p53 and Fas/CD95 death receptor in combined treated cells vs single-agent or 2-drug combinations.22

In fact, the in vitro synergy was confirmed in a trial using this combination in advanced premalignant lesions (ie, moderate to severe dysplasia).22 In a phase 2 clinical trial for the advanced premalignant lesions (eg, moderate to severe dysplasia) of the head and neck, the combination of isotretinoin, interferon alfa-2a, and vitamin E was used.23 There were major pathologic responses in as many as 50% of cases with advanced premalignant lesions,23 which is observed with the use of single-agent retinoids only when they are used in early premalignant lesions (ie, hyperplasia or mild dysplasia).3,4

These encouraging data support the investigational use of combination bioadjuvant therapy in high-risk, locally advanced head and neck cancers. This combination regimen is being tested in a randomized fashion in a currently ongoing phase 3 study of bioadjuvant therapy vs observation through the Eastern Cooperative Oncology Group in patients with locally advanced SCCHN. The starting dose of the treated group was reduced to −1 dose level (80% of the phase 2 dose) of the phase 2 study since the reduced dose is expected to be better tolerated. This study is hoped to establish a role for bioadjuvant therapy in this devastating disease.

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Article Information

Correspondence: Dong M. Shin, MD, Winship Cancer Institute, Emory University, 1365-C Clifton Rd, Room C3090, Atlanta, GA 30322 (Dong_Shin@emoryhealthcare.org).

Submitted for Publication: July 16, 2004; final revision received September 24, 2004; accepted December 16, 2004.

References
1.
Jemal  AMurray  TSamuels  AGhafoor  AWard  EThun  MJ Cancer statistics, 2003. CA Cancer J Clin 2003;535- 26
PubMedArticle
2.
Lotan  RXu  XCLippman  SM  et al.  Suppression of retinoic acid receptor-β in premalignant oral lesions and its up-regulation by isotretinoin. N Engl J Med 1995;3321405- 1410
PubMedArticle
3.
Hong  WKEndicott  JItri  LM  et al.  13-cis-Retinoic acid in the treatment of oral leukoplakia. N Engl J Med 1986;3151501- 1505
PubMedArticle
4.
Lippman  SMBatsakis  JGToth  BB  et al.  Comparison of low-dose isotretinoin with beta carotene to prevent oral carcinogenesis. N Engl J Med 1993;32815- 20
PubMedArticle
5.
Chiesa  FTradati  NMaruzza  M  et al.  Prevention of local relapses and new localisations of oral leukoplakias with the synthetic retinoid fenretinide (4-HPR): preliminary results. Eur J Cancer B Oral Oncol 1992;28B97- 102
PubMedArticle
6.
Hong  WKLippman  SMItri  LM  et al.  Prevention of second primary tumors with isotretinoin in squamous-cell carcinoma of the head and neck. N Engl J Med 1990;323795- 801
PubMedArticle
7.
Benner  SEPajak  TFLippman  SMEarley  CHong  WK Prevention of second primary tumors with isotretinoin in patients with squamous cell carcinoma of the head and neck: long-term follow up. J Natl Cancer Inst 1994;86140- 141
PubMedArticle
8.
Bolla  MLefur  RTon Van  J  et al.  Prevention of second primary tumors with etretinide in squamous cell carcinoma of the oral cavity and oropharynx: results of a multicenter double-blind randomized study. Eur J Cancer 1994;30A767- 772
PubMedArticle
9.
Khuri  FRLee  JJLippman  SM  et al Isotretinoin effects on head and neck cancer recurrence and second primary tumors.  In: Proceedings from the American Society of Clinical Oncology; May 31–June 3, 2003; Chicago, Ill. Abstract 359
10.
Shin  DMKhuri  FRMurphy  B  et al.  Combined interferon-alfa, 13-cis-retinoic acid and alpha-tocopherol in locally advanced head and neck squamous cell carcinoma: novel bioadjuvant phase II trial. J Clin Oncol 2001;193010- 3017
PubMed
11.
Forastiere  AKoch  WTrotti  ASidransky  D Head and neck cancer. N Engl J Med 2001;3451890- 1900
PubMedArticle
12.
Schantz  SPHarrison  LBForastiere  AA Tumors of the nasal cavity and paranasal sinuses, nasopharynx, oral cavity and oropharynx.  In: DeVita  JR, Hellman  S, Rosenberg  SA, eds.Cancer: Principles and Practice of Oncology. 5th ed. Philadelphia, Pa: JB Lippincott Co; 1997:741-782
13.
Tupchong  LScott  CBBlitzer  PH  et al.  Randomized study of preoperative versus postoperative radiation therapy in advanced head and neck carcinoma: long-term follow up of RTOG study 73-03. Int J Radiat Oncol Biol Phys 1991;2021- 28
PubMedArticle
14.
Cooper  JSPajak  TFRubin  P  et al.  Second malignancies in patients who have head and neck cancer incidence, effects on survival and implications based on the RTOG experience. Int J Radiat Oncol Biol Phys 1989;17449- 456
PubMedArticle
15.
Licciardello  JTSpitz  MRHong  WK Multiple primary cancer in patients with cancer of the head and neck: second cancer of the head and neck, esophagus and lung. Int J Radiat Oncol Biol Phys 1989;17467- 476
PubMedArticle
16.
Tepperman  BSFitzpatrick  PJ Second respiratory and upper digestive tract cancer after oral cancer. Lancet 1981;2547- 549
PubMedArticle
17.
Smith  MAParkinson  DRCheson  BD  et al.  Retinoids in cancer therapy. J Clin Oncol 1992;10839- 864
PubMed
18.
Pinto  HLoprinzi  CKardinal  CAdams  GPandya  K Phase III trial of low-dose 13-cis-retinoic acid for prevention of second primary cancers in stage I/II head and neck cancer: an Eastern Cooperative Oncology Group study.  In: Proceedings from the American Society of Clinical Oncology; May 12-15, 2001; San Francisco, Calif. Abstract 886
19.
DeLaney  TFAfridi  NTaghian  AG  et al.  13-cis-Retinoic acid with alpha 2a-interferon enhances radiation cytotoxicity in head and neck squamous cell carcinoma in vitro. Cancer Res 1996;562277- 2280
PubMed
20.
Toma  SMonteghirfo  STasso  P  et al.  Antiproliferative and synergistic effect of interferon alpha-2a, retinoids and their association in established human cancer cell lines. Cancer Lett 1994;82209- 216
PubMedArticle
21.
Lingen  MWPolverini  PJBouck  NP Retinoic acid and interferon alpha act synergistically as antiangiogenic and antitumor agents against human head and neck squamous cell carcinoma. Cancer Res 1998;585551- 5558
PubMed
22.
Shin  DMWang  ZKFong  CLi  MMyers  E Biochemopreventive combination (13-cis-retinoic acid, interferon-α2a and α-tocopherol) may have synergistic effect over single-agents or 2-drug combinations in vitro culture of squamous cell carcinoma of the head and neck cells [abstract]. Proc Am Assoc Cancer Res200243311a . Abstract 1546
23.
Papadimitrakopoulou  VAClayman  GLShin  DM  et al.  Biochemoprevention for dysplastic lesions of the upper aerodigestive tract. Arch Otolaryngol Head Neck Surg 1999;1251083- 1089
PubMedArticle
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