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Combined Interferon-Alfa, 13-cis-Retinoic Acid, and Alpha-Tocopherol in Locally Advanced Head and Neck Squamous Cell Carcinoma: Novel Bioadjuvant Phase II Trial

From the Departments of Thoracic/Head and Neck Medical Oncology, Diagnostic Imaging, Head and Neck Surgery, Biostatistics, Radiation Oncology, and Clinical Cancer Prevention, The University of Texas M.D. Anderson Cancer Center, Houston, TX; Division of Medical Oncology, Vanderbilt University, Nashville, TN; and Head and Neck Cancer Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA.

Address reprint requests to Dong M. Shin, MD, Head and Neck Cancer Program, University of Pittsburgh Cancer Institute, 200 Lothrop St, MUH N-755, Pittsburgh, PA 15213-2582; email: shindm{at}msx.upmc.edu

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: Retinoids and interferons (IFNs) have single-agent and synergistic combined effects in modulating cell proliferation, differentiation, and apoptosis in vitro and clinical activity in vivo in the head and neck and other sites. Alpha-tocopherol has chemopreventive activity in the head and neck and may decrease 13-cis-retinoic acid (13-cRA) toxicity. We designed the present phase II adjuvant trial to prevent recurrence or second primary tumors (SPTs) using 13-cRA, IFN-, and -tocopherol in locally advanced-stage head and neck cancer.

PATIENTS AND METHODS: After definitive local treatment with surgery, radiotherapy, or both, patients with locally advanced SCCHN were treated with 13-cRA (50 mg/m²/d, orally, daily), IFN- (3 x 10⁶ IU/m², subcutaneous injection, three times a week), and -tocopherol (1,200 IU/d, orally, daily) for 12 months, with a dose modification. Screening for recurrence or SPTs was performed every 3 months.

RESULTS: Tumors of 11 (24%) of the 45 treated patients were stage III, and 34 (76%) were stage IV. Thirty-eight (86%) of 44 patients completed the full 12-month treatment (doses modified as needed). Toxicity generally was consistent with previous IFN and 13-cRA reports and included mild to moderate mucocutaneous and flu-like symptoms; occasional significant fatigue (grade 3 in 7% of patients), mild to moderate hypertriglyceridemia in 30% of patients who continued treatment along with antilipid therapy, and mild hematologic side effects. Six patients did not complete the planned treatment because of intolerable toxicity or social problems. At a median 24-months of follow-up, our clinical end point rates were 9% for local/regional recurrence (four patients), 5% for local/regional recurrence and distant metastases (two patients), and 2% for SPT (one patient), which was acute promyelocytic leukemia (ie, not of the upper aerodigestive tract). Median 1- and 2-year rates of overall survival were 98% and 91%, respectively, and of disease-free survival were 91% and 84%, respectively.

CONCLUSION: The novel biologic agent combination of IFN-, 13-cRA, and -tocopherol was generally well tolerated and promising as adjuvant therapy for locally advanced squamous cell carcinoma of the head and neck. We are currently conducting a phase III randomized study of this combination (v no treatment) to confirm these phase II study results.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
WITH 43,300 NEW cases and 11,500 deaths in the year 2000, squamous cell carcinoma of the head and neck (SCCHN) accounts for 4% to 5% of all newly diagnosed cancers in the United States.¹ More than two thirds of these patients present with locally advanced (stages III or IV) SCCHN, which has a poor 5-year survival rate after surgery, radiation therapy, or both.^2,3

The past two decades of neoadjuvant and adjuvant chemotherapy research, including large-scale trials,^4-7 have failed to improve survival of locally advanced SCCHN, despite the decreases in distant metastases^8-10 achieved by neoadjuvant chemotherapy. Because the highest rate of treatment failure occurs in the head and neck region, it is likely that improved adjuvant control of local/regional disease must accompany improved neoadjuvant control of distant metastasis before survival will improve.

If they are fortunate enough to overcome the high risk of recurrence, SCCHN survivors remain at high risk for developing second primary tumors (SPTs).^11-14 Future improvements in diagnostic and therapeutic techniques that increase survival rates will increase SCCHN survivors’ lifetime risk of SPTs, which are usually fatal.¹¹ One of the most promising strategies for preventing SPTs is chemoprevention.¹⁵ We previously conducted a placebo-controlled phase III chemoprevention trial demonstrating that single-agent retinoids could prevent SPTs associated with SCCHN.¹⁶ This trial, however, did not achieve significant improvements in survival because there was no effect on local, regional, or distant recurrences of the initial cancer.¹⁶

Retinoids and interferons (IFNs) have single-agent activity and synergistic combined effects^17-20 in modulating cell proliferation, differentiation, and apoptosis in vitro and clinical activity in vivo in the head and neck and other sites.^21-23 Alpha-tocopherol has chemopreventive activity in the head and neck and may decrease 13-cis-retinoic acid (13-cRA) toxicity. Therefore, we designed a prospective nonrandomized phase II study of IFN plus 13-cRA plus -tocopherol to prevent both recurrence and SPTs in patients with stages III or IV SCCHN after complete resection, postoperative radiotherapy, or both. This article presents the toxicity and clinical results of this novel bioadjuvant combination.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patient Eligibility
The major eligibility criteria were a confirmed diagnosis of squamous cell carcinoma of the oral cavity, oropharynx, larynx, or hypopharynx; locally advanced stage III or IV disease; enrolled a minimum of 3 weeks and maximum of 24 weeks after definitive local therapy with surgery, radiotherapy, or both; should not have received chemotherapy, immunotherapy, or hormonal therapy before entry onto the study; must have recovered from the acute toxic effects of surgery, radiotherapy, or both; and must be able to swallow the pills without breaking them. Other eligibility criteria included a life expectancy of 12 weeks, a Karnofsky performance status rating of 80%, adequate bone marrow function (defined as a leukocyte count of 3,000/µL and platelet count of 100,000/µL), and adequate renal (creatinine 1.5 mg/100 mL) and hepatic (total bilirubin 1.5 mg/100 mL) functions.

Patients were ineligible if they were taking megadoses of vitamin A (> 25,000 IU), if they were women of child-bearing potential who were not practicing adequate birth control, and if they had a baseline triglyceride level twice the normal range. Informed written consent was obtained from each patient. The protocol was approved by the institutional review board of The University of Texas M.D. Anderson Cancer Center and that of Vanderbilt University.

Treatment Plan
Before starting the treatment, all patients gave a complete medical history and had a physical examination, complete blood count, serum chemistry (hepatic and renal function tests and electrolytes), urinalysis, and lipid battery tests. All patients underwent chest radiography and computed tomography or magnetic resonance imaging of the indicator sites to confirm that no active primary or nodal disease was present. Patients were monitored during treatment by monthly complete blood count with differential, lipid battery, history and physical examination, thyroid function tests (T4, thyroid stimulating hormone) if indicated, and pill counts. One month was considered to be one course, and the total planned treatment consisted of 12 courses, or 12 months. All participating patients are being observed for a minimum of 4 years.

The bioadjuvant therapy regimen consisted of IFN (3 x 10⁶ IU/m², subcutaneous injection, three times a week), 13-cRA (50 mg/m²/d, orally, daily), and -tocopherol (1,200 IU/d, orally, daily) for 12 months. Doses were modified (Table 1) according to toxic effects that had developed in the previous month of treatment. A complete head and neck examination, pertinent computed tomography or magnetic resonance imaging scans, and chest radiography were performed every 3 months to identify any recurrent disease, metastases, or SPTs. Protocol compliance was measured by pill counts (of 13-cRA and -tocopherol) and a drug calendar detailing the injection time of IFN and when the pills were taken.

Study End Points and Survival Rate Evaluation
The primary study end points were assessment of incidence of disease recurrence and SPT development. The secondary end points were evaluation of toxic effects and estimation of progression-free survival and overall survival rates. The duration of progression-free survival was computed as the time between a patient’s registration onto the protocol and the development of recurrent disease, SPTs, or both. Duration of overall survival was computed as the time between a patient’s registration onto the study and his or her death or, in case of continuing survival, the end of study follow-up care. Survival curves were computed by the Kaplan-Meier method.²⁵

	RESULTS

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Patient Characteristics
Forty-five patients were entered onto this study from November 1997 to September 1999. Length of survival for all patients was assessable. Forty-four cases were assessable for analyses of recurrence and SPT development; one case was not assessable because the patient already had recurrent disease at the time of registration. The detailed patient characteristics are listed in Table 2. The median age of patients was 52 years, and two thirds of the patients had a good Karnofsky performance status ( 90%). The most common primary tumor site was the oropharynx, followed by the oral cavity, the larynx, and the hypopharynx, in decreasing order. The tumor-node-metastasis staging of all patients entered is listed in Table 3. There were 11 patients (24%) with stage III and 34 patients (76%) with stage IV tumors. Stage N2 and N3 nodal disease was present in 31 patients (69%), and T3 and T4 primary tumors were present in 20 patients (44%) before they underwent definitive local treatment. Twenty-seven patients (60%) had surgery and radiation therapy, 15 (33%) had radiation therapy alone, and three (7%) had surgery alone before being enrolled onto the protocol. The median time interval from the last definitive local therapy to registration on the adjuvant therapy was 13 weeks (range, 2.9 to 23.9 weeks).

Toxic Effects
As listed in Table 4, toxic effects generally were consistent with previous reports of toxicity associated with the constituent agents given singly or in combinations (eg, IFN plus 13-cRA).^22,23,26 Nonhematologic toxic effects included mild to moderate mucocutaneous side effects, flu-like symptoms (eg, arthralgia or myalgia, transient fever, or headache), anorexia, and weight loss. Fatigue occurred in 14 patients (33%) at the grade 2 level and in three patients (7%) at grade 3. Peripheral neuropathy (eg, numbness or tingling sensation) occurred in four patients (9%) at grade 2 and in one (2%) at grade 3. One patient developed a vision change (grade 3) with a moderate degree of optic neuritis by ophthalmologic examination after five courses of treatment. Detailed examination by an ophthalmologist was serially performed and did not show any abnormalities of the cornea, lens, or retina. There was a mild to moderate degree of evidence of nonspecific inflammation at the head of the optic nerve. All three study drugs were completely stopped, and the patient’s vision recovered gradually thereafter. After approximately 3 months of withholding the drugs, the vision became completely normal. Mild to moderate degrees of hypertriglyceridemia occurred in 13 patients (30%), and the study treatment was continued in all of these patients, along with antilipid treatment. One patient had a severe throat infection (beta-hemolytic streptococci) without neutropenia and required emergency tracheostomy. This patient eventually fully recovered with intravenous antibiotic therapy and was able to complete the planned 12 months of adjuvant treatment. Hematologic side effects were mild. No patients required RBC or platelet transfusions, and none required growth factor support.

View larger version (11K): [in this window] [in a new window]   Fig 1. Overall survival curve for 45 patients; 1-year and 2-year survival rates were 98% (95% CI, 94% to 100%) and 91% (95% CI, 81% to 100%), respectively.

View larger version (11K): [in this window] [in a new window]   Fig 2. Disease-free survival curve for 45 patients; 1-year and 2-year disease-free survival rates were 91% (95% CI, 83% to 100%) and 84% (95% CI, 73% to 97%), respectively.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

The extensive preclinical and clinical study of reti-noids^26-31 includes previous clinical trials demonstrating the significant chemopreventive efficacy of 13-cRA in head and neck carcinogenesis (both SPT prevention¹⁶ and the reversal of premalignant lesions).^32-35 We previously conducted a placebo-controlled phase III trial of adjuvant high-dose 13-cRA (100 mg/m²/d for 12 months) in patients with stages I to IV (M0) SCCHN. After 32 months’ median follow-up, significantly fewer SPTs developed in the 13-cRA group compared with the placebo group (P = .005).¹⁶ At 55 months’ median follow-up, the 13-cRA group continued to have fewer upper aerodigestive tract SPTs (14% v 33%; P = .042).³⁶ Although impressive, these SPT results did not produce a survival advantage, primarily because recurrence rates in the 13-cRA and placebo groups were not significantly different. For patients with recurrent or metastatic head and neck cancer, the Head and Neck Interferon Cooperative Study Group conducted a phase III trial of modulation of cisplatin/fluorouracil chemotherapy by IFN-2b. Modulation of cisplatin/fluorouracil with single-agent IFN, as used in this study, did not improve the response rate or the median survival rate in this study.³⁷

A recently completed large phase III trial of another retinoid, retinyl palmitate, and N-acetylcysteine, was ineffective in 2,592 patients with head and neck or lung cancer, most of whom were current or former smokers.³⁸ After 49 months’ median follow-up, no statistically significant differences were observed in overall survival, event-free survival, or incidence of SPTs between patients who did and those who did not receive a form of treatment.³⁸ There currently is an ongoing large-scale intergroup placebo-controlled phase III trial of 13-cRA (30 mg/m² for 3 years) to prevent SPTs in patients with stage I or II SCCHN who are disease free after surgery, radiation, or both.³⁹ The completion and final analyses of this major trial are anticipated in the future.

Combined IFN and 13-cRA has shown synergistic effects in certain preclinical studies^17-20,40-44 and significant activity in head and neck cancer cell lines^18,21 and clinical trials involving squamous cell carcinoma of the skin or cervix.^22,23 The results of our study lend support to the hypothesis that combined IFN and 13-cRA can reduce the incidence of recurrence and SPTs in locally advanced head and neck cancer.

Recent molecular studies of IFN/retinoic acid (RA) interactions in head and neck and other cancer sites may help in understanding the clinical activity of our study. Both RA and IFN signaling are involved in cell growth, differentiation, apoptosis, and angiogenesis.^45-48 RA can modulate IFN signaling by regulating the expression of IFN, IFN-signaling proteins, and IFN-stimulated genes.^49-51 IFN can upregulate nuclear RA receptors.^46,52,53 RA and IFN directly regulate the transcription of p21 through their upstream promotion regulatory elements, suggesting that p21 protein represents a potential point of intersection between the RA- and IFN-signaling pathways for the control of cellular proliferation and differentiation.^54,55 Therefore, RA/IFN mechanisms seem to collaborate synergistically in regulating the transcription of p21, which eventually may control cell proliferation and differentiation.

We recently completed a biomarker-driven translational study of 12 months’ administration of IFN, 13-cRA, and -tocopherol in patients with advanced premalignant lesions.²⁶ The pathologic complete response rate in laryngeal lesions was more than 50% at 6 months. The p53 status in these patients seems to be an important factor for predicting responsiveness to treatment.⁵⁶ A higher pathologic response rate occurred in patients with low tissue expression of p53 than with high p53 expression. Our sequencing analyses showed that lesions expressing the wild-type p53 gene and maintaining the wild-type during therapy achieved a high rate of pathologic responses, whereas lesions expressing mutant p53 gene at baseline or developing mutant p53 during treatment achieved a very low rate of pathologic responses.^56,57 This study clearly showed that retention of p53 function seems to be a critical parameter for determining the outcome of this combination biologic therapy. The results probably hinges on the mediation of apoptotic cell death by a functional p53 gene, which has been demonstrated in many systems.^57,58 Because IFNs have antiangiogenic effects and, in combination with retinoids, enhance antiangiogenesis,^18,19 it is reasonable to hypothesize that the combination of IFN and 13-cRA may shut down tumor vascularization or inhibit tumor cluster formation in recurrence.

Loss of heterozygosity (LOH) at 3p14 and 9p21 is common in premalignant and malignant head and neck lesions.⁵⁹ LOH at 9p21 persists in advanced premalignant lesions after treatment with IFN, 13-cRA, and -tocopherol, even in those that respond pathologically.⁶⁰ Apparently, some of the advanced premalignant clones with certain genetic changes, such as altered p53, are sensitive to the agent combination^56,60; however, clones with other genetic abnormalities, such as LOH at 9p21 (or subclones with other genetic abnormalities), are insensitive to the agents, remain, and become the sources of disease progression and recurrence. Therefore, incorporating molecular markers such as LOH at 9p21 into clinical trials is critical to understanding and predicting therapeutic outcomes of bioadjuvant therapy.⁶¹

Our novel bioadjuvant combination therapy was generally well tolerated for 12 months, and 86% of the patients were able to complete the planned courses of treatment. However, only 28% of all courses were given at dose level 0, and 50% were given at dose level -1. Therefore, dose level -1 would be more tolerable in future trials. In contrast to cytotoxic chemotherapy, hematologic side effects were minimal. The major dose-limiting toxic effect seemed to be fatigue, which may have been associated with IFN therapy and increased by the addition of 13-cRA. The cutaneous side effects, however, were mild to moderate and might have been ameliorated by the addition of -tocopherol, which is known to reduce retinoid-induced side effects.^62,63

Our study was promising, with excellent survival and low recurrence and SPT rates. These preliminary findings prompted a follow-up phase III randomized trial to confirm the beneficial effects of combined IFN, 13-cRA, and -tocopherol in locally advanced SCCHN.

	ACKNOWLEDGMENTS

 
Supported in part by National Cancer Institute grants no. CA9025 and CA75603 (D.M.S.) and Roche Laboratory, Inc. W.K.H. holds an American Cancer Society Clinical Research Professorship.

We thank the participating patients and their families, Julia Starr for editorial assistance, and Vanessa Valiare for preparation of the manuscript.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
1. Greenlee RT, Murray T, Bolden S, et al: Cancer statistics, 2000. CA Cancer J Clin 50: 7-33, 2000[Abstract]

2. Vokes EE, Weichselbaum RR, Lippman SM, et al: Head and neck cancer. N Engl J Med 328: 184-194, 1993[Free Full Text]

3. Forastiere AA, Metch B, Schuller DE, et al: Randomized comparison of cisplatin plus fluorouracil and carboplatin plus fluorouracil versus methotrexate in advanced squamous-cell carcinoma of the head and neck: A Southwest Oncology Group Study. J Clin Oncol 10: 1245-1251, 1992[Abstract/Free Full Text]

4. Forastiere AA: Randomized trials of induction chemotherapy: A critical review. Hematol Oncol Clin North Am 5: 725-736, 1991[Medline]

5. Ensley JF, Jacobs JR, Weaver A, et al: Correlation between response to cisplatinum-combination chemotherapy and subsequent radiotherapy in previously untreated patients with advanced squamous cell cancers of the head and neck. Cancer 54: 811-814, 1984[Medline]

6. Vokes EE, Weichselbaum RR, Mick R, et al: Favorable long-term survival following induction chemotherapy with cisplatin, fluorouracil, and leucovorin and concomitant chemoradiotherapy for locally advanced head and neck cancer. J Natl Cancer Inst 84: 877-882, 1992[Abstract/Free Full Text]

7. Laramore GE, Scott CB, Al-Sarraf M, et al: Adjuvant chemotherapy for resectable squamous cell carcinomas of the head and neck: Report on Intergroup Study 0034. Int J Radiat Oncol Biol Phys 23: 705-713, 1992[Medline]

8. The Department of Veterans Affairs Laryngeal Cancer Study Group: Induction chemotherapy plus radiation compared with surgery plus radiation in patients with advanced laryngeal cancer. N Engl J Med 324: 1685-1690, 1991[Abstract]

9. Jacobs C, Makuch R: Efficacy of adjuvant chemotherapy for patients with resectable head and neck cancer: A subset analysis of the Head and Neck Contracts Program. J Clin Oncol 8: 838-847, 1990[Abstract]

10. Schuller DE, Metch B, Stein DW, et al: Preoperative chemotherapy in advanced resectable head and neck cancer: Final report of the Southwest Oncology Group. Laryngoscope 98: 1205-1211, 1988[Medline]

11. Licciardello JT, Spitz MR, Hong 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 17: 467-476, 1989[Medline]

12. McDonald S, Haie C, Rubin P, et al: Second malignant tumors in patients with laryngeal carcinoma: Diagnosis, treatment, and prevention. Int J Radiat Oncol Biol Phys 17: 457-465, 1989[Medline]

13. McGuirt WF, Matthews B, Koufman JA: Multiple simultaneous tumors in patients with head and neck cancer: A prospective, sequential panendoscopic study. Cancer 50: 1195-1199, 1982[Medline]

14. Lippman SM, Hong WK: Second malignant tumors in head and neck squamous call carcinoma: The overshadowing threat for patients with early-stage disease. Int J Radiat Oncol Biol Phys 17: 691-694, 1989[Medline]

15. Meyskens FL Jr: Coming of age: The chemoprevention of cancer. N Engl J Med 323: 825-827, 1990[Medline]

16. Hong WK, Lippman SM, Itri LM, et al: Prevention of second primary tumors with isotretinoin in squamous-cell carcinoma of the head and neck. N Engl J Med 323: 795-801, 1990[Abstract]

17. DeLaney TF, Afridi N, Taghian 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 56: 2277-2280, 1996[Abstract/Free Full Text]

18. Lingen MW, Polverini PJ, Bouck NP: Retinoic acid and interferon alpha act synergistically as antiangiogenic and antitumor agents against human head and neck squamous cell carcinoma. Cancer Res 58: 5551-5558, 1998[Abstract/Free Full Text]

19. Lindner DJ, Borden EC, Kalvakolanu DV: Synergistic antitumor effects of a combination of interferons and retinoic acid on human tumor cells in vitro and in vivo. Clin Cancer Res 3: 931-937, 1997[Abstract]

20. Kolla V, Weihua X, Kalvakolanu DV: Modulation of interferon action by retinoids: Induction of murine STAT1 gene expression by retinoic acid. J Biol Chem 272: 9742-9748, 1997[Abstract/Free Full Text]

21. Gaboli M, Gandini D, Delva L, et al: Acute promyelocytic leukemia as a model for cross-talk between interferon and retinoic acid pathways: From molecular biology to clinical applications. Leuk Lymphoma 30: 11-22, 1998[Medline]

22. Lippman SM, Parkinson DR, Itri LM, et al: 13-cis-retinoic acid and interferon alpha-2a: Effective combination therapy for advanced squamous cell carcinoma of the skin. J Natl Cancer Inst 84: 235-241, 1992[Abstract/Free Full Text]

23. Lippman SM, Kavanagh JJ, Paredes-Espinoza M, et al: 13-cis-retinoic acid plus interferon-alpha 2a in locally advanced squamous cell carcinoma of the cervix. J Natl Cancer Inst 85: 499-500, 1993[Free Full Text]

24. Ajani JA, Welch SR, Raber MN, et al: Comprehensive criteria for assessing therapy-induced toxicity. Cancer Invest 8: 147-159, 1990[Medline]

25. Kaplan E, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53: 457-481, 1958

26. Papadimitrakopoulou VA, Clayman GL, Shin DM, et al: Biochemoprevention for dysplastic lesions of the upper aerodigestive tract. Arch Otolaryngol Head Neck Surg 125: 1083-1089, 1999

27. Sporn MB, Roberts AB: Role of retinoids in differentiation and carcinogenesis. J Natl Cancer Inst 73: 1381-1387, 1984

28. Evans RM: The steroid and thyroid hormone receptor superfamily. Science 240: 889-895, 1988[Abstract/Free Full Text]

29. Oridate N, Lotan D, Xu XC, et al: Differential induction of apoptosis by all-trans-retinoic acid and N-(4-hydroxphenyl) retinamide in human head and neck squamous cell carcinoma cell lines. Clin Cancer Res 2: 855-863, 1996[Abstract]

30. Mayne S, Lippman S: Retinoids and carotenoids, in DeVita VT Jr, Hellman S, Rosenberg SA (eds): Cancer: Principles and Practice of Oncology ( ed 5 ). Philadelphia, PA: Lippincott-Raven, 1997, pp 585-599

31. Kraemer KH, DiGiovanna JJ, Moshell AN, et al: Prevention of skin cancer in xeroderma pigmentosum with the use of oral isotretinoin. N Engl J Med 318: 1633-1637, 1988[Abstract]

32. Castaigne S, Chomienne C, Daniel MT, et al: All-trans retinoic acid as a differentiation therapy for acute promyelocytic leukemia: Clinical results. Blood 76: 1704-1709, 1990[Abstract/Free Full Text]

33. Lippman SM, Benner SE, Hong WK: Cancer chemoprevention. J Clin Oncol 12: 851-873, 1994[Abstract]

34. Hong WK, Endicott J, Itri LM, et al: 13-cis-retinoic acid in the treatment of oral leukoplakia. N Engl J Med 315: 1501-1505, 1986[Abstract]

35. Lippman SM, Batsakis JG, Toth BB, et al: Comparison of low-dose isotretinoin with beta carotene to prevent oral carcinogenesis. N Engl J Med 328: 15-20, 1993[Abstract/Free Full Text]

36. Benner SE, Pajak TF, Lippman SM, et al: 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 86: 140-141, 1994[Free Full Text]

37. Schrijvers D, Johnson J, Jimenez U, et al: Phase III trial of modulation of cisplatin/fluorouracil chemotherapy by interferon alpha-2b in patients with recurrent or metastatic head and neck cancer. Head and Neck Interferon Cooperative Study Group. J Clin Oncol 16: 1054-1059, 1998[Abstract]

38. Van Zandwijk N, Dalesio O, Pastorino U, et al: EUROSCAN, a randomized trial of vitamin A and N-acetylcysteine in patients with head and neck cancer or lung cancer. For the European Organization for Research and Treatment of Cancer Head and Neck and Lung Cancer Cooperative Groups. J Natl Cancer Inst 92: 977-986, 2000[Abstract/Free Full Text]

39. Khuri FR, Lee JJ, Winn RJ, et al: Interim analysis of randomized chemoprevention trial of head and neck squamous cell cancer. Proc Am Soc Clin Oncol 18: 389a, 1999 (abstr 1503)

40. Wadler S, Schwartz EL: Antineoplastic activity of the combination of interferon and cytotoxic agents against experimental and human malignancies: A review. Cancer Res 50: 3473-3486, 1990[Abstract/Free Full Text]

41. Hemmi H, Breitman TR: Combinations of recombinant human interferons and retinoic acid synergistically induce differentiation of the human promyelocytic leukemia cell line HL-60. Blood 69: 501-507, 1987[Abstract/Free Full Text]

42. Marth C, Daxenbichler G, Dapunt O: Synergistic antiproliferative effect of human recombinant interferons and retinoic acid in cultured breast cancer cells. J Natl Cancer Inst 77: 1197-1202, 1986

43. Marth C, Kirchebner P, Daxenbichler G: The role of polyamines in interferon and retinoic acid mediated synergistic antiproliferative action. Cancer Lett 44: 55-59, 1989[Medline]

44. Frey JR, Peck R, Bollag W: Antiproliferative activity of retinoids, interferon alpha and their combination in five human transformed cell lines. Cancer Lett 57: 223-227, 1991[Medline]

45. Li G, Walch E, Yang X, et al: Cloning and characterization of the human retinoid X receptor alpha gene: Conservation of structure with the mouse homolog. Biochem Biophys Res Commun 269: 54-57, 2000[Medline]

46. Boudjelal M, Wang Z, Voorhees JJ, et al: Ubiquitin/proteasome pathway regulates levels of retinoic acid receptor gamma and retinoid X receptor alpha in human keratinocytes. Cancer Res 60: 2247-2252, 2000[Abstract/Free Full Text]

47. Gianni M, Zanotta S, Terao M, et al: Interferons induce normal and aberrant retinoic-acid receptors type alpha in acute promyelocytic leukemia cells: Potentiation of the induction of retinoid-dependent differentiation markers. Int J Cancer 68: 75-83, 1996[Medline]

48. Clifford JL, Menter DG, Wang M, et al: Retinoid receptor-dependent and -independent effects of N-(4-hydroxyphenyl)retinamide in F9 embryonal carcinoma cells. Cancer Res 59: 14-18, 1999[Abstract/Free Full Text]

49. Lancillotti F, Giandomenico V, Affabris E, et al: Interferon alpha-2b and retinoic acid combined treatment affects proliferation and gene expression of human cervical carcinoma cells. Cancer Res 55: 3158-3164, 1995[Abstract/Free Full Text]

50. Clippitelli M, Ye J, Viggiano V, et al: Retinoic acid-induced transcriptional modulation of the human interferon-gamma promoter. J Biol Chem 271: 26783-26793, 1996[Abstract/Free Full Text]

51. Kolla V, Lindner DJ, Xiao W, et al: Modulation of interferon (IFN)-inducible gene expression by retinoic acid: Up-regulation of STAT1 protein in IFN-unresponsive cells. J Biol Chem 271: 10508-10514, 1996[Abstract/Free Full Text]

52. Widschwendter M, Daxenbichler G, Dapunt O, et al: Effects of retinoic acid and gamma-interferon on expression of retinoic acid receptor and cellular retinoic acid-binding protein in breast cancer cells. Cancer Res 55: 2135-2139, 1995[Abstract/Free Full Text]

53. Bauvois B, Djavaheri-Mergny M, Rouillard D, et al: Regulation of CD26/DPPIV gene expression by interferons and retinoic acid in tumor B cells. Oncogene 19: 265-272, 2000[Medline]

54. Chin YE, Kitagawa M, Su WC, et al: Cell growth arrest and induction of cyclin-dependent kinase inhibitor p21^WAF1/CIP1 medicated by STAT1. Science 272: 719-722, 1996[Abstract]

55. Liu M, Iavarone A, Freedman LP: Transcriptional activation of the human p21^(WAF1/CIP1) gene by retinoic acid receptor: Correlation with retinoid induction of U937 cell differentiation. J Biol Chem 271: 31723-31728, 1996[Abstract/Free Full Text]

56. Shin DM, Mao L, Papadimitrakopoulou VM, et al: Biochemopreventive therapy for patients with premalignant lesions of the head and neck and p53 gene expression. J Natl Cancer Inst 92: 69-73, 2000[Free Full Text]

57. Shin DM, Xu XC, Lippman SM, et al: Accumulation of p53 protein and retinoic acid receptor-ß in retinoid chemoprevention. Clin Cancer Res 3: 875-880, 1997[Abstract]

58. Lowe SW, Ruley HE, Jacks T, et al: P53-dependent apoptosis modulates the cytotoxicity of anticancer agents. Cell 74: 957-967, 1993[Medline]

59. Zhan Q, Carrier F, Fornace AJ Jr: Induction of cellular p53 activity by DNA-damaging agents and growth arrest. Mol Cell Biol 13: 4242-4250, 1993[Abstract/Free Full Text]

60. Mao L, Lee JS, Fan YH, et al: Frequent microsatellite alterations at chromosomes 9p21 and 3p14 in oral premalignant lesions and their value in cancer risk assessment. Nature Med 2: 682-685, 1996[Medline]

61. Mao L, El-Naggar AK, Papadimitrakopoulou V, et al: Phenotype and genotype of advanced premalignant head and neck lesions after chemopreventive therapy. J Natl Cancer Inst 90: 1545-1551, 1998[Abstract/Free Full Text]

62. Besa EC, Abraham JL, Bartholomew MJ, et al: Treatment with 13-cis-retinoic acid in transfusion-dependent patients with myelodysplastic syndrome and decreased toxicity with addition of alpha-tocopherol. Am J Med 89: 739-747, 1990[Medline]

63. Dimery IW, Hong WK, Lee JJ, et al: Phase I trial of alpha-tocopherol effects on 13-cis-retinoic acid toxicity. Ann Oncology 8: 85-89, 1997[Abstract/Free Full Text]

Submitted November 15, 2000; accepted March 12, 2001.

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