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Journal of Clinical Oncology, Vol 25, No 15 (May 20), 2007: pp. 1974-1978
Published by the American Society of Clinical Oncology
DOI: 10.1200/JCO.2006.05.9873
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Randomized Trial of Adjuvant 13-cis-Retinoic Acid and Interferon Alfa for Patients With Aggressive Skin Squamous Cell Carcinoma

Abenaa M. Brewster, J. Jack Lee, Gary L. Clayman, John L. Clifford, Mary Jo T. Necesito Reyes, Xian Zhou, Anita L. Sabichi, Sara S. Strom, Robert Collins, Christina A. Meyers, Scott M. Lippman

From the Departments of Clinical Cancer Prevention, Biostatistic and Applied Mathematics, Head and Neck Surgery, Thoracic/Head and Neck Medical Oncology, Epidemiology and Neuro-oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX; and the Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center and Feist-Weiller Cancer Center, Shreveport, LA

Address reprint requests to Scott M. Lippman, MD, Department of Thoracic and Head and Neck Medical Oncology, Unit 432, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77230-1439; e-mail: slippman{at}mdanderson.org


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 AUTHORS' DISCLOSURES OF...
 AUTHOR CONTRIBUTIONS
 REFERENCES
 
Purpose: To conduct a phase III trial of adjuvant 13-cis-retinoic acid (13cRA) plus interferon alfa (IFN-{alpha}) for preventing tumor recurrence and second primary tumors (SPTs) of skin squamous cell carcinoma (SCC) among patients with aggressive skin SCC.

Patients and Methods: Sixty-six patients with aggressive skin SCC were randomly assigned to receive either 6 months of combined 13cRA (1 mg/kg/d orally) and IFN-{alpha} (3 x 106 U subcutaneously three times per week) or no adjuvant therapy (control group) after SCC surgery and/or radiation.

Results: At 21.5 months median follow-up, treatment did not improve the time to tumor recurrence and SPT versus control (hazard ratio [HR], 1.13; 95% CI, 0.53 to 2.41), time to tumor recurrence (HR, 1.08; 95% CI, 0.43 to 2.72), or time to SPT (HR, 0.89; 95% CI, 0.27 to 2.93). Adjuvant 13cRA and IFN-{alpha} was moderately tolerable; 29% of patients in the treatment arm required dose reductions for grade 3 or 4 toxicities.

Conclusion: Results of this phase III trial do not support 13cRA plus IFN-{alpha} for adjuvant therapy of aggressive skin SCC. With high rates of tumor recurrence and SPTs, patients with aggressive skin SCC continue to have an unmet medical need, with devastating mortality, morbidity, and financial consequences. Promising agents with preclinical and early clinical results relevant to aggressive skin SCC deserve a high priority for future clinical drug development.


   INTRODUCTION
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 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
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Squamous cell cancer (SCC) of the skin is the second most common cancer in the United States, with approximately 200,000 patients diagnosed annually.1 Although the overall prognosis of skin SCC is excellent, there are certain clinical pathologic features that are associated with more aggressive disease and reduced disease-specific survival.2 These features include invasion beyond subcutaneous tissue, perineural invasion, large tumor size, increased depth of invasion, lymph node metastasis, and origin in the lip or ear.3-6

The overall 5-year rate of recurrence of primary skin SCC is 8%, whereas aggressive skin SCC has far higher (20% to 25%) rates of recurrence and metastasis.3,4 In addition, there is an increased risk of developing skin SCC second primary tumors (SPTs) that worsen patient morbidity. Despite the high mortality and morbidity associated with aggressive skin SCC after definitive surgical and/or radiation therapy, adjuvant systemic therapy has not been evaluated previously in this setting.

Adjuvant treatment of microscopic residual disease has substantial clinical relevance to patients with aggressive skin SCC, whose morbidity stems primarily from local and regional disease progression. The rationale behind combined 13-cis-retinoic acid (13cRA) and interferon alfa (IFN-{alpha}) for preventing skin SCC recurrence and SPTs is strong and includes in vitro data showing that IFN-{alpha} and retinoids have synergistic antitumor activity, and clinical data showing that IFN-{alpha} and retinoid combinations have produced high response rates in patients with SCC.7,8

The substantial burden of aggressive skin SCC and promise of combined 13cRA and IFN-{alpha} for alleviating this burden led us to conduct this phase III clinical trial for preventing recurrence or SPTs in patients after surgical excision and/or radiation therapy of their aggressive skin SCC.


   PATIENTS AND METHODS
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 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 AUTHORS' DISCLOSURES OF...
 AUTHOR CONTRIBUTIONS
 REFERENCES
 
Patient Eligibility
We enrolled patients for this study from a cohort of nonmelanoma skin cancer patients who were recruited consecutively and observed prospectively at The University of Texas M.D. Anderson Cancer Center (Houston, TX) from 1996 to 2002.3 Eligible patients were required to have pathologically confirmed skin SCC that exhibited one of the following characteristics: size ≥ 2 cm in greatest diameter; perineural invasion; pathologic or radiologic evidence of deep invasion defined as invasion of muscle, cartilage, or bone, or clinical evidence of fixation to these structures; or pathologically or cytologically proven regional metastasis. Patients could have more than one eligible skin SCC lesion. They could have no clinical or radiographic evidence of disease after surgery. Radiotherapy treatment was administered for tumors with perineural invasion, more than two positive nodes, extracapsular nodal disease, or microscopic positive margins. The following eligibility criteria also were required: age ≥ 18 years, Zubrod performance status 0 to 2, adequate liver function (bilirubin ≤ 2.0 mg/100 mL; AST < 46 UL), adequate renal function (creatinine ≤ 1.5 mg/100 mL), normal hematologic parameters (WBC ≥ 3,000 K/UL; platelets ≥ 100,000 K/UL), and signed informed consent. The study protocol was reviewed and approved by the M.D. Anderson Cancer Center institutional review board.

Clinical Trial Design
This randomized controlled clinical trial was designed to prevent skin SCC recurrence or SPT. Patients were randomly assigned within 3 months of surgery or radiation therapy to receive either 13cRA (1 mg/kg/d orally) and IFN-{alpha} (3 x 106 U subcutaneously three times weekly) or no adjuvant therapy for 6 consecutive months; follow-up continued for 18 months after treatment stopped. This 24-month clinical design was a revision of a 36-month design in the original protocol, as discussed in Statistical Analysis. If grade 3 or 4 toxicity occurred, the drugs were withdrawn until the toxicity abated or subsided to grade 1. Drug dosages were restarted at 75% of the protocol starting dosages after grade 3 toxicity had subsided and at 50% of the protocol starting dosages (13cRA orally every other day and 50% reduced volume of subcutaneous IFN injection) after grade 4 toxicities had subsided. If grade 3 or 4 toxicity recurred, the drugs were restarted at 50% of the previously reduced dose after the toxicity recurrence had subsided.

Before surgery, all eligible patients were presented at the interdisciplinary head and neck oncology planning conference. A head and neck surgeon performed a comprehensive evaluation of each patient's skin SCC. This evaluation included bidimensional measurements, assessment of depth of invasion, perineural involvement, lymphatic or vascular involvement, extracapsular spread, nodal involvement, and imaging and pathology assessments. A pretreatment photograph of the sun-exposed areas of the skin and any lesion suggestive of keratosis or superficial skin SCC was evaluated. Patients also underwent a baseline neuropsychological evaluation.

Postbaseline (after random assignment) clinical assessments were scheduled as follows: complete physical and skin examinations at months 3, 6, 18, and 24; a neuropsychological evaluation at month 3. Clinical pathologic evaluations were performed only as indicated for new or recurrent cancers.

Statistical Analysis
This study used a permuted block randomization within strata to balance patient factors. Patients were stratified before random assignment according to deeply invasive tumors, perineurally invasive tumors, and regionally metastatic tumors. On the basis of a report by Weber et al9 and a prospectively collected cohort at M.D. Anderson, original study design assumptions were as follows: 3-year recurrence or SPT rate of 80%; 50% reduction in the 3-year event rate by treatment; time to event after an exponential distribution; two-sided type I error of .05, and 3 years of accrual plus an additional 3 years of follow-up. We conservatively estimated a 10% dropout rate and 5% inassessable rate. Therefore, with an overall accrual goal of 66 randomly assigned patients (27 estimated events), the study would have 85% power. An interim analysis was planned at year 3. Because of a low projected accrual rate and because of data indicating that most primary end point events would occur in the first 2 years, the protocol was revised to reduce the follow-up period to 2 years. With the same time-to-event distributions, projected treatment effect, and overall accrual goal, this revision extrapolates to an 80% power (with a two-sided type I error of .05) to detect a hazard ratio (HR) of 0.32. The design called for an intent-to-treat analysis.

The study end point was time to tumor recurrence or development of SPT. Secondary end points were qualitative and quantitative toxicity during 6 months of 13cRA and IFN-{alpha} therapy. Time to event was calculated from the date of random assignment to the date of first clinical evidence of tumor recurrence or SPT. Patients were censored after withdrawing from the study, after developing a second primary nonskin cancer, or for not meeting the study end point at 24 months of follow-up time.

Cox proportional hazards regression model was used to determine the relative hazard of the study end point for the treatment compared with the control group. The Kaplan-Meier method was used to estimate the time-to-event end points in the treatment and control groups.10 The nonparametric estimate of HR and its 95% bootstrap CI was used to assess the treatment effect on time to tumor recurrence or SPT.11 Statistical analyses were performed using the muhaz package in S-PLUS 6.2 and STATA statistical software 8.0 (STATA Corp, College Station, TX) All tests of statistical significance were performed using a two-sided 5% type 1 error rate.


   RESULTS
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 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 AUTHORS' DISCLOSURES OF...
 AUTHOR CONTRIBUTIONS
 REFERENCES
 
Patient Characteristics
Sixty-six patients were enrolled and randomly assigned at M.D. Anderson Cancer Center. Sixty-five patients were included in this intent-to-treat analysis because one patient withdrew consent for study participation immediately after random assignment. The scheduled interim analysis was not performed because the 5 years needed to complete accrual was longer than planned. The study was concluded after all randomly assigned patients were observed for up to 2 years per protocol. Table 1 lists the patient demographic and tumor characteristics. The majority of patients were white males older than age 60 years. The skin SCC lesions that met study eligibility criteria numbered 32 in the treatment group and 39 in the control group (some patients had multiple eligible lesions). Tumors in the majority of patients in both groups were ≥ 2 cm, and treatment-arm patients had slightly higher rates of perineural invasion and lymph node involvement than did control-arm patients. There were no statistically significant demographic, tumor eligibility, or prior treatment differences between the two groups.


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  		Table 1. Patient Characteristics

 
Recurrence and SPTs
Among the 65 randomly assigned, eligible, and assessable patients, the median duration of follow-up from the date of random assignment was 21.5 months (range, 0.4 to 26 months). Fifty-five of these patients (83%) either reached the primary study end point or completed 24 months of follow-up. In the 10 patients who had less than 24 months of follow-up, six had less than 12 months, two had 12 to 18 months, and two had at least 18 months of follow-up. Table 2 summarizes the results of the univariate analysis. Tumor size ≥ 2 cm, lymph node involvement, and perineural invasion were not statistically significantly associated with either tumor recurrence, SPT, or the combined study end point. The only statistically significant finding was that the surgery-alone group had a lower risk for the study end point (recurrence or SPT) compared with the group receiving surgery with radiation (HR, 0.28; 95% CI, 0.09 to 0.95). Sixteen (of the 65 eligible) patients had surgery alone, three of whom experienced disease recurrence or developed an SPT. Forty-nine patients had surgery and radiation, and there was a total of 24 recurrences or SPT events. The majority (89%) of patients who had a tumor recurrence were treated initially with surgery followed by radiation therapy.


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  		Table 2. Univariate Hazard Ratio of Treatment Failure by Age, Prior Treatment, and Tumor Characteristics

 
The HRs of the study treatment and control groups for tumor recurrence and SPT are listed in Table 3. There was no statistically significant difference between the treatment and control groups for time to tumor recurrence or SPT (HR, 1.13; 95% CI, 0.53 to 2.41) or for developing a tumor recurrence (HR, 1.08; 95% CI, 0.43 to 2.72) or SPT (HR, 0.89; 95% CI, 0.27 to 2.93) alone. Eighteen patients (28%) developed a tumor recurrence, and 11 patients (17%) developed a skin SPT. Of the 18 patients with a tumor recurrence, seven developed distant metastatic disease and 11 had a local or regional recurrence. Two patients with a tumor recurrence were diagnosed simultaneously with a skin SPT. Three patients (one in the treatment group, two in the control group) developed a second primary nonskin cancer (prostate carcinoma, adenocarcinoma of unknown primary, and lung cancer). These nonskin SPTs were not included in the primary end point data.


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  		Table 3. Hazard of Treatment Failure Type for Participants in Treatment Group Compared With Control Group

 
Kaplan-Meier estimates for tumor recurrence or SPT-free survival were compared between the treatment and control groups (Fig 1). The 1-year cumulative recurrence- and SPT-free survival rates were 70% for treatment and control groups and the 2-year cumulative rates were 51.6% (treatment) and 62.4% (control). Figure 2 shows the treatment effect over time; the 95% CI band for the HR covers 1, indicating that there was no statistically significant difference.


Figure 1
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  		Fig 1. Kaplan-Meier estimates of tumor recurrence or second primary skin squamous cell carcinoma (SCC) by treatment assignment. E, number of SCC recurrences or SPTs; N, number of patients.

 

Figure 2
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  		Fig 2. Nonparametric estimations of hazard ratio of tumor recurrence or second primary skin squamous cell carcinoma and 95% CIs.

 
Compliance and Toxicity
Seven patients discontinued the study prematurely: one withdrew consent immediately after random assignment, three were lost to follow-up (at 7, 12, and 18 months of follow-up, respectively), two died as a result of a cardiac arrest (one cardiac arrest occurred 5 months after completing treatment and one cardiac arrest occurred in a patient assigned to the observation group), and one patient dropped out because of adverse events (after 1 week of IFN-{alpha} and 13cRA). The incidence of selected toxicities related to IFN-{alpha} and 13cRA is summarized in Table 4. Thirty-one patients in the treatment group were available for the toxicity analysis of the combined IFN-{alpha} and 13cRA regimen. Patients received IFN-{alpha} and 13cRA for a median duration of 4.9 months (range, 0.3 to 6.0 months). The combination regimen caused no treatment-related deaths. The most frequent adverse effects associated with the combined regimen were dry skin, fatigue, and generalized eye and lip reactions. Nine patients underwent dose reductions for grade 3 and 4 toxicities as dictated by prespecified protocol guidelines.


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  		Table 4. Incidence of Selected 13cRA and IFN-{alpha} Adverse Events

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
AUTHORS' DISCLOSURES OF...
 AUTHOR CONTRIBUTIONS
 REFERENCES
 
This is the first randomized trial of adjuvant systemic treatment for patients with aggressive skin SCC after surgery and/or radiation. Despite preclinical and clinical data that support 13cRA and IFN-{alpha} for the treatment of advanced skin SCC, the combination regimen did not improve the time to recurrence or time to an SPT in this trial.

Combined 13cRA (1 mg/kg/d) and IFN (3 million U/d) administered for at least 2 months had modest clinical activity as primary therapy for advanced skin SCC in a previous phase II trial we conducted.7 However, the response rate was statistically significantly associated with extent of disease (23% in patients with distant metastatic disease v 90% in patients with locally advanced disease). We then tried to improve the response rate of metastatic skin SCC by testing cisplatin added to IFN-{alpha} and 13cRA in another phase II trial, but the metastatic (distant) disease response rate was only 17%.12 The collective results of the phase II primary treatment studies and our current adjuvant study indicate that metastatic skin SCC, whether gross or microscopic, is highly aggressive and resistant to IFN-{alpha} and 13cRA.

Treatment-arm patients in this present study received IFN-{alpha} and 13cRA for a median duration of 4.9 months. Among all study participants, the cumulative probabilities of being free of tumor recurrence or SPT at 6 months, 1 year, and 2 years were 77%, 68%, and 56%, respectively, indicating that patients with aggressive skin SCC are at a very high risk of an event during the first 2 years after definitive surgical or radiation treatment. When we designed the trial in 1996, we projected that the event (recurrence or SPT) -free rate at 2 years would be 34% based on the available retrospective data from M.D. Anderson Cancer Center9 (subsequent prospective data showed a disease-specific survival of 70% in similar patients observed for a median of 22 months3). Therefore, our study was underpowered to detect an HR of 0.32 for the study end point or to detect a significant difference between arms in either recurrence or SPT alone, limiting the interpretation of our results. Based on the actual 2-year event rate of approximately 40% (27 events) in this trial, the statistical power would be only 67% or 44% for an HR of 0.4 or 0.5, respectively. Nevertheless, the high rate of tumor recurrence or SPT in the 49 higher risk patients (who received surgery and radiation before our trial [discussed in Methods]) emphasizes the need for effective systemic adjuvant treatment in these patients. Events (two recurrences, one SPT) were relatively infrequent in the 16 high-risk patients (who had previously received primary surgery alone) compared with the 49 higher risk patients, suggesting that these patients may not need adjuvant radiation or systemic therapy.

The expressions of specific retinoid receptors, such as the ß isoform of the retinoic acid receptor, and of one or more of the IFN-stimulated gene factor 3 (ISGF3) proteins (Stat1{alpha}/ß, Stat2, p48) are suppressed in skin SCC and the skin premalignancy actinic keratoses.13,14 It is postulated that decreased sensitivity to retinoids and IFN may promote skin carcinogenesis because retinoids induce apoptosis and promote cell differentiation by binding to retinoic acid receptor, and IFN-{alpha} potently suppresses proliferation and induces apoptosis through the ISGF3 complex in skin cancer cells.12,15-19 This clinical rationale of IFN for controlling aggressive skin SCC has been challenged because preliminary laboratory data indicate that Stat2 knock-out mice (which cannot form the ISGF3 transcriptional factor complex) do not develop more tumors than do matched wild-type controls after exposure to the skin two-stage chemical carcinogenesis protocol (J. Clifford, personal communication, December 2005). Future experiments are planned to test potential ISGF3-independent type I IFN signaling pathways in mediating antitumor activities of IFN-{alpha}/ß, and to correlate the clinical outcome of tumor recurrence in the present clinical study with the status of these targets in the adjacent skin tissue at baseline and at the site of resection during treatment.

There currently is no recommended adjuvant chemotherapy for patients with aggressive SCC after definitive surgical and radiation treatment. With 2-year incidences of approximately 28% for tumor recurrence and 18% for SPT, these patients have an unmet medical need. A major hurdle facing new trials designed to meet this need is the problem of accruing a sufficiently large sample size to achieve adequate study power. Our study's long period (5 years) to accrue only 65 assessable patients illustrates how difficult it can be to accrue patients with aggressive skin SCC even at a tertiary cancer center with a major skin cancer program. Therefore, to accrue sufficiently large populations to detect a clinically meaningful treatment effect, multiple cancer centers will have to collaborate on future trials of new adjuvant approaches with the potential to improve disease-free and overall survival of skin SCC patients at a well-defined high risk of recurrence or SPT.


   AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 AUTHORS' DISCLOSURES OF...
AUTHOR CONTRIBUTIONS
 REFERENCES
 
The authors indicated no potential conflicts of interest.


   AUTHOR CONTRIBUTIONS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 AUTHORS' DISCLOSURES OF...
 AUTHOR CONTRIBUTIONS
REFERENCES
 
Conception and design: Gary L. Clayman, Sara S. Strom, Christina A. Meyers, Scott M. Lippman

Administrative support: Gary L. Clayman

Provision of study materials or patients: Mary Jo T. Necesito Reyes, Anita L. Sabichi, Sara S. Strom, Robert Collins, Scott M. Lippman

Collection and assembly of data: Abenaa M. Brewster, Gary L. Clayman, Mary Jo T. Necesito Reyes, Anita L. Sabichi, Sara S. Strom, Robert Collins, Christina A. Meyers

Data analysis and interpretation: Abenaa M. Brewster, J. Jack Lee, Gary L. Clayman, John L. Clifford, Xian Zhou, Scott M. Lippman

Manuscript writing: Abenaa M. Brewster, J. Jack Lee, John L. Clifford, Scott M. Lippman

Final approval of manuscript: Abenaa M. Brewster, J. Jack Lee, Gary L. Clayman, John L. Clifford, Mary Jo T. Necesito Reyes, Xian Zhou, Anita L. Sabichi, Sara S. Strom, Robert Collins, Christina A. Meyers, Scott M. Lippman

Other: Mary Jo T. Necesito Reyes [General protocol operation and patient management]


   NOTES
 
Supported by Grants No. P01-5P01CA68233 and CA16672 from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 AUTHORS' DISCLOSURES OF...
 AUTHOR CONTRIBUTIONS
 REFERENCES
 
1. Jemal A, Murray T, Ward E, et al: Cancer statistics, 2005. CA Cancer J Clin 55: 10-30, 2005[Abstract/Free Full Text]

2. Alam M, Ratner D: Cutaneous squamous-cell carcinoma. N Engl J Med 344: 975-983, 2001[Free Full Text]

3. Clayman GL, Lee JJ, Holsinger FC, et al: Mortality risk from squamous cell skin cancer. J Clin Oncol 23: 759-765, 2005[Abstract/Free Full Text]

4. Rowe DE, Carroll RJ, Day CL Jr: Prognostic factors for local recurrence, metastasis, and survival rates in squamous cell carcinoma of the skin, ear, and lip: Implications for treatment modality selection. J Am Acad Dermatol 26: 976-990, 1992[Medline]

5. Veness MJ, Palme CE, Smith M, et al: Cutaneous head and neck squamous cell carcinoma metastatic to cervical lymph nodes (nonparotid): A better outcome with surgery and adjuvant radiotherapy. Laryngoscope 113: 1827-1833, 2003[CrossRef][Medline]

6. Garcia-Serra A, Hinerman RW, Mendenhall WM, et al: Carcinoma of the skin with perineural invasion. Head Neck 25: 1027-1033, 2003[CrossRef][Medline]

7. 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]

8. 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]

9. Weber R, Lippman SM, McNeese M: Advanced basal and squamous cell carcinomas of the skin of the head and neck, in Jacobs C (ed): Carcinomas of the Head and Neck: Evaluation and Management. Boston, MA, Kluwer Academic, 1990

10. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53: 457-481, 1958[CrossRef]

11. Hess KR, Serachitopol DM, Brown BW: Hazard function estimators: A simulation study. Stat Med 18: 3075-3088, 1999[CrossRef][Medline]

12. Shin DM, Glisson BS, Khuri FR, et al: Phase II and biologic study of interferon alfa, retinoic acid, and cisplatin in advanced squamous skin cancer. J Clin Oncol 20: 364-370, 2002[Abstract/Free Full Text]

13. Sun SY, Lotan R: Retinoids and their receptors in cancer development and chemoprevention. Crit Rev Oncol Hematol 41: 41-55, 2002[Medline]

14. Clifford JL, Walch E, Yang X, et al: Suppression of type I interferon signaling proteins is an early event in squamous skin carcinogenesis. Clin Cancer Res 8: 2067-2072, 2002[Abstract/Free Full Text]

15. Yaar M, Karassik RL, Schnipper LE, et al: Effects of alpha and beta interferons on cultured human keratinocytes. J Invest Dermatol 85: 70-74, 1985[CrossRef][Medline]

16. Rodriguez-Villanueva J, McDonnell TJ: Induction of apoptotic cell death in non-melanoma skin cancer by interferon-alpha. Int J Cancer 61: 110-114, 1995[Medline]

17. Clifford JL, Yang X, Walch E, et al: Dominant negative signal transducer and activator of transcription 2 (STAT2) protein: Stable expression blocks interferon alpha action in skin squamous cell carcinoma cells. Mol Cancer Ther 2: 453-459, 2003[Abstract/Free Full Text]

18. Parmar S, Platanias LC: Interferons: Mechanisms of action and clinical applications. Curr Opin Oncol 15: 431-439, 2003[CrossRef][Medline]

19. Kalvakolanu DV, Borden EC: An overview of the interferon system: Signal transduction and mechanisms of action. Cancer Invest 14: 25-53, 1996[Medline]

Submitted February 9, 2006; accepted September 11, 2006.


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