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Journal of Clinical Oncology, Vol 20, Issue 2 (January), 2002: 364-370
© 2002 American Society for Clinical Oncology

Phase II and Biologic Study of Interferon Alfa, Retinoic Acid, and Cisplatin in Advanced Squamous Skin Cancer

By Dong M. Shin, Bonnie S. Glisson, Fadlo R. Khuri, John L. Clifford, Gary Clayman, Steven E. Benner, Arlene A. Forastiere, Lawrence Ginsberg, Diane Liu, J. Jack Lee, Jeffrey Myers, Helmuth Goepfert, Reuben Lotan, Waun Ki Hong, Scott M. Lippman

From the Departments of Thoracic/Head and Neck Medical Oncology, Diagnostic Imaging, Biostatistics, Head and Neck Surgery, and Clinical Cancer Prevention, The University of Texas M.D. Anderson Cancer Center, Houston, TX, and Division of Medical Oncology, Johns Hopkins Oncology Center, Baltimore, MD.

Address reprint requests to Scott M. Lippman, MD, Departments of Thoracic/Head and Neck Medical Oncology and Clinical Cancer Prevention, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Box 236, Houston, TX 77030-4095; email: slippman{at}mdanderson.org


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
PURPOSE: The purpose of this study was to test interferon alfa (IFN{alpha}), 13-cis-retinoic acid (13cRA), and cisplatin biochemotherapy in advanced squamous cell carcinoma (SCC) of the skin.

PATIENTS AND METHODS: Patients with advanced skin SCC received IFN{alpha} (5 x 106 IU/m2, subcutaneous injection, three times a week), 13cRA (1 mg/kg, orally, daily), and cisplatin (20 mg/m2, intravenous injection, weekly) in a phase II trial. The growth inhibition, cell-cycle, and apoptosis activity of these agents was evaluated in two skin SCC cell lines (SRB1-m7 and SRB12-p9).

RESULTS: Thirty-nine patients were enrolled. All were assessable for survival, 35 for response and toxicity (median follow-up was 38 months). The overall and complete response rates were 34% and 17%, respectively, with median durations of 9 and 35.4 months, respectively. The response rate was higher in locally advanced (67%) than metastatic (17%) disease (P = .007). Median survival was 14.6 months. One-, 2-, and 5-year survival rate estimates were 58%, 32%, and 21%, respectively. Toxicity included generally mild to moderate fatigue and mucocutaneous dryness, moderate to severe neutropenia (38%), and neutropenic fever (6%). There were no treatment-related deaths. In vitro growth inhibition and apoptosis effects of cisplatin were differential and inversely associated with those of retinoic acid and especially IFN{alpha} in two skin SCC lines.

CONCLUSION: The rising incidence, morbidity, and mortality of advanced skin SCC are a major challenge for clinical oncologists. Combined 13cRA, IFN{alpha}, and cisplatin was clinically active in extensive locally advanced disease. Each agent had independent, non–cross-resistant biologic effects in vitro, which may account for the combination’s clinical activity.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
NONMELANOMA SKIN cancer (NMSC) is the most common cancer in the United States, with more than 1.3 million new cases of the two most common forms, squamous and basal cell carcinoma, anticipated in 2001. The more clinically aggressive form is squamous cell carcinoma (SCC) of the skin, which has been increasing in incidence since the 1960s at annual rates from 4% to as high as 10% in recent years.1,2 Approximately 95% of skin SCC cases are diagnosed at an early stage and are easily controlled. Unlike early-stage SCC, advanced SCC is aggressive, often resistant to local therapy, requires repeated surgical resections and courses of radiotherapy, and accounts for approximately 2,000 deaths in the United States each year. Advanced disease–related and treatment-related morbidity have a profound impact on patients’ quality of life, frequently producing cosmetic deformity, loss of function, and psychosocial problems. Better management of advanced skin SCC is clearly necessary, presenting a great challenge to clinical oncologists.1,3

Single-agent interferon alfa (IFN{alpha}),4 13-cis-retinoic acid (13cRA),5 and cisplatin6 have shown activity, as have cisplatin-based and non–cisplatin-based cytotoxic combinations,7-9 in previous small clinical series in advanced skin SCC. The activity of combined IFN{alpha} and 13cRA in this setting was demonstrated in a previous phase II trial.10 On the basis of this trial,10 the activity of cisplatin6 in skin SCC, and relevant preclinical data,11,12 we conducted the present phase II trial and biologic studies to assess cisplatin integrated with IFN{alpha} and 13cRA.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patient Eligibility
All patients were required to have advanced SCC of the skin, defined as tumor >= 2 cm in diameter with histologic confirmation of SCC and to meet at least one of the following criteria: (1) tumor is unresectable; (2) surgical resection would result in a significant functional or cosmetic defect; and (3) the tumor is deeply invasive, involving muscle, nerve, bone, or lymph nodes. Other eligibility criteria included a life expectancy of >= 12 weeks, a Zubrod performance status <= 2, adequate bone marrow function (defined as an absolute neutrophil count of >= 1,500/mm3 and platelet count of >= 100,000/mm3), and adequate hepatic and renal function. The protocol was approved by the institutional review board, and informed, signed consent was required of each patient.

Treatment Plan
Within 1 week of study entry, all patients received a complete history and physical examination, complete blood count, serum chemistries, urinalysis, and ECG. If indicated, patients underwent chest radiography and computed tomography (CT) or magnetic resonance imaging (MRI) of the indicator sites within 4 weeks of starting therapy. If the disease was not well visualized by CT or MRI scan, photographic documentation with measurement of two dimensions of the lesion was performed. Patients were monitored during treatment by a weekly complete blood count.

The treatment regimen (at starting doses) consisted of IFN{alpha} (5 x 106 IU/m2, subcutaneous injection, three times a week), 13cRA (1 mg/kg, orally, daily), and cisplatin (20 mg/m2, intravenous injection, weekly with dexamethasone and ondansetron premedication). The doses and schedules of IFN{alpha} and cisplatin were based primarily on an earlier phase I study of the two agents combined13; 13cRA does not seem to increase IFN{alpha} or cisplatin toxicity.10,12,14 13cRA rapidly isomerizes to the retinoic acid (RA) receptor ligand all-trans retinoic acid (ATRA) in human skin15 and has pharmacokinetic advantages over ATRA (longer half-life; levels are maintained with repetitive dosing)16 for the treatment of skin SCC and other solid tumors.17-23 The three agents were administered frequently (13cRA daily, IFN{alpha} three times per week, and cisplatin weekly) in the present study to maximize the favorable interactions in vivo indicated by the preclinical evidence. Follow-up history and physical examination, tumor or lesion measurement and photographic documentation, and side-effect assessment were performed every 4 weeks. Doses were modified (Table 1) according to toxicities that had developed in the previous 4 weeks of treatment.


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  		Table 1.  Dose Level Modifications
 
Response and Survival Evaluation
Standard criteria for complete response (CR), partial response (PR), stable disease, and progressive disease were used.24 Duration of response was calculated as the time from the first documentation of major responses (CR or PR) to first documentation of disease progression. Responses were assessed after each course of treatment if disease was measurable by physical examination or after every two to three courses if CT or MRI scans were required to determine response. Survival duration was computed as the time between a patient’s registration onto the protocol and his or her death or, in cases of continuing survival, the end of study follow-up. Survival curves were computed by the Kaplan-Meier Method.25

Toxicity Evaluation
Toxicity was graded according to standard criteria, which contain the National Cancer Institute common toxicity criteria.26 Patients were evaluated weekly for hematologic toxic effects and every 4 weeks (before each new treatment course) for nonhematologic toxicity.

Laboratory Methods
Cells and cell viability assay. SRB1-m7 and SRB12-p9 cells were cultured in a humidified atmosphere at 5% CO2 in a 1:1 mixture of Dulbecco’s modified Eagle’s medium and Ham’s F12 plus 10% fetal bovine serum. We performed a calcein AM fluorescence-based cell viability assay.27 Cells were plated at a starting number of 600 cells/well in triplicate in 96-well plates and treated with 10 µmol/L cisplatin for 1 hour followed by culture in growth media for 5 days, with 100 nmol/L ATRA or 100 U/mL IFN{alpha} continuously for 5 days, or with combinations of these drugs. To detect the relative number of viable cells versus dead cells per well, the fluorescent dye calcein AM was added to the medium (100 nmol/L) 30 minutes before the termination of the assay. The plates were fluorometrically analyzed using a Biolumin 960 fluorescence plate reader (Molecular Dynamics, Inc, Piscataway, NJ). The excitation and emission wavelengths for calcein AM were set at 485 and 530 nm, respectively. The intensity of fluorescence of enzymatically cleaved calcein AM was used to count the cell number. The growth inhibition was calculated using the following equation: (1 - R/C) x 100, with R and C representing the mean number of cells in triplicate samples of treated and control cultures, respectively. All calcein AM assay results were confirmed by manual cell counting using a Coultronics (Beckman Coulter, Inc, Fullerton, CA) particle counter.

Apoptosis assay and cell-cycle determination. The induction of apoptosis was visualized and quantitated using a 4',6-diamidino-2-phenylindole (DAPI) staining assay as previously described.28 Cells were plated at a density of 2 x 105 cells/10-cm dish and allowed to attach overnight before treatment. Apoptosis was quantitated as follows: cells were trypsinized and incubated in growth medium containing 5 µmol/L DAPI dye at 37°C for 15 minutes. Approximately 3 x 104 cells were attached to slides using a Cytospin centrifuge (Shandon and Lipshaw, Inc, Philadelphia, PA) and scored visually for quantitation of apoptosis. The final apoptosis result was the mean percentage of apoptotic cells calculated for at least 150 cells observed (at x200) in three separate fields with a fluorescence microscope equipped with a filter for DAPI dye. Fluorescence-activated cell-cycle flow cytometry based on cellular DNA content was performed using an Epics Profile II cell sorter (Beckman Coulter, Inc) as previously described.29 Resuspended cells were fixed in 70% ethanol at 4°C, washed twice in phosphate-buffered saline, incubated in 1 mg/mL RNase A (59 Kunitz U/mg, Sigma-Aldrich, St. Louis, MO) for 30 minutes at 37°C, centrifuged, and resuspended in phosphate-buffered saline at a concentration of approximately 106 cells/mL. Propidium iodide was added to a final concentration of 50 µg/mL immediately before sample analysis. The percentage of cells in the different phases of the cell cycle was determined using the Epics Elite Flow Cytometry software.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Patient Characteristics
Thirty-nine patients were entered onto this study from March 1993 to April 1999. All were assessable for survival, and 35 were assessable for response and toxicity. For the four patients who were not assessable for response, two refused treatment after one course, one was lost to follow-up, and one died early (as a result of massive progression of disease and unrelated to toxicity). Most lesions were located at head and neck sites, and most patients had been previously treated with surgery and radiotherapy (Table 2). At the time of entry, 12 patients (31%) had locally advanced disease, 16 (41%) had regional metastasis, and 11 (28%) had distant metastasis, seven of whom also had regional metastases.


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  		Table 2.  Patient Characteristics
 
Response and Survival
The median duration and range of follow-up for all patients were 37.9 months and 3.3 to 80.4 months, respectively. The CR, PR, and overall response rates were 17% (six of 35), 17% (six of 35), and 34% (12 of 35), respectively, with median durations of 35.4 months (range, 6.8 to 60.8+ months; 95% confidence interval [CI], 9.0 to not-reached months), 4.1 months, and 9.0 months, respectively. With respect to disease extent, major responses occurred in 67% of patients (eight of 12) with locally advanced disease (four with CR and four with PR), 25% of patients (three of 12) with regional metastasis, and 9% of patients (one of 11) with distant metastasis (Table 3). The response rate of patients with locally advanced disease was significantly higher than that of patients with metastatic disease (regional, distant, or both) (67% [eight of 12] v 17% [four of 23]; P = .007 by Fisher’s exact test). Median survival was 14.6 months (95% CI, 9.2 months to 32.2 months), and 1-, 2-, and 5-year survival rate estimates were 58%, 32%, and 21%, respectively (Fig 1).


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  		Table 3.  Response Status by Disease Site
 


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  		Fig 1. Overall survival curve of 39 patients. Median survival of all patients was 14.6 months (95% CI, 9.2 to 32.2 months), and 1-, 2-, and 5-year survival rates were 58%, 32%, and 21%, respectively.

 
Toxic Effects
A total of 114 courses were administered (median, 2.9 courses; range, one to 11): 11 courses (10%) at +1 level; 80 (70%) at 0; 18 (16%) at -1, and five (4%) at -2. The regimen was relatively well tolerated, with no treatment-related deaths (Table 4). Nonhematologic toxicity included generally mild to moderate fatigue, flu-like symptoms, mucocutaneous dryness, hypertriglyceridemia, emesis, and peripheral neuropathy. Moderate to severe (grade 3 or 4) neutropenia occurred in 13 patients (38%). A majority of these patients, however, recovered within 3 to 4 weeks without the use of hematopoietic growth factors. The exceptions were two patients who required granulocyte colony-stimulating factor. Thrombocytopenia and anemia also were frequent, and five patients required either platelet or RBC transfusions. Two patients (6%) had neutropenic fever, and both recovered with antibiotic therapy. After two courses of treatment, four patients (11%) had prolonged thrombocytopenia, which required skipping cisplatin on week 4 of the 4-week cycle. No prolonged gastrointestinal distress was observed.


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  		Table 4.  Toxicity
 
In Vitro Growth Inhibition, Cell Cycle, and Apoptosis
An initial series of dose-response experiments indicated that significant growth inhibition effects could be achieved for cisplatin and IFN{alpha} at pharmacologically achievable concentrations of 10 µmol/L and 100 U/mL, respectively (data not shown). ATRA at 100 nmol/L produced 25.8% growth inhibition in SRB12-p9 cells, and this effect was not significantly greater at higher concentrations (data not shown). The SRB1-m7 cells were more sensitive to the growth-inhibition effect of 10 µmol/L cisplatin (54% growth inhibition) than were the SRB12-p9 cells (17.4% growth inhibition). Conversely, the SRB12-p9 cells were more sensitive to the growth inhibition effect of 100 U/mL of IFN{alpha} than were the SRB1-m7 cells (53.8% and 19.1%, respectively). Treatment of either cell line with combinations of cisplatin and ATRA, cisplatin and IFN{alpha}, or all three agents together resulted in additive or subadditive growth inhibition effects (Fig 2).



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  		Fig 2. Cell growth inhibition effects of cisplatin (DDP), RA, IFN{alpha}, and their combinations on the SRB12-p9 (white bars) and SRB1-m7 (black bars) skin SCC cell lines. Error bars represent the SE for triplicate samples.

 
The agents’ patterns of cell-cycle effects and apoptosis differed from one another and in sensitive versus resistant cells (Table 5). Cisplatin produced slight increases in the percentages of G2- and S-phase cells and a greater than two-fold increase in apoptosis (compared with IFN) in cisplatin-sensitive cells (SRB1-m7) and far lesser effects in cisplatin-resistant cells (SRB12-p9). IFN produced a partial G1 arrest and greater than two-fold increase in apoptosis (compared with cisplatin) in IFN-sensitive cells (SRB12-p9) and far lesser effects in IFN-resistant cells (SRB1-m7). The pattern of RA effects was similar to that of IFN, although RA was less active with respect to growth inhibition in sensitive SRB12-p9 cells. RA-induced apoptosis, however, was nearly two-fold greater than was cisplatin-induced apoptosis in the SRB12-p9 cells.


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  		Table 5.  Effects of DDP, ATRA, and IFN{alpha} on Cell-Cycle Profile, Growth Inhibition, and Apoptosis in SRB12-p9 and SRB1-m7 Human Skin SCC Cells
 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
This phase II trial achieved overall response and CR rates of 34% (9 months median duration) and 17% (35.4 months median duration), respectively. The major activity occurred in locally advanced disease: overall response and CR rates of 67% (eight of 12) and 33% (four of 12), respectively. These rates are significantly higher than those in metastatic disease. Toxicity was acceptable in this setting and generally consistent with previous reports of toxicity associated with the constituent agents given singly or in certain combinations (eg, IFN plus 13cRA or cisplatin).3-14,17-22

Certain important comparisons can be made between the present trial and our previous phase II trial demonstrating the activity of only 13cRA and IFN{alpha} in advanced skin SCC.10 Although both phase II trials were most active in locally advanced disease, results of the present trial suggest that it was more active than our former trial. Patients in the present study were far more advanced than those in the previous study, as reflected by higher rates of metastases and combined-modality therapy and, most prominently, by a greatly increased severity of local disease. Most of the present patients had T3 (> 5 cm diameter) or T4 (deep invasion of muscle or bone) lesions,30 whereas none of the former patients with advanced local disease had T3 or T4 lesions. The present study’s 9-month response duration in more advanced patients nearly doubled that (5 months) of the previous study in less advanced patients, likely because of cisplatin cytotoxic effects. With respect to distant metastatic disease, both trials were relatively inactive, even though a major objective of the present trial was to improve on the metastatic results of the former trial through the addition of cisplatin. With respect to toxicity, the earlier trial produced more grade 3 to 4 fatigue (likely attributable to more frequent IFN dosing),10 and the present trial produced more grade 3 to 4 myelosuppression (likely attributable to the IFN-cisplatin interaction)13 and more nausea, vomiting, and peripheral neuropathy.

The in vitro studies were designed to provide complementary data that parallel and provide biologic insight into the clinical results of cisplatin integrated with RA and IFN in skin SCC. Although we found that combining RA or IFN{alpha} with cisplatin increased growth inhibition (compared with single-agent activity) in skin SCC, the increases were not supra-additive or synergistic, as reported in certain other tumor types.11,12 Our growth inhibition results indicated inverse cell-line sensitivities and resistances to the different drugs in our regimen (Fig 2). SRB1-m7 was sensitive to cisplatin and resistant to RA or IFN{alpha}. SRB12-p9 was resistant to cisplatin and sensitive to IFN{alpha} or, to a lesser degree, RA. Drug effects on cell-cycle distribution did not contribute substantially to growth inhibition, because cell-cycle alterations were relatively small, even in the presence of substantial (> 50%) growth inhibition (Table 5). In both cell lines, however, the patterns of agent effects on apoptosis correlated with growth inhibition, and the degree of apoptosis (increased > two-fold in sensitive v insensitive cells) seemed to account primarily for the growth inhibition we observed over the 5-day in vitro treatment. A previous study of a higher IFN{alpha} concentration31 showed that the SRB12 parental cell line (but not the SRB1 parental line) is sensitive to apoptosis induction by IFN{alpha}, which is consistent with our IFN results and suggests that the degree of apoptosis is related to the IFN{alpha} concentration. Therefore, our in vitro data suggest that the clinical activity of cisplatin, IFN{alpha}, and 13cRA was primarily attributable to independent, non–cross-resistant growth inhibition (mainly through apoptosis) in different cell populations within heterogeneous squamous cell tumors.

In recent in vivo translational studies, we identified profound molecular defects of advanced skin SCC in IFN-signaling proteins,32 nuclear retinoid receptors,33 and RA- and IFN-regulated genes.34 These studies provide insights into the mechanisms of the RA and IFN components of the present study’s regimen.

Limited by the high cure rates achieved with standard local therapy in early disease,1 the study of systemic therapy in advanced or recurrent skin SCC has not included any previous phase II or III trials of cytotoxic regimens.3,4 Cisplatin (75 to 100 mg/m2 every 3 to 4 weeks) for skin SCC has been involved in only two previous series with greater than 10 patients.8,9 One (involving various cisplatin combinations) produced seven responses in 12 patients,8 and one (involving various combinations of cisplatin plus fluorouracil plus bleomycin) produced 11 responses in 14 patients.9 Because these series involved predominantly locally advanced cases, their response data should be compared with our present results in locally advanced disease. These two series were associated with more severe (grade 3 to 5) and primarily gastrointestinal and bone marrow toxicity.

The rising incidence, morbidity, and mortality of advanced skin SCC pose a major treatment challenge for clinical oncologists. Our present trial suggests the promise of its novel regimen and illustrates the serious impact this disease has on survival: 1-, 2-, and 5-year survival rate estimates of only 58%, 32%, and 21%, respectively (Fig 1). These data highlight the need for better control of advanced skin SCC, which, because of its relatively low incidence, tends to be overlooked by the medical profession at large and oncologists in particular. Our previous phase II study10 established the clinical activity of 13cRA plus IFN in advanced skin SCC and preceded several clinical and translational studies,12,16-22,32-34 including the present phase II trial integrating cisplatin. Our present results suggest that it is now time to conduct a phase III trial to confirm the activity of IFN{alpha}, 13cRA, and cisplatin in locally advanced skin SCC, possibly comparing this regimen with more standard cytotoxic chemotherapy3,4,6-9 or combined IFN{alpha} and 13cRA,3,4,10 both of which also have been shown to be active primarily in locally advanced disease.


   ACKNOWLEDGMENTS
 
Supported in part by grant nos CA68233 and CA16672 from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services. S.M.L. holds the Anderson Clinical Faculty Chair for Cancer Treatment and Research.

We thank Marites Francisco, RN, and Lori Martinez, RN, for patient care and Kendall Morse for editorial assistance.


   REFERENCES
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 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
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Submitted July 6, 2000; accepted August 27, 2001.


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A. M. Brewster, J. J. Lee, G. L. Clayman, J. L. Clifford, M. J. T. N. Reyes, X. Zhou, A. L. Sabichi, S. S. Strom, R. Collins, C. A. Meyers, et al.
Randomized Trial of Adjuvant 13-cis-Retinoic Acid and Interferon Alfa for Patients With Aggressive Skin Squamous Cell Carcinoma
J. Clin. Oncol., May 20, 2007; 25(15): 1974 - 1978.
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J. R. Inglefield, C. J. Larson, S. J. Gibson, H. Lebrec, and R. L. Miller
Apoptotic Responses in Squamous Carcinoma and Epithelial Cells to Small-Molecule Toll-like Receptor Agonists Evaluated with Automated Cytometry
J Biomol Screen, September 1, 2006; 11(6): 575 - 585.
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S. E. Touma, J. S. Goldberg, P. Moench, X. Guo, S. K. Tickoo, L. J. Gudas, and D. M. Nanus
Retinoic Acid and the Histone Deacetylase Inhibitor Trichostatin A Inhibit the Proliferation of Human Renal Cell Carcinoma in a Xenograft Tumor Model
Clin. Cancer Res., May 1, 2005; 11(9): 3558 - 3566.
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J. R. Rigas and K. H. Dragnev
Emerging Role of Rexinoids in Non-Small Cell Lung Cancer: Focus on Bexarotene
Oncologist, January 1, 2005; 10(1): 22 - 33.
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J. L. Clifford, X. Yang, E. Walch, M. Wang, and S. M. Lippman
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., May 1, 2003; 2(5): 453 - 459.
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J. L. Clifford, E. Walch, X. Yang, X. Xu, D. S. Alberts, G. L. Clayman, A. K. El-Naggar, R. Lotan, and S. M. Lippman
Suppression of Type I Interferon Signaling Proteins Is an Early Event in Squamous Skin Carcinogenesis
Clin. Cancer Res., July 1, 2002; 8(7): 2067 - 2072.
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E. E.W. Cohen and E. E. Vokes
Searching for a Standard
J. Clin. Oncol., January 15, 2002; 20(2): 359 - 361.
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