1213
`
`Phase II Clinical Trial of 13-Cis-Retinoic Acid and
`Interferon-a-2a in Patients with Advanced
`Esophageal Carcinoma
`
`Peter C. Enzinger, M.D.
`David H. Ilson, M.D., Ph.D.
`Leonard B. Saltz, M.D.
`Lisa K. Martin
`David P. Kelsen, M.D.
`
`Gastrointestinal Oncology Service, Division of Solid
`Tumor Oncology, Department of Medicine, Memo-
`rial Sloan-Kettering Cancer Center, New York, New
`York and Department of Medicine, Cornell Medical
`College, Ithaca, New York.
`
`Preliminary results of this study presented at the
`Meeting of the American Society of Clinical Oncol-
`ogy, Los Angeles, California, May 20 –23, 1995.
`
`Supported in part by National Cancer Institute
`Grant UO1# 69913.
`
`Address for reprints: David Ilson, M.D., Ph.D., De-
`partment of Medicine, Memorial Sloan-Kettering
`Cancer Center, 1275 York Avenue, New York, NY
`10021.
`
`Received June 1, 1998; accepted October 15,
`1998.
`
`© 1999 American Cancer Society
`
`BACKGROUND. Interferon in combination with 5-fluorouracil has been shown to be
`active in squamous cell carcinoma (SCC) and adenocarcinoma (AC) of the esoph-
`agus. 13-cis-retinoic acid (CRA) has chemopreventive activity in SCC of the head
`and neck, and, in combination with interferon, has antitumor activity in SCC of the
`skin and cervix.
`METHODS. The activity and toxicity of CRA and interferon-a-2a (IFN) in patients
`with advanced esophageal carcinoma was evaluated in a Phase II single institution
`trial. Patients had unresectable or metastatic AC or SCC of the esophagus. One
`prior chemotherapy regimen was allowed. IFN was given by daily subcutaneous
`injection at a dose of 3 million U and CRA was taken orally at a dose of 1 mg/kg/day
`in 2 divided doses. Treatment was given in cycles of 4 weeks and continued until
`documented disease progression.
`RESULTS. Of the 19 patients entered, 15 were evaluable for response and toxicity.
`One patient was evaluable for response only and one patient was evaluable for
`toxicity only. Evaluable patients were predominantly male (15 patients), and had
`AC (13 patients). All had AJCC Stage IV disease and 12 were pretreated. Patients
`completed an average of two cycles of therapy (range, one to six cycles) prior to
`progression of disease. National Cancer Institute Common Toxicity Criteria Grade
`3/4 toxicity was notable for nausea (25%) and fatigue (31%). No major objective
`responses were recorded. Eleven patients with AC and 3 patients with SCC had
`rapid progression of disease. One patient with AC was found to have a minor
`response for 22 weeks and 1 patient with AC had stable disease for 45 weeks.
`CONCLUSIONS. This regimen had no significant activity in patients with advanced
`AC of the esophagus. Further evaluation of IFN plus CRA, using this dose and
`schedule, is not recommended. In comparison with prior trials of this therapy, a
`surprising amount of severe nausea and fatigue was observed in this trial. Cancer
`1999;85:1213–7. © 1999 American Cancer Society.
`
`KEYWORDS: esophageal carcinoma, 13-cis-retinoic acid, interferon-a, adenocarci-
`noma.
`
`In 1997, approximately 12,500 Americans were diagnosed with
`
`esophageal carcinoma. With current treatment modalities, 5-year
`survival is only 5–10%. In metastatic disease, trials with cisplatin and
`5-fluorouracil (5-FU) have demonstrated a 25–35% major response
`rate. Response duration often is #5 months with a median survival of
`4 – 8 months.1,2 New therapeutic drugs therefore are needed.
`Interferon-a-2a (IFN) has shown antitumor activity in a number
`of gastrointestinal malignancies. Significant clinical responses were
`reported for IFN in combination with 5-FU in colorectal carcinoma.3
`We performed a Phase II trial of IFN and 5-FU in patients with
`
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`

`1214
`
`CANCER March 15, 1999 / Volume 85 / Number 6
`
`metastatic or unresectable esophageal carcinoma, and
`reported results comparable to those of cisplatin-
`based regimens with a major response observed in 10
`of 37 patients (27%).4 Our subsequent trial with 5-FU,
`cisplatin, and IFN showed a 53% response in 24 evalu-
`able patients. However, the median response duration
`of 5 months was brief.5
`A number of clinical trials have shown the efficacy
`of retinoids as chemopreventive and chemotherapeu-
`tic agents. Hong et al. reported a decrease in the size
`of the primary lesion and a reversal in the degree of
`dysplasia in patients with oral leukoplakia treated with
`13-cis-retinoic acid (CRA).6 A second study by Hong et
`al. showed a decreased incidence of second primary
`tumors in patients treated with CRA after curative
`treatment of locoregional head and neck carcinoma.7,8
`Preclinical studies have demonstrated synergy be-
`tween retinoids and cytokines in a variety of cell
`lines.9 –12 The mechanism of synergy is not understood
`completely. Ultimately, retinoic acid appears to in-
`crease expression of a transcription factor that regu-
`lates IFN gene expression and thereby may modulate
`IFN-induced cell death and apoptosis.13
`Based on preclinical data, Lippman et al. reported
`a 68% overall response rate to CRA (1 mg/kg/day) and
`IFN (3 million U/day) in heavily pretreated patients
`with advanced squamous cell carcinoma (SCC) of the
`skin.14 This group then used a similar regimen for
`patients with previously untreated, locally advanced
`SCC of the cervix. Of 26 patients, 13 had a major
`response including 4 patients with a clinical complete
`response.15,16
`Analogous to nonsmall cell lung carcinoma, both
`SCC and adenocarcinoma (AC) of the esophagus have
`a similar natural history with the early development of
`disseminated disease. Response proportions for the
`two histologies overlap in chemotherapy trials.17–19
`Based on the enhanced activity of 5-FU observed with
`IFN in patients with esophageal carcinoma and the
`antitumor activity of IFN plus CRA observed in pa-
`tients with SCC of the skin and cervix, a trial of IFN
`plus CRA for SCC or AC of the esophagus was initiated.
`
`PATIENTS AND METHODS
`Study Design
`This was a Phase II, single institution trial. After ap-
`proval by the Internal Review Board at the Memorial
`Sloan-Kettering Cancer Center, this study was con-
`ducted from August 1993 until April 1995.
`
`Eligibility
`Patients with histologic confirmation of SCC or AC of
`the esophagus were required to have unresectable or
`metastatic disease. Lesions had to be bidimensionally
`
`measurable by chest X-ray or computed tomography
`scan or evaluable as measured by barium swallow.
`Patients were required to have a Karnofsky perfor-
`mance status $60%. Prior treatment with no more
`than one chemotherapy regimen was permitted. Pa-
`tients could have no previous exposure to IFN or CRA.
`Radiation therapy had to be completed at least 4
`weeks prior to the initiation of protocol therapy. Ad-
`equate bone marrow function (defined as a leukocyte
`count $ 3000 cells/mm3 and platelet count $ 100,000/
`mm3), liver function (defined as bilirubin , 1.5 mg/
`dL), and renal function (defined as serum creatinine #
`2 mg/dL or creatinine clearance of $ 50 mL/minute)
`was required. Signed informed consent was obtained
`from all patients prior to the initiation of therapy.
`
`Treatment Plan
`Pretreatment evaluation included complete history
`and physical examination, blood work, computed to-
`mography of the chest and abdomen, and barium
`esophagram if clinically indicated.
`IFN (Roferont-A; Hoffman-La-
`Recombinant
`Roche, Nutley, NJ) and CRA were supplied by the
`Investigational Drug Branch of the National Cancer
`Institute. IFN was given at a dose of 3 million u daily
`by subcutaneous injection. CRA was given at a dose of
`1 mg/kg/day orally in 2 divided doses, preferably with
`a fat-containing meal. Because gelatin capsules of CRA
`were available in 10 mg, 20 mg, and 40 mg dosages,
`doses were rounded to the nearest 10 mg. Patients
`were encouraged to premedicate with acetaminophen
`prior to IFN injection and to continue acetaminophen
`every 4 hours as needed for fever and myalgia. Ther-
`apy was administered in cycles of 4 weeks.
`Standard response criteria were used.20 Reassess-
`ment of tumor status by appropriate studies occurred
`at least every 8 weeks until maximum response and
`then every 2–3 months thereafter. Patients were taken
`off protocol if they developed disease progression,
`defined as a .25% increase in the sum of all measured
`lesions or size of an individual lesion or the appear-
`ance of new lesions.
`Toxicity was graded according to National Cancer
`Institute Common Toxicity Criteria. Fatigue was as-
`sessed by Cancer and Acute Leukemia Group B toxic-
`ity criteria. Dose adjustment for anticipated IFN-asso-
`ciated toxicity (such as fatigue or granulocytopenia)
`was made for all Grade 2 or higher neurologic toxicity
`and for all other Grade 3/4 toxicities, except hemato-
`logic toxicity manifested by low hemoglobin. In all
`cases both IFN and CRA were withheld until toxicity
`was reduced to #Grade 1. CRA then was resumed and
`IFN attenuated to a dose of 1 daily injection 5 days per
`week. Further attenuation to the delivery of IFN to 3
`
`ALVOGEN, Exh. 1018, p. 0002
`
`

`

`IFN and CRA for Advanced Esophageal Carcinoma/Enzinger et al.
`
`1215
`
`TABLE 1
`Demographics
`
`Entered
`Eligible
`Evaluable for response
`Evaluable for toxicity
`Male/female
`Median age (yrs) (range)
`Median Karnofsky performance status (range)
`Squamous cell carcinoma: adenocarcinoma
`Prior chemotherapy only
`Prior radiotherapy only
`Prior chemotherapy and radiotherapy
`
`19
`18
`16
`16
`15:1
`59 (30–73)
`80 (90–70)
`3:13
`4
`0
`8
`
`days per week occurred if the significant toxicity re-
`curred.
`Dose adjustment for anticipated CRA-associated
`toxicity (such as dry skin, cheilitis, hypertriglyceride-
`mia, conjunctivitis, or epistaxis) was made for Grade 4
`skin toxicity and all other Grade 3/4 toxicity. CRA was
`withdrawn until toxicity declined to either Grade 2
`skin toxicity or Grade 1 other toxicity and then read-
`ministered at a dose of 0.5 mg/kg/day. CRA was dis-
`continued if significant toxicity recurred at the atten-
`uated dose. For Grade 3/4 toxicity in which IFN and
`CRA overlapped, (such as nausea/emesis), both drugs
`were withheld and a dose attenuation of IFN was
`made first.
`
`RESULTS
`Demographic Characteristics
`Nineteen patients were entered into the trial. Of these,
`one patient was found to be ineligible because he had
`received two prior chemotherapeutic regimens. Of the
`18 eligible patients, 16 were evaluable for response
`and toxicity. One patient was unable to swallow the
`CRA and therefore was inevaluable for response and
`toxicity. Another developed Grade 4 nausea and eme-
`sis after 1 week of therapy and was not evaluable for
`response. One patient had rapid clinical progression
`after 4 days of treatment and was inevaluable for tox-
`icity.
`Of the 16 patients evaluable for response, all had
`Stage IV disease with 13 demonstrating AC histology.
`Eight patients previously had received chemotherapy
`and radiation therapy; four had received chemother-
`apy only and four had received no prior therapy. Che-
`motherapy included cisplatin and 5-FU (seven pa-
`tients), paclitaxel
`(two patients), or
`cisplatin,
`paclitaxel, and 5-FU (two patients). Patient character-
`istics are outlined in Table 1.
`
`Toxicities
`IFN-related toxicity was predominant. Ten patients
`(63%) had Grade 2 or higher neurosensory toxicity and
`
`TABLE 2
`Toxicities
`
`Toxicity grade (n 5 16 patients)
`
`Hematologic
`Anemia
`Leukopenia
`Granulocytopenia
`Thrombocytopenia
`Other
`Fatigue
`Nausea
`Emesis
`Alkaline phosphatase
`Neurosensory
`Pulmonary
`Stomatitis
`Skin/cheilitis
`Alopecia
`Epistaxis
`Diarrhea
`Neuroconstipation
`Fever
`Chills
`Pain
`
`1
`
`8
`4
`1
`5
`
`2
`4
`4
`5
`2
`7
`5
`10
`1
`6
`9
`1
`5
`1
`0
`
`2
`
`4
`2
`2
`1
`
`8
`6
`4
`2
`8
`2
`0
`3
`0
`0
`1
`3
`6
`2
`3
`
`3
`
`2
`1
`0
`0
`
`5
`3
`0
`3
`2
`2
`1
`0
`0
`0
`0
`0
`0
`0
`0
`
`4
`
`0
`0
`0
`0
`
`0
`1
`1
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`
`5 patients (31%) had Grade III fatigue. Two patients
`were admitted for fatigue and dehydration. CRA-re-
`lated toxicity was limited with little skin toxicity and
`no significant hypertriglyceridemia. Overlapping tox-
`icity of IFN and CRA was notable for Grade 3/4 nausea
`in 4 patients (25%) and alkaline phosphatase elevated
`to Grade 3 levels in 3 patients (19%). One 73-year-old
`patient had a mild stroke after 2 days of therapy (ad-
`judicated as nontreatment-related) and continued his
`regimen 1 week later for 8 more weeks of treatment.
`Toxicities are reported in Table 2.
`
`Response to Treatment
`No major responses were observed. Eleven patients
`with AC and 3 patients with SCC developed disease
`progression. Only 1 patient with AC was found to have
`a minor response in skin nodules lasting 22 weeks and
`1 patient with AC had stable disease lasting 45 weeks.
`Both patients were taken off protocol due to disease
`progression. The median time to progression was 5
`weeks. The median survival was 22 weeks.
`
`DISCUSSION
`Despite the early reports of response to combination
`IFN and CRA in patients with SCC of the skin and
`cervix, a number of subsequent studies have failed to
`show benefit in patients with more advanced or
`heavily pretreated disease. For instance, in 13 refrac-
`tory patients with SCC of the cervix treated with IFN
`and CRA, no complete or partial responses were ob-
`
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`
`

`

`1216
`
`CANCER March 15, 1999 / Volume 85 / Number 6
`
`served.21 Combined IFN and CRA also were examined
`in patients with recurrent SCC of the head and neck.
`Of 21 evaluable patients only 1 had a partial response
`and 2 had minor responses.22 Similarly, only 1 of 34
`patients with advanced nonsmall cell lung carcinoma
`(17 of whom had squamous histology) treated with
`IFN and CRA had a brief partial response.23
`A Phase I study by Toma et al. of SCC patients
`treated with combined IFN and CRA hinted that this
`regimen may have promising activity in patients with
`esophageal carcinoma.24 Both patients who had pre-
`viously undergone resection of an SCC of the esoph-
`agus had a complete response. However, Phase II tri-
`als have been disappointing. Slabber et al. examined
`this regimen in previously untreated patients with in-
`operable SCC of the esophagus. Of 15 evaluable pa-
`tients, no objective responses were documented, with
`a median survival of 15 weeks.25 A letter by Kok et al.
`confirms these findings.26 In their study of 10 patients
`with previously untreated metastatic SCC of
`the
`esophagus, no objective responses were observed.26
`The poor results achieved in patients with advanced
`SCC of the esophagus, cervix, head and neck, and
`lung, may suggest that the benefit of this regimen is
`reserved primarily for chemoprevention and not for
`the treatment of advanced or treatment-refractory dis-
`ease.
`The toxicity in our study was higher than that in
`many previously reported trials of IFN and CRA. Slab-
`ber et al. administered the same dose of CRA and
`twice the dose of IFN used in this study to previously
`untreated esophageal carcinoma patients and found it
`to be well tolerated with only one patient developing a
`Grade 3 toxicity requiring dose modification.25 Nota-
`bly, no significant nausea, emesis, or fatigue were
`noted in patients who at baseline were divided evenly
`between Eastern Cooperative Oncology Group perfor-
`mance statuses 1 and 2. Similarly, Kok et al. reported
`little toxicity in their previously untreated esophageal
`carcinoma group.26
`Toxicity varied greatly among other studies as
`well. For instance in two studies by the same authors,
`toxicity ranged from negligible in patients with previ-
`ously untreated cervix carcinoma16 to severe in pa-
`tients with previously treated SCC of the skin.15 Mul-
`tiple studies have demonstrated that Grade 3 fatigue
`may range from a low of 3% to a high of 43%.14,16,21–23
`Generally, it appears that toxicity in these studies cor-
`relates well with the degree of pretreatment. This may
`account for the relatively high toxicity observed in our
`study.
`Given the absence of response in a total of 28
`patients in 3 Phase II studies of SCC of the esophagus
`and 13 patients with AC of the esophagus, further
`
`evaluation of this regimen in patients with advanced
`esophageal carcinoma is not warranted.
`
`2.
`
`5.
`
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`