2326

Intensive Recombinant Interleukin-2 and Alpha-Interferon Therapy in Patients with Advanced Head and Neck Squamous Carcinoma Susan G. Urba, M.D.,* Arlene A. Forastiere, M.D.,t Gregoy T. Wolf, M.D.,$ and Philip C. Amrein, M.D.4

Background. Cellular immune deficiency is a consis- tent finding in patients with advanced head and neck cancer. Interleukin-2 and alpha-interferon are modula- tors of the immune system.

Methods. Eleven patients with recurrent head and neck cancer were treated in a Phase I1 study of recombi- nant human interleukin-2 (rIL-2) and alpha-2a-inter- feron (Roferon-A, Hoffmann-La Roche, Inc., Nutley, NJ). Each course consisted of rIL-2, 3 X lo6 U/mz/day, as a continuous intravenous infusion over 24 hours for 4 days, and recombinant alpha-2a-interferon, 5 x lo6 U/ mz/day intramuscularly or subcutaneously daily for 4 days. This treatment was repeated weekly for 4 weeks, and then a second cycle was given after a &week break.

Results. Two patients (18%) achieved a partial re- sponse. Toxic effects were substantial. Three of 11 pa- tients experienced Grade 3 hypotension, 3 patients had Grade 3 oliguria, and Grade 3 fatigue was one of the most common reasons for withdrawal from the study. There were no deaths or need for intensive care monitoring.

Conclusions. In view of the 18% response rate, addi- tional investigation of biologic therapy in advanced head and neck cancer is warranted. Cancer 1993: 712326-31.

Key words: head and neck cancer, interleukin-2, alpha- interferon, immunotherapy.

Interleukin-2 (IL-2), a lymphokine produced by T-lym- phocytes, is involved in the induction of immune re-

~~

From the *Division of Oncology and $Department of Otolaryn- gology-Head and Neck Surgery, University of Michigan Medical Center, Ann Arbor, Michigan; the tDepartment of Oncology, Johns Hopkins Oncology Center, Baltimore, Maryland; and the §Depart- ment of Hematology and Oncology, Massachusetts General Hospital, Boston, Massachusetts.

Supported by Hoffmann-La Roche, Inc. Address for reprints: Susan G. Urba, M.D., University of Michi-

gan Medical Center, Division of Oncology, 1500 E. Medical Center Drive, 3118 Taubman Center, Ann Arbor, MI 48109.

Accepted for publication October 29, 1992.

sponse by stimulation of differentiation and prolifera- tion of cytotoxic T-lymphocytes.' It also has been asso- ciated with antitumor activity in vitro,2 in murine r n ~ d e l s , ~ and in patient trials4

Human leukocyte interferon has become available for clinical trials in the last 10 years because recombi- nant DNA-derived interferon now is produced success- fully in bacteria and purified in large q~antit ies.~ Inter- feron has immune regulatory function due to augmen- tation of natural killer activity and antiviral effect.6 Interferon also displays the ability to affect cell prolifer- ation and differentiation in preclinical models, thus providing a rationale for its incorporation into cancer trial^.^ There is substantial documentation of antitumor effect in several cancers, including hairy cell leukemia,' malignant melanoma,' and renal cell carcinoma."

The combination of IL-2 and alpha-interferon ap- pears to have synergistic antitumor activity. Bash et al. demonstrated that murine hepatic metastases from a colon cancer cell line were resistant to alpha-interferon alone, but a reduction in tumor burden resulted from combination treatment with interferon and IL-2." This synergism in murine models also has been documented by other^.'^,'^ Rosenberg et al. treated 74 assessable pa- tients with renal cell cancer and melanoma with esca- lating doses of IL-2 and alpha-interfer~n.'~ The re- sponse rate of 41% in 27 patients treated at the highest dose levels was better than that in any reported series of patients treated with these agents individually. One possible explanation for the synergism of the two cyto- kines is based on the ability of interferon to cause a 5-fold to 10-fold increase in human leukocyte antigen gene mRNA within 4 hours of exposure to tumor cells, and this elevation may persist for 24 hours.I5 This in- crease in major histocompatibility complex class I anti- gens may allow for better tumor cell recognition by IL- 2-stimulated T-cells.

It has been demonstrated repeatedly that many pa- tients with advanced head and neck cancer have im-

IL-2 and IFN in Head and Neck CancerlUrba e t al . 2327

paired cellular immunity,“ and immune activity has been correlated with progn~s is .”~’~ Therefore, to take advantage of the immune system modulation and anti- tumor effects of IL-2 and interferon, a trial of combina- tion therapy with these agents was designed and con- ducted for patients with advanced unresectable head and neck carcinoma.

Materials and Methods

Patient Eligibility

All patients were required to have metastatic or locally recurrent squamous cell cancer of the head and neck or previously untreated bulky Stage IV disease, and they were considered incurable with conventional therapy. The patients had to be at least 18 years old, with a Karnofsky performance status of at least 70% and mea- surable disease. Good renal function was required: cre- atinine levels less than 2.0 mg/dl, creatinine clearance less than 50 ml/minute, and serum albumin levels greater than 3 g/dl. All patients had good hepatic func- tion: bilirubin level less than 1.6 mg/dl, serum glutamic oxaloacetic transaminase level less than four times the upper limit of normal, prothroinbin time and partial thromboplastin time less than 1.5 times control, and no clinically significant ascites. Hematologic requirements were as follows: hemoglobin level greater than 10 g/dl, platelet count greater than 100,000/mm3, and granulo- cyte count greater than 1500/mm3. Patients were ineli- gible if they had significant pulmonary dysfunction, car- diovascular abnormalities, central nervous system dis- ease, a calcium level greater than 12 mg/dl, or symptomatic hypercalcemia.

Other exclusion criteria were a prior or concurrent malignant neoplasm (other than basal cell carcinoma or carcinoma in situ of the cervix), the presence of pleural effusion, organ allografts, significant intercurrent ill- ness, infection, or peptic ulcer disease. Patients requir- ing chronic treatment with beta-adrenergic calcium channel blockers or steroids were excluded from the study. No patient had received IL-2 or alpha-interferon

Table 1. Treatment Schema

previously. Prior treatment with other immunotherapy, chemotherapy, or radiation therapy was allowed, as long as there was a 4-week treatment-free interval be- fore enrollment in this protocol. Women of childbear- ing potential and fertile men were excluded unless they were using effective contraception during the treatment period.

Baseline studies before initiation of treatment in- cluded history and physical examination, tumor mea- surement, evaluation of Karnofsky performance status, complete blood count, blood chemistries, serum drawn for anti-recombinant human interleukin-2 (rIL-2) and anti-alpha-2a-recombinant human interferon (rHuIFN) antibodies, urinalysis, chest radiograph, electrocardio- gram, and computed tomography or magnetic reso- nance imaging of the brain.

Treatment Plan

The treatment regimen consisted of two 4-week courses of induction therapy in the inpatient setting (Table 1). The courses were separated by a 2-week break. Each course consisted of rIL-2,3 X lo6 U/m2/day, as a con- tinuous intravenous infusion over 24 hours every day on days 1-4 and alpha-2a-rHuIFN, 5 X lo6 U/m2/day intramuscularly or subcutaneously every night on days 1-4. This treatment was repeated each week for 4 weeks, which constituted one complete course.

After the second course of induction therapy, pa- tients whose tumors had responded or remained stable were eligible to receive maintenance therapy for four additional courses in the outpatient setting through a permanent intravenous port. The doses for mainte- nance were administered as follows: rIL-2, 2 X lo6 U/ m2/day by continuous infusion on days 1-4, and al- pha-2a-interferon (Roferon- A, Hoffmann-La Roche, Inc., Nutley, NJ), 6 X lo6 U/m2/day intramuscularly or subcutaneously on days 1 and 4. This would be re- peated each week for 4 weeks, followed by a 2-week rest period.

At the discretion of the investigator, patients were able to receive the following medications concomitant

Studv dav

Treatment 1 2 3 4 5 6 7 Dose

rlL-2 X X X X 3 X lo6 U/m2/d

Alpha-2a- X X X X 5 X 10’ U/m2/d 1M interferon* or subcutaneously

rIL-2: recombinant interleukin-2; IM: intramuscularly. Note: Induction took place during weeks 1-4 and 7-10. * Roferon-A, Hoffmann-La Roche, Inc., Nutlev, NI.

continuous infusion

2328 CANCER April 2 , 2993, Volume 71, No. 7

with treatment: acetaminophen, 650 mg orally every 4 hours as needed for fever; indomethacin, 25 mg orally every 6 hours as needed for fever; diphenhydramine, 50 mg orally every 4 hours as needed for rash or itching; prochlorperazine maleate (Compazine, SmithKline, Philadelphia, PA), 10 mg intravenously or per rectum every 4 hours as needed for nausea; and meperidine, 25-50 mg intravenously every 2 hours as needed for chills.

only. The primary sites of disease included the follow- ing: oral cavity, three patients; nasopharynx, three pa- tients; hypopharynx, one patient; and larynx, four pa- tients. All patients had received prior therapy: six had prior surgery and radiation therapy; three had prior surgery, radiation therapy, and chemotherapy; one had radiation therapy only; and 1 had received radiation therapy and chemotherapy.

Response to Treatment Dose Modifications for Toxic Effects

Guidelines were established for dose modification based on toxic effects. Grade 1 and 2 toxic effects re- quired no change of treatment. However, treatment was withheld for Grade 3 toxic effects until the symp- toms improved to less than Grade 1. If this improve- ment did not occur within 4 weeks, treatment was stopped and the patient was removed from the study. If the toxic effects resolved rapidly when the drug was withheld, it was restarted at a 50% dose reduction. If any patient experienced Grade 3 neurotoxic or cardio- toxic effects, or any Grade 4 toxic effects, treatment was stopped and the patient was withdrawn from the study.

Assessment of Response

Response to treatment was defined as complete if there was disappearance of all clinically detectable disease for a period of at least 4 weeks. A partial response indi- cated a 50% or greater decrease in the sum of the prod- ucts of the two greatest perpendicular diameters of all measurable lesions for at least 4 weeks. No simulta- neous increase in the size of any lesion or the appear- ance of a new lesion was allowed. Stable disease was defined as a less than 25% increase or less than 50% decrease in tumor size and no appearance of new le- sions. Progressive disease was defined as a greater than 25% increase in measurable disease or the appearance of any new lesions.

Results

Patient Population

Between February 1989 and January 1990, 11 patients were enrolled in this protocol. Four patients were treated at the University of Michigan, five patients at the Johns Hopkins Oncology Center, and two at the Massachusetts General Hospital Cancer Center. Seven were men and four were women. The age range was 26-64 years, and the initial Karnofsky performance sta- tus was 80-100%. All patients had recurrent disease. Eight patients had local/regional disease, two had local and distant disease, and one had metastatic disease

All 11 patients were assessable for response, toxic ef- fects, and survival. Seven patients tolerated 1-4 weeks of therapy, and four patients received 5-8 weeks of treatment. Reasons for withdrawal were tumor progres- sion in five patients and toxic effects of treatment in six. No patient received maintenance therapy.

There were two partial responses (l8%), and four patients had stable disease (36%). The patients with stable disease were removed from the study early be- cause of toxic effects at 1, 1.5,2, and 5.5 weeks of treat- ment. There were five cases of progression (46%).

Of the two patients who showed partial responses, one was a 59-year-old man with a recurrent 5 X 6 cm squamous cell carcinoma of the left retromolar trigone, who tolerated 7 weeks of therapy. After 4 weeks of treatment, the tumor had regressed to 2 X 3 cm, and after the second course of treatment there was complete disappearance of the tumor mass, leaving a 2 X 2 cm area of induration. Posttreatment biopsy showed small nests of carcinoma and intense infiltration of neutro- phils. The patient refused maintenance therapy be- cause of extreme fatigue, and he maintained his re- sponse without therapy for 3 months. Progressive dis- ease eventually developed, and he was treated with chemotherapy, with excellent response.

The second patient who responded to IL-2/inter- feron therapy was a 59-year-old man with a history of recurrent laryngeal cancer, who had a 2.5 X 1.5 cm ulcerative neck lesion and a 2 X 2 cm neck nodule. After 1 week of treatment, the ulcer had decreased to 1.0 X 1.3 cm, and the neck nodule measured 2 X 1 cm. The therapy was withheld because of the development of Staphylococcus pneumonia, possibly related to place- ment of a central venous catheter. After 1 month with- out treatment, tumor progression was observed and treatment resumed. The patient received 2 more weeks of treatment with IL-2/interferon without response and then was withdrawn from the study because of hypotension.

Six patients were removed from the study within 4 weeks because of toxic effects; therefore, although they did not respond, the time of exposure to the drugs may have been inadequate to effect a response. Among the five patients with progression of disease, in three it oc-

IL-2 and IFN in Head and Neck Cancer/Urba et al. 2329

curred within the first 3-4 weeks and two patients had progression after 7-8 weeks of treatment.

over the next year. Other common side effects were fluid retention, fever, anemia, and nausea, which re- solved promptly after cessation of therapy.

Toxic Effects Survival

The toxic effects were substantial, but there were no treatment-related deaths and no patient was trans- ferred to the intensive care unit. However, four patients required a delay in treatment, and six patients were re- moved from the study early because of toxic effects. No patient received maintenance therapy after the inten- sive induction period. The most frequently encountered toxic effects are listed in Table 2. Grade 3 hypotension was experienced by three patients and generally was controlled with intravenous fluids. Three patients had Grade 3 oliguria develop, which responded to hydra- tion, albumin, and low-dose dopamine. Severe fatigue was one of the most common reasons for patient with- drawal from the study. Although diarrhea was bother- some but tolerable in six patients, two patients had se- vere symptoms. Hematochezia developed in one of these patients. On colonoscopic examination, hemor- rhagic areas were observed between 60 and 70 cm, and a stricture was seen at 70 cm, which was thought to be compatible with ischemia or possible volvulus. Biopsy specimens were interpreted as compatible with chronic inflammatory disease. He was removed from the study and experienced no long-term gastrointestinal sequelae

Table 2. Toxic Effects

Grade

Toxic Effect I 2 3 4

Hypotension 27% 27% 27% - Fatigue 18% - 36% - Oliguria” - - 27% -

Weight gain - 1 8% 18% -

Dyspnea 18% - 18% - Fever - 55% 9% -

Chills 27% 9% 9 Yo - Cutaneous effects 9 YO ISYO 9 yo - Diarrhea 18% 36% 9% 9 yo Nausea/vomiting 36% 9% 9 Yo - S toma titis - - 9% - Hypocalcemia - 36% 27% - Hyponatremia 36% 18% Anemia 9% 55% Leukopenia 9% 9% Granulocytopenia 9 90 - 9% H ypomagnesemia - 9 % 9% -

- -

- - - -

-

- - - Hypokalemia 18% Uremia 9 % - - -

* Grade 0 = >80 ml per 8 hours; Grade 1 ,2 = no criteria; Grade 3 = 4 0 ml per 8 hours; Grade 4 = anuria > 8 hours.

Patient numbers were too small to allow conclusions to be drawn regarding survival. One patient was lost to follow-up. Of the 10 assessable patients, 1 was alive with disease at 2 years and the other 9 patients died. Their survival length ranged from 3.5 months to 21 months.

Discussion

This regimen of IL-2 and interferon was intensive and toxic, and required long periods of hospitalization. However, two partial responses occurred in heavily pretreated patients, including one response that lasted for 3 months without treatment. It is particularly inter- esting that these responses were seen in patients with far advanced disease, who typically represent the most profoundly immunologically compromised patients. The findings suggest that this immunotherapeutic regi- men with IL-2 and interferon has some activity in head and neck squamous carcinoma.

Cellular immune deficiency is a consistent finding in patients with advanced head and neck c a n ~ e r . ’ ~ * ~ ~ Recent studies have documented that decreased levels of CD8-positive cytotoxic T-lymphocytes correlate with prognosis in patients with head and neck cancer.’l Be- cause IL-2 and interferon each have been shown to augment in vitro lymphokine-activated killer cell and natural killer cell cytotoxic effects, respectively, against head and neck squamous carcinoma cell the responses observed may have resulted from improved lymphocyte-mediated immunity. Wanebo et al. demon- strated in vitro that immune deficiency of patients with head and neck cancer was reversed by the addition of IL-2, which restored lymphocyte function to normal control levels.25 The combination of IL-2 and alpha-in- terferon can result in lymphokine-activated killer cell generation and increased levels of cytotoxic effects.26 The ability of IL-2 and interferon to restore immune function in vitro provided the rationale for clinical in- vestigations of these agents in patients with head and neck cancer.

Our study is one of a very few studies that have evaluated clinical response to IL-2 and interferon in head and neck cancer. Tamura et a]. administered IL-2 and beta-interferon to 26 patients with advanced malig- nant neoplasms in a Phase I study.” Two of these pa- tients had a primary tumor in the pharynx, and one of these patients with adenoid cystic carcinoma experi-

2330 CANCER April I , 2993, Volume 71, No. 7

enced a 25% reduction in lung metastases. Natural killer cell and lymphokine-activated killer cell activity increased during treatment but decreased during the rest period, suggesting a definite but short-lived effect from the immunotherapy.

Schantz et al. treated 10 patients with head and neck carcinoma with IL-2 and alpha-interferom2* They reported a significant increase in the number of CD56-positive lymphocytes and natural killer cell activ- ity in response to treatment in eight assessable patients.

Some investigators have explored the integration of chemotherapy with IL-2 and interferon. In three studies conducted for patients with metastatic melanoma, IL-2 and interferon were combined with regimens that in- cluded cisplatin, dacarbazine, carmustine, vinblastine, or tamoxifen, and the response rate was an encouraging 56-57Y0.”-~~ A s imilar approach could be attempted in patients with head and neck cancer, although investi- gators from M. D. Anderson Cancer Center did not see improved response rates when cisplatin and 5-fluoro- uracil were combined with either single-agent inter- f e r ~ n ~ ~ or IL-233 in patients with head and neck cancer. Response rates were 30% and 35%, respectively.

Our study demonstrated that it is possible to safely administer extremely intensive therapy with IL-2 and alpha-interferon. The number of patients studied was too small to indicate whether response to treatment translates into improved quality of life or survival. Mod- ulation of dose or schedule could improve results ob- tained thus far in reported clinical trials. Future studies that carefully assess pretreatment immune function and monitor the immune response at the primary tumor site may provide a better understanding of those patient and tumor characteristics associated with response to therapy and allow better definition of the potential role of this biologic therapy in head and neck cancer.

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