A Randomized Phase 111 Study of Cisplatin With or Without Methotrexate for Recurrent Squamous Cell

Carcinoma of the Head and Neck

A Northern California Oncology Group Study

CHARLOTTE JACOBS, MD,' FREDERICK MEYERS, MD,t CHARLES HENDRICKSON, MD,* MARSHA KOHLER, MSPH.5 AND STEVE CARTER, MD$

Eighty patients with recurrent squamous cell cancer of the head and neck were randomized to cisplatin (80 mg/m2) every 3 weeks or cisplatin plus weekly methotrexate (250 mg/m2) with leucovorin. The overall response rate to cisplatin was 18%, with 10% complete responses. The overall response to the combination was 33% with 18% complete responses (P = 0.11). There was no difference in response duration, time to progression, or survival. There was no difference in renal toxicity between the 2 arms (creatinine > 2 mg/dl in 6% of the patients). There was significantly more leukopenia (64%), throm- bocytopenia (18%), anemia (18%), and mucositis (33%) in the combination arm. This combination of two of the best agents for head and neck cancer did not improve response, but resulted in added toxicity.

Cancer 52:1563-1569, 1983.

ESPITE optimal treatment with surgery and radia- D tion therapy, patients with advanced squamous cell cancers of the head and neck have a high incidence of recurrence. Salvage therapy is rarely effective and is of poor quality because of frequent extensive local involvement. Survival is sh01-t;~ thus, there is a need to develop effective chemotherapy regimens for recurrent disease.

To date, the best single agents for squamous cell can- cer of the head and neck are methotrexate, cisplatin, and ble~mycin.~ Response rates to these drugs vary from 20% to 60%,6-10 but most are partial responses of short duration. Effective palliation is limited to a small num- ber of patients.

From the Northern California Oncology Group, Palo Alto, Cali-

Supported by the American Cancer Society Clinical Fellowship

Division of Oncology. Department of Medicine, Stanford Uni-

t Division of Hematology and Oncology, University of California.

+ Kaiser Foundation Hospital, San Francisco, California. 9 Northern California Oncology Group, Palo Alto, California. Address for reprints: Charlotte Jacobs, MD, Stanford University

Medical Center, Oncology Day Care Center C005, Stanford, CA 94305.

The authors thank Melanie Gribble for data analysis and protocol writing.

Accepted for publication August 13. 1982.

fornia.

Grant and the NCI grant 2RIO CA21744-03.

versity School of Medicine.

Davis School of Medicine, Sacramento, California.

Numerous trials of different combinations of che- motherapeutic agents have been described for head and neck cancer. Responses have been quite high (60%- 100%) in some studies with increased numbers of com- plete responses' '-I5 compared to single agents. Several authors have reported significant toxicities.' ' . I 6 It is often difficult to make specific recommendations based on current studies. There is seldom comparability of drug combinations, doses, and schedules between studies. It is also difficult to compare studies because of variations in patient populations, particularly with respect to prior treatment. Few trials have been reported comparing combination chemotherapy to single agents in terms of response rates, survival, and toxicity.

This study compares in a prospective randomized trial the combination of cisplatin and methotrexate to cis- platin alone in terms of response rate, duration of re- sponse, survival, and toxicity.

Methods

Patient Selection

Between June, 1979 and June, 198 1 ,6 1 patients with recurrent squamous cell carcinoma of the head and neck were randomized in a prospective study to receive either cisplatin alone or cisplatin plus methotrexate. Nineteen patients were initially randomized at Stanford Univer-

0008-543)</83/1 101/1563 $1.15 0 American Cancer Society

1563

1564 CANCER November 1 1983 Vol. 52

TABLE I . Patient Characteristics

Cisplatin and Cisplatin Methotrexate

Total no. patients Mean Age Sex

Male Female

Primary site Oropharynx Oral cavity Nasopharynx Larynx Hypopharynx Sinus

Recurrence site Local Metastatic

Karnofsky Performance Status 60-70 80- I00

Prior treatment Surgery Radiation therapy

Histologic differentiation Well differentiated Moderately differentiated Poorly differentiated Not determined

41 56

30 I I

9 9 9 7 4 3

28 13

15 26

28 40

12 12 14 3

39 55

30 9

I I 9 6 8 2 3

23 16

18 21

30 37

4 15 15 5

sity from June 1977 to June 1979,” for a total of 80 patients.

Seventy-eight patients had measurable recurrent dis- ease not amenable to surgery or radiation therapy. One patient in each arm had no prior treatment. All pa- thology specimens were reviewed by the Northern Cal- ifornia Oncology Group (NCOG) Central Pathology Repository. Stratification variables included primary site of disease, site of recurrence, Karnofsky performance status, prior radiation therapy, prior chemotherapy, and institution.

Pretreatment evaluation included a complete history and physical examination, complete blood count, cre- atinine clearance, urinalysis, blood urea nitrogen, au- diogram, magnesium, liver function tests, chest x-ray, and appropriate radiographs and scintiscans to measure disease. For study entry, patients required Karnofsky performance status of at least 60%, and a creatinine clear- ance of 250 ml/minute.

Treatment Schedules Cisplatin at a dose of 80 mg/m2 was delivered by 24-

hour infusion with the total dose divided into 6 liters of 5% dextrose in ‘/z normal saline (D5 Yz NS).9 This was followed by 24 hours of rehydration. Magnesium, po- tassium chloride and/or furosemide were added as nec- essary. Cisplatin was repeated every 3 weeks.

Methotrexate at a dose of 250 mg/m2 was given 24 hours prior to cisplatin and repeated weekly. Patients were prehydrated with a liter of 5% dextrose in water (D5W) with sodium bicarbonate as necessary to alka- linize the urine. Methotrexate was infused over 30 min- utes and followed by a liter of D5W plus sodium bicar- bonate. At 24 hours, patients received leucovorin, 25 mg, then 10 mg every 6 hours for 6 doses.

Evaluation

Response was evaluated every 3 weeks, and tumor measurements were made. A complete response was defined as the complete disappearance of all clinically detectable tumor. A partial response was defined as de- crease of 250% in the sums of the products of the longest diameters of all measurable lesions without appearance of new lesions. Shrinkage of the lesion must have per- sisted for more than 4 weeks. Following progression of disease, the treatment plan was determined by the pri- mary physician. Time to failure was calculated from study entry to documented progression. Survival time was calculated from study entry to death.

Methods of analysis: Overall response rates and tox- icity rates were compared by chi-squared statistics.” Survival functions and time to failure functions were estimated by the Kaplan-Meier product limit method.” Differences between these curves were tested by the log- rank method. Multivariate analysis of response was an- alyzed by Cox’s linear logistic regression method.*’ The method of multivariate survival analysis used was the Cox-Breslow proportional hazards model. 19-”

Results

Patient Characteristics

Table 1 shows the patient characteristics for the two treatment arms. There were no significant imbalances with respect to age, sex, primary site of disease, site of recurrence, Karnofsky performance status, prior treat- ment, or histologic differentiation. For the total group, the mean age was 55.4 years, and 75% were males. The primary sites included the oropharynx (25%), oral cavity (23%). nasopharynx (19%), larynx (19%), hypopharynx (8%), and sinus (8%). Sixty-four percent of patients had locoregional recurrences, and 36% had metastatic disease, predominately in the lung.

The Karnofsky performance status was 60 to 70 in 4 1% of the patients and 80 to 100 in 59% of the patients. All but two patients had prior therapy: 96% had previous radiation therapy and 73% had previous surgery. Only three patients had prior chemotherapy. One patient in the single-agent arm and two in the combination arm

No. 9 CISPLATIN f METHOTREXATE FOR HEAD A N D NECK C A * Jacobs et a/. 1565

0.2

had prior bleomycin. The histologic differentiation was as follows: well differentiated, 20%; moderately differ- entiated, 34%; poorly differentiated, 36%; not avail- able, 10%.

The median number of courses given in the single arm was 5 (range, 1- 1 1). The median number of courses given in the combination arm was 4 (range, 1-10). The mean percent of calculated dose of cisplatin delivered in the single-agent arm was 90%. The mean percent of calculated dose of cisplatin delivered in the combination arm was 89%, and for methotrexate was 70%.

- - - - 0 - -

- I I I I I I I I I I I I I I

Therapeutic Results

Of the 40 evaluable patients who received cisplatin alone, 8% had a complete response and 10% had a partial response, for an overall response rate of 18%. Of the 39 evaluable patients who received cisplatin plus metho- trexate, 15% had a complete response and 18% had a partial response for an overall response rate of 33% (P = 0.1 1 ) (Table 2). Even after adjusting for the most significant prognostic variable, Karnofsky performance status, in a multiple logistic regression, the P value for arm dropped to 0.09. Only one of the 80 patients was not evaluable: this patient was on the single agent arm, and following his first dose of chemotherapy, he was switched to another combination.

1.0

t 1141

L 0 0.4 a

TABLE 2. Results of Treatment

Cisplatin and Cisplatin Methotrexate

Evaluable patients 40 39

Partial responses (>50%) 4 (10%) 7 (18%) Complete responses 3 (890) 6 (15%) P = .23

Overall (CR + PR > 50%) 7 ( 18%) 13 (33%) P = . I I (18 f 6%)* (33 f 7.5%)

CR: complete response: PR: partial response * *SE.

In the cisplatin arm, 13% of the patients responded after 1 course and an additional 5% responded after the 2 courses of chemotherapy. In the combination arm, 3 1 % of patients responded after 1 course and 3% after 2 courses. No new responses were observed after 2 courses of chemotherapy.

The median time to failure for the responders in the single-agent group was 228 days, and in the combination group, 133 days (Fig. 1) . There was no statistically sig- nificant difference in survival between the two groups (Fig. 2). The median survival for all patients receiving cisplatin alone was 188 days, and for patients who re- sponded to cisplatin it was 337 days. The median sur- vival for all patients receiving the combination was 208

1566 CANCER November 1 1983 Vol . 52

1 .o

0.8

0.6 h 5 4 .d

P a P

a 0 L 0.4

0.2

0.0

E t t

0 200 400 600 800 Time in Days

FIG. 2. Overall survival of patients treated with cisplatin(A) compared to those treated with cisplatin + methotrexate(B) (log-rank P = 0.95).

days, and for all patients who responded to the com- bination it was 267 days.

Prognostic Variables

The influence of the following prognostic variables on response and survival was analyzed in both a univariate and multivariate fashion: treatment arm, Karnofsky per- formance status, age, sex, site of recurrence, prior surgery, primary site and histologic differentiation. Karnofsky performance status was the only variable that predicted response or survival (Fig. 3) with a linear logistic regression on response P value of 0.02 and a proportional hazards survival P value of <O.O 1.

Toxicity

There was significantly more hematologic toxicity in the combination chemotherapy group (Table 3). Sixty- four percent of patients had a leukocyte count of less than 3000/mm3, and there were three mild infections in this group. One patient with a large nasopharyngeal recurrence died of meningitis the day following initia- tion of chemotherapy. In the cisplatin-alone group, 20% ofpatients had a leukocyte count of less than 3000/mm3,

and there was one mild infection. In the single-agent group, only 3% of patients had a platelet count of less than 50000/mm3 as compared to 18% in the combi- nation group. Two patients in this arm had severe hem- orrhages. Five percent of patients in the cisplatin alone group had a hemoglobin of less than 7.5 g/dl compared to 18% in the combination group.

There was no difference in renal toxicity between the two arms. Twenty-six percent of the patients treated with cisplatin alone had a creatinine level 2 1.5 mg/dl, and only one patient had a creatinine level > 2 mg/dl. Thirty- one percent of the patients treated with cisplatin and methotrexate had a creatinine level 2 1.5 mg/dl, and 4 patients had a creatinine level > 2 mg/dl. The highest creatinine level was 3.9 mg/dl, and all creatinine elevations were reversible.

Magnesium levels fell to less than 1.4 in 1 1 patients in the single-agent arm and 6 in the combination group; however, 27 patients did not have routine magnesium levels. There were no reported instances of tetany. One patient in the single-agent arm had a hearing loss of 55 db, and two patients on the combination arm had hear- ing losses of t 4 0 db. The only cases of peripheral neu- ropathy were two patients with mild paresthesias in each

No. 9 CISPLATIN k METHOTREXATE FOR HEAD A N D NECK C A * Jacobs el a/. 1567

1 .o

0.8

0.6

n 0 L 0.4 a

0.2

0.0 0 200 400 600 800

Time in Days FIG. 3. Overall survival of patients with Karnofsky performance status 60-70(X) compared to those with Karnofsky status of 80-100(Y) (log-

rank P < 0.01).

group. Two patients had hallucinations. There was no allergic reaction to cisplatin.

There was no difference in gastrointestinal toxicity between the two groups. Overall, 22% had no vomiting, 52% had occasional vomiting, 25% had moderate vom- iting, and 1 % had severe vomiting. Eight percent had diarrhea. The incidence of mucositis in patients who received methotrexate was as follows: 26%, patchy mu- cositis; 396, confluent mucositis; 5%, ulcerative mucos- itis.

tients with no prior treatment.l2.I3 This group of patients appears to have a higher response rate to chemotherapy than patients with recurrent disease.I2

Combination chemotherapy has been widely accepted despite the often increased toxicity. There are few re- ported randomized studies which compare combination chemotherapy to single agents. A preliminary report comparing cisplatin, vincristine, and bleomycin to methotrexate alone showed no difference in the two

TABLE 3. Toxicity Discussion

The goal of combination chemotherapy is to improve response rates and survival without additional toxicity. Combination chemotherapy has been shown to be su- perior to single agents in a variety of tumors. Numerous combinations of agents for head and neck cancer have been reported,"-'5 often with high response rates and often with substantial toxicity.' ' . I 6 It is difficult to com- pare these studies to single agent data, particularly be- cause of differences in patient populations. Phase I1 trials often include patients with prior chemotherapy, whereas many of the clinical trials of combinations include pa-

Hematologic Leukocyte count < 3000/m' Platelets < 50.000/mm3 Hemoglobin < 7.5 g '70

Creatinine Renal

1.5-2 mg YO >2 mg 'YO

M ucositis

Cisplatin (N = 40)

8 (20%) I (3%) 2 ( 5 % )

9 (23%) I (3%) 0

Cisplatin and Methotrexate

(N = 39)

25 (64'4%) P < .01 7 ( 18%) P = .03 7 (18%) P = .08

8 (21%1) 4 (10%)

13 ( 3 3 8 )

N: number.

1568 CANCER November 1 I983 Vol. 52

arms in terms of response rate or toxicity.22 Davis and Kessler” compared cisplatin (3 mg/kg), methotrexate (50 mg/m2 days 1 and 1 3 , and bleomycin ( 1 5 mg/m2 twice weekly) to cisplatin alone. There was no difference in response rate ( 1 3% and 1 I %, respectively), but severe myelosuppression occurred in almost 50% of the pa- tients on the combination regimen.

randomized patients to cisplatin (50 mg/m2 day 6), methotrexate (40 mg/m2 days 1 and 1 3 , and bleomycin ( 10 mg days I , 8, and 15) or meth- otrexate alone. The response rate in the combination group (46%) was significantly better than the single-agent group (26%), but there was no difference in survival.

Our study shows no significant difference in response to cisplatin and methotrexate compared to cisplatin alone for the treatment of recurrent head and neck can- cer. The median time to relapse and survival are similar in the two groups. Most responses occurred following 1 cycle of chemotherapy. All patients who responded did so by 2 cycles.

The dose of methotrexate (250 mg/m2) plus leuco- vorin was chosen because of a suggestion of enhanced response to a higher dose” without added toxicity. At initiation of this study, randomized dose-response stud- ies of methotrexate had not yet been published.26 For patients with recurrent head and neck cancer, the op- timal dose of cisplatin has not been established. Early single-agent trials utilized a variety of doses ( 1 20 mg/m2 every 3 weeks, 50 mg/m2 bimonthly, 80 mg/m2 every 3 weeks, 40 mg/m2 weekly, 3 mg/kg every 3 weeks) all with similar response rates (27% to 39%).27 The response to cisplatin in this study was lower than that reported in our Phase I1 trial (39%).9 This may reflect differences in patient population, as Davis and Kessle?3 utilizing cisplatin at a dose of 3 mg/kg had a response rate of 1 I%, compared to 30% reported by Wittes ef a/.* utiliz- ing the same dose. When we added methotrexate to cis- platin, the same percent calculated dose of cisplatin was delivered in both arms.

This study shows that methotrexate with leucovorin can safely be added to cisplatin without increased neph- rotoxicity. Only 10% of patients had a creatinine ele- vation > 2 mg/dl, and those were reversible. Hemato- logic toxicity was more severe in the combination group, although this resulted in only one possible chemother- apy-related death.

There are several prognostic factors in head and neck cancer which influence response to chemotherapy. These include primary site of disease,2* degree of tumor dif- f e r en t i a t i~n ,~~ performance status,30 and prior treat- ment.” In our study the only variable that was predictive of response and survival was Karnofsky performance

An ECOG

status. Prior treatment could not be assessed since most patients had prior therapy.

In conclusion, the combination of two of the best single agents for head and neck cancer, cisplatin and methotrexate, did not significantly improve results for treatment of recurrent disease. Combinations which ap- pear to have improved results should be compared to single agents.

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