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Interleukin-2- and Interferon Alfa-2a-Based Immunochemotherapy in Advanced Renal Cell Carcinoma: A Prospectively Randomized Trial of the German Cooperative Renal Carcinoma Chemoimmunotherapy Group (DGCIN)
Abstract
We conducted a prospectively randomized clinical trial to compare the efficacy of three outpatient therapy regimens in 341 patients with progressive metastatic renal cell carcinoma.
Patients were stratified according to known clinical predictors and were subsequently randomly assigned. Treatment arms were: arm A (n = 132), subcutaneous interferon alfa-2a (sc-IFN-α-2a), subcutaneous interleukin-2 (sc-IL-2), and intravenous (IV) fluorouracil; arm B (n = 146): arm A treatment combined with per oral 13-cis-retinoic acid; and arm C (n = 63), sc-IFN-α-2a and IV vinblastine.
Treatment (according to the standard 8-week Hannover Atzpodien regimen) arms A, B, and C yielded objective response rates of 31%, 26%, and 20%, respectively. Arm B, but not arm A, showed a significantly improved progression-free survival (PFS) compared with arm C (P = .0248). Both arm A (median overall survival, 25 months; P = .0440) and arm B (median overall survival, 27 months; P = .0227) led to significantly improved overall survival (OS) compared with arm C (median OS, 16 months). All three sc-IFN-α-2a–based therapies were moderately or well tolerated.
Renal cell carcinoma (RCC) accounts for 2% to 3% of all malignant tumors in adults.1 Patients with untreated metastatic RCC have an overall median survival of no more than 12 months and a 5-year survival of less than 10%. Because conventional therapy regimens such as single-agent chemotherapy or hormonal therapy have shown unsatisfactory results, new strategies are needed.
Promising results were reported with the use of recombinant cytokines, notably interleukin-2 (IL-2), given intravenously,2 subcutanously alone, or in combination in outpatient therapy regimens, with objective response rates between 6% and 31%.3-6 Subcutaneous interferon-α-2a (sc-INF-α-2) was evaluated at single doses of 3MU or more, yielding objective response rates of approximately 17%.7 Cytokine outpatient therapy treatments were associated with overall moderate drug-related toxicities. The combination of cytokines with chemotherapeutic agents further enhanced antineoplastic activity. Although immunotherapies combined with intravenous (IV) fluorouracil (FU) achieved objective response rates between 12%8 and 39%,9 the widely used addition of IV vinblastine to immunotherapies reached objective response rates between 24%10 and 39%11 in patients with advanced RCC.
Oral 13-cis-retinoic acid (po13cRA), which is known to regulate cell differentiation, enhanced antitumor efficacy in IFN-α–or IFN-α plus IL-2–treated RCC patients, with objective response rates between 17%12 and 30%.13
Here we prospectively compared the long-term therapeutic efficacy of three outpatient combination regimens: (A) sc-IFN-α-2a, sc-IL-2, and IV-FU; (B) sc-IFN-α-2a, sc-IL-2, and IV-FU combined with po-13cRA; and (C) sc-IFN-α-2a and IV vinblastine.
Between January 1995 and October 1998, 398 patients with metastastic RCC were stratified: 57 high-risk patients received individual care outside the study, and 341 intermediate- and low-risk patients were treated in this multicenter randomized clinical trial (Table 1). Median follow-up of these patients was 22 months (range, 2 to 80 months). Fourteen patients were lost to follow-up, with a median follow-up of 11 months. Patient pretreatment included radical tumor nephrectomy (88%), radiotherapy (3%), hormonal therapy (4%), chemotherapy (1%), immunotherapy (5%), chemoimmunotherapy (2%), and naturopathic therapy (7%; Table 1).
Criteria for entry onto the study were histologically confirmed progressive and irresectable metastatic renal cell carcinoma; expected survival duration of more than 3 months; Karnofsky performance status more than 80%; age between 18 and 80 years; WBC count more than 3,500/μL; platelet count more than 100,000/μL; hematocrit more than 30%; serum bilirubin and creatinine less than 1.25 of the upper normal limit; no evidence of congestive heart failure; no severe coronary artery disease; no cardiac arrhythmias; no clinically symptomatic CNS disease or seizure disorders; no HIV infection; no evidence of chronic active hepatitis; and no concomitant corticosteroid therapy. In all patients treated, no chemotherapy or immunmodulatory treatment had been performed during the previous 4 weeks. Pregnant and lactating women were excluded.
This study was approved by the Institutional Review Board of the Medizinische Hochschule Hannover; written informed consent was obtained from all patients before their entry onto the study. There was a central registration, with Medizinische Hochschule Hannover as the coordinating center. The 33 participating centers (listed on the first page) entered a total of 341 eligible patients onto this trial.
Patients were stratified according to a validated model of known clinical predictors14 to allow for equal risk distribution in all treatment arms (Tables 2 and 3). Given that all treatment regimens were designed to be administered in the outpatient setting, this required selection of patients with good or fair performance status. Thus, patients who were stratified for high risk were not randomly assigned, because of their poor prognosis, and we offered individual and supportive care outside the present study. Only patients stratified for low risk (median overall survival, 28 months) and intermediate risk (median overall survival, 21 months) were randomly assigned according to a per-center 2:2:1 (arm A:arm B:arm C) randomization to receive sc-IFN-α-2a, sc-IL-2, and IV-FU (arm A); sc-IFN-α-2a, sc-IL-2, and IV-FU combined with po-13cRA (arm B); or sc-IFN-α-2a and IV vinblastine (arm C; Fig 1). On written receipt of patient prestudy evaluation, per-center block randomization was performed to rule out center-related statistical bias. There was no statistically significant imbalance of risk factors and risk scores when comparing all three treatment arms (Table 3).
Treatment arm A consisted of sc-IFN-α-2a (Roferon; Hoffmann-La Roche, Grenzach-Wyhlen, Germany) 5 × 106 U/m2 day 1, weeks 1 + 4 and days 1, 3, and 5, weeks 2 + 3; 10 × 106 U/m2 days 1, 3, and 5, weeks 5 to 8; sc-IL-2 (Proleukin; Chiron, Emeryville, CA) 10 × 106 U/m2 twice daily days 3 to 5, weeks 1 + 4 and 5 × 106 U/m2, days 1, 3, and 5, weeks 2 + 3; and IV-FU 1,000 mg/m2 day 1, weeks 5 to 8. Treatment arm B consisted of treatment arm A combined with po-13cRA 20 mg three times daily over 8 weeks; treatment arm C consisted of sc-IFN-α-2a 5 × 106 U/m2 days 1, 3, and 5, week 1; 10 × 106 U/m2 days 1, 3, and 5, weeks 2 to 8; and IV vinblastine 6 mg/m2 day 1, weeks 2, 5, and 8.
Eight-week treatment cycles were repeated for up to three courses unless progression of disease occurred. If patients achieved a complete remission in the third cycle, a fourth cycle was added. After the first 8 weeks of therapy, on disease progression, patients primarily treated with arm C (sc-IFN-α-2a/IV vinblastine) subsequently crossed over to arm B (sc-IFN-α-2a/sc-IL-2/IV-FU/po-13cRA), wherever performance status allowed further systemic therapy. Patients with progressive disease on arm A or B left study to receive subsequent individual care. Reevaluation of the patient's tumor status was performed between treatment cycles. Patients on arms A, B, and C received a mean of 1.8, 1.9, and 1.7 (without crossover) 8-week cycles, respectively (range, 1 to 6 cycles). Concomitant medication was given as needed to control adverse effects of immunochemotherapy. Twenty-eight percent of patients (arm A: 20%; arm B: 32%; arm C: 34%) did not complete cycle 1, because of early progression before the first response evaluation (11%), intolerance (14%), or both early disease progression and intolerance (3%). Less than 2% of patients required inpatient care throughout treatment. All patients were seen at regular weekly or biweekly intervals by oncologic specialists; additional care was provided whenever needed.
Response to therapy was evaluated according to WHO criteria on an intent-to-treat basis. All responses were reviewed by board-certified expert radiologists; however, a second external review of responses was not performed. In the case of progression on first re-evaluation after 8 weeks of treatment, progression-free survival was calculated at 0 months. Survival was measured from start of therapy to date of death or to the last date the patient was known to be alive. All patients had to be followed up for survival for at least 3 years as cutoff. Systemic maximum toxicity was evaluated at weekly intervals using a grading system adapted from the WHO.
The statistical end points in our analysis were (1) objective response (the primary end point), (2) progression-free survival, and (3) overall survival of patients. The probability of overall survival and progression-free survival was plotted over time according to the method of Kaplan and Meier.15 Statistical significance was assessed using the Breslow test. P values were not adjusted for multiple comparisons. The potential objective response rates were hypothized to show a 15% advantage of arm B over arm A (45% v 30%) and a 30% advantage of arm B over arm C (45% v 15%). Using an α of 0.05 (one-sided) a sample size of 128 patients (arm A and B) and 28 patients (arm C), respectively, was needed to have 80% power to statistically establish the assumed difference in response rates. To detect a 0.20 difference in 3-year-survival rates between IL-2–based treatments regimens (arms A and B) and arm C, 64 patients per treatment arm were needed to have 80% power using an α of 0.05 (one-sided). To meet these statistical end points, randomization was performed 2:2:1, with cohort sizes of 128 patients (arm A), 128 patients (arm B), and 64 patients (arm C), respectively.
Three hundred forty-one stratified low or intermediate risk metastatic RCC patients were prospectively randomly assigned to receive sc-IFN-α-2a, sc-IL-2 and IV-FU (arm A, n = 132); sc-IFN-α-2a, sc-IL-2, and IV-FU combined with po-13cRA (arm B, n = 146); or sc-IFN-α-2a and IV vinblastine (arm C; n = 63).
Seven arm A (sc-IFN-α-2a/sc-IL-2/IV-FU)–treated patients (5%) achieved a complete response, and 34 patients (26%) had a partial remission (Table 4). The overall objective response rate was 31% (95% CI, 22 to 38). Thirty-six patients (27%) showed disease stabilization, and 55 patients (42%) exhibited continuous disease progression despite therapy.
In arm B (sc-IFN-α-2a/sc-IL-2/IV-FU/po-13cRA), there were 12 complete responders (8%) and 26 partial responders (18%), with an overall objective response rate of 26% (95% CI, 19 to 33). Fifty-nine patients (40%) had disease stabilization, and in 49 patients (34%), a continuous disease progression was observed.
In arm C (IFN-α-2a/IV vinblastine), four patients (6%) achieved a complete response, and nine patients (14%) had a partial remission. The overall objective response rate was 20% (95% CI, 10 to 31). Twenty-one patients (34%) showed disease stabilization, and 29 patients (46%) exhibited continuous disease progression despite therapy. There were no statistically significant differences in objective response rates comparing all three arms.
One hundred thirteen patients (86%) in arm A (IFN-α-2a/sc-IL-2/IV-FU), 122 patients (84%) in arm B (IFN-α-2a/sc-IL-2/IV-FU/po-13cRA), and 58 patients (92%) in arm C (IFN-α-2a/IV vinblastine) exhibited tumor progression. The median progression-free survival was significantly prolonged (P = .0248) in arm B (IFN-α-2a/sc-IL-2/IV-FU/po-13cRA; 7 months; range, 0 to 77 months) when compared with arm C (IFN-α-2a/IV vinblastine; 5 months; range, 0 to 69 months), but not when compared with arm A (IFN-α-2a/sc-IL-2/IV-FU; 6 months; range, 0 to 69 months; Fig 2).
Three-year progression-free survival was calculated at 15.58%, 17.73% and 8.35% for arm A (IFN-α-2a/sc-IL-2/IV-FU), arm B(IFN-α-2a/sc-IL-2/IV-FU/po-13cRA), and arm C (IFN-α-2a/IV vinblastine) patients, respectively. Arm A and arm B progression-free survival did not differ significantly (P = .2395).
Thirty-three patients (25%) in arm A (IFN-α-2a/sc-IL-2/IV-FU), 39 patients (27%) in arm B (IFN-α-2a/sc-IL-2/IV-FU/po-13cRA), and 12 patients (19%) in arm C (IFN-α-2a/IV vinblastine) continued to be alive at last follow-up. Both arm A (IFN-α-2a/sc-IL-2/IV-FU; median survival, 25 months; range, 2 to 73 months; P = .0440) and arm B (IFN-α-2a/sc-IL-2/IV-FU/po-13cRA; median survival, 27 months; range, 2 to 80 months; P = .0227) patients exhibited a significantly improved overall survival when compared with arm C (IFN-α-2a/IV vinblastine; median survival, 16 months; range, 2 to 69 months; Fig 3).
Three-year overall survival was calculated at 37.24%, 41.02%, and 21.40% for arm A (IFN-α-2a/sc-IL-2/IV-FU), arm B (IFN-α-2a/sc-IL-2/IV-FU/po-13cRA), and arm C (IFN-α-2a/IV vinblastine) patients, respectively. Arm A and arm B overall survival did not differ significantly (P = .9752).
All three sc-IFN-α-2a–based therapies were moderately or well tolerated and could be administered in the outpatient setting. Most side effects were limited to WHO grades 1 and 2; no toxic deaths occurred. All toxicities reversed spontaneously following completion of immunochemotherapy.
More than 5% of patients experienced grade 3 or 4 treatment-related anorexia (21% in arm B and 26% in arm C), malaise (18% in arm B and 11% in arm C), CNS toxicity or disorientation (11% in arm C), chills (6% in arm B), nausea or vomiting (6% in arm B), and hypotension (6% in arm B). Four percent of arm A (IFN-α-2a/sc-IL-2/IV-FU), 6% of arm B (IFN-α-2a/sc-IL-2/IV-FU/po-13cRA), and 8% of arm C (IFN-α-2a/IV vinblastine) patients discontinued treatment due to toxicity. Table 5 summarizes all treatment-related adverse effects by grade.
In this prospectively randomized trial, we reported the results of 341 patients with progressive metastatic renal cell carcinoma who received (A) sc-IFN-α-2a/sc-IL-2/IV-FU, (B) sc-IFN-α-2a/sc-IL-2/IV-FU/po-13cRA, or (C) sc-IFN-α-2a/IV vinblastine.
Patients with advanced renal cell carcinoma reached objective response rates of 31% (arm A), 26% (arm B), and 20% (arm C), respectively, which did not statistically differ, and which were comparable to results of other authors reporting objective response rates of 12% to 39% (sc-IFN-α/IV IL-2/IV-FU),8,9,16 17% (sc-IFN-α/sc-IL-2/po-13cRA),12 24% (IFN-α-2a/IV vinblastine),10 39% (sc-IFN-α/sc-IL-2/IV vinblastine),11 and 42% (sc-IFN-α/sc-IL-2/IV-FU/IV vinblastine/po-13cRA).17 Thus, the primary response end point of the current trial was not reached. It should be noted that because no central review of responses was mandatory, there might have been considerable variability as to assessment of treatment response.
Our present results demonstrated a significantly prolonged progression-free survival (P = .0248) when comparing arm B with arm C. In a previous randomized phase III trial, patients treated with po-13cRA plus sc-IFN-α-2a achieved an improved progression-free survival when compared with single agent sc-IFN-α-2a therapy.18
Here we could also demonstrate significant improvements in overall survival when comparing both arm B therapy (sc-IFN-α-2a/sc-IL-2/IV-FU/po-13cRA; median, 27 months; P = .0440) and arm A therapy (sc-IFN-α-2a/sc-IL-2/IV-FU; median, 25 months; P = .0227) against arm C therapy (sc-IFN-α-2a/IV vinblastine; median, 16 months). Overall, arm C (sc-IFN-α-2a/IV vinblastine) patients seemed to display a more aggressive malignancy with less frequent nephrectomies and more patients with bone metastases and CNS involvement, whereas there was no significant difference in risk scores comparing arm C (sc-IFN-α-2a/IV vinblastine) with arm B (sc-IFN-α-2a/sc-IL-2/IV-FU/po-13cRA) and arm A (sc-IFN-α-2a/sc-IL-2/IV-FU) patients; the survival impact of nephrectomy and CNS metastasis was previously assessed and rendered insignificant on multivariate analysis.14,19
Notably, the addition of 13cRA (arm B) did not significantly contribute to a prolonged overall survival when compared with the 13cRA-free arm A, a result established in prior observations of other authors.18
Previous randomized clinical trials in advanced renal cancer gave evidence of a significantly increased progression-free survival when using the IV IL-2 plus sc IFN-α-2a combination in comparison with either agent alone20 and of a statistical equality in objective response rates comparing high-dose IV IL-2 with outpatient sc-IL-2 as single agents.21
Although arm A (sc-IFN-α-2a/sc-IL-2/IV-FU) and arm B (sc-IFN-α-2a/sc-IL-2/IV-FU/po-13cRA) were similar with respect to response and overall survival, our data suggest that grade 3 and 4 constitutional symptoms, such as chills, malaise, and anorexia, may have been more prevalent in arm B compared with the 13cRA-free arm A; however, no statistical significance was reached. Potentially, the limited toxicity in all three treatment arms was also due to positive selection of patients who were capable of receiving outpatient therapy. This was mainly achieved by patient risk stratification and subsequent exclusion of patients at highest risk.
In summary, this present prospectively randomized clinical trial established the safety and the improved long-term therapeutic efficacy of sc-IL-2 plus sc-INF-α-2a–based outpatient immunochemotherapies following the standard Atzpodien regimen in comparison with sc-INF-a-2a/IV vinblastine on a large controlled multicenter basis; it also demonstrated that addition of 13cRA is of no substantial benefit to the present immunochemotherapy regimen.
The authors indicated no potential conflicts of interest.
Fig 1. Trial profile. *Initial risk stratification was performed to allow for equal risk distribution in all treatment arms. †Patients in the high-risk group were treated optionally outside this study. sc IL-2, subcutaneous interleukin-2; sc IFN-α, subcutaneous interferon alfa; IV, intravenous; po 13-cRA, oral 13-cis-retinoic acid; CR, complete response, PR, partial response; SD, stable disease.
Fig 2. Progression-free survival (PFS): Kaplan-Meier estimates. Arm A, interleukin-2, interferon alfa-2a, and fluorouracil; n = 132; median PFS, 6 months; 3-year PFS,15.58%. Arm B, interleukin-2, interferon alfa-2a, fluorouracil, and per oral 13-cis-retinoic acid; n = 146; median PFS, 7 months; 3-year PFS, 17.73%. Arm C, interferon alfa-2a and vinblastine; n = 63; median PFS, 5 months; 3-year PFS, 8.35%.
Fig 3. Overall survival (OS): Kaplan-Meier estimates. Arm A, interleukin 2, interferon alfa-2a, and fluorouracil; n = 132; median OS, 25 months; 3-year overall survival, 37.24%. Arm B, interleukin-2, interferon alfa-2a, fluorouracil, and per oral 13-cis-retinoic acid; n = 146; median OS, 27 months; 3-year OS, 41.02%. Arm C, interferon alfa-2a and vinblastine; n = 63; median OS, 16 months; 3-year OS, 21.40%.
|
| Characteristic | Therapy | ||||||
|---|---|---|---|---|---|---|---|
| All Patients (N = 341) | Arm A* (n = 132) | Arm B† (n = 146) | Arm C‡ (n = 63) | ||||
| Age, years | |||||||
| Median | 59 | 61 | 59 | 58 | |||
| Range | 19-77 | 31-77 | 19-73 | 34-76 | |||
| Sex, % | |||||||
| Male | 75 | 78 | 75 | 71 | |||
| Female | 25 | 22 | 25 | 29 | |||
| Pretreatment, % | |||||||
| Radical tumor nephrectomy | 88 | 94 | 90 | 78 | |||
| Radiotherapy | 3 | 2 | 5 | 3 | |||
| Hormonal therapy | 4 | 7 | 2 | 2 | |||
| Chemotherapy | 1 | 1 | 1 | 0 | |||
| Immunotherapy | 5 | 7 | 8 | 0 | |||
| Chemoimmunotherapy | 2 | 4 | 1 | 2 | |||
| Naturopathic therapy | 7 | 9 | 10 | 2 | |||
| Metastatic sites, % | |||||||
| Lung | 73 | 73 | 71 | 76 | |||
| Lymph nodes | 34 | 34 | 34 | 33 | |||
| Bone | 20 | 17 | 18 | 25 | |||
| Liver | 13 | 10 | 17 | 11 | |||
| CNS | 2 | 1 | 1 | 3 | |||
| Others§ | 16 | 21 | 16 | 12 | |||
*Arm A, subcutaneous interleukin-2, subcutaneous interferon alfa-2a, and intravenous fluorouracil.
†Arm B, same treatment as Arm A, plus oral 13-cis retinoic acid.
‡Arm C, subcutaneous interferon alfa-2a and intravenous vinblastine.
§Including local relapse, contralateral kidney, and adrenals.
|
| Prognostic Variable | Risk Score |
|---|---|
| Erythrocyte sedimentation rate > 70 mm/hr | 2 |
| Lactic dehydrogenase > 280 U/L | 2 |
| Neutrophilic granulocytes > 6,000/μL | 1 |
| Hemoglobin < 10 g/dL | 1 |
| Extrapulmonary metastases only | 1 |
| Bone metastases | 1 |
NOTE. Individual risk was defined as a cumulative risk score comprising the sum of six independent variables: low risk (score = 0); intermediate risk (score = 1-3); low risk v intermediate risk (Breslow P < .0312); high risk (score > 4).
|
| Risk Group | Arm A* | Arm B† | Arm C‡ | Total | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| No. of Patients | Mean Risk Score | No. of Patients | Mean Risk Score | No. of Patients | Mean Risk Score | No. of Patients | Mean Risk Score | |||||
| Low§ | 45 | 0.0 | 50 | 0.0 | 26 | 0.0 | 121 | 0.0 | ||||
| Intermediate‖ | 87 | 1.45 | 96 | 1.7 | 37 | 1.58 | 220 | 1.58 | ||||
| Total | 132 | 1.45 | 146 | 1.7 | 63 | 1.58 | 341 | 1.58 | ||||
NOTE. Patients in the high-risk group were treated optionally outside this study.
*Arm A, subcutaneous interleukin 2, subcutaneous interferon alfa 2a, and intravenous fluorouracil.
†Arm B, treatment same as Arm A, plus oral 13-cis retinoic acid.
‡Arm C, subcutaneous interferon alfa 2a and intravenous vinblastine.
§Median overall survival, 23 months (95% CI, 22 to 34).
‖Median overall survival, 21 months (95% CI, 16 to 26).
|
| Therapy and Risk | Response | (%) | ||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Complete Response | Partial Response | Stable Disease | Progressive Disease | Total | ||||||||||||||
| No. of Patients | % | No. of Patients | % | No. of Patients | % | No. of Patients | % | |||||||||||
| Arm A* | ||||||||||||||||||
| Low | 2 | 4 | 12 | 27 | 12 | 27 | 19 | 42 | 45 | 34 | ||||||||
| Intermediate | 5 | 6 | 22 | 25 | 24 | 27 | 36 | 42 | 87 | 66 | ||||||||
| All | 7 | 5 | 34 | 26 | 36 | 27 | 55 | 42 | 132 | 100 | ||||||||
| 95% CI, objective response, % | 22 to 38 | |||||||||||||||||
| Arm B† | ||||||||||||||||||
| Low | 4 | 8 | 12 | 24 | 23 | 46 | 11 | 22 | 50 | 34 | ||||||||
| Intermediate | 8 | 8 | 14 | 15 | 36 | 37 | 38 | 40 | 96 | 66 | ||||||||
| All | 12 | 8 | 26 | 18 | 59 | 40 | 49 | 34 | 146 | 100 | ||||||||
| 95% CI, objective response, % | 19 to 33 | |||||||||||||||||
| Arm C‡ | ||||||||||||||||||
| Low | 1 | 4 | 3 | 11 | 14 | 54 | 8 | 31 | 26 | 41 | ||||||||
| Intermediate | 3 | 8 | 6 | 16 | 7 | 19 | 21 | 57 | 37 | 59 | ||||||||
| All | 4 | 6 | 9 | 14 | 21 | 34 | 29 | 46 | 63 | 100 | ||||||||
| 95% CI, objective response, % | 10 to 31 | |||||||||||||||||
*Arm A, subcutaneous interleukin 2, subcutaneous interferon alfa 2a, and intravenous fluorouracil.
†Arm B, treatment same as Arm A, plus oral 13-cis retinoic acid.
‡Arm C, subcutaneous interferon alfa 2a and intravenous vinblastine.
|
| Side Effects* (WHO Criteria) | % Patients | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Arm A† | Arm B‡ | Arm C§ | |||||||||
| I/II | III/IV | I/II | III/IV | I/II | III/IV | ||||||
| Fever‖ | 78 | 3 | 73 | 3 | 58 | — | |||||
| Chills | 47 | 3 | 58 | 6 | 58 | — | |||||
| Malaise | 72 | 3 | 67 | 18 | 53 | 11 | |||||
| Nausea or vomiting | 44 | — | 68 | 6 | 47 | — | |||||
| Anorexia | 47 | — | 44 | 21 | 21 | 26 | |||||
| Diarrhea | 13 | 3 | 26 | 3 | 16 | — | |||||
| Respiratory distress | 41 | 3 | 35 | 3 | 11 | — | |||||
| Skin or allergies | 28 | 3 | 32 | 2 | 13 | — | |||||
| Mucositis | 19 | — | 21 | 3 | 5 | — | |||||
| Hypotension | 3 | — | 23 | 6 | 11 | — | |||||
| Alopecia | 3 | — | 18 | 3 | 26 | — | |||||
| Arrythmias | 9 | — | 18 | 3 | 5 | — | |||||
| CNS or disorientation | 3 | — | 15 | — | 5 | 11 | |||||
| Paresthesias | 9 | — | 6 | 3 | 5 | — | |||||
| Fluid retention or edema | — | — | 9 | — | 5 | — | |||||
| Leucocyte counts | 18 | — | 18 | 3 | 26 | — | |||||
| Thrombocyte counts | — | — | 3 | — | — | — | |||||
| Hemoglobin levels | 25 | 4 | 31 | — | 12 | — | |||||
*No life-threatening complications or toxic deaths occurred.
†Arm A, subcutaneous interleukin 2, subcutaneous interferon alfa 2a, and intravenous fluorouracil.
‡Arm B, treatment same as Arm A, plus oral 13-cis retinoic acid.
§Arm C, subcutaneous interferon alfa 2a and intravenous vinblastine.
‖All patients received a standard regimen of fever-reducing treatment using oral paracetamol.
Supported by grants from Deutsche Krebshilfe, Wilhelm-Sander-Stiftung, and Deutsche Gesellschaft zur Förderung immunologischer Krebstherapien eingetragener Verein (J.A.).
Authors’ disclosures of potential conflicts of interest are found at the end of this article.
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