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Keywords:

  • immunochemotherapy;
  • metastatic renal cell carcinoma;
  • interleukin-2;
  • interferon-α;
  • 5-fluorouracil;
  • vinblastine

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHIDS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

BACKGROUND

The current study evaluated the efficacy and toxicity of interleukin-2 (IL-2), interferon-α (IFN-α), 5-fluorouracil (5-FU), and vinblastine (VBL) in the treatment of metastatic renal cell carcinoma (MRCC).

METHODS

Sixty-two MRCC patients, median age 63 years, received immunochemotherapy. Eastern Cooperative Oncology Group performance status was 1 for 45 patients and 2 for 17 patients. Fifty-four patients underwent nephrectomy prior to treatment. Sites of disease were lungs, lymph nodes, bone, kidney, and liver. Treatment consisted of IL-2 10 MIU/m2 subcutaneous (SC), three times per week, Weeks 1-4; IFN-α 6 MIU/m2 SC, once per week, Weeks 1-4 and 9 MIU/m2, three times per week, Weeks 5-7; 5-FU 600 mg/m2 and VBL 6 mg/m2, intravenous bolus, Day 1 of Weeks 5 and 7.

RESULTS

In a median followup of 34 months, 62 patients were evaluated for tumor response. Four patients achieved complete response for 26+, 34+, 51+, and 56+ months, respectively; 14 patients achieved partial response for a median of 14 months; and 20 patients achieved stable disease for a median of 9 months. Seven patients (5 partial response, 2 stable disease) underwent complete resection of residual tumor. Five patients remained alive with no evidence of disease for 27, 32, 36, 42, and 48 months, respectively. Nine patients achieved long-term complete response for a median of 36 months. Three-year survival rate for the entire group and for 11 complete responders was 88%. Common side effects were flu-like symptoms, nausea, headache, and depression. Four patients were excluded because of treatment intolerance, and one patient died after nephrectomy.

CONCLUSIONS

Immunochemotherapy is effective and well-tolerated by patients with MRCC. Surgical intervention for resection of residual disease is justified. Cancer 2002;95:1644–9. © 2002 American Cancer Society.

DOI 10.1002/cncr.10842

There is no standard treatment for patients with metastatic renal cell carcinoma (MRCC), but clinical trials during the past decade have centered on immunochemotherapy. Interleukin-2 (IL-2) and interferon-α (IFN-α) have been shown to have anti-tumor activity in renal cell carcinoma, and the addition of vinblastine (VBL) and 5-fluorouracil (5-FU) has increased the effect of the combination.1–6 Following the report of Hanninen et al.,7 we conducted a Phase II study to evaluate the efficacy and toxicity of a modified Atzpodien combination immunochemotherapy in MRCC. The object of these trials was to evaluate the efficacy and toxicity of IL-2, IFN-α, 5-FU, and VBL in patients with progressive MRCC. The endpoints were: response rate, duration of response, disease-free survival, overall survival, and toxicity.

MATERIALS AND METHIDS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHIDS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

Inclusion Criteria

Inclusion criteria were biopsy-proven renal cell carcinoma inoperable or metastatic disease, Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2, life expectancy greater than three months, normal cardiac function (left ventricular ejection fraction > 45%), no prior immunochemotherapy, no brain metastases, no active cardiac disease, serum creatinine < 1.3 mg/dL, bilirubin < 20U, hemoglobin > 10gr%, white blood cells > 4,000/mm3, and platelets > 100,000/mm3. The patient's written consent was necessary.

Pretreatment Evaluation

Evaluation of patients before treatment included complete blood count, blood biochemistry, brain, chest and abdominal computed tomography scans, bone scan, and cardiac echogram or multi-gated angiography (MUGA).

Patients

Sixty-seven patients with renal cell carcinoma entered the study. Five patients were excluded, four because they received less than one week of treatment and one with primary renal cell carcinoma but with metastatic disease from a second lung carcinoma. Therefore, the current study group consisted of 62 patients with the following characteristics (Table 1): 39 males and 23 females, median age 63 years, ECOG performance status 1 in 45 patients and 2 in 17 patients. In addition to renal carcinoma, 63% suffered from hypertension, ischemic heart disease, peripheral vascular disease, and diabetes mellitus. Thirty patients were diagnosed with metastatic disease, of whom 22 underwent nephrectomy. The other 32 patients were diagnosed with local disease, all of whom underwent nephrectomy and developed metastases within a median interval of 22 months. Tumor histology was clear cell carcinoma in 46 patients, spindle cell sarcomatoid type in 2, and mixed tumor in 8. Tumor grade was 1 in 3 patients, 2 in 8 patients, and 3 in 20 patients. Sites of metastases were lungs in 41 patients, lymph nodes in 31 patients, bones in 22 patients, and liver in 4 patients. The number of metastatic sites per patient was 1 in 24 patients (39%), 2 sites in 17 patients (27%), and 3+ sites 21 patients (34%).

Table 1. Patient Characteristics
CharacteristicNo.
  1. ECOG: Eastern Cooparative Oncology Group.

 No. of evaluated patients62
 Median age in years (range)63 (26–80)
 Gender M:F39:23
 ECOG performance status 1:245:17
Other diseases 
 Hypertension14 (23%)
 Ischemic heart disease9 (15%)
 Diabetes mellitus12 (19%)
 Peripheral vascular disease4 (6%)
Stage and nephrectomy at diagnosis 
 Patients diagnosed with local disease32
 Patients who underwent nephrectomy for localized disease32
 Patients diagnosed with metastatic disease30
 Patients with metastatic disease who underwent nephrectomy22
Tumor histology and grade 
 Clear cell carcinoma46 (74%)
 Spindle cell sarcomatoid2 (3%)
 Mixed tumor8 (13%)
 Unknown6 (10%)
 Grade 13 (5%)
 Grade 28 (13%)
 Grade 320 (32%)
 Unknown31 (50%)
Site of disease and metastases 
 Lungs41 (66%)
 Lymph nodes31 (50%)
 Bones22 (35%)
 Liver4 (8%)
 Primary tumor8 (13%)

Treatment Plan

Treatment consisted of IL-2 10 MIU/m2 three times per week, Weeks 1-4, IFN-α 6 MIU/m2 once weekly, Weeks 1-4, and 9 MIU/m2 three times per week, Weeks 5-7, both by subcutaneous injection, and 5-FU 600 mg/m2 and VBL 6 mg/m2, Days 29 and 43, both by intravenous injection. The immunochemotherapy was combined with paracetamol given before treatment and modal during treatment. The eight weeks of treatment were followed by two weeks of rest and re-evaluation. Continuation of treatment depended on anti-tumor response and toxicity. In cases of complete response, treatment was stopped after one additional course. At least two courses of treatment were needed to determine stabilization or partial response. In cases of partial response, treatment was continued until stabilization and was then stopped. In patients with partial or stabilization response and resectable residual disease, surgery was recommended with no further treatment following complete resection of the residual disease. In cases of progression, treatment was stopped.

Response to treatment was determined by standard criteria.8 The toxicity of immunochemotherapy was evaluated and recorded weekly. The toxicity was graded according to World Health Organization criteria. The treatment schedule was modified according to toxicity as follows: Grade 1, no change; Grade 2, 25% reduction in dose without change in treatment schedule; Grade 3, 50% reduction in dose without change in treatment schedule; Grade 4, interruption of treatment until full recovery from the toxicity. In these patients, treatment was renewed at 50% of the last dosage.

Statistical Analysis

A power analysis test was used to estimate the required number of subjects needed for various comparisons. This was done at 0.05 significance level and 0.90 power level.

The current study was carried out in two steps. In the first step, 38 patients entered the study and 34 were analyzed for response and toxicity. Three patients achieved complete response and seven achieved partial response, for a total 29% objective response, which is comparable with the Atzpodien results.9

Frequencies, percentages, and distribution were computed for categorical variables, such as patient and disease characteristics. Distribution for categorical parameters was compared by chi squared test (large samples) and the Fisher-Irwin exact test (small samples). For continuous variables, such as age and blood counts, parameters, ranges, medians, means, and standard deviations were computed and the results analyzed.10, 11 The Kaplan-Meier method was used to calculate the probability of survival as a function of time.11 The log-rank test was used to compare pairs of Kaplan-Meier curves.12 Duration of response was calculated from the first day of treatment until evidence of progression or last visit if response continued. Survival was calculated from the first day of treatment until the last visit or death. After each course of treatment, there was a re-evaluation to determine response to treatment.

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHIDS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

Response to Immunochemotherapy

All 62 patients with MRCC included in the current study were evaluated for toxicity and response to treatment. Complete response was achieved in 4 patients (6.5%), partial response in 14 patients (22.5%), and stable disease in 20 patients (32%). The four complete responders were in remission for 26+, 34+, 51+, and 56+ months, respectively, at the time of writing. Seven patients, five with partial response and two with stable disease, underwent surgical resection of residual disease and were entered in surgical complete response. Pathologic examination revealed residual disease in all seven patients. Sites of resection were lungs, mediastinum, and retroperitoneum. Two of these seven patients relapsed after 17 and 24 months, respectively, following surgery. The other five remained in complete remission for 27+, 32+, 36+, 42+, and 48+ months, respectively. Complete response was achieved in 11 patients (18%) for a median of 36 months (range, 17–56 months).

The influence of patient and disease characteristics on response rate was analyzed. The following parameters were analyzed: performance status, age, gender, concurrent disease, previous hormonal therapy, histology, tumor grade, nephrectomy at metastatic disease, and site of metastases. Performance status, site of metastases and nephrectomy influence had significant influence on response to treatment (Table 2). The probability of response (complete or partial) was 29% and 0% in patients with ECOG performance status 1 and 2 (P = 0.011), 14% and 26% in patients with and without bone metastases (P = 0.037), and 31% and 6% in patients who did and did not undergo nephrectomy (P = 0.05), respectively.

Table 2. Response to Immunochemotherapy by Patient and Disease Characteristics
Patient and disease characteristicProbability of response % ± SD (95% CI)P value
  1. SD: standard deviation; CI: confidence interval; ECOG: Eastern Cooperative Oncology Group.

ECOG performance status: 1 vs. 229 ± 7% (15–44%) vs. 0%0.011
Bone: yes vs. no14 ± 7% (4–32%) vs. 26 ± 8% (11–42%)0.037
Nephrectomy (all patients): yes vs. no31 ± 8% (16–46%) vs. 6 ± 5% (15–22%)0.05

Survival

The probability of survival at three years for all 62 patients was 30% (95% confidence interval, 17–42%). The influence of patient and disease characteristics on probability of survival was evaluated. The following parameters were analyzed: performance status, age, gender, concurrent disease, previous hormonal therapy, histology, tumor grade, nephrectomy at metastatic disease, and site of metastases. Factors found to be associated with significantly better three-year survival included good performance status, no concurrent disease, and absence of bone metastases (Table 3). The probability of three-year survival was 40% and 0% for patients with ECOG performance status 1 and 2 (P = 0.001), 15% and 46% in patients with and without other concurrent disease (P = 0.02), and 14% and 26% in patients with and without bone metastases (P = 0.037), respectively. The probability of survival by response is shown in Fig. 1: 88% three-year survival for 11 patients who achieved complete response by immunochemotherapy and surgery, 35% for 18 patients who achieved stabilization response, and no three-year survival for 9 partial responders who did not undergo resection of residual disease and for 20 patients who did not respond to treatment. The difference in overall survival between patients who achieved complete response versus those who achieved partial response and stabilization was significant (P = 0.03 and P = 0.05, respectively).

Table 3. The Probability of Three-year Survival by Patient and Disease Characteristics
Patient and disease characteristicProbability of three-year survival % ± SD (95% CI)P value
  1. SD: standard deviation; CI: confidence interval; ECOG: Eastern cooperative Oncology Group.

ECOG performance status: 1 vs. 240 ± 8% (24–55%) vs. 0%0.001
Other concurrent disease: yes vs. no17 ± 9% (6–33%) vs. 46 ± 85 (23–65%)0.02
Bone: yes vs. no14 ± 8% (4–30%) vs. 26 ± 9% (12–42%)0.037
thumbnail image

Figure 1. Time to treatment progression by response to immunochemotherapy. PD: progressive disease; PR: partial response; SD: stable disease; CR: complete response.

Download figure to PowerPoint

The effect of nephrectomy on survival was analyzed in 30 patients diagnosed with metastatic disease: three-year survival for 22 patients who underwent nephrectomy was 38% as compared to 28% in patients who did not (P = 0.5).

Toxicity

Side effects during the first course of treatment are summarized in Table 4 and consisted mainly of a flu-like syndrome (fever with chills, asthenia, myalgia and arthralgia), pruritus and rash, nausea, headache, drowsiness, and depression. Four patients stopped treatment during the first course because of shortness of breath, chest pain without myocardial ischemic signs, and intolerance to treatment. No deaths occurred during immunochemotherapy treatment. One patient with liver metastases who responded to the immunochemotherapy died following nephrectomy.

Table 4. Side Effects (WHO Criteria) of Treatment During First Course
Side effectIncidence (%)
Grade 1Grade 2Grade 3
  1. WHO: World Health Organization.

Fever and chills24751
Asthenia63634
Arthralgia113131
Myalgia113133
Pruritus18164
Skin rash11137
Nausea67290
Vomiting4094
Diarrhea3892
Allopecia900
Dyspnea1844
Headache5370
Drowsiness1640
Depression1840

DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHIDS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

Renal cell carcinoma is a chemoresistant disease, the treatment approach is still experimental, and the five-year survival rate for metastatic disease is approximately 10%.13 Clinical trials have shown anti-tumor activity and a synergistic effect of interferon-α and interleukin-2 in renal cell carcinoma.2, 14–18 The addition of vinblastine and 5-fluorouracil may increase the anti-tumor effects of interferon-α and interleukin-2.4, 9, 19–21

Following the report of Hanninen et al. of a 42% objective response rate (17% complete response and 25% partial response), we decided to conduct a similar study.7 The results of the current study are similar: 11 patients (18%) achieved complete response, 4 with immunochemotherapy and 7 with surgery. All residual masses were found to be malignant residual disease. Sites of residual metastases were lungs in three patients, retroperitoneum in three patients, and the mediastinum in one patient. Median duration of complete response was 36 months, with a range of 17-56 months. Nine of the 11 patients were in complete response for a median of three years. These results show that the stabilization response in MRCC should be regarded as a good prognostic factor; survival curves support this conclusion.

Resection of residual disease is also recommended by others.22–25 Good performance status, absence of bone metastases, and prior nephrectomy were associated with higher response rates. The impact of nephrectomy on response is questionable because patients who did not undergo nephrectomy had tumor extension outside the kidney, which makes the condition inoperable.

The three-year survival rate for the entire group was 30%. There was a positive correlation between response to treatment and survival. The three-year survival rate for complete remission (by immunochemotherapy and surgery) was 88% and for stabilization was 35%; for those who neither achieved partial remission nor underwent surgery and for those who did not respond, the three-year survival rate was 0%.

The difference in survival between complete and partial responders was statistically significant. This finding may reflect the natural history of the disease. The influence of patient characteristics on survival was evaluated, and three prognostic factors were found: good performance status, absence of bone metastases, and no other concomitant disease.

We evaluated the influence of nephrectomy before treatment in patients diagnosed with metastatic disease but did not find a significant effect on survival. The benefit of nephrectomy in MRCC is controversial. The rationale for this approach is that systemic therapy may be more effective in setting a lower tumor burden advantage, and some investigators have suggested that there may be a survival benefit.26–30 A randomized trial carried out recently by the European Organization for Research and Treatment of Cancer (EORTC) and the South West Oncology Group (SWOG) showed the benefit of nephrectomy in time-to-progression and survival.30, 31 Side effects were usually moderate and consisted mainly of a flu-like syndrome, headache, nausea, vomiting, and depression. Most importantly, there were no drug-related deaths.

In conclusion, immunochemotherapy in patients with metastatic renal cell carcinoma is relatively effective, and patients who achieved complete remission had durable remission and survival. Resection of residual disease improved the results of immunochemotherapy. Therefore, immunochemotherapy with surgical intervention for resection of residual disease is justified.

Acknowledgements

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHIDS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

The authors thank Mrs. S. Gan for statistical analysis and Mrs. M. Perlmutter for her assistance in the preparation of this article.

REFERENCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHIDS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES
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