SWOG 8949

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Flanigan RC, et al. "Nephrectomy followed by interferon alfa-2b compared with interferon alfa-2b alone for metastatic renal-cell cancer". The New England Journal of Medicine. 2001. 345(23):1655-9.
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Clinical Question

In patients with metastatic renal cell carcinoma, does cytoreductive nephrectomy followed by interferon therapy result in longer survival than interferon alone?

Bottom Line

Cytoreductive nephrectomy followed by interferon therapy results in longer survival among patients with metastatic renal cell carcinoma (RCC) than does interferon therapy alone.

Major Points

Prior to this study, it was not known whether cytoreductive nephrectomy, which is the removal of the primary tumor in patients with metastatic RCC, would improve clinical outcomes in this patient population. Retrospective studies suggested a benefit, but reported rates of surgical morbidity and mortality were prohibitively high in early, small series of patients treated with this approach. This was the first randomized trial to demonstrate that cytoreductive nephrectomy was safe and improves survival in metastatic RCC when followed by interferon alfa immunotherapy.

In this Southwest Oncology Group study by Flanagan et al. (SWOG 8949), 246 patients with metastatic RCC and ECOG PS 0 or 1 were randomized to cytoreductive nephrectomy followed by interferon, or to interferon alone. With a median follow-up of approximately 1 year, the median overall survival favored the nephrectomy group (11.1 vs. 8.1 months; P=0.05). One-year survival was 49.7% in the nephrectomy group compared with 36.8% in the interferon-only group. The main criticisms were the borderline significance of the survival benefit with cytoreductive nephrectomy, imbalanced performance status between groups that favored the nephrectomy group, and slow enrollment that may have led to selection bias.[1]

The study's findings were similar to a 2001 European Organisation for Research and Treatment of Cancer (EORTC) study with a similar design.[2] The EORTC study found that cytoreductive nephrectomy plus interferon alfa resulted in improved median overall survival when compared to interferon alfa alone (17 vs. 7 months). A combined analysis of 331 patients from the SWOG and EORTC studies similarly revealed a survival benefit with nephrectomy (13.6 vs. 7.8 months).[3] As a result, cytoreductive nephrectomy has been incorporated into the standard of care for selected patients with metastatic RCC, and is recommended by both NCCN and ESMO guidelines.[4][5]

Whether the benefits of cytoreductive nephrectomy will be maintained in the era of tyrosine kinase inhibitors is unknown. At least one retrospective study suggested a benefit in this setting.[6] The CARMENA[7] and SURTIME[8] studies will help address this issue prospectively.

Finally, these data apply largely to clear-cell RCC. An analysis of SEER data suggests that cytoreductive nephrectomy may also benefit selected patients with metastatic non-clear-cell RCC.[9]

Guidelines

NCCN Guidelines for Kidney Cancer (2014, adapted)[4]

  • Among surgically fit patients, recommend cytoreductive nephrectomy for metastatic RCC (category 2A)

Design

  • Multicenter, randomized, controlled trial
  • N=246 enrolled, 241 eligible
  • Eligible patients
    • Nephrectomy + interferon (n=120)
    • Interferon alone (n=121)
  • Setting: 80 centers in the United States
  • Enrollment: 1991-1998
  • Median follow-up: 368 days (~1 year)
  • Primary outcome: Overall survival

Population

Inclusion Criteria

  • Histologically confirmed metastatic RCC in at least one lesion or the primary tumor with any nodal status
  • Primary tumor considered amenable to surgical removal by the surgeon
  • Patients with thrombosis of the inferior vena cava below the hepatic vein were not excluded
  • ECOG PS 0 or 1

Exclusion Criteria

  • Prior treatment with chemotherapy, hormonal therapy, interferon, interleukin-2, lymphocyte-activated killer cells, or other biological response modifiers
  • Prior or concomitant radiation therapy to the primary tumor or to metastatic sites
  • Serum bilirubin greater than three times the upper limit of the normal value at the institution
  • Serum creatinine greater than 3.0 mg/dl
  • Patients with uncontrolled cardiac arrhythmias
  • Previous history of cancer unless cancer-free for a minimum of 5 years, or if the cancers were adequately treated basal-cell skin cancer, squamous-cell skin cancer, or in-situ cervical cancer

Baseline Characteristics

Comparisons are nephrectomy + interferon vs. interferon alone.

  • Mean age: 60 years
  • Male sex: 69%
  • Measurable metastatic lesion: 79%
  • Performance status 1: 45% vs. 58% (P=0.04)
  • Only lung metastasis: 66%

Interventions

  • Prior to randomization, patients were stratified by performance status, presence of lung metastasis, and presence of at least one metastatic lesion not to be resected
  • Randomized with dynamic balancing based on the stratification factors (1:1) to either nephrectomy + interferon or interferon alone
  • Dosage of subcutaneous interferon:
    • Induction: 1.25 million units/square meter of BSA with escalation to a starting dose of 5 million units/square meter on the first day of treatment
    • Interferon continued at a dose of 5 million units/square meter of BSA each M/W/F until progression was detected
    • Dosage was modified if toxic effects were observed and was based on the highest-grade toxic effect observed. Toxic effects monitored included hematologic, hepatic, gastrointestinal, and hypotension
  • Radical nephrectomy was performed transabdominally or via a flank approach
    • Defined as excision of the tumor outside Gerota's fascia with early ligation of the renal artery and vein
    • Surgery was performed within 4 weeks of enrollment
    • Limits of lymphadenectomy were not defined
    • Surgeon noted whether or not grossly involved lymph nodes were left unresected at the time of nephrectomy

Outcomes

Comparisons are nephrectomy + interferon vs. interferon alone.

Primary Outcomes

Median overall survival
11.1 (95% CI 5.4-9.5) vs. 8.1 (95% CI 9.2-16.5) months (P=0.05)

Subgroup Analysis

Subgroups were prospectively defined.

Measurable disease (p=0.010)

  • Measurable disease
    • Nephrectomy + interferon median survival: 10.3 months
    • Interferon alone median survival: 7.8 months
  • No measurable disease
    • Nephrectomy + interferon median survival: 16.4 months
    • Interferon alone median survival: 11.2 months

Performance status (p=0.080)

  • Performance status 0
    • Nephrectomy + interferon median survival: 17.4 months
    • Interferon alone median survival: 11.7 months
  • Performance status 1
    • Nephrectomy + interferon median survival: 6.9 months
    • Interferon alone median survival: 4.8 months

Note: in the proportional-hazards regression model including treatment group, performance status, and the interaction between treatment group and performance status, the interaction term was not significant suggesting that the imbalance in performance status between the two groups did not explain the survival results.

Type of metastasis (p=0.080)

  • Lung only
    • Nephrectomy + interferon median survival: 14.3 months
    • Interferon alone median survival: 10.3 months
  • Other
    • Nephrectomy + interferon median survival: 10.2 months
    • Interferon alone median survival: 6.3 months

Criticisms

  • Groups were imbalanced, with more ECOG PS 1 patients in the interferon-alone arm, which by itself may have accounted for their poorer survival.[1]
  • The statistical significance of cytoreductive nephrectomy was questionable, with overlapping confidence intervals and a borderline P value (P=0.05).[1]
  • Slow enrollment (approximately 1 per institution every 2 years) suggests selection based on occult criteria.[1]

Funding

  • NCI Public Health Service Cooperative Agreements

Further Reading

  1. 1.0 1.1 1.2 1.3 Tannock IF, et al. "Removing the Primary Tumor after the Cancer Has Spread." N Engl J Med. 2001; 345:1699-1700
  2. Mickisch GH, et al. "Radical nephrectomy plus interferon-alfa-based immunotherapy compared with interferon alfa alone in metastatic renal-cell carcinoma: a randomised trial." Lancet. 2001 Sep 22;358(9286):966-70.
  3. Flanigan RC, et al. "Cytoreductive nephrectomy in patients with metastatic renal cancer: a combined analysis." J Urol. 2004 Mar;171(3):1071-6.
  4. 4.0 4.1 NCCN Guidelines for Kidney Cancer Version 3.2014
  5. Escudier B, et al. "Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up." Ann Oncol. 2012 Oct;23 Suppl 7:vii65-71.
  6. Abern MR, et al. "Survival of patients undergoing cytoreductive surgery for metastatic renal cell carcinoma in the targeted-therapy era." Anticancer Res. 2014 May;34(5):2405-11.
  7. Clinical Trial to Assess the Importance of Nephrectomy (CARMENA). ClinicalTrials.gov Identifier NCT00930033.
  8. Immediate Surgery or Surgery After Sunitinib Malate in Treating Patients With Metastatic Kidney Cancer (SURTIME). ClinicalTrials.gov Identifier NCT01099423.
  9. Aizer AA, et al. "Cytoreductive nephrectomy in patients with metastatic non-clear-cell renal cell carcinoma (RCC)." BJU Int. 2014 May;113(5b):E67-74.