What alternative therapies are used in the treatment of renal cell carcinoma?

Alternative Therapies for Renal Cell Carcinoma

When standard targeted therapies or immunotherapies cannot be safely administered, interferon-alpha and interleukin-2 represent alternative systemic treatment options, though they are now considered inferior to modern agents and should only be used in very selected cases. 1

Historical Context and Current Role

The term "alternative therapies" in RCC traditionally refers to cytokine-based immunotherapies that preceded the targeted therapy era. These agents are no longer first-line treatments but remain options when modern therapies are contraindicated.

Cytokine-Based Immunotherapy

Interferon-alpha (IFN-α):

• Graded as Level I-D evidence for use in good or intermediate prognosis patients with clear cell RCC 1
• Should only be considered when VEGF-targeted agents (sunitinib, pazopanib, bevacizumab) or immunotherapy combinations cannot be safely administered 1
• Response rates are significantly lower than modern targeted therapies 2, 3
• Has been used as the control arm in pivotal trials, demonstrating inferiority to sunitinib, pazopanib, and bevacizumab combinations 1

Interleukin-2 (IL-2):

• Graded as Level III-C evidence, representing even weaker support than interferon-alpha 1
• Reserved for very selected cases only 1
• A small percentage of patients may achieve complete remission, but overall response rates remain low 2
• Requires careful patient selection due to significant toxicity profile 3

Non-Systemic Alternative Approaches

Surgical Alternatives

Active Surveillance:

• Recommended as an alternative to immediate intervention for patients ≥75 years with substantial comorbidities and solid renal tumors measuring <4 cm 1
• Justified because some RCC have very indolent courses, and a period of observation before starting treatment should be considered even in metastatic disease 1
• This approach prioritizes quality of life over aggressive intervention in selected elderly or frail patients 4

Ablative Treatments:

• Radiofrequency ablation, cryoablation, or microwave ablation serve as alternatives to surgery in elderly patients with small cortical tumors (≤3 cm) 1
• Also appropriate for patients with hereditary RCC and multiple bilateral tumors 1
• These techniques preserve renal function while avoiding surgical morbidity 4

Radiation-Based Alternatives

Stereotactic Radiosurgery (SRS) and Stereotactic Body Radiotherapy (SBRT):

• Can be considered for metastatic lesions after multidisciplinary review 1
• Particularly useful for brain metastases as an alternative to whole-brain radiotherapy, especially for patients with single unresectable lesions 1
• Whole-brain radiotherapy (20-30 Gy in 4-10 fractions) remains an alternative for multiple brain metastases 1

Conventional Radiotherapy:

• Has limited role in primary RCC management but serves as an alternative for unresectable local or recurrent disease 1
• No role in adjuvant or neoadjuvant settings (four negative trials support this) 1

Supportive Care Alternatives

Bisphosphonate Therapy:

• Zoledronic acid reduces skeletal-related events in patients with bone metastases 1
• Graded as Level II-A evidence 1
• Represents an alternative or adjunct to systemic therapy for patients with predominantly skeletal disease 1

Corticosteroids:

• Provide effective temporary relief of cerebral symptoms in patients with brain metastases 1
• Serve as an alternative to immediate radiation in select cases requiring symptom control 1

Best Supportive Care:

• For many poor-prognosis patients, best supportive care remains the only suitable treatment option 1
• This alternative prioritizes quality of life over potentially toxic systemic therapies with minimal expected benefit 1

Critical Caveats

Common Pitfall: Clinicians should not interpret "alternative therapies" as complementary or integrative medicine approaches—the evidence base refers specifically to older immunotherapies and non-systemic interventions that have been superseded by modern targeted agents and checkpoint inhibitors 1, 5.

Selection Bias: The decision to use these alternatives must be based on contraindications to standard therapy, not on physician preference or availability issues, as modern agents demonstrate superior outcomes in mortality and quality of life 1, 6.

Non-Clear Cell Histology: For patients with non-clear-cell RCC, enrollment in clinical trials is the preferred alternative, though sunitinib, sorafenib, or temsirolimus may be considered based on limited evidence 1.