What is a suitable neoadjuvant regimen including paclitaxel for an elderly lady with clinical stage (c)T2N0 triple-negative breast cancer, diabetes, and stage 3 Chronic Kidney Disease (CKD)?

Neoadjuvant Paclitaxel-Based Regimen for cT2N0 Triple-Negative Breast Cancer with Comorbidities

For this elderly patient with cT2N0 triple-negative breast cancer, diabetes, and stage 3 CKD, the recommended neoadjuvant regimen is weekly paclitaxel 80 mg/m² for 12 weeks followed by dose-dense doxorubicin 60 mg/m² and cyclophosphamide 600 mg/m² every 2 weeks for 4 cycles, with careful monitoring of renal function and cardiac toxicity. 1

Rationale for Regimen Selection

Why Sequential Anthracycline-Taxane Approach

• The NCCN 2024 guidelines designate dose-dense AC followed by weekly paclitaxel as a "preferred regimen" (Category 1) for triple-negative breast cancer in the neoadjuvant setting. 1
• Sequential administration (taxane first, then anthracycline) is acceptable and allows for response assessment, which is particularly valuable in this patient with comorbidities. 1
• Weekly paclitaxel demonstrates superior disease-free survival compared to every-3-week paclitaxel (HR 1.27,95% CI 1.03-1.57, P=0.006). 1

Critical Modifications for This Patient's Comorbidities

Renal considerations (Stage 3 CKD):

• Paclitaxel does not require dose adjustment for renal impairment as it undergoes hepatic metabolism. 2
• Cyclophosphamide is acceptable in stage 3 CKD but requires adequate hydration monitoring. 1
• Avoid carboplatin-containing regimens due to significant renal clearance and increased toxicity risk in CKD. 3

Cardiac monitoring (diabetes increases cardiovascular risk):

• Baseline cardiac assessment with echocardiogram or MUGA scan is mandatory before anthracycline initiation. 4
• Repeat cardiac function assessment every 3 months during anthracycline therapy. 5
• Doxorubicin cumulative dose should not exceed 240 mg/m² (4 cycles at 60 mg/m²). 1

Age-related considerations:

• Elderly patients (≥65 years) experience more severe myelosuppression with standard regimens, requiring close monitoring. 1
• Dose-dense regimens with growth factor support are appropriate and maintain efficacy in older adults. 1

Specific Treatment Protocol

Phase 1: Weekly Paclitaxel (Weeks 1-12)

• Paclitaxel 80 mg/m² IV over 3 hours weekly for 12 consecutive weeks. 1, 2
• Mandatory premedication 30-60 minutes before each infusion: 2
  • Dexamethasone 20 mg PO at 12 and 6 hours before paclitaxel
  • Diphenhydramine 50 mg IV
  • Ranitidine 50 mg IV or cimetidine 300 mg IV
• Monitor for peripheral neuropathy weekly; reduce dose by 20% if grade 3-4 neuropathy develops. 2
• Hold treatment if neutrophils <1,500 cells/mm³ or platelets <100,000 cells/mm³. 2

Phase 2: Dose-Dense AC (Weeks 13-20)

• Doxorubicin 60 mg/m² IV + Cyclophosphamide 600 mg/m² IV every 2 weeks for 4 cycles with G-CSF support. 1
• Administer G-CSF (filgrastim or pegfilgrastim) starting 24-72 hours after each AC cycle. 1
• Hold treatment if neutrophils <1,500 cells/mm³; reduce subsequent doses by 20% if neutrophils <500 cells/mm³ for ≥1 week. 2
• Monitor cardiac function before cycle 3 and after completion. 4

Why NOT to Include Carboplatin or Pembrolizumab

Carboplatin Omission Justified

• Carboplatin is NOT routinely indicated for cT2N0 (node-negative) triple-negative breast cancer. 3
• The NCCN 2024 guidelines recommend carboplatin primarily for node-positive disease or in conjunction with pembrolizumab-based regimens. 3
• Stage 3 CKD significantly increases carboplatin toxicity risk (thrombocytopenia, anemia, nephrotoxicity). 6, 7
• The BrighTNess trial showed carboplatin increased pathological complete response but with substantially higher hematologic toxicity (grade 3-4 neutropenia 56%, anemia 29%, thrombocytopenia 12%). 6

Pembrolizumab Omission Justified

• Pembrolizumab is recommended for high-risk stage II-III triple-negative breast cancer, but cT2N0 represents lower-risk disease. 3
• The KEYNOTE-522 protocol showing benefit included predominantly node-positive patients. 3
• For cT2N0 disease, pembrolizumab may be considered but is not mandatory (Category 2A for individualized use). 1, 3
• Adding pembrolizumab would require carboplatin inclusion (per KEYNOTE-522 protocol), which is contraindicated by this patient's renal dysfunction. 3

Monitoring and Supportive Care

Laboratory Monitoring Schedule

• CBC with differential before each paclitaxel dose and before each AC cycle. 2
• Comprehensive metabolic panel (including creatinine) every 3 weeks to monitor renal function. 2
• Hemoglobin A1c monthly to assess diabetes control during treatment. 1

Diabetes Management During Treatment

• Expect hyperglycemia from dexamethasone premedication; coordinate with endocrinology for insulin adjustment. 1
• Consider reducing dexamethasone to 10 mg PO (instead of 20 mg) if hyperglycemia becomes uncontrolled, though this increases hypersensitivity reaction risk. 2

Neuropathy Prevention and Management

• Baseline neurologic examination documenting any pre-existing neuropathy. 2
• Weekly assessment during paclitaxel phase using patient-reported outcomes. 1
• If grade 2 neuropathy develops, continue current dose but monitor closely. 2
• If grade 3-4 neuropathy develops, reduce paclitaxel dose by 20% for all subsequent doses. 2

Common Pitfalls to Avoid

Never give chemotherapy and endocrine therapy concurrently - this patient has triple-negative disease, so endocrine therapy is not indicated. 4

Never use TC (docetaxel-cyclophosphamide) as the sole regimen - while listed as "preferred" for some breast cancers, anthracycline-containing regimens are superior for triple-negative disease. 1

Never delay G-CSF support with dose-dense regimens - elderly patients require prophylactic growth factor support to maintain dose intensity. 1

Never base radiation therapy decisions on post-chemotherapy staging - radiation planning should be based on pre-treatment clinical stage. 4

Never assume paclitaxel requires renal dose adjustment - it does not, but cyclophosphamide requires adequate hydration monitoring in CKD. 2

Expected Outcomes and Surgery Timing

• Pathological complete response rates with AC followed by weekly paclitaxel range from 31-41% in triple-negative breast cancer. 1
• Surgery should be scheduled 3-4 weeks after final chemotherapy cycle to allow count recovery. 1
• Post-operative radiation therapy is indicated for cT2 disease and should begin 3-4 weeks after surgery. 4