Oxaliplatin (Eloxatin)

How Oxaliplatin Works

Platinum Mechanism

Oxaliplatin is a third-generation platinum compound (after cisplatin and carboplatin):

1. Activation: Inside cells, oxaliplatin undergoes chemical changes that activate it
2. DNA binding: Active form binds to DNA strands
3. Crosslink formation: Creates platinum-DNA adducts that crosslink DNA strands
   • Both within a single DNA strand (intrastrand)
   • Between two DNA strands (interstrand)
4. Blocks replication: DNA polymerase can't copy damaged DNA
5. Cell cycle arrest: Cell can't divide, triggers apoptosis (cell death)

Advantages Over Other Platinums

• Different DNA adducts: Oxaliplatin creates different crosslinks than cisplatin
  • May overcome cisplatin resistance
  • Different spectrum of activity
• Less kidney toxicity: Compared to cisplatin (doesn't require aggressive IV hydration)
• Less nausea: Than cisplatin
• No significant hearing loss: Unlike cisplatin
• But unique neuropathy: Cold-sensitive nerve damage (see below)

Synergy with 5-FU

Oxaliplatin works particularly well when combined with fluoropyrimidines (5-FU/capecitabine):

• 5-FU inhibits DNA repair of platinum-induced damage
• Complementary mechanisms enhance cancer cell kill
• This synergy is why FOLFOX and CAPOX are so effective

FDA-Approved Uses

Colorectal Cancer

Adjuvant Treatment (After Surgery)

• Stage III colon cancer: Standard of care
  • FOLFOX regimen for 6 months (12 cycles)
  • Reduces recurrence risk by 30-40%
  • Improves disease-free survival
  • 3-year disease-free survival: ~73% with FOLFOX vs ~67% with 5-FU alone
• High-risk stage II colon cancer: Considered in select patients
  • T4 tumors, perforation, <12 lymph nodes examined
  • Benefit smaller than stage III but still used

Metastatic Colorectal Cancer

• First-line treatment: FOLFOX or CAPOX
  • Often combined with bevacizumab (Avastin) or cetuximab/panitumumab (if RAS wild-type)
  • Response rates: 45-55% with combination
  • Median progression-free survival: 8-10 months
  • Median overall survival: 20-30 months with modern combinations
• Conversion therapy: For initially unresectable liver/lung metastases
  • FOLFOX can shrink tumors enough to allow surgery
  • 15-30% of patients become resectable
  • Potential for cure if complete resection achieved

Off-Label Uses (Common)

• Gastric/gastroesophageal cancer: FLOT regimen (5-FU, leucovorin, oxaliplatin, docetaxel)
• Pancreatic cancer: FOLFIRINOX regimen (adds irinotecan)
• Ovarian cancer: Alternative to carboplatin in some situations
• Neuroendocrine tumors
• Hepatobiliary cancers

Common Regimens

FOLFOX (Most Common)

Every 2 weeks (14-day cycle):

• Day 1:
  • Oxaliplatin 85 mg/m² IV over 2 hours
  • Leucovorin 400 mg/m² IV over 2 hours (given simultaneously with oxaliplatin using Y-connector)
  • 5-FU 400 mg/m² IV bolus
  • 5-FU 2400 mg/m² IV continuous infusion over 46 hours (portable pump)
• Days 2-14: Rest
• Repeat cycle

Variations:

• mFOLFOX6: Modified version (standard in US)
• FOLFOX4: Older version with different 5-FU dosing

CAPOX (XELOX)

Every 3 weeks (21-day cycle):

• Day 1: Oxaliplatin 130 mg/m² IV over 2 hours
• Days 1-14: Capecitabine 1000 mg/m² PO twice daily (with food)
• Days 15-21: Rest
• Repeat cycle

Advantages:

• No infusion pump needed (capecitabine is oral)
• Equivalent efficacy to FOLFOX
• Patient preference (less hospital time)

FOLFIRINOX

For pancreatic cancer - very intensive:

• Oxaliplatin 85 mg/m² + irinotecan + 5-FU + leucovorin
• Every 2 weeks
• Higher toxicity but very effective for fit patients

Administration

Infusion Details

• Infusion time: 2 hours (some centers use 6-hour infusion to reduce neuropathy)
• Line requirements:
  • Peripheral IV line acceptable
  • Central line (port, PICC) often preferred for repeated cycles
  • Never use aluminum needles or IV sets (oxaliplatin degrades)
• Reconstitution: Must dilute in 5% dextrose (D5W)
  • NEVER use saline or chloride-containing solutions
  • Chloride degrades oxaliplatin

Premedications

• Anti-nausea:
  • 5-HT3 antagonist (ondansetron, granisetron)
  • Dexamethasone
  • Oxaliplatin is moderately emetogenic (50-60% nausea without prophylaxis)
• No routine need for:
  • IV hydration (unlike cisplatin)
  • Magnesium/potassium supplementation
  • Mannitol diuresis

Duration of Treatment

• Adjuvant (after surgery): 6 months = 12 cycles of FOLFOX or 8 cycles of CAPOX
  • Recent studies suggest 3 months may be adequate for low-risk stage III
  • Reduces cumulative neuropathy
• Metastatic disease: Continue until progression, unacceptable toxicity, or cumulative neuropathy
  • Some oncologists stop oxaliplatin after 4-6 months to prevent severe neuropathy
  • Continue 5-FU/capecitabine as maintenance
  • Can rechallenge with oxaliplatin later if needed

Peripheral Neuropathy - The Defining Side Effect

Most significant and dose-limiting toxicity of oxaliplatin

Two Types of Neuropathy

1. Acute Cold-Sensitive Neuropathy

• Timing: Within hours to days of infusion, lasts 3-7 days
• Incidence: 85-95% of patients experience this
• Symptoms (triggered or worsened by cold):
  • Tingling, numbness in fingers, toes
  • Jaw tightness, difficulty swallowing (pharyngolaryngeal dysesthesia)
  • Muscle cramps, spasms
  • Sensitivity to cold objects
  • Feeling of "electric shocks"
• Mechanism: Thought to be due to oxalate metabolite affecting voltage-gated sodium channels
• Resolution: Typically resolves between treatments
• Management: Strict cold avoidance (see below)

2. Cumulative Chronic Neuropathy

• Development: Gradual, cumulative over multiple cycles
• Incidence: Depends on cumulative dose
  • Grade 1-2 (mild-moderate): 70-80% by end of treatment
  • Grade 3 (severe): 10-20% (dose-limiting)
• Symptoms:
  • Persistent numbness, tingling in hands/feet (glove-and-stocking distribution)
  • Impaired fine motor skills (buttoning shirts, picking up coins)
  • Difficulty walking, balance problems
  • Loss of sensation (can't feel temperature, pain)
  • Affects quality of life significantly if severe
• Risk factors:
  • Higher cumulative dose (>750-850 mg/m²)
  • Longer infusion duration needed
  • Pre-existing neuropathy (diabetes)
  • Age (elderly at higher risk)
• Reversibility:
  • Improves in most patients after stopping (60-80%)
  • But can take 6-18 months or longer
  • 10-20% have persistent symptoms
  • Severe neuropathy less likely to fully resolve

Cold Avoidance Strategies (CRITICAL)

Starting day of infusion through 5-7 days after:

• No cold drinks:
  • Drink only room temperature or warm beverages
  • No ice, no cold water, no refrigerated drinks
  • Can trigger throat tightness, difficulty swallowing
• No cold foods:
  • Avoid ice cream, popsicles, frozen foods
  • Let food from refrigerator warm to room temperature
• Protect hands:
  • Wear gloves when touching refrigerator, freezer
  • Use oven mitts to get items from freezer
  • Wear gloves outside if weather is cold
• Cover face/neck:
  • Scarf over mouth/nose if going outside in cold
  • Cold air on throat can trigger spasms
• Temperature control:
  • Keep home comfortably warm
  • Avoid air conditioning blowing directly on you
  • Warm shower, not cold
• During infusion:
  • Bring warm blankets to infusion center
  • Drink warm fluids
  • Ask staff to adjust air conditioning

Neuropathy Grading and Dose Modifications

Neuropathy Prevention and Treatment

Prevention strategies (none proven highly effective):

• Calcium/magnesium infusions:
  • Controversial - some early studies suggested benefit but not confirmed
  • Not routinely recommended
• Shorter treatment duration: 3 months vs 6 months for adjuvant treatment (reduces cumulative dose)
• Dose reduction: When grade 2 symptoms develop
• Stop-and-go approach: Oxaliplatin holidays in metastatic setting

Treatment of established neuropathy:

• Duloxetine (Cymbalta):
  • Most evidence for benefit (modest improvement)
  • 30-60 mg daily
  • Can reduce pain associated with neuropathy
• Gabapentin or pregabalin: For neuropathic pain
• Physical/occupational therapy: For functional impairments
• Time: Most important factor - symptoms improve slowly after stopping oxaliplatin

Other Side Effects

Common Side Effects (>20%)

• Fatigue (60-70%)
• Nausea/vomiting (50-60% without prophylaxis, much less with anti-nausea meds)
• Diarrhea (40-50%) - often more from 5-FU component of FOLFOX
• Peripheral neuropathy (85-95% - see extensive section above)
• Mucositis/stomatitis (mouth sores) (30-40%) - mainly from 5-FU
• Decreased appetite (20-30%)

Myelosuppression (Bone Marrow Suppression)

• Neutropenia (low white blood cells): 40-50%
  • Grade 3-4 severe neutropenia: 10-20%
  • Nadir (lowest point): Days 10-14
  • Check CBC before each cycle
  • Hold treatment if ANC <1500 (some protocols <1000)
• Thrombocytopenia (low platelets): 30-40%, usually mild
• Anemia (low red blood cells): 60-70%, cumulative over cycles
• Less myelosuppression than cisplatin

Allergic/Hypersensitivity Reactions

• Incidence: 10-15% (increases with more cycles)
• Symptoms:
  • Rash, hives, itching
  • Flushing
  • Shortness of breath, wheezing
  • Chest tightness
  • Hypotension (low blood pressure)
  • Anaphylaxis (rare but possible)
• Timing: Usually during infusion or within hours
• Risk increases: After 6-8 cycles
• Management:
  • Stop infusion immediately
  • Antihistamines, steroids, epinephrine if severe
  • Desensitization protocol possible but difficult
  • May need to switch to different regimen

Pulmonary Toxicity (Rare but Serious)

• Pulmonary fibrosis: Very rare (<1%)
• Interstitial pneumonitis
• Symptoms: Shortness of breath, cough, fever
• Requires stopping oxaliplatin, may need steroids

Hepatotoxicity

• Elevated liver enzymes: Common (40-50%) but usually mild
• Sinusoidal obstruction syndrome (SOS): Rare but serious
  • More common with prolonged exposure (months)
  • Can lead to portal hypertension
  • Important consideration if planning liver resection
• Monitor liver function tests

Other Side Effects

• Kidney toxicity: Much less than cisplatin (no routine need for IV hydration)
• Hearing loss: Rare (unlike cisplatin)
• Electrolyte abnormalities: Hypokalemia (low potassium), hypomagnesemia (low magnesium) - less common than cisplatin
• Dysgeusia: Altered taste (metallic taste common)

Monitoring During Treatment

Before Each Cycle

• Complete blood count (CBC): Check ANC, platelets, hemoglobin
• Comprehensive metabolic panel: Kidney function (creatinine), liver enzymes, electrolytes
• Neuropathy assessment:
  • Questionnaire (CIPN-20, FACT-NTX)
  • Physical exam (reflexes, sensation, balance)
  • Functional assessment (can you button shirt? Pick up coins?)
• Performance status: Overall health and ability to function

Tumor Response Assessment

• CT scans every 8-12 weeks (every 4-6 cycles)
• CEA tumor marker (if initially elevated) before each cycle or monthly

Special Monitoring

• If planning liver resection: MRI to assess sinusoidal obstruction syndrome
• If pulmonary symptoms: Chest X-ray or CT, pulmonary function tests

Patient Tips and FAQs

During the Week After Infusion

• Temperature awareness: Keep everything at room temperature or warmer
• Hydration: Drink plenty of fluids (room temperature)
• Activity: Rest if fatigued, gentle activity as tolerated
• Diet: Eat small, frequent meals if nauseated
• Monitor: Watch for fever, excessive diarrhea, severe throat tightness

Managing Daily Life

• Work: Many patients work during treatment, may need flexible schedule
• Driving: Okay unless severe fatigue or neuropathy affecting coordination
• Exercise: Encouraged - gentle walking, yoga; avoid if counts very low
• Social activities: Maintain when possible; avoid crowds if neutropenic

When to Call Your Oncologist

• Fever ≥100.4°F (38°C)
• Severe diarrhea (4+ stools/day above baseline)
• Chest pain, severe shortness of breath
• Severe throat tightness preventing swallowing
• Worsening neuropathy affecting daily activities
• Rash, itching, hives (possible allergic reaction)
• Signs of infection

Frequently Asked Questions

Why can't I have cold drinks during treatment?

Oxaliplatin's metabolite (oxalate) causes nerve hypersensitivity specifically triggered by cold. Drinking cold liquids can cause severe throat tightness (pharyngolaryngeal dysesthesia) and jaw spasms - it can feel like your throat is closing. This acute cold sensitivity affects 85-95% of patients in the first week after infusion. Room temperature drinks are safe. This cold sensitivity is unique to oxaliplatin among chemotherapy drugs.

How long does cold sensitivity last?

Acute cold sensitivity typically lasts 3-7 days after each infusion, then resolves until the next treatment. However, some patients develop persistent cold sensitivity with cumulative doses. The good news is that acute cold sensitivity is predictable and manageable with strict cold avoidance during the first week after treatment.

Will neuropathy get better after I stop treatment?

Yes, in most cases. About 60-80% of patients experience improvement in neuropathy symptoms after completing oxaliplatin, but recovery is slow (6-18 months or longer). Mild-moderate neuropathy (grade 1-2) usually improves significantly. Severe neuropathy (grade 3) is less likely to completely resolve, with 10-20% having persistent symptoms. This is why dose modification when grade 2 develops is important - to prevent progression to severe, potentially irreversible neuropathy.

How do I know if neuropathy is getting worse?

Warning signs include: difficulty with fine motor tasks (buttoning shirts, writing, picking up small objects), problems walking or balance issues, dropping things frequently, inability to tell hot from cold, or numbness spreading up arms/legs. If these occur, report immediately to your oncologist. Early dose modification can prevent progression. Don't wait for symptoms to become severe.

Can I stop oxaliplatin and continue the rest of FOLFOX?

Yes, absolutely. For cumulative neuropathy or allergic reactions, oxaliplatin is stopped and treatment continues with 5-FU/leucovorin alone. While oxaliplatin adds significant benefit, 5-FU alone still has anti-cancer activity. In metastatic disease, some oncologists use "stop-and-go" strategies - stopping oxaliplatin after 4-6 months to prevent severe neuropathy, continuing 5-FU, then reintroducing oxaliplatin if needed. In adjuvant treatment, completing at least 3 months of FOLFOX provides substantial benefit even if oxaliplatin must be stopped early.

How is oxaliplatin different from cisplatin?

While both are platinum drugs that crosslink DNA, they differ significantly in side effects. Oxaliplatin causes less kidney damage (no IV hydration needed), less nausea, and no hearing loss compared to cisplatin. However, oxaliplatin causes unique cold-sensitive neuropathy. Cisplatin causes more severe nausea/vomiting requiring aggressive prophylaxis and aggressive IV hydration for kidney protection. They're used for different cancers - oxaliplatin primarily for colorectal/GI cancers, cisplatin for lung, testicular, bladder, and head/neck cancers.

Why do I need the 5-FU pump for 2 days?

In FOLFOX, the 46-hour continuous 5-FU infusion mimics "continuous infusion" 5-FU, which is more effective than quick IV push (bolus) 5-FU. The constant low-dose exposure affects more cancer cells as they move through their division cycle. The portable pump allows you to go home during infusion. While the pump can be cumbersome, it's essential for FOLFOX efficacy. CAPOX is an alternative if you prefer avoiding the pump - you take capecitabine pills instead.

Can I exercise during oxaliplatin treatment?

Yes, exercise is encouraged and may actually help reduce some side effects, including fatigue and neuropathy. Aim for 150 minutes of moderate activity weekly if possible. However, avoid exercise if your blood counts are very low (ANC <500), you have severe fatigue, or significant neuropathy affecting balance. Start slow and listen to your body. Avoid cold swimming pools for the first week after infusion. Walking, gentle yoga, and stretching are good options.

Should I take any vitamins or supplements?

Discuss all supplements with your oncologist before starting. Some patients take vitamin B supplements hoping to reduce neuropathy, but evidence is limited. Avoid high-dose antioxidants (vitamin E, vitamin C >1000mg) during chemotherapy as they may interfere with treatment. Calcium/magnesium infusions before oxaliplatin were studied for neuropathy prevention but showed inconsistent results and are not standard. A regular multivitamin is generally safe.

How long is treatment?

For adjuvant (after surgery) treatment: traditionally 6 months (12 cycles of FOLFOX), but recent studies show 3 months (6 cycles) may be adequate for low-risk stage III colon cancer with less neuropathy. For metastatic disease: continue as long as cancer is responding and side effects are tolerable - can be 6-12+ months. Some strategies use oxaliplatin intermittently to balance efficacy with neuropathy prevention.