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A - Regimen Name

GDCRBP Regimen
gemcitabine-dexamethasone-CARBOplatin


Disease Site
Hematologic - Lymphoma - Hodgkin
Hematologic - Lymphoma - Non-Hodgkin's Intermediate Grade

Intent
Palliative

Regimen Category
Evidence-Informed :

Regimen is considered appropriate as part of the standard care of patients; meaningfully improves outcomes (survival, quality of life), tolerability or costs compared to alternatives (recommended by the Disease Site Team and national consensus body e.g. pan-Canadian Oncology Drug Review, pCODR).  Recommendation is based on an appropriately conducted phase III clinical trial relevant to the Canadian context OR (where phase III trials are not feasible) an appropriately sized phase II trial. Regimens where one or more drugs are not approved by Health Canada for any indication will be identified under Rationale and Use.


Rationale and Uses

For the treatment of relapsed or refractory non-Hodgkin's or Hodgkin's lymphoma in transplant ineligible patients who are unable to receive or tolerate cisplatin.

 


Supplementary Public Funding

dexamethasone
ODB - General Benefit (dexamethasone) (ODB Formulary )

 
B - Drug Regimen

gemcitabine
1000 mg /m² IV Days 1 and 8
dexamethasone
40 mg PO Days 1 to 4
CARBOplatin
AUC 5 IV Day 1
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C - Cycle Frequency

REPEAT EVERY 21 DAYS

After 2-3 cycles, responding patients may be considered for high-dose chemotherapy and autologous stem cell transplant.

Patients with stable disease who were not candidates for stem cell transplant or patients who had any response after 2-3 cycles of GDCRBP may receive up to 6 cycles of treatment.

 
D - Premedication and Supportive Measures

Antiemetic Regimen:

Moderate + NK1 antagonist (Carboplatin AUC ≥ 5) (D1)
Low (D8)

Other Supportive Care:

Also refer to CCO Antiemetic Recommendations.

Consider growth factor support and antibiotic prophylaxis for febrile neutropenia, if required.

 
E - Dose Modifications

Doses should be modified according to the protocol by which the patient is being treated. The following recommendations have been adapted from clinical trials or product monographs and may be considered. Patients should have ANC ≥ 1.5 x 109/L and platelets ≥ 100 x 109/L prior to starting therapy.

Dosage with toxicity

 Suggested dose modifications on Day 1 of cycle:

Worst Toxicity in Previous Cycle

 
Gemcitabine

Carboplatin

Non-hematologic
 
Hematologic
% Full Dose*
% Full dose*
 
Grade 3
or

Febrile neutropenia, thrombocytopenic bleeding 

 
75%

75%

              Grade 4
or
Day 8 holds on > 1 cycle
 
 
 
Discontinue
Discontinue
  • Pneumonitis
  • Hemolytic Uremic Syndrome (HUS)
  • Stevens-Johnson syndrome (SJS)
  • Toxic epidermal necrolysis (TEN)
  • Capillary Leak Syndrome (CLS)
  • Posterior reversible encephalopathy syndrome (PRES)
   
Discontinue
Discontinue

*Do not start new cycle until ANC ≥ 1.5, platelets ≥ 100 and non-hematologic toxicity ≤ grade 2

Suggested dose modifications on Day 8 of cycle:

Non-hematologic
 
Hematologic
Gemcitabine
% Full Dose
ANC
(x 109/L)
 
Platelets
(x 109/L)
≤ grade 2
and
≥ 1.0
and
≥ 50
100%
≤ grade 2
and
0.5-1.0
 
or
50-100
↓ to 75%*
grade 3 or 4
or
< 0.5
or
< 50
Omit*

Pneumonitis
HUS
SJS
TEN
CLS or PRES

 
-
 
-
Discontinue

*Subsequent cycles may proceed at full dose if ANC ≥ 1.0, platelets ≥ 50, non-hematological toxicity ≤ grade 2



Hepatic Impairment

Bilirubin
 
AST/ALT
Carboplatin
Gemcitabine
2-3 x ULN
or
> 3 x ULN
No dose adjustment required
Use with caution; no specific recommendation found. 
> 3 x ULN
or
> 5 x ULN
Discontinue or reduce dose

 


Renal Impairment

Creatinine Clearance (ml/min)

Carboplatin

 

Gemcitabine

20 - 50

Use Calvert or Chatelut formula

 

Use with caution; no specific recommendation found.

< 20

Discontinue

 

Discontinue

 


Dosage in the Elderly

For gemcitabine, clearance is lower in the elderly but no dose adjustment needed. For carboplatin, caution should be exercised and dose reduction considered as elderly patients may have more severe myelosuppression and neuropathy.

 


 
F - Adverse Effects

Refer to gemcitabine, dexamethasone, CARBOplatin drug monograph(s) for additional details of adverse effects


Very common (≥ 50%)

Common (25-49%)

Less common (10-24%)

Uncommon (< 10%),

but may be severe or life-threatening

  • Increased LFTs (may be severe)
  • Nausea, vomiting
  • Myelosuppression +/- infection, bleeding (may be severe)
  • Fatigue
  • Flu-like symptoms
  • Abnormal electrolytes
  • Proteinuria
  • Nephrotoxicity (may be severe)
  • Rash (may be severe)

 

  • Edema
  • Musculoskeletal pain
  • Hearing impairment
  • Alopecia
  • Diarrhea
  • Steroid effects (e.g. weight gain, hyperglycemia, GI irritation, mood changes; may be severe)
  • Arterial / venous thromboembolism
  • Arrhythmia
  • Cardiotoxicity
  • Hypersensitivity
  • Peripheral neuropathy
  • Capillary leak syndrome
  • Hemolytic uremic syndrome
  • Pneumonitis
  • ARDS
  • PRES
  • Vasculitis
  • Secondary malignancy
 
G - Interactions

Refer to gemcitabine, dexamethasone, CARBOplatin drug monograph(s) for additional details


  • Avoid nephrotoxic and ototoxic drugs (i.e. aminoglycosides) due to additive effects.
  • Carboplatin may reduce serum phenytoin level; monitor closely and adjust the phenytoin dose if required
  • Both carboplatin and gemcitabine may increase INR and bleeding risk in patients taking warfarin; monitor closely and adjust INR as needed
 
H - Drug Administration and Special Precautions

Refer to gemcitabine, dexamethasone, CARBOplatin drug monograph(s) for additional details


Administration

Gemcitabine:

  • May dilute reconstituted drug in normal saline for IV infusion, resulting in a minimum final concentration of at least 0.1 mg/mL.
  • Infuse over 30 minutes through free-flowing IV. Infusion time beyond 60 minutes has been shown to increase toxicity.


CARBOplatin:

  • Mix in 100mL to 250mL bag (5% Dextrose or Normal Saline); infuse IV over 15 to 60 minutes.
  • Incompatible with sets, needles or syringes containing aluminum – leads to precipitation and loss of potency.
  • Protect from light.

Dexamethasone:

  • Oral tablets for self-administration
  • Given with food, preferably in the morning
  • Store tablets at room temperature

Contraindications

  • Patients who have a hypersensitivity to gemcitabine or platinum-containing compounds
  • Patients with severe renal impairment, severe myelosuppression or bleeding

Other warnings/precautions

  • Patients with impaired hepatic function, including concurrent liver metastases or a previous history of hepatitis, alcoholism or liver cirrhosis
  • Patients with abnormal renal function or who are receiving concomitant nephrotoxic drug
  • Patients who have received extensive prior treatment, have poor performance status and those over 65 years of age
  • Patients receiving concurrent radiation while receiving full dose gemcitabine should be closely monitored for reactions

Pregnancy and lactation

  • These drugs are not recommended in pregnancy.  Adequate contraception should be used by both sexes during treatment, and for at least 6 months after the last dose.
  • Breastfeeding is not recommended.

 

 
I - Recommended Clinical Monitoring

Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.

Recommended Clinical Monitoring

  • CBC; Baseline and before each dose
  • Liver function tests; Baseline and before each cycle
  • Renal function tests and electrolytes; Baseline and before each cycle
  • Clinical toxicity assessment of flu-like symptoms, hypersensitivity reactions, infection, bleeding, GI, respiratory, cardiovascular and CNS effects; At each visit
  • Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version

Suggested Clinical Monitoring

  • INR for patient receiving warfarin; Baseline and regular
  • Urinalysis; Baseline and regular

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J - Administrative Information

Pharmacy Workload (average time per visit)
28.715 minutes
Nursing Workload (average time per visit)
40.417 minutes
 
K - References

Carboplatin and gemcitabine drug monographs, Cancer Care Ontario.

Gopal AK, Press OW, Shustov AR, et al. Efficacy and safety of gemcitabine, carboplatin, dexamethasone, and rituximab in patients with relapsed/refractory lymphoma: a prospective multi-center phase II study by the Puget Sound Oncology Consortium. Leuk Lymphoma. 2010 Aug;51(8):1523-9.

June 2019 Updated emetic risk category


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L - Other Notes

Calvert Formula

DOSE (mg) = target AUC X (GFR + 25)

  • AUC = product of serum concentration (mg/mL) and time (min)
  • GFR (glomerular filtration rate) expressed as measured Creatinine Clearance or estimated from Serum Creatinine (by Cockcroft and Gault method or Jelliffe method)

(Calvert AH, Newell DR, Gumbrell LA, et al, Carboplatin dosage: Prospective evaluation of a simple formula based on renal function. J Clin Oncol, 1989; 7: 1748-1756)

 
M - Disclaimer

Regimen Abstracts
A Regimen Abstract is an abbreviated version of a Regimen Monograph and contains only top level information on usage, dosing, schedule, cycle length and special notes (if available). It is intended for healthcare providers and is to be used for informational purposes only. It is not intended to constitute or be a substitute for medical advice, and all uses of the Regimen Abstract are subject to clinical judgment. Such information is provided on an “as-is” basis, without any representation, warranty, or condition, whether express, or implied, statutory or otherwise, as to the information’s quality, accuracy, currency, completeness, or reliability, and Cancer Care Ontario disclaims all liability for the use of this information, and for any claims, actions, demands or suits that arise from such use.
Information in regimen abstracts is accurate to the extent of the ST-QBP regimen master listings, and has not undergone the full review process of a regimen monograph.  Full regimen monographs will be published for each ST-QBP regimen as they are developed.
Regimen Monographs
Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.
The information set out in the drug monographs, regimen monographs, appendices and symptom management information (for health professionals) contained in the Drug Formulary (the "Formulary") is intended for healthcare providers and is to be used for informational purposes only. The information is not intended to cover all possible uses, directions, precautions, drug interactions or adverse effects of a particular drug, nor should it be construed to indicate that use of a particular drug is safe, appropriate or effective for a given condition. The information in the Formulary is not intended to constitute or be a substitute for medical advice and should not be relied upon in any such regard. All uses of the Formulary are subject to clinical judgment and actual prescribing patterns may not follow the information provided in the Formulary.
The format and content of the drug monographs, regimen monographs, appendices and symptom management information contained in the Formulary will change as they are reviewed and revised on a periodic basis. The date of last revision will be visible on each page of the monograph and regimen. Since standards of usage are constantly evolving, it is advised that the Formulary not be used as the sole source of information. It is strongly recommended that original references or product monograph be consulted prior to using a chemotherapy regimen for the first time.
Some Formulary documents, such as the medication information sheets, regimen information sheets and symptom management information (for patients), are intended for patients. Patients should always consult with their healthcare provider if they have questions regarding any information set out in the Formulary documents.
While care has been taken in the preparation of the information contained in the Formulary, such information is provided on an “as-is” basis, without any representation, warranty, or condition, whether express, or implied, statutory or otherwise, as to the information’s quality, accuracy, currency, completeness, or reliability.
CCO and the Formulary’s content providers shall have no liability, whether direct, indirect, consequential, contingent, special, or incidental, related to or arising from the information in the Formulary or its use thereof, whether based on breach of contract or tort (including negligence), and even if advised of the possibility thereof. Anyone using the information in the Formulary does so at his or her own risk, and by using such information, agrees to indemnify CCO and its content providers from any and all liability, loss, damages, costs and expenses (including legal fees and expenses) arising from such person’s use of the information in the Formulary.