Cisplatin (Cisplatinum)


Article Author:
Joann Gold


Article Editor:
Avais Raja


Editors In Chief:
David Wood
Andrew Wilt
Hajira Basit


Managing Editors:
Avais Raja
Orawan Chaigasame
Khalid Alsayouri
Kyle Blair
Radia Jamil
Erin Hughes
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Navid Mahabadi
Hussain Sajjad
Steve Bhimji
Muhammad Hashmi
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Abbey Smiley
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beenish Sohail
Hajira Basit
Phillip Hynes
Sandeep Sekhon


Updated:
9/22/2019 12:01:46 PM

Indications

Cisplatin is an antineoplastic agent. Cisplatin, while highly toxic, is one of the most heavily utilized chemotherapeutic agents for hematologic and solid tumor malignancies. It can be used as a single-agent or in combination therapy for induction and neoadjuvant therapy. 

Adult indications:

Cisplatin is FDA approved for the treatment of advanced ovarian cancer, testicular cancer, and bladder carcinoma.[1][2] However, cisplatin is frequently used in an off-label fashion when the benefits may outweigh the risks of adverse drug effects. 

Malignancies that predominate in women such as breast cancer, cervical and endometrial carcinoma, and gestational trophoblastic neoplasia sometimes receive treatment with cisplatin in combination with other medications such as taxane derivatives, 5-FU, and doxorubicin.[3][4][5] While hormone-sensitive and Her2neu, positive tumors may respond well to targeted therapy, cisplatin is also useful in the treatment of triple-negative breast cancer as a single agent neoadjuvant therapy.[3]

Gastrointestinal malignancies such as esophageal, gastric, and hepatobiliary cancer have also been treated off-label with this medication, in addition to radiation.[6][7][8] Lung cancer, both small cell and non-small cell, can be treated off-label with combination therapy of etoposide and cisplatin.[9][10]

Other off-label uses include treatment for metastatic, advanced, and refractory cancers; this includes the treatment of Hodgkin lymphoma, non-Hodgkin lymphoma, penile cancer, thymoma, head and neck cancers, osteosarcoma, multiple myeloma, and mesothelioma.[11][12][13]

Pediatric indications:

Cisplatin has few indications for treatment in children. When utilized, its indications are for historically aggressive tumors. It is sometimes used to treat germ cell tumors, hepatoblastoma, medulloblastoma, neuroblastoma, and osteosarcoma, but universal guidelines on dosing and duration are not available.[14][15][16][17][18][17]

Mechanism of Action

Cisplatin acts via non-cell cycle specific cytotoxicity, which is achieved through covalent binding of platinum to the purine bases guanine and adenine. This covalent binding leads to intra-strand and inter-strand crosslinks causing subsequent strand breaks. While DNA repair mechanisms are at play, cells often undergo apoptotic or non-apoptotic cell death due to remnant damaged DNA, RNA, and proteins.[19] Cisplatin chemotherapy is particularly effective at targeting rapidly dividing cells as appreciated in rapidly growing malignant tumors.[20] Theoretically, cisplatin may not be as useful for slow-growing tumors.

Administration

Cisplatin can be administered as an injectable agent both intravenously and as an intra-arterial agent.[21] Cisplatin can also be utilized as an intraperitoneal agent as seen in the treatment of carcinomatosis and primary peritoneal carcinoma, however, this use is not FDA approved and is referred to as “off-label” use.[22] Before administration, the patient must achieve adequate hydration. Adequate hydration and urinary output should be maintained for 24 hours after administration. Anti-emetic agents can be utilized prophylactically to prevent nausea and vomiting.[23]

Dosing runs from 20 mg/m^2 to 100 mg/m^2, in 21 to 28-day cycles, depending on the malignancy treated.

Adverse Effects

Extravasation - If extravasation is suspected, the infusion should stop immediately. Any obvious fluid collection should get aspirated, and the extremity elevated. The antidote, sodium thiosulfate, should be administered.[24]

Secondary malignancy - Leukemia is the most common secondary malignancy after treatment with cisplatin, and this typically occurs many years after completion of treatment.[25][26]

Tumor lysis syndrome can occur after treatment with many chemotherapeutic agents, which manifests as hyperuricemia, alteration in hemodynamics, hyperkalemia, and azotemia. Uric acid-reducing treatments may be necessary.[25][27]

Common side effects of cisplatin include[27]:

  • Mild nausea
  • Vomiting 
  • Diarrhea
  • Temporary hair loss
  • Loss in the ability to taste food
  • Hiccups
  • Dry mouth
  • Dark urine
  • Decreased sweating
  • Dry skin
  • Dehydration

Drug interactions

Caution is necessary when administering cisplatin with any of the following medications. Most drug interactions result in cumulative and dose-dependent hematologic, renal, and neurotoxic effects. Cisplatin should also not be used with immunosuppressive medications due to cumulative myelosuppression.[28][29] 

  • Alpha-lipoic acid
  • Aminoglycosides
  • Baricitinib
  • BCG
  • Chloramphenicol
  • Clozapine
  • Deferiprone
  • Denosumab
  • Dipyrone
  • Echinacea
  • Fosphenytoin
  • Leflunomide
  • Lenogristim
  • Lipefilgrastim
  • Natalizumab
  • Nivolumab
  • Ocrelizumab
  • Palifermin
  • Pidotimod
  • Pimecrolimus
  • Promazine
  • Roflumilast
  • Siponimod
  • Sipuleleucel-T
  • Tacrolimus
  • Taxane derivatives
  • Tertomotide
  • Topotecan
  • Trastuzumab
  • Vaccinations
  • Vinorelbine

Contraindications

There are few absolute contraindications for cisplatin use for the treatment of malignancies. Severe hypersensitivity to cisplatin would preclude its administration. Cisplatin has been shown to cross the placenta and may cause fetal harm.[30][31] Women of reproductive age should use reliable contraception during treatment and up to a year from the final treatment date. Cisplatin is also present in the breastmilk of lactating women on a cisplatin regimen.[32] Breastfeeding is not recommended during treatment.[32] If hypersensitivity occurs, the provider should discontinue cisplatin immediately.[33] Cisplatin is absolutely contraindicated in patients who have had severe hypersensitivity reactions, and rechallenge is not recommended.

Monitoring

A pregnancy test is necessary to determine pregnancy status in female patients before administration of cisplatin.[30]

Hematologic - The clinician should order a complete blood count (CBC) before initiation of treatment and before each subsequent treatment course.[25]

Renal function - Serum creatinine, blood urea nitrogen, creatinine clearance, and electrolytes (Na, K, Ca, Mg) requires an assessment before treatment administration.[34][35]

Hearing and vestibular - Audiometric testing should be ordered in pediatric patients to determine baseline and before each administration. After discontinuing therapy, audiometric testing should continue for several years.[25][35][36]

Infusion - The site of infusion should be assessed before, during, and after drug administration to assess for infection and extravasation. The patient should be monitored clinically for complications of administration.[24][37][38]

One also has to monitor the patient for neuropathy, ocular changes, and signs of systemic infection.

Toxicity

Gastrointestinal toxicity - Nausea and vomiting are dose-related side effects can be severe and lead to metabolic derangements; this can persist for up to 1 week after administration. The strong recommendation is for prophylactic treatment with antiemetic agents.[39][25]

Myelosuppression - The chief concern with myelosuppression secondary to cisplatin use is the morbidity and mortality associated with infection. Monitor CBC and frequently assess for signs of infection. High clinical suspicion is necessary for infection and warrants a full workup.[25] Hematologic toxicity may require total treatment interruption. Often it will require dose modification if treatment is to continue.[25]

Neurotoxicity - Cisplatin is a dose-dependent neurotoxin.[40] Dose-related neurotoxicity most commonly manifests as peripheral neuropathy. This neuropathy may progress after discontinuation and in some cases may be irreversible.[25][41] While dosage may require alteration in the face of neuropathy, high-grade peripheral neuropathy may require total treatment discontinuation. 

Nephrotoxicity - Severe renal toxicity, including acute renal failure, may occur with Cisplatin administration. These effects are cumulative and dose-related. Pretreatment hydration plays a significant role in preventing renal toxicity.[25][34][35] The dose of cisplatin may have to be adjusted based on renal function with close monitoring of the glomerular filtration rate (GFR).[33]

Ocular toxicity/retinopathy - This adverse effects can manifest in a variety of ways from loss of color discrimination to cortical blindness. Improvement usually occurs after discontinuation of cisplatin, and in some cases, total recovery may be possible.[25][42]

Ototoxicity - Monitoring for ototoxicity includes assessing the patient for ringing in the ears, high-frequency hearing loss, and decreased the ability to follow conversations. Deafness has been reported but is not a common effect of cisplatin use. Loss of hearing acuity can be detrimental to the development of language in pediatric populations.[25][35]

Gonadotoxicity - Cisplatin is toxic to the gonads; it can cause impairment of spermatogenesis and dose-dependent ovarian failure leading to premature menopause.[25]

Enhancing Healthcare Team Outcomes

Interprofessional collaboration and care coordination between physicians, nurses, pharmacists, and other related healthcare providers enhances team performance and patient outcomes.[43] Working as a team while caring for patients undergoing treatment with cisplatin is of great importance.[44] As a team, monitoring for side effects and toxicity can be more efficient with fewer poor outcomes and earlier intervention.[45][44] Communication among healthcare professionals is crucial. For example, any dose greater than 100 mg/m^2 for a single treatment course requires verification with the initial medication prescriber. The oncology specialty-trained pharmacist should also monitor for the extensive drug-drug interactions that can occur with cisplatin, and alert the ordering clinician promptly upon finding ant reason for concern.

Nurses need to be aware of the importance of hydration and monitoring the site of IV infusion for extravasation. Also, all clinicians should monitor the patient for signs of infection, renal impairment, and development of tumor lysis syndrome. Open communication between the interprofessional team is vital to prevent the adverse effects of this agent while optimizing its therapeutic effect. [Level V]


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Cisplatin (Cisplatinum) - Questions

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A 54-year-old male receives chemotherapy for a refractory lymphoma and presents to the clinic for follow up. He has been struggling with nausea, vomiting, and fatigue since initiating therapy but is in good spirits. He reports noticing a strange sound while watching television that his wife did not notice although he doesn’t seem concerned by this. His physical exam is notable for signs of mild dehydration and generalized lymphadenopathy. His most recent labs revealed leukopenia but were otherwise within normal limits. What is another common side effect of the most likely offending agent?



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A patient is receiving cisplatin following the removal of the right testis. Which of the following is a toxic effect of this drug?



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A 61-year-old man born in the US, diagnosed with advanced testicular cancer presents postoperatively, to the clinician for medical management. He has not previously received radiation or chemotherapy for his condition. He has no history of travel and was fully vaccinated as a child and is currently up to date on vaccinations. His review of systems is positive for fatigue. The left testicle has been surgically removed. The physical exam is otherwise unremarkable. Preoperative chest X-ray was unremarkable with no infiltrations noted. The patient is to be started on a chemotherapy regimen, including cisplatin. Which of the following must be included in the initial workup before administering cisplatin?



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A 62-year-old male is receiving treatment for advanced bladder cancer. After infusion, he experienced symptoms that lead to elevated blood urea nitrogen (BUN) and electrolyte disturbance on a follow up the metabolic panel. Pretreatment with which of the following medications could have prevented these derangements?



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Which of the following chemotherapeutic agents is known to cause significant nephrotoxicity?



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A 6-year-old boy is brought to his pediatrician for an annual visit. The patient has a history of advanced osteosarcoma and finished treatment last week. He has a history of asthma and is treated with an albuterol rescue inhaler as needed. He is recovering from acute otitis media one month prior. He has no pertinent family history and lives at home with his mother, father, and sisters in a carpeted home with a pet dog. His mother mentions during the visit that she often has to say his name multiple times to get his attention and that sometimes “he seems oblivious to what is happening around him” and she wonders if he is haven’t trouble with attention like his sister who was diagnosed with ADHD. You have to speak loudly to get his attention, and he continuously tries to play with his toys instead of participating in the examination. The physical exam is unremarkable. He is afebrile and reports no ear pain when on the manipulation of the pinna and denies discharge from the ear. What is the next best step in the assessment?



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A 54-year-old female being treated for stage 3 ovarian cancer presents to her oncologist for follow up after her second round of chemotherapy. The review of systems is negative, except for decreased sensation in her hands and ringing in her ears over the last few days. On physical exam, she is found to have decreased sensation to pinprick in her toes and fingertips bilaterally. The rest of the physical exam is within normal limits. The physician notes that the patient should be referred for audiometry for further testing. On review of her most recent labs, she is found to have an elevated creatinine 25% over her baseline with electrolytes within normal limits. Which medication is the patient most likely taking for treatment of her ovarian cancer?



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While receiving chemotherapy for metastatic ovarian carcinoma, a patient begins to experience discomfort at the site of infusion shortly after the infusion is started. She describes the pain as a burning sensation. On examination, there is localized swelling and erythema at the port site. What is the next best step in the management of this patient?



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Cisplatin (Cisplatinum) - References

References

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