Chapter 28: Ovarian Cancer

Epidemiology

Pathology

WHO classification of malignant ovarian tumors

1. Common epithelial tumors (60% of all neoplasms of ovary; 90% of all malignant neoplasms of ovary)

2. Sex cord–stromal tumor (5% of malignant neoplasms of ovary)

3. Lipid (lipoid) cell tumors (rare)

4. Gonadoblastoma (rare)

Tumor Grade

• Grade 1—Well differentiated

• Grade 2—Moderately differentiated

• Grade 3—Poorly differentiated

Note: Serous carcinoma can be classified into either low grade or high grade

Ozols RF, Schwartz PE, Eifel PJ. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds. Cancer: Principles & Practice of Oncology, 6th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2001:1596–1632

5-year Relative Survival by Stage at Diagnosis

Treatment and survival by stage cannot be summarized simply for ovarian cancer. Each stage is strongly influenced by whether the disease is amenable to surgery, by the histologic type and grade, by the bulk of residual disease after the completion of surgery, and by other factors

Differences in survival among patients with the same stage of disease may indicate incomplete staging. When comprehensive staging is performed, a substantial number of patients initially believed to have disease confined to the pelvis will be staged upward

Work-up

1. Personal and family history, physical examination

2. Liver function tests, BUN, creatinine, LDH

3. CBC with platelets, PT, PTT, INR

4. Tumor markers (CA-125, α-fetoprotein (AFP), HCG)

5. CT scan of abdomen and pelvis, and chest x-ray. CT of chest if chest x-ray is abnormal

6. Radiographic tests of unclear utility: MRI of abdomen and pelvis, PET scan

Staging

Surgery

1. Ideally, a gynecologic oncologist should perform all surgical procedures for ovarian cancer, including:

   • Initial staging and debulking surgery

   • Second-look procedure (if done)

   • Any interval surgical debulking procedure

2. Goals of initial surgical procedure:

   • Stage disease

   • Remove all visible disease from the abdominopelvic cavity; or, if surgeon cannot remove all visible disease, remove all disease possible (debulking surgery)

3. Debulking important because subsequent survival and response to chemotherapy are linked to:

   • Dimension of the largest remaining tumor lesion after completion of surgery

   • Possibly, the overall volume of residual disease

4. Surgery alone is the preferred approach to patients with good-prognosis, early stage epithelial ovarian cancer:

   • Stage: Ia or Ib

   • Any epithelial histology other than clear cell

   • Well-differentiated or moderately well-differentiated histologic grade (low grade). (Any early stage patient other than the latter should have postsurgery chemotherapy.)

5. Neoadjuvant chemotherapy (has not received widespread acceptance):

   • Two to 3 cycles of chemotherapy before an initial staging and debulking procedure

   • Data suggest a less-morbid operation with reduced blood loss and a shorter operative procedure

Hoskins WJ et al. Am J Obstet Gynecol 1994;170:974–979; discussion 979–980

Schwartz PE, Zheng W. Gynecol Oncol 2003;90:644–650

Schwartz PE et al. Gynecol Oncol 1999;72:93–99

Germ Cell Tumors

The recommended laboratory evaluation for germ cell tumors should include:

1. A comprehensive metabolic panel, CBC with platelets, magnesium level, LDH, AFP, and HCG levels

2. Pulmonary function studies may be obtained

3. Complete surgical staging is recommended as initial surgery, with fertility-sparing surgery considered in those desiring fertility

Stage I dysgerminoma or immature teratoma

1. Patients who have had complete surgical staging and no evidence of disease is found outside the ovary should be observed

2. Patients who have had incomplete surgical staging for whom observation without chemotherapy is being considered, should undergo a complete staging procedure. If no evidence of disease is found outside the ovary these patients may be observed. If, at the time of a complete surgical staging, tumor is found outside the ovary, patients should receive bleomycin + etoposide + cisplatin (BEP) in the postoperative period

Stages II–IV dysgerminoma or stage I, grades 2–3 immature teratoma or embryonal tumors or endodermal sinus tumors

1. These patients should receive chemotherapy for 3–4 cycles with bleomycin + etoposide + cisplatin (BEP)

2. Patients achieving a complete clinical response should be observed clinically every 2–4 months with AFP and HCG levels (if initially elevated) for 2 years

3. Patients with radiographic evidence of residual tumor but with normal AFP and HCG levels should be considered for surgical resection of the tumor; observation can be considered

4. Patients with persistently elevated AFP and/or HCG after chemotherapy, or with clinically or radiographically evident disease, should receive chemotherapy or radiation or supportive care. Acceptable regimens for recurrent disease include:

   • Cisplatin + etoposide

   • VIP (etoposide + ifosfamide + cisplatin)

   • VeIP (vinblastine + ifosfamide + cisplatin)

   • VAC (vincristine + dactinomycin + cyclophosphamide)

Radiation

1. External beam radiation therapy:

   • Very useful in the treatment of some subsets of patients with early stage disease

   • Has fallen out of favor in the United States

   • Commonly used in some academic centers in Canada and Europe

   • Major drawback is the reduction in reserve function of organs within the radiation field, such as the bone marrow

   • Useful in the management of tumor masses that might cause extreme pain, bleeding, or other medical problems and in cases in which surgery is not a good option

   • On occasion, large lesions in the pelvis or metastases to bone (unusual) respond readily to radiation

2. Intraperitoneal colloidal ³²P:

   • Useful in the treatment of early stage disease

   • Can be of palliative value in other settings

   • Has fallen out of favor in the United States

3. Gamma-knife, intensity-modulated radiation therapy (IMRT), and standard whole-brain radiation:

   • Metastases to the brain occur uncommonly but are no longer considered rare

   • Several approaches are effective in controlling CNS disease

   • Use of these approaches depends on the clinical setting and the technology available

Ovarian Stromal Tumors

1. Patients with stages IA–C ovarian stromal tumors desiring fertility should be treated with fertility-sparing surgery. Otherwise, complete staging is recommended to all other patients

2. Those with surgical findings of stage I tumor should be observed

3. Patients having high-risk stage I (tumor rupture, poorly differentiated tumor, tumor size >10–15 cm) or stages II–IV tumors can be observed, or can receive radiation therapy or undergo cisplatin-based chemotherapy with germ cell regimens preferred

4. Patients subsequently having a clinical relapse may consider secondary cytoreductive surgery, enter a clinical trial, or be offered supportive care

Toxicities: Ovarian Cancer Chemotherapy

1. Myelosuppression

   Associated with all the agents listed in this chapter except tamoxifen. All 3 lineages are affected. Persistent thrombocytopenia is associated with the platinum compounds

2. Nausea and vomiting

   Preventive treatment is very important. Delayed nausea and vomiting is very common. Steroids, serotonin (HT₃)-receptor antagonists, and neurokinin (NK₁)-receptor antagonists are recommended for routine use with platinum-containing regimens

3. Renal dysfunction

   Seen with cisplatin and with carboplatin, but usually more clinically significant with cisplatin. Serum creatinine may be normal in the face of a markedly reduced creatinine clearance. This is important because other drugs that are eliminated by the kidney may be needed (eg, antibiotics). Platinum-related renal insufficiency is nonoliguric: be vigilant

4. Neurotoxicity

   Clinically occurs before detectable changes on EMG/NCTs. Bilateral paresthesias in stocking-and-glove distribution usually are progressive with repeated platinum doses and can become severe. Cisplatin is more likely to cause this problem than carboplatin

5. Fatigue/weakness

   May be related to anemia, but is a common side effect of several newer agents, including gemcitabine and topotecan

6. Altered sexual function

   A common side effect, but is seldom discussed spontaneously by a patient. It can be an underlying contributing factor to family disruption and clinical reactive depression; usually is a combined function of surgery and effect of neuroactive anticancer agent (platinum agents)

7. Clinical depression

   A common side effect. Many patients request medication for this. Sometimes may be a severe problem

8. Rare toxicities

   Acute hypersensitivity to paclitaxel. Acute hypersensitivity to cisplatin/carboplatin (usually occurs after 6–8 cycles of therapy). Desensitization is occasionally appropriate and can be successful. On most occasions, switch to another agent right away

Epithelial Ovarian Cancer (EOC), Primary Peritoneal Cancer (PPC), Fallopian Tube Cancer: Chemotherapy: Expert Opinion

Early stage disease [IA, IB, IC]

1. IA, grades 1/2 and IB, grades 1/2 (good prognosis, early stage disease):

   • Surgery alone is adequate therapy with a 95% 10-year survival rate

2. IA, grade 3, IB, grade 3, IC, grades 1/2/3, and some IA/IB grade 2 (early stage patients who are at increased risk for recurrence):

   • Three cycles of cisplatin + cyclophosphamide: reduced risk of recurrence, and improved survival

   • A comparable European study gives similar data for cisplatin alone versus ³²P

   • Three to 6 cycles of paclitaxel and carboplatin may offer as much benefit, but the data are not yet conclusive

Bolis G et al. Ann Oncol 1995;6:887–893

Young RC et al. J Clin Oncol 2003;21:4350–4355

Young RC. Semin Oncol 2000;27(3 Suppl 7):8–10

Advanced stage disease (Stage II, III or IV)

1. Standard of care for advanced stage disease:

   • Six to 8 cycles of paclitaxel + carboplatin, after debulking surgery

2. Additional standard option in <1 cm, optimally debulked, Stages II/II patients:

   • Intraperitoneal (IP) chemotherapy every 3 weeks for 6 cycles

     • (Day 1) Paclitaxel 135 mg/m² by continuous intravenous infusion over 24 hours

     • (Day 2) Cisplatin 75–100 mg/m² intraperitoneally

     • (Day 8) Paclitaxel 60 mg/m² intraperitoneally

3. Three-drug combinations in this setting provide no added benefit

   • GOG 182/ICON5: Five-arm randomized trial, to determine if adding either topotecan, gemcitabine, or pegylated liposomal doxorubicin in the frontline setting would extend PFS or OS. Control arm = paclitaxel and carboplatin IV every 3 weeks × 8 cycles. Accrual >1200 patients/year; 4312 women enrolled. None of the 3-drug regimens demonstrated an improvement in either PFS or OS. Survival analyses of groups defined by size of residual disease (optimal or suboptimal cytoreduction) also failed to show experimental benefit in any subgroup (Bookman et al. J Clin Oncol 2009)

4. Dose-dense weekly paclitaxel

   • A randomized phase III trial comparing a dose-dense regimen of weekly paclitaxel (days 1, 8, and 15) in combination with carboplatin every 3 weeks versus both agents administered once every 3 weeks, showed statistically significant improvement with the dose-dense paclitaxel regimen in: (a) PFS (28.0 vs. 17.2) and (b) OS at 3 years (72.1% vs. 65.1% [hazard ratio = 0.75; confidence interval, 0.57–0.98]). However, patient dropout was higher in the dose-dense group, primarily related to hematologic toxicity (Katsumata et al. Lancet 2009)

5. Generally, dose-intense approaches requiring stem cell support are ill advised

6. Benefit of "consolidation" therapy is uncertain (ie, several additional cycles of single-agent paclitaxel or a paclitaxel combination, after an initial 6 cycles of systemic treatment)

7. Whether maintenance therapy can increase PFS and, most importantly, increase OS is under evaluation. Most maintenance therapy strategies continue a regimen with lower toxicity and often include agents used in the primary treatment regimen

   • SWOG and GOG randomized women who achieved a CR with primary therapy to either 3 or 12 cycles of maintenance IV paclitaxel. Twelve cycles resulted in a 7-month PFS advantage but an uncertain OS advantage because of early termination

   • In Europe, Pecorelli et al. reported no gains in PFS or OS in patients given an additional 6 cycles of paclitaxel after a complete response from initial therapy

   • GOG 212 is ongoing (Paclitaxel or Polyglutamate Paclitaxel or Observation in Treating Patients With Stage III or Stage IV Ovarian Epithelial or Peritoneal Cancer or Fallopian Tube Cancer)

8. The benefit of adding bevacizumab to a standard frontline IV paclitaxel/carboplatin regimen administered every 3 weeks is under debate. Evidence suggests that in standard-risk patients, it does not confer any benefit. It remains to be determined whether it may be beneficial in high-risk patients. The GOG-218 and ICON7 trials suggest a role for maintenance bevacizumab in ovarian cancer; however, the absolute benefit in PFS is very modest, and neither trial showed an OS benefit. There is no level I evidence for (a) the use of bevacizumab in patients receiving intraperitoneal (IP) chemotherapy, or (b) the use of bevacizumab as neoadjuvant chemotherapy prior to surgical cytoreduction. In addition to resolving whether this therapy is indicated, future trials will need to address (a) an optimal bevacizumab dosage (7.5 mg/kg or 15 mg/kg every 3 weeks); (b) the optimal duration of bevacizumab maintenance (1 year, until progression, or beyond progression); and (c) any biologic predictors given bevacizumab's modest activity and substantial toxicity and cost

   • GOG 218 (3 arms): (a) cyclophosphamide + paclitaxel (CP); (b) CP + concomitant bevacizumab only, and (c) CP + concomitant and maintenance bevacizumab. After a median follow-up of 17.4 months, PFS was significantly prolonged with CP + concomitant and maintenance bevacizumab compared with CP alone (14.1 vs. 10.3 months; hazard ratio [HR] = 0.717; p <0.0001). Importantly there was no PFS advantage for CP + concomitant bevacizumab only over the CP-alone control arm (11.2 vs. 10.3 months; HR = 0.908; p = 0.080)

   • ICON7: Median PFS 19.8 months for women receiving concurrent and maintenance bevacizumab compared with 17.4 months for those in the control arm (P = 0.039). Overall survival, among all participants was not improved (HR for death of 0.85, 95% CI, 0.69–1.04). But in the high risk subgroup—stage III with ≥1 cm residual tumor after surgery and all stage IV patients—the HR was 0.64, 95% CI, 0.48–0.85, P = 0.002

Bookman MA et al. J Clin Oncol 2009;27:1419–1425. Erratum in: J Clin Oncol 2009;27:2305

Burger RA et al. Proc Am Soc Clin Oncol 2010;28(15S, Part I of II):5s [abstract LBA1]

du Bois A et al. Ann Oncol 2005;16(Suppl 8):viii7–viii12

Katsumata N et al. Lancet 2009;374:1331–1338

Kristensen G. Proc Am Soc Clin Oncol 2011;29(18S, Part II of II):781s [abstract LBA5006]

McGuire WP et al. N Engl J Med 1996;334:1–6

Ozols RF et al. J Clin Oncol 2003;21:3194–3200

Papadimitriou C et al. Bone Marrow Transplant 2008;41:547–554

Recurrent disease

1. Treatment of recurrent disease is complex. Decisions should be based on:

   • Likelihood of sensitivity/resistance to agents given in the past: platinum-sensitive or -resistant disease

   • Residual toxicity from prior treatments

   • Comorbid illnesses including renal, hepatic, and cardiac function

   • Desires of the patient

   Definitions:

   Platinum-refractory disease

   • Disease that grows through initial platinum-containing therapy

   • Platinum-sensitive disease

   • Epithelial ovarian cancer that recurs, ≥1–2 years after platinum-based chemotherapy

   • Response rate to retreatment with another platinum agent-based regimen tends to be high (<70%)

   Platinum-resistant disease

   • Definition: Disease progression in the face of appropriate initial platinum-based treatment or disease recurrence within the first 6 months after an initial response to platinum-based therapy

   • Prognosis: Poor, especially if disease progresses during the initial 6 cycles of therapy with platinum agents

   • Chemotherapy recommendations: Use of non–cross-resistant agents in the second-line and third-line settings is critically important

2. Patients with disease progression without evidence of benefit after the initial 2 therapies should either be enrolled on a clinical trial or enroll in hospice

3. Patients who have not received chemotherapy should be approached as discussed above under Advanced stage disease (Stage II, III, or IV)

4. Patients with "platinum-sensitive disease" can receive platinum doublets including:

   • Carboplatin + paclitaxel

   • Cisplatin + paclitaxel

   • Cisplatin + cyclophosphamide

   • Carboplatin + weekly paclitaxel

   • Carboplatin + docetaxel

   • Carboplatin + gemcitabine

   • Carboplatin + liposomal doxorubicin

   • Cisplatin + gemcitabine

   • Single-agent cisplatin

   • Single-agent carboplatin

   • Bevacizumab

5. Agents with activity in both platinum-sensitive and platinum-refractory disease include:

   • Docetaxel

   • Pemetrexed

   • Oral etoposide

   • Gemcitabine

   • Liposomal doxorubicin

   • Weekly paclitaxel

   • Topotecan

   • Fluorouracil

   • Altretamine (hexamethylmelamine)

6. Bevacizumab seems to be well tolerated and active in second-line and third-line treatments of patients with EOC/PPC. However, there is no evidence indicating that this is better tolerated or more active than myriad other agents previously examined in similar patients. Evidence must yet be developed to support its use in the second-line (or later) setting as a single agent or in combination with a cytotoxic drug (Burger RA et al. J Clin Oncol 2007; Cannistra SA et al. J Clin Oncol 2007)

   • OCEANS: A phase III trial comparing carboplatin and gemcitabine ± bevacizumab in women with platinum-sensitive recurrent ovarian cancer. A 3.7-month PFS advantage for women using bevacizumab, with an interim analysis of OS demonstrating a 5.6-month advantage for the bevacizumab arm

Burger RA et al. J Clin Oncol 2007;25:5165–5171

Cannistra SA et al. J Clin Oncol 2007;25:5180–5186

Leitao MM, Jr et al. Gynecol Oncol 2003;91:123–129

Markman M et al. Gynecol Oncol 2004;93:699–701

Markman M et al. J Cancer Res Clin Oncol 2004;130:25–28

Reed E et al. Gynecol Oncol 1992;46:326–329

Epithelial Ovarian Cancer (EOC), Primary Peritoneal Cancer (PPC), Fallopian Tube Cancer: Surgery: Expert Opinion

1. Ideally, a gynecologic oncologist should perform all surgical procedures for ovarian cancer, including:

   • Initial staging and debulking surgery

   • "Second look" procedures (if done)

   • Any interval surgical debulking procedure

2. Goals of initial surgical procedure:

   • Stage the disease

   • Remove all visible disease from the abdominopelvic cavity, or

   • If surgeon cannot remove all visible disease, remove all disease possible (debulking surgery)

3. Debulking is important because subsequent survival and response to chemotherapy are linked to:

   • Dimension of the largest remaining tumor lesions after the completion of surgery

   • Possibly the overall volume of residual disease

4. Surgery alone, is the preferred approach to patients with good prognosis early stage epithelial ovarian cancer:

   • Stages: IA or IB

   • Histology: Any epithelial histology other than clear cell

   • Histologic grade: Well-differentiated or moderately well-differentiated (any early stage patient other than these should have chemotherapy after surgery)

5. Neoadjuvant chemotherapy:

   • Two to 3 cycles of chemotherapy before an initial staging and debulking procedure

   • Data suggest a less-morbid operation, with reduced blood loss and a shorter operative procedure

   • Has not received widespread acceptance

Hoskins WJ et al. Am J Obstet Gynecol 1994;170:974–979; discussion 979–980

Schwartz PE et al. Gynecol Oncol 1999;72:93–99

Schwartz PE, Zheng W. Gynecol Oncol 2003;90:644–650

Platinum-Sensitive Regimen: Carboplatin + Paclitaxel

Ozols RF et al. J Clin Oncol 2003;21:3194–3200

Note: Regimen for optimally debulked ovarian cancer and suboptimally debulked disease as well

Premedication for paclitaxel:

Dexamethasone 10 mg/dose; administer orally for 2 doses 12 hours and 6 hours before paclitaxel, or

Dexamethasone 20 mg/dose; administer intravenously over 10–15 minutes, 30–60 minutes before paclitaxel (total dose/cycle = 20 mg)

Diphenhydramine 50 mg; administer by intravenous injection 30 minutes before paclitaxel

Cimetidine 300 mg (or ranitidine 50 mg, famotidine 20 mg, or an equivalent histamine receptor [H₂]-subtype antagonist); administer intravenously over 15–30 minutes, 30–60 minutes before paclitaxel

Paclitaxel 175 mg/m²; administer intravenously in a volume of 0.9% sodium chloride injection (0.9% NS) or 5% dextrose injection (D5W) sufficient to produce a concentration within the range 0.3–1.2 mg/mL, over 3 hours, on day 1, every 3 weeks (total dosage/cycle = 175 mg/m²)

Carboplatin (calculated dose) AUC = 7.5^✫; administer intravenously in 0.9% NS or D5W 100–500 mL over 60 minutes, on day 1 after completing paclitaxel, every 3 weeks for 6 cycles (total dosage/cycle calculated to produce a target AUC = 7.5 mg/mL · min)

In practice, creatinine clearance (Clcr) is used in place of glomerular filtration rate (GFR). Clcr can be calculated from the equation of Cockcroft and Gault:

Calvert AH et al. J Clin Oncol 1989;7:1748–1756

Cockcroft DW, Gault MH. Nephron 1976;16:31–41

Jodrell DI et al. J Clin Oncol 1992;10:520–528

Sorensen BT et al. Cancer Chemother Pharmacol 1991;28:397–401

Note: On October 8, 2010, the U.S. Food and Drug Administration (FDA) identified a potential safety issue with carboplatin dosing based on recent changes in the measurement of serum creatinine. By the end of 2010, all clinical laboratories in the United States began using the standardized isotope dilution mass spectrometry (IDMS) method to measure serum creatinine, which could result in an overestimation of the GFR in some patients with normal renal function. A carboplatin dose calculated with an IDMS-measured serum creatinine result using the Calvert formula could exceed an expected exposure (AUC) and result in increased drug-related toxicity

Provided actual GFR measurements are made to assess renal function, carboplatin can be safely dosed according to the Calvert formula described in product labeling

If GFR (or creatinine clearance) is estimated based on serum creatinine measurements by the IDMS method, the FDA recommends capping an estimated GFR at 125 mL/min for any targeted AUC value for patients with normal renal function. No greater estimated GFR values should be used

U.S. FDA. Carboplatin dosing. [online] October 8, 2010. Available from: http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm228974.htm

Supportive Care

Antiemetic prophylaxis

Emetogenic potential is HIGH. Potential for delayed symptoms

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is NOT indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

 Antimicrobial primary prophylaxis to be considered:

• Antibacterial—not indicated

• Antifungal—not indicated

• Antiviral—not indicated unless patient previously had an episode of HSV

See Chapter 47 for more information

Treatment Modifications

Toxicity (Carboplatin: N = 392)

Patient Population Studied

A randomized study of 792 women with pathologically verified Stage III epithelial ovarian cancer who were left with no residual disease >1 cm in diameter; 400 cisplatin arm and 392 carboplatin arm. McGuire et al. (N Engl J Med 1996;334:1–6) had shown that cisplatin plus paclitaxel was superior to cisplatin plus cyclophosphamide in advanced-stage epithelial ovarian cancer. This study was a noninferiority trial of cisplatin and paclitaxel versus carboplatin and paclitaxel to show equivalence of the 2 regimens

Efficacy (Carboplatin: N = 392)

Therapy Monitoring

Before repeated cycles: PE, CBC with differential, and serum electrolytes, magnesium, calcium, BUN, and creatinine

Platinum-Sensitive Regimen: Cisplatin + Paclitaxel

Ozols RF et al. J Clin Oncol 2003;21:3194–3200

Premedication with Dexamethasone 10 mg/dose; administer orally for 2 doses 12 hours and 6 hours before paclitaxel, or

Dexamethasone 20 mg; administer intravenously over 10–15 minutes, 30–60 minutes before paclitaxel (total dose/cycle = 20 mg)

Diphenhydramine 50 mg; administer by intravenous injection 30 – 60 minutes before paclitaxel

Cimetidine 300 mg (or Ranitidine 50 mg, Famotidine 20 mg, or an equivalent histamine receptor [H₂]-subtype antagonist); administer intravenously over 15 – 30 minutes, 30 – 60 minutes before paclitaxel

Paclitaxel 135 mg/m²; administer intravenously in a volume of 0.9% sodium chloride injection (0.9% NS) or 5% dextrose injection sufficient to produce a concentration within the range 0.3–1.2 mg/mL, over 24 hours on day 1, every 3 weeks, for 6 cycles (total dosage/cycle = 135 mg/m²)

Cisplatin 75 mg/m²; administer intravenously in 0.9% NS 100–250 mL over 1 hour, on day 2 after completing paclitaxel, every 3 weeks, for 6 cycles (total dosage/cycle = 75 mg/m²)

Note: Encourage patients to increase oral intake of nonalcoholic fluids, and provide electrolyte replacement as needed (potassium, magnesium, sodium)

Supportive Care

Antiemetic prophylaxis

Emetogenic potential during paclitaxel administration is LOW

Emetogenic potential during and after cisplatin administration is HIGH. Potential for delayed symptoms

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is NOT indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

 Antimicrobial primary prophylaxis to be considered:

• Antibacterial—not indicated

• Antifungal—not indicated

• Antiviral—not indicated unless patient previously had an episode of HSV

See Chapter 47 for more information

Efficacy (Comparison of Regimens)

Toxicity

Treatment Modifications

Notes

There were no differences in efficacy between the cisplatin + paclitaxel and the carboplatin + paclitaxel treatment regimens. However, there were differences with respect to toxicities. The authors interpreted the data as showing that the carboplatin + paclitaxel regimen was equally efficacious and significantly less toxic than the cisplatin + paclitaxel regimen

Platinum-Sensitive Regimen: Intraperitoneal Cisplatin and Paclitaxel

Armstrong DK et al. N Engl J Med 2006;354:34–43

Walker JL et al. Gynecol Oncol 2006;100:27–32

GOG Protocol #0172

Note: Regimen for Stage III epithelial ovarian or peritoneal carcinoma optimally debulked with no residual mass greater than 1 cm in diameter after surgery. Suboptimally debulked disease should not be treated with this regimen

Premedication for paclitaxel:

Dexamethasone 10 mg/dose; administer orally for 2 doses 12 hours and 6 hours before paclitaxel, or

Dexamethasone 20 mg/dose; administer intravenously over 10–15 minutes, 30–60 minutes before paclitaxel (total dose/cycle = 20 mg)

Diphenhydramine 50 mg; administer by intravenous injection 30 minutes before paclitaxel

Cimetidine 300 mg (or ranitidine 50 mg, famotidine 20 mg, or an equivalent histamine receptor [H₂]-subtype antagonist); administer intravenously over 15–30 minutes, 30–60 minutes before paclitaxel

Paclitaxel 135 mg/m²; administer intravenously in a volume of 0.9% sodium chloride injection (0.9% NS) or 5% dextrose injection (D5W) sufficient to produce a concentration within the range 0.3–1.2 mg/mL, over 24 hours on day 1, every 21 days, for 6 cycles (total dosage of paclitaxel intravenously/cycle = 135 mg/m²)

Intraperitoneal cisplatin

Hydration before cisplatin: ≥1000 mL 0.9% NS; administer by intravenous infusion over a minimum of 2–4 hours

Note: If a large amount of ascites is present, it should be drained prior to the instillation of cisplatin

Cisplatin 100 mg/m²; administer intraperitoneally as rapidly as possible in warmed (37°C [98.6°F]) 0.9% NS 2000 mL through an implanted peritoneal catheter on day 2, every 21 days, for 6 cycles (total dosage/21-day cycle = 100 mg/m²). Following the infusion, patients alternate position from prone, supine, and left and right lateral decubitus every 15 minutes over 2 hours to maximize drug distribution throughout the peritoneal cavity

Note: Do not attempt to retrieve the infusate

Hydration after cisplatin: ≥1000 mL 0.9% NS; administer by intravenous infusion over a minimum of 3–4 hours. Also encourage high oral fluid intake. Goal is to achieve a urine output of ≥100 mL/hour

Intraperitoneal paclitaxel

Note: If a large amount of ascites is present, it should be drained prior to the instillation of paclitaxel

Paclitaxel 60 mg/m²; administer intraperitoneally as rapidly as possible in warmed (37°C [98.6°F]) 0.9% NS or D5W 1000 mL through an implanted peritoneal catheter, followed by an additional 1000 mL of 0.9% NS or D5W on day 8, every 21 days, for 6 cycles (total dosage of paclitaxel administered intraperitoneally/21-day cycle = 60 mg/m²)

Note: Do not attempt to retrieve the infusate

Systemic cisplatin

If intraperitoneal therapy is discontinued, substitute:

Cisplatin 75 mg/m²; administer intravenously in 250 mL 0.9% NS over 30–60 minutes on day 2, every 21 days, for 3 cycles (total dosage/cycle = 75 mg/m²)

Supportive Care

Antiemetic prophylaxis

Emetogenic potential on days 1 and 8 is LOW

Emetogenic potential on day 2 is HIGH. Potential for delayed symptoms

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is NOT indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

 Antimicrobial primary prophylaxis to be considered:

• Antibacterial—not indicated

• Antifungal—not indicated

• Antiviral—not indicated unless patient previously had an episode of HSV

See Chapter 47 for more information

Arthralgia and myalgia G ≦2 associated with chemotherapy

Dexamethasone 4–8 mg/dose orally twice daily for 6 doses after chemotherapy

Treatment Modifications

Toxicity (N = 201)

Patient Population Studied

A study of 205 women with Stage III epithelial ovarian or peritoneal carcinoma optimally debulked with no residual mass greater than 1 cm in diameter after surgery. All patients had a Gynecologic Oncology Group (GOG) performance status of 0–2

Efficacy (N = 205)

Notes

1. Among all randomized phase III trials conducted by the GOG among patients with advanced ovarian cancer, this therapy yielded the longest median survival (65.6 months)

2. Only 42% of patients received all 6 cycles of intraperitoneal therapy

3. The primary reason for discontinuation of intraperitoneal therapy was catheter-related complications

4. Among 205 patients randomly allocated to the intraperitoneal arm, 58% (119) did not complete all 6 cycles of intraperitoneal therapy. Of these 119 patients, 34% (40/119 = 34%) discontinued intraperitoneal therapy primarily as a result of catheter complications, whereas 29% (34/119 = 29%) discontinued for unrelated reasons. Additionally, 37% (45/119 = 37%) discontinued for reasons that were possibly related to the intraperitoneal treatment (see table under toxicities)

5. Hysterectomy, appendectomy, small bowel resection, and ileocecal resection were not associated with failure to complete 6 cycles

6. There appears to be an association between rectosigmoid colon resection and the ability to initiate intraperitoneal therapy. Intraperitoneal therapy was not initiated 16% of patients who had a left colon or rectosigmoid colon resection versus 5% of those who did not have such a resection (p = 0.015)

7. Intraperitoneal therapy should begin as soon as possible after surgery. A delay of intraperitoneal therapy allows opportunity for adhesions to develop and may limit intraperitoneal distribution of the IP fluid

8. The 2 L of intraperitoneal fluid administered with the intraperitoneal therapy does not replace the need for intravascular hydration administration and adequate urine output. Administration of at least 1 L of 0.9% sodium chloride injection both prior to and after cisplatin is essential

Armstrong DK et al. N Engl J Med 2006;354:34–43

Walker JL et al. Gynecol Oncol 2006;100:27–32

Therapy Monitoring

1. Prior to start of therapy: PE, CBC with differential, electrolytes, serum creatinine, BUN, mineral panel, LFTs, CA-125, audiogram only in patients with a history of hearing loss, and chest x-ray

2. Weekly: CBC with differential

3. Prior to each cycle: PE, CBC with differential, electrolytes, serum creatinine, BUN, mineral panel, LFTs

Platinum-Sensitive Regimen: Cisplatin And Cyclophosphamide

Young RC et al. J Clin Oncol 2003;23:4350–4355

Cyclophosphamide 1000 mg/m²; administer intravenously in 1000 mL 0.9% sodium chloride injection (0.9% NS) over 30–60 minutes, on day 1, every 21 days, for 3 cycles (total dosage/cycle = 1000 mg/m²)

Cisplatin 100 mg/m²; administer intravenously in 250 mL 0.9% NS over 30–60 minutes, on day 1, after cyclophosphamide, every 21 days, for 3 cycles (total dosage/cycle = 100 mg/m²)

Note: Encourage patients to increase oral intake of nonalcoholic fluids, and provide electrolyte replacement as needed (potassium, magnesium, sodium)

Supportive Care

Antiemetic prophylaxis

Emetogenic potential is HIGH. Potential for delayed symptoms

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis may be indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

 Antimicrobial primary prophylaxis to be considered:

• Antibacterial—not indicated

• Antifungal—not indicated

• Antiviral—not indicated unless patient previously had an episode of HSV

See Chapter 47 for more information

Patient Population Studied

Prospective randomized clinical trial conducted by the GOG of 251 patients: 124 patients randomized to ³²P and 127 randomized to chemotherapy. Eligible patients were either FIGO Stage Ia or Ib (grade 3), or Stage Ic or II (any grade). In addition, all Stages I and II patients with clear cell histology (any grade) were eligible

Efficacy

Toxicity

Therapy Monitoring

Before repeated cycles: PE, CBC with differential, and serum electrolytes, magnesium, calcium, BUN, and creatinine

Notes

Although compared with intraperitoneal ³²P, there were no statistically significant differences in survival, the authors concluded: "The lower cumulative recurrence seen with CP (cisplatin + cyclophosphamide) and complications of ³²P administration make platinum-based combinations the preferred adjuvant therapy for early ovarian cancer patients at high-risk for recurrence"

Treatment Modifications

Platinum-Sensitive Regimen: Platinum Retreatment (Cisplatin or Carboplatin)

Leitao M et al. Gynecol Oncol 2003;91:123–129

Hydration before cisplatin: ≥1000 mL 0.9% sodium chloride injection (0.9% NS); administer intravenously over a minimum of 3–4 hours. Monitor and replace magnesium/electrolytes as needed

Cisplatin 80–100 mg/m²; administer intravenously in 100–500 mL 0.9% NS over 30–60 minutes on day 1, every 3 weeks, for a maximum of 8 cycles (total dosage/3-week cycle = 80–100 mg/m²)

Hydration after cisplatin: ≥1000 mL 0.9% NS; administer intravenously over a minimum of 3–4 hours. Also encourage high oral fluid intake. Goal is to achieve a urine output of ≥100 mL/hour

or

Carboplatin (calculated dose) AUC = 6; administer by intravenous infusion in 50–150 mL D5W over 15–30 minutes on day 1, every 3 weeks (total dosage/cycle calculated to produce an AUC = 6 mg/mL · min)

^✫Carboplatin dose is based on a formula described by Calvert et al. to achieve a target area under the plasma concentration versus time curve (AUC)

In practice, creatinine clearance (Clcr) is used in place of glomerular filtration rate (GFR). Clcr can be estimated from the equation of Cockcroft and Gault, thus:

Calvert AH et al. J Clin Oncol 1989;7:1748–1756

Cockcroft DW, Gault MH. Nephron 1976;16:31–41

Jodrell DI et al. J Clin Oncol 1992;10:520–528

Sorensen BT et al. Cancer Chemother Pharmacol 1991;28:397–401

Note: On October 8, 2010, the U.S. Food and Drug Administration (FDA) identified a potential safety issue with carboplatin dosing based on recent changes in the measurement of serum creatinine. By the end of 2010, all clinical laboratories in the United States began using the standardized isotope dilution mass spectrometry (IDMS) method to measure serum creatinine, which could result in an overestimation of the GFR in some patients with normal renal function. A carboplatin dose calculated with an IDMS-measured serum creatinine result using the Calvert formula could exceed an expected exposure (AUC) and result in increased drug-related toxicity

Provided actual GFR measurements are made to assess renal function, carboplatin can be safely dosed according to the Calvert formula described in product labeling

If GFR (or creatinine clearance) is estimated based on serum creatinine measurements by the IDMS method, the FDA recommends capping an estimated GFR at 125 mL/min for any targeted AUC value for patients with normal renal function. No greater estimated GFR values should be used

U.S. FDA. Carboplatin dosing. [online] October 8, 2010. Available from: http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm228974.htm

Supportive Care

Antiemetic prophylaxis

Emetogenic potential is MODERATE–HIGH (carboplatin) or HIGH (cisplatin). Potential for delayed symptoms with either carboplatin or cisplatin

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is indicated with 1 of the following:

 Filgrastim (G-CSF) 5 mcg/kg per day by subcutaneous injection, or

 Pegfilgrastim (pegylated filgrastim) 6 mg/0.6 mL, by subcutaneous injection for 1 dose

• Begin use from 24–72 hours after myelosuppressive chemotherapy is completed

• Continue daily filgrastim use until ANC ≥10,000/mm³ on 2 measurements separated temporally by ≥12 hours

• Discontinue daily filgrastim use at least 24 hours before repeating myelosuppressive treatment. Do not administer pegfilgrastim within 14 days before administering myelosuppressive treatment

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW–INTERMEDIATE

 Antimicrobial primary prophylaxis to be considered:

• Antibacterial—consider a fluoroquinolone or no prophylaxis

• Antifungal—not indicated

• Antiviral—not indicated unless patient previously had an episode of HSV

See Chapter 47 for more information

Arthralgia and myalgia G ≥2 associated with chemotherapy

Dexamethasone 4–8 mg/dose orally twice daily for 6 doses after chemotherapy

Treatment Modifications

Efficacy (N = 30)

Patient Population Studied

A study of 30 patients with platinum-resistant ovarian cancer, who received nonplatinum chemotherapy for recurrent epithelial ovarian cancer before additional platinum therapy. Platinum resistance was defined as less than a partial response to platinum therapy or progression within 6 months of the last platinum therapy

Therapy Monitoring

1. Before repeated cycles: PE, CBC with differential, serum electrolytes, magnesium, calcium, BUN, and creatinine

2. Every month: Serum CA-125 level

3. Every 2–3 months: Restaging radiographic studies

Toxicity

Epithelial Ovarian Cancer Regimen: Gemcitabine + Carboplatin

Pfisterer J et al. J Clin Oncol 2006;24:4699–4707

Gemcitabine 1000 mg/m² per dose; administer intravenously in 50–250 mL 0.9% sodium chloride injection (0.9% NS) over 30–60 minutes for 2 doses, on days 1 and 8, every 21 days (total dosage/cycle = 2000 mg/m²)

Note: On day 1, administer after hydration for carboplatin, then follow with carboplatin

Carboplatin (calculated dose) AUC = 4 mg/mL · min^✫; administer intravenously in 0.9% NS or 5% dextrose injection 100–500 mL over 1 hour, on day 1 after completing gemcitabine, every 3 weeks (total dosage/cycle calculated to produce a target AUC = 4 mg/mL · min)

In practice, creatinine clearance (Clcr) is used in place of glomerular filtration rate (GFR). Clcr can be estimated from the equation of Cockcroft and Gault, thus:

Calvert AH et al. J Clin Oncol 1989;7:1748–1756

Cockcroft DW, Gault MH. Nephron 1976;16:31–41

Jodrell DI et al. J Clin Oncol 1992;10:520–528

Sorensen BT et al. Cancer Chemother Pharmacol 1991;28:397–401

Note: On October 8, 2010, the U.S. Food and Drug Administration (FDA) identified a potential safety issue with carboplatin dosing based on recent changes in the measurement of serum creatinine. By the end of 2010, all clinical laboratories in the United States began using the standardized isotope dilution mass spectrometry (IDMS) method to measure serum creatinine, which could result in an overestimation of the GFR in some patients with normal renal function. A carboplatin dose calculated with an IDMS-measured serum creatinine result using the Calvert formula could exceed an expected exposure (AUC) and result in increased drug-related toxicity

Provided actual GFR measurements are made to assess renal function, carboplatin can be safely dosed according to the Calvert formula described in product labeling

If GFR (or creatinine clearance) is estimated based on serum creatinine measurements by the IDMS method, the FDA recommends capping an estimated GFR at 125 mL/min for any targeted AUC value for patients with normal renal function. No greater estimated GFR values should be used

U.S. FDA. Carboplatin dosing. [online] October 8, 2010. Available from: http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm228974.htm

Supportive Care

Antiemetic prophylaxis

Emetogenic potential on days with gemcitabine alone is LOW

Emetogenic potential on days with carboplatin is MODERATE. Potential for delayed symptoms

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is NOT indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

 Antimicrobial primary prophylaxis to be considered:

• Antibacterial—not indicated

• Antifungal—not indicated

• Antiviral—not indicated unless patient previously had an episode of HSV

See Chapter 47 for more information

Patient Population Studied

Patients with platinum-sensitive recurrent ovarian cancer were randomly assigned to receive either gemcitabine plus carboplatin or carboplatin alone. The primary objective was to compare progression-free survival (PFS)

Dose Modifications

Toxicity

Efficacy

Therapy Monitoring

1. Baseline: LFTs, serum chemistry, CBC with differential and platelet count, and CA-125. Complete history and physical examination including a gynecologic examination

2. Follow-up: CBC with differential and platelet count on days 1, 8, and 15 of each cycle

Epithelial Ovarian Cancer Regimen: Liposomal Doxorubicin + Carboplatin

Pujade-Lauraine E et al. J Clin Oncol 2010;28:3323–3329

Doxorubicin HCl liposome injection (liposomal doxorubicin) 30 mg/m²; administer intravenously in 250 mL (doses ≤90 mg) 5% dextrose injection over 60 minutes, on day 1 before carboplatin, every 4 weeks (total dosage/cycle = 30 mg/m²)

Note: Doxorubicin HCl liposome injection should be administered at an initial rate of 1 mg/min to minimize the risk of infusion reactions. If no infusion-related adverse events are observed, the rate of infusion can be increased to complete administration of the drug over 1 hour

Note: Experience with doxorubicin HCl liposome injection at high cumulative doses is too limited to have established its effects on the myocardium. Therefore, it should be assumed that it will have myocardial toxicity similar to conventional formulations of doxorubicin HCl. Irreversible myocardial toxicity leading to congestive heart failure often unresponsive to cardiac supportive therapy may be encountered as the total cumulative lifetime dosage of doxorubicin HCl approaches 450–550 mg/m². Prior anthracyclines or anthracenediones will reduce the total dose of doxorubicin HCl that can be given without associated cardiac toxicity. Cardiac toxicity also may occur at lower cumulative doses in patients receiving concurrent cyclophosphamide therapy

Carboplatin (calculated dose) AUC = 5^✫; administer intravenously in 0.9% sodium chloride injection or D5W 100–500 mL over 60 minutes, on day 1 after completing liposomal doxorubicin administration, every 4 weeks (total dosage/cycle calculated to produce a target AUC = 5 mg/mL · min)

In practice, creatinine clearance (Clcr) is used in place of glomerular filtration rate (GFR). Clcr can be estimated from the equation of Cockcroft and Gault, thus:

Calvert AH et al. J Clin Oncol 1989;7:1748–1756

Cockcroft DW, Gault MH. Nephron 1976;16:31–41

Jodrell DI et al. J Clin Oncol 1992;10:520–528

Sorensen BT et al. Cancer Chemother Pharmacol 1991;28:397–401

Note: On October 8, 2010, the U.S. Food and Drug Administration (FDA) identified a potential safety issue with carboplatin dosing based on recent changes in the measurement of serum creatinine. By the end of 2010, all clinical laboratories in the United States began using the standardized Isotope Dilution Mass Spectrometry (IDMS) method to measure serum creatinine, which could result in an overestimation of the GFR in some patients with normal renal function. A carboplatin dose calculated with an IDMS-measured serum creatinine result using the Calvert formula could exceed an expected exposure (AUC) and result in increased drug-related toxicity

Provided actual GFR measurements are made to assess renal function, carboplatin can be safely dosed according to the Calvert formula described in product labeling

If GFR (or creatinine clearance) is estimated based on serum creatinine measurements by the IDMS method, the FDA recommends capping an estimated GFR at 125 mL/min for any targeted AUC value for patients with normal renal function. No greater estimated GFR values should be used

U.S. FDA. Carboplatin dosing. [online] October 8, 2010. Available from: URL: http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm228974.htm

Supportive Care

Antiemetic prophylaxis

Emetogenic potential is MODERATE. Potential for delayed symptoms

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is NOT indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

 Antimicrobial primary prophylaxis to be considered:

• Antibacterial—not indicated

• Antifungal—not indicated

• Antiviral—not indicated unless patient previously had an episode of HSV

See Chapter 47 for more information

Hand-foot reaction (palmar-plantar erythrodysesthesia, PPE)

For patients who develop a hand-foot reaction, use topical emollients (eg, Aquaphor), topical or orally administered steroids, antihistamine agents (H₁-receptor antagonists), or pyridoxine

• Pyridoxine may provide relief for discomfort/pain associated with PPE although the mechanism through which this occurs remains unclear

• The suggested pyridoxine starting dose is 50 mg/day, which may be increased to a maximum of 200 mg/day

Patients who have developed G1/2 PPE while receiving doxorubicin HCl liposome injection may receive a fixed daily dose of pyridoxine 200 mg. This may allow for treatment to be completed without dosage reduction, treatment delay, or recurrence of PPE

Patient Population Studied

Patients with histologically proven ovarian cancer with recurrence ≥6 months after first- or second-line platinum and taxane-based therapies. Randomization against paclitaxel + carboplatin. Primary end point was progression-free survival (PFS); secondary end points were toxicity, quality of life, and overall survival

Efficacy

Therapy Monitoring

1. Baseline: LFTs, serum chemistry, CBC with differential and platelet count, and CA-125. Complete history and physical examination including a gynecologic examination

2. Baseline ECG and left ventricular ejection fraction measurement by echocardiogram or multigated angiography. A left ventricular ejection fraction measurement before each course of therapy if cumulative anthracycline dose exceeds 450 mg/m²

3. Follow-up: CBC with differential and platelet count on days 1, 8, and 15 of each cycle, and LFTs prior to commencing repeated cycles

Toxicity

Dose Modifications

Epithelial Ovarian Cancer Regimen: Carboplatin + Docetaxel

Strauss HG et al. Gynecol Oncol 2007;104:612–616

Premedication with Dexamethasone 8 mg/dose; administer orally twice daily for 3 days (6 doses), starting on the day before docetaxel administration (total dose/cycle = 48 mg) or

Dexamethasone 4 mg/dose; administer orally for 3 doses during the evening before, morning of, and evening after docetaxel administration (total dose/cycle = 12 mg)

Docetaxel 75 mg/m²; administer intravenously in a volume of 0.9% sodium chloride injection (0.9% NS) or 5% dextrose injection (D5W) sufficient to produce a docetaxel concentration within the range 0.3–0.74 mg/mL over 30 minutes on day 1 before carboplatin, every 3 weeks for 6 cycles (total dosage/cycle = 75 mg/m²), followed by:

Carboplatin [calculated dose] AUC = 5^✫; administer intravenously in 0.9% NS or D5W 100–500 mL over 60 minutes, on day 1 after completing docetaxel, every 3 weeks for 6 cycles (total dosage/cycle calculated to produce a target AUC = 5 mg/mL · min)

In practice, creatinine clearance (Clcr) is used in place of glomerular filtration rate (GFR). Clcr can be estimated from the equation of Cockcroft and Gault, thus:

Calvert AH et al. J Clin Oncol 1989;7:1748–1756

Cockcroft DW, Gault MH. Nephron 1976;16:31–41

Jodrell DI et al. J Clin Oncol 1992;10:520–528

Sorensen BT et al. Cancer Chemother Pharmacol 1991;28:397–401

Note: On October 8, 2010, the U.S. Food and Drug Administration (FDA) identified a potential safety issue with carboplatin dosing based on recent changes in the measurement of serum creatinine. By the end of 2010, all clinical laboratories in the United States began using the standardized isotope dilution mass spectrometry (IDMS) method to measure serum creatinine, which could result in an overestimation of the GFR in some patients with normal renal function. A carboplatin dose calculated with an IDMS-measured serum creatinine result using the Calvert formula could exceed an expected exposure (AUC) and result in increased drug-related toxicity

Provided actual GFR measurements are made to assess renal function, carboplatin can be safely dosed according to the Calvert formula described in product labeling

If GFR (or creatinine clearance) is estimated based on serum creatinine measurements by the IDMS method, the FDA recommends capping an estimated GFR at 125 mL/min for any targeted AUC value for patients with normal renal function. No greater estimated GFR values should be used

U.S. FDA. Carboplatin dosing. [online] October 8, 2010. Available from: http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm228974.htm

Supportive Care

Antiemetic prophylaxis

Emetogenic potential is MODERATE. Potential for delayed symptoms

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is NOT indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

 Antimicrobial primary prophylaxis to be considered:

• Antibacterial—not indicated

• Antifungal—not indicated

• Antiviral—not indicated unless patient previously had an episode of HSV

See Chapter 47 for more information

Patient Population Studied

Eligible patients had recurrent ovarian, peritoneal or tubal cancer (platinum-free interval >6 months), performance status 0–2. Patients with had undergone surgical debulking for recurrent disease were excluded from the study. First-line chemotherapy in 25 patients included carboplatin/paclitaxel (21), carboplatin/docetaxel (1), carboplatin/cyclophosphamide (1), and carboplatin alone (2). Patients with preexisting peripheral neuropathy G ≥2 (NCI Common Toxicity Criteria, version 2.0; 1998) were excluded

Efficacy

Dose Modifications

Toxicity

Therapy Monitoring

1. Baseline: LFTs, serum chemistry, CBC with differential and platelet count, and CA-125. Complete history and physical examination, including a gynecologic examination

2. Follow-up: CBC with differential and platelet count at least weekly through leukocyte and platelet count nadirs, and prior to beginning repeated cycles, and LFTs before commencing repeated cycles

Epithelial Ovarian Cancer Regimen: Carboplatin + Docetaxel

Kushner DM et al. Gynecol Oncol 2007;105:358–364

Premedication:

Dexamethasone 4 mg/dose; administer orally for 3 doses during the evening before, morning of, and evening after docetaxel administration (total dose/cycle = 12 mg)

Docetaxel 35 mg/m² per dose (maximum single dose limited to 70 mg)^✫; administer intravenously in a volume of 0.9% sodium chloride injection (0.9% NS) or 5% dextrose injection (D5W) sufficient to produce a final docetaxel concentration within the range 0.3–0.74 mg/mL, over 60 minutes for 3 doses, before carboplatin on days 1, 8, and 15, every 28 days (total dosage/cycle = 105 mg/m²; maximum dose/cycle = 210 mg), followed by:

Carboplatin (calculated dose) AUC = 2^†; administer intravenously in 0.9% NS or D5W 100–500 mL over 30 minutes for 3 doses, after completing docetaxel on days 1, 8, and 15, every 28 days (total dosage/cycle calculated to produce a cumulative target AUC = 6 mg/mL · min)

Notes: Carboplatin hypersensitivity led to 11 subjects coming off trial (31%). Diphenhydramine premedication produced a nonsignificant decrease in reaction rate

In the clinical trial, treatment was continued until evidence of disease progression, intolerable toxicity, patient refusal of further treatment, or physician decision that it was in the best interest of a patient to discontinue therapy. Patients who achieved a complete response (CR) continued therapy for 2 cycles following documentation of CR

In practice, creatinine clearance (Clcr) is used in place of glomerular filtration rate (GFR). Clcr can be estimated from the equation of Cockcroft and Gault, thus:

Calvert AH et al. J Clin Oncol 1989;7:1748–1756

Cockcroft DW, Gault MH. Nephron 1976;16:31–41

Jodrell DI et al. J Clin Oncol 1992;10:520–528

Sorensen BT et al. Cancer Chemother Pharmacol 1991;28:397–401

Note: On October 8, 2010, the U.S. Food and Drug Administration (FDA) identified a potential safety issue with carboplatin dosing based on recent changes in the measurement of serum creatinine. By the end of 2010, all clinical laboratories in the United States began using the standardized isotope dilution mass spectrometry (IDMS) method to measure serum creatinine, which could result in an overestimation of the GFR in some patients with normal renal function. A carboplatin dose calculated with an IDMS-measured serum creatinine result using the Calvert formula could exceed an expected exposure (AUC) and result in increased drug-related toxicity

Provided actual GFR measurements are made to assess renal function, carboplatin can be safely dosed according to the Calvert formula described in product labeling

If GFR (or creatinine clearance) is estimated based on serum creatinine measurements by the IDMS method, the FDA recommends capping an estimated GFR at 125 mL/min for any targeted AUC value for patients with normal renal function. No greater estimated GFR values should be used

U.S. FDA. Carboplatin dosing. [online] October 8, 2010. Available from: http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm228974.htm

Supportive Care

Antiemetic prophylaxis

Emetogenic potential is MODERATE

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is NOT indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

 Antimicrobial primary prophylaxis to be considered:

• Antibacterial—not indicated

• Antifungal—not indicated

• Antiviral—not indicated unless patient previously had an episode of HSV

See Chapter 47 for more information

Patient Population Studied

Thirty-six patients were enrolled in a prospective phase II study of a weekly docetaxel and carboplatin regimen. Patients eligible for the trial had an initial diagnosis of ovarian or primary peritoneal carcinoma. Initial treatment with a platinum-based regimen was required, with a treatment-free interval of at least 3 months. Patients could have received 1 prior regimen for recurrence. At the time of enrollment, patients were required to have a Gynecologic Oncology Group performance status of <2, neuropathy (sensory and motor) grade ≤2 (NCI Common Toxicity Criteria), and recovered from effects of recent surgery, radiotherapy, or chemotherapy. Biologically evaluable disease (CA-125) could be followed only if measurable disease was not present. The majority of patients had ovarian cancer (89%) and Stages III/IV (97%) disease, with a median initial disease-free interval of 12 months. Most subjects were treated for first recurrence (81%) and had measurable disease (58%)

Toxicity

Dose Modifications

Efficacy

Therapy Monitoring

1. Baseline: LFTs, serum chemistry, CBC with differential and platelet count, and CA-125. Complete history and physical examination, including a gynecologic examination

2. Follow-up: CBC with differential and platelet count on days 1, 8, and 15, and LFTs before commencing repeated cycles

Epithelial Ovarian Cancer Regimen: Cisplatin + Gemcitabine

Rose PG et al. Gynecol Oncol 2003;88:17–21

Gemcitabine 750 mg/m² per dose; administer intravenously in 50–250 mL sodium chloride injection (0.9% NS) over 30–60 minutes for 2 doses, on days 1 and 8, every 21 days (total dosage/cycle = 1500 mg/m²), followed by:

Hydration before cisplatin with ≥1000 mL 0.9% NS; administer intravenously over a minimum of 3–4 hours

Cisplatin 30 mg/m² per dose; administer intravenously in 100–500 mL 0.9% NS over 30–60 minutes for 2 doses, on days 1and 8, every 21 days (total dosage/cycle = 60 mg/m²)

Hydration after cisplatin with ≥1000 mL 0.9% NS; administer intravenously over a minimum of 3–4 hours

Notes: Encourage increased oral intake of nonalcoholic fluids. Goal is to achieve a urine output ≥100 mL/hour. Monitor and replace electrolytes as needed (potassium, magnesium, sodium)

Supportive Care

Antiemetic prophylaxis

Emetogenic potential is MODERATE–HIGH. Potential for delayed symptoms

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is NOT indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

 Antimicrobial primary prophylaxis to be considered:

• Antibacterial—not indicated

• Antifungal—not indicated

• Antiviral—not indicated unless patient previously had an episode of HSV

See Chapter 47 for more information

Patient Population Studied

Thirty-six patients with ovarian or peritoneal cancers whose disease was platinum- and paclitaxel-refractory, and who had failed to benefit from multiple second-line agents, were treated with a combination of gemcitabine and cisplatin. Tumors were defined as platinum-resistant if disease had progressed on or within 6 months after patients had completed their most recent platinum regimen. Patients had received a median of 2 (range: 1–5) prior platinum- or paclitaxel-based regimens, were heavily pretreated, and had received a median of 3 nonplatinum/nonpaclitaxel regimens (range: 0–6 regimens). Despite this, the majority of patients had an excellent performance status: ECOG = 0

Efficacy

Toxicity

Dose Modifications

Therapy Monitoring

1. Baseline: LFTs, serum chemistry (including potassium, magnesium, and sodium), CBC with differential and platelet count, and CA-125. Complete history and physical examination, including a gynecologic examination

2. Follow-up: CBC with differential and platelet count at least weekly through leukocyte and platelet count nadirs, and serum potassium, magnesium, and sodium before repeated treatment

3. Repeat LFTs before commencing repeated cycles

Epithelial Ovarian Cancer Regimen: Carboplatin + Weekly (Dose-Dense) Paclitaxel

Katsumata N et al. Lancet 2009;374:1331–1338

Note: Regimen for optimally debulked ovarian cancer. Suboptimally debulked disease can be treated with this regimen as well

Premedication:

Dexamethasone 10 mg/dose; administer orally for 2 doses 12 hours and 6 hours before paclitaxel, or

Dexamethasone 20 mg/dose; administer intravenously over 10–15 minutes, 30–60 minutes before paclitaxel on days 1, 8, and 15 (total dose/cycle = 60 mg)

Diphenhydramine 50 mg; administer by intravenous injection 30–60 minutes before paclitaxel

Cimetidine 300 mg (or ranitidine 50 mg, famotidine 20 mg, or an equivalent histamine receptor [H₂]-subtype antagonist); administer intravenously over 15–30 minutes, 30–60 minutes before paclitaxel

Paclitaxel 80 mg/m² per dose; administer intravenously in a volume of 0.9% sodium chloride injection (0.9% NS) or 5% dextrose injection (D5W) sufficient to produce a concentration within the range 0.3–1.2 mg/mL, over 60 minutes for 3 doses, on days 1, 8, and 15, every 3 weeks (total dosage/cycle = 240 mg/m²)

Carboplatin (calculated dose) AUC = 6^✫; administer intravenously in 0.9% NS or D5W 100–500 mL over 60 minutes, on day 1 after completing paclitaxel, every 3 weeks (total dosage/cycle calculated to produce a target AUC = 6 mg/mL · min)

In practice, creatinine clearance (Clcr) is used in place of glomerular filtration rate (GFR). Clcr can be estimated from the equation of Cockcroft and Gault, thus:

Calvert AH et al. J Clin Oncol 1989;7:1748–1756

Cockcroft DW, Gault MH. Nephron 1976;16:31–41

Jodrell DI et al. J Clin Oncol 1992;10:520–528

Sorensen BT et al. Cancer Chemother Pharmacol 1991;28:397–401

Note: On October 8, 2010, the U.S. Food and Drug Administration (FDA) identified a potential safety issue with carboplatin dosing based on recent changes in the measurement of serum creatinine. By the end of 2010, all clinical laboratories in the United States began using the standardized isotope dilution mass spectrometry (IDMS) method to measure serum creatinine, which could result in an overestimation of the GFR in some patients with normal renal function. A carboplatin dose calculated with an IDMS-measured serum creatinine result using the Calvert formula could exceed an expected exposure (AUC) and result in increased drug-related toxicity

Provided actual GFR measurements are made to assess renal function, carboplatin can be safely dosed according to the Calvert formula described in product labeling

If GFR (or creatinine clearance) is estimated based on serum creatinine measurements by the IDMS method, the FDA recommends capping an estimated GFR at 125 mL/min for any targeted AUC value for patients with normal renal function. No greater estimated GFR values should be used U.S. FDA. Carboplatin dosing. [online] October 8, 2010. Available from: http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm228974.htm

Supportive Care

Antiemetic prophylaxis

Emetogenic potential on days with carboplatin is HIGH. Potential for delayed symptoms

Emetogenic potential on days with paclitaxel alone is LOW

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is NOT indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

 Antimicrobial primary prophylaxis to be considered:

• Antibacterial—not indicated

• Antifungal—not indicated

• Antiviral—not indicated unless patient previously had an episode of HSV

See Chapter 47 for more information

Patient Population Studied

Phase III, open-label, randomized trial conducted in 95 centers in Japan. Patients had a histologically or cytologically proven diagnosis of Stages II to IV epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer. Eastern Cooperative Oncology Group (ECOG) performance status of 0–3, and adequate organ function. Patients were excluded if they had an ovarian tumor with a low malignant potential. Previous chemotherapy was not allowed

Dose Modifications

Efficacy

Toxicity

Therapy Monitoring

1. Baseline: LFTs, serum chemistry, CBC with differential and platelet count, and CA-125. Complete history and physical examination, including a gynecologic examination

2. Follow-up: CBC with differential and platelet count at least weekly through leukocyte and platelet count nadirs, and before beginning repeated cycles

3. Before beginning repeated cycles: Repeat LFTs

Epithelial Ovarian Cancer Regimen: Pemetrexed

Miller DS et al. J Clin Oncol 2009;27:2686–2691

Vergote I et al. Eur J Cancer 2009;45:1415–1423

Ancillary medications:

Folic acid 350–1000 mcg; administer daily beginning 1–2 weeks before the first dose of pemetrexed and continue until 3 weeks after the last pemetrexed dose

Cyanocobalamin (vitamin B₁₂) 1000 mcg; administer by intramuscular injection every 9 weeks, beginning 1–2 weeks before the first dose of pemetrexed, and continue until 3 weeks after the last pemetrexed dose

Dexamethasone 4 mg; administer orally twice daily for 3 days (6 doses) starting the day before each pemetrexed dose (total dose/cycle = 24 mg)

Notes: Nonsteroidal antiinflammatory drugs should be held for 2 days before and 2 days after pemetrexed administration

Pemetrexed 500 mg/m²; administer intravenously in 10 mL 0.9% sodium chloride injection (0.9% NS) over 10 minutes on day 1, every 21 days, for a maximum of 6 cycles (unless there was earlier evidence of disease progression or intolerance of the study treatment) (total dosage/cycle = 500 mg/m²)

Note: In a randomized double blind phase II study, pemetrexed 500 mg/m² had comparable activity with a more favorable toxicity profile than a dosage of 900 mg/m²

Supportive Care

Antiemetic prophylaxis

Emetogenic potential is LOW

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is NOT indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

 Antimicrobial primary prophylaxis to be considered:

• Antibacterial—not indicated

• Antifungal—not indicated

• Antiviral—not indicated unless patient previously had an episode of HSV

See Chapter 47 for more information

Dose Modifications

Patient Population Studied

Patients with histologically confirmed recurrent or metastatic epithelial ovarian cancer or primary peritoneal cancer. Their disease had to be considered platinum-resistant or refractory according to standard GOG criteria (treatment-free interval after platinum-based therapy of less than 6 months or progression during platinum-based therapy). Patients must have had, and were allowed to receive, no more than 1 prior platinum-based chemotherapeutic regimen, containing carboplatin, cisplatin, or another organoplatinum compound, for management of primary disease. GOG performance status of 0–2

Therapy Monitoring

1. Baseline: LFTs, serum chemistry, CBC with differential and platelet count, and CA-125. Complete history and physical examination including a gynecologic examination

2. Follow-up: CBC with differential and platelet count at least weekly through leukocyte and platelet count nadirs, and before beginning repeated cycles

3. Before beginning repeated cycles: Repeat LFTs

Efficacy^✫

Toxicity

Epithelial Ovarian Cancer Regimen: Docetaxel

Kaye SB et al. Eur J Cancer 1995;31A(Suppl 4):S14–S17

Premedication:

Dexamethasone 8 mg/dose; administer orally twice daily for 3 days (6 doses) starting on the day before docetaxel administration (total dose/cycle = 48 mg) or

Dexamethasone 4 mg/dose; administer orally for 3 doses during the evening before, morning of, and evening after docetaxel administration (total dose/cycle = 12 mg)

Docetaxel 75–100 mg/m²; administer intravenously in a volume of 0.9% sodium chloride injection or 5% dextrose injection sufficient to produce a docetaxel concentration within the range of 0.3–0.74 mg/mL over 60 minutes on day 1, every 21 days, for 4 cycles (total dosage per cycle = 75–100 mg/m²)

Supportive Care

Antiemetic prophylaxis

Emetogenic potential is LOW–MODERATE

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is NOT indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

 Antimicrobial primary prophylaxis to be considered:

• Antibacterial—not indicated

• Antifungal—not indicated

• Antiviral—not indicated unless patient previously had an episode of HSV

See Chapter 47 for more information

Patient Population Studied

Evaluation of docetaxel administration in 293 patients with advanced ovarian cancer in 3 phase II trials. All patients had previously received cisplatin and/or carboplatin as first-line treatment. In all 3 studies, docetaxel 100 mg/m² was administered every 3 weeks, without premedication for hypersensitivity reactions or emesis. At the time of the analysis, 200 patients were evaluable for response

Therapy Monitoring

1. Baseline: LFTs, serum chemistry, CBC with differential and platelet count, and CA-125. Complete history and physical examination including a gynecologic examination

2. Follow-up: CBC with differential and platelet count at least weekly through leukocyte and platelet count nadirs, and prior to beginning repeated cycles

3. Before beginning repeated cycles: Repeat LFTs

Toxicity

Treatment Modifications

Efficacy

Platinum-Refractory or Platinum-Resistant Regimen: Fluorouracil + Leucovorin

Reed E et al. Gynecol Oncol 1992;46:326–329

Leucovorin 500 mg/m² per dose; administer intravenously in 25–100 mL 0.9% sodium chloride injection or 5% dextrose injection over 30 minutes, daily for 5 consecutive days, on days 1–5, every 21 days (total dosage/cycle = 2500 mg/m²), followed after 1 hour by:

Fluorouracil 375 mg/m² per dose; administer by intravenous injection over 3–5 minutes, daily, 1 hour after the completion of leucovorin, for 5 consecutive days, days 1–5, every 21 days (total dosage/cycle = 1875 mg/m²)

Supportive Care

Antiemetic prophylaxis

Emetogenic potential is LOW

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is NOT indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

 Antimicrobial primary prophylaxis to be considered:

• Antibacterial—not indicated

• Antifungal—not indicated

• Antiviral—not indicated unless patient previously had an episode of HSV

See Chapter 47 for more information

Patient Population Studied

A study of 29 patients with recurrent advanced-stage ovarian cancer of epithelial histology who had progressive disease while receiving or had suffered relapse after high-dose cisplatin therapy

Efficacy (N = 29)

Toxicity (N = 29/204 Cycles)