a report by

D r A l a n N G o r d on

Clinical Professor of Obstetrical Gynecology, University of Arizona School of Medicine

Long- term Sur v iva l Advantage for Recurrent Ovar ian Cancer Pat ient sRece iv ing Pegy la ted L iposomal Doxorub ic in

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Pharmacological Therapy OVARIAN CANCER

Ovarian cancer remains the leading cause of deathfrom gynaecologic malignancies. Althoughendometrial cancer occurs more frequently, thevast majority of patients who develop this diseasepresent with post-menopausal or other irregularbleeding problems and are usually diagnosed withearly-stage disease and experience long survival. Incontrast, the presenting signs and symptoms ofovarian cancer are non-specific and almost 75% ofpatients already have extensive abdominal disease atthe time of diagnosis (stage IIIC and IV). Thefailure to be able to detect ovarian cancer at earlierstages has led to it being labelled ‘the silent killer’.

The use of extensive debulking procedures, whichmay include resections of the gastrointestinal (GI)or urinary tracts, can decrease the tumour burdenfor cytotoxic chemotherapy and help to prolongsurvival. The addition of taxanes to platinum-basedtherapy have led to significant improvement inboth progression-free and overall survival inpatients with either optimally reduced or sub-optimally reduced advanced-stage disease.

Currently, ovarian cancer patients are living longerand as the disease tends to remain within theperitoneal cavity without affecting vital organs,patients may maintain a good performance statusfor a long time. Unfortunately, disease usuallyrelapses. Relapse may be heralded by elevation ofCA-125 and eventually symptoms and evidence ofdisease will appear, leading to treatment ofrecurrent disease. With patients living longer andreceiving therapy for longer periods of time, thereis a need for agents that are well tolerated, lackingof cumulative toxicity and able to maintain qualityof life rather than worsen it due to unintended side effects.

Treatment at time of relapse has been guided bythe interval from the patients’ prior platinumexposure. Those patients who had demonstratedprogression of disease while on platinum-basedtherapy, or relapsed within six months from theirlast platinum therapy, were thought to beplatinum-resistant and should be treated with othernon-cross-resistant agents. Patients who had

initially responded and demonstrated clinicalprogression more than six months after their lastplatinum therapy were thought to have potentiallyplatinum-sensitive disease and would be re-treatedwith platinum agents.

The probability of responding to re-treatmentincreases with time from the last platinumexposure. After a platinum-free interval of twoyears, response rates may approach 60%, which issimilar to initial response rates in untreated disease.Although response rates at earlier intervals werelower, prior to the late 1990s there were no agentsthat were thought to have significant activity inrelapsed ovarian cancer and platinum-based therapywas the standard.

Paclitaxel did exhibit activity in recurrent ovariancancer but, based on several studies, quickly movedinto first-line therapy as part of a taxane andplatinum-based combination. Then, several agentsin phase II trials showed promising activity inrelapsed ovarian cancer. A phase III trial,comparing topotecan with paclitaxel, showedstatistically equivalent response rates and survivaldata in paclitaxel naïve patients. Based largely onthis data, topotecan was approved for use inrelapsed ovarian cancer by the US Food and DrugAdministration (FDA). Phase II trials withpegylated liposomal doxorubicin (PLD) that hadbeen underway had shown activity for PLD inplatinum refractory ovarian cancer. It was thendecided to proceed with a phase III trial comparingPLD with topotecan.

The results of this phase III trial were initiallyreported in 2001. There were 474 patients enrolledfrom 104 sites from around the world. Patientswere stratified upon enrollment based on platinumsensitivity or resistance and on the presence orabsence of bulky disease. There was no differencein response rates in the overall or any subgroupanalysis. In the survival data that were available,there was no difference in progression-free oroverall survival for the entire group. However,there was a significant improvement inprogression-free survival and an even greater

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DOI: 10.17925/OHR.2005.00.00.83

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improvement in overall survival for the platinum-sensitive patients initially treated with PLD. Therewas a large number of censored events as many ofthe patients had not progressed or died at the timeof the report. After more than 90% of the patientshad recurred or died, a planned updated analysiswas performed to re-evaluate the survival data.

With long-term follow-up, overall survival for allpatients now showed a statistically significantimprovement for initial therapy with PLD.Although the median survivals were similar at 63weeks for PLD versus 60 weeks for topotecan,there was an 18% risk reduction in death for allpatients that was significant, with p=0.032. Therewere still no significant differences in the patientswith platinum-resistant disease. However, in theplatinum-sensitive group, patients initially treatedwith PLD did significantly better. The mediansurvival was 27 months for initial treatment withPLD versus 17.5 months for initial treatment withtopotecan. Overall, there was a 30% risk reduction

in death for initial treatment with PLD that wassignificant at p=0.017.

What does this mean for patients with platinumrefractory disease? Currently, there are threerandomised phase III trials of single agents inplatinum-resistant disease. All agents have shownsimilar activity whether measured by response orsurvival data. No single agent has been shown to besuperior to another; therefore, in patients withplatinum-refractory disease, the choice of agentshould be based on toxicity and quality of lifecriteria. The lack of alopecia, minimal nausea/vomiting, minimal myelosuppression and ease ofadministration, with a lack of cumulative toxicity,would favour PLD as an initial choice for manypatients with platinum-refractory disease. Someauthors have shown activity for the combination of gemcitabene and cisplatinum in patients withresistant disease; however, there is significanttoxicity with this regimen and a randomisedcomparison has not been performed.

In patients with platinum-sensitive disease, severalphase III trials have compared non-platinumagents; however, there are no available datacomparing platinum with a non-platinum agent inplatinum-sensitive disease. Response rates for allagents in all the randomised trials are about 30%,which is similar to the response rates reported forplatinum re-treatment in the 12- to 24-monthplatinum-free interval. In view of the prolongedprogression-free and overall survival seen withPLD relative to topotecan, response rates may not

be the best measure of activity in this group ofpatients. It is still not possible to compare a non-platinum agent with a platinum analogue;however, based on the improved progression-freeand overall survival with PLD, this should be thefirst choice of the non-platinum agents.

Recently, two randomised trials have comparedsingle-agent carboplatin with carboplatincombination in platinum-sensitive patients. ICON4 used paclitaxel as the second agent anddemonstrated significantly improved response rates,progression-free survival and overall survival in thepatients receiving the combination. The AGO-

Table 1: Patient Demographics

ICON 4 30–49 AGO

>12 75% 44% 60%

months

No Prior 58% 26% 32%

Taxane

Figure 1: PLD Relative to ICON 4

1-year survival (%) 2-year survival (%) Median survival (months) Response (months)

PLD

Carbo

T+C79 78

83

5550

57

2824

29 29

54

66

100

75

50

25

0

With long-term follow-up, overall survival for all patients

now showed a statistically significant improvement for initial

therapy with PLD.

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ABBREVIATED PRESCRIBING INFORMATION

Caelyx 10ml contains doxorubicin hydrochloride 2mg/ml in a liposome formulation for intravenous infusion.Uses: Caelyx is indicated as monotherapy for patients withmetastatic breast cancer, where there is an increased cardiac risk; for treatment of advanced ovarian cancer in women who have failed a first-line platinum-basedchemotherapy regimen; for treatment of AIDS-relatedKaposi’s sarcoma (KS) in patients with low CD4 counts < 200 CD4 lymphocytes/mm3) and extensive muco-cutaneous or visceral disease, as first-line or second linechemotherapy of disease that has progressed with, or inpatients intolerant to, prior combination systemicchemotherapy comprising at least two of the followingagents: a vinca alkaloid, bleomycin and standard doxoru-bicin (or other anthracycline).Dosage: Breast Cancer/Ovarian cancer: Caelyx is adminis-tered intravenously at a dose of 50mg/m2 once every 4weeks for as long as the disease does not progress and thepatient continues to tolerate treatment.For doses < 90mg: dilute Caelyx in 250ml 5% (50mg/ml)glucose solution for infusion.For doses ≥ 90mg: dilute Caelyx in 500ml 5% (50mg/ml)glucose solution for infusion.To minimize the risk of infusion reactions, the initial dose isadministered at a rate no greater than 1mg/minute. If noinfusion reaction is observed, subsequent Caelyx infusionsmay be administered over a 60 minute period.AIDS-related KS: Caelyx should be administered intra-venously at 20mg/m2 every two-three weeks. Intervalsshorter than 10 days should be avoided to prevent drugaccumulations and possible increased toxicity. Treatmentshould last for 2-3 months to achieve a therapeuticresponse and continued as needed to maintain response.

Contra-indications: Patients with history of hypersensitiv-ity to doxorubicin or other components, or who arebreast-feeding. Caelyx should not be used in AIDS-KS thatmay be effectively treated with local therapy or systemicalfa-interferon.Precautions and Warnings: As with all doxorubicin treat-ment, patients should undergo frequent ECG monitoringfor reduction of QRS which may indicate cardiac toxicityand monitoring of cardiac function (eg echocardiographyor MUGA). Patients with history of cardiovascular diseaseshould only receive Caelyx if the benefits outweigh poten-tial risk. Infusion-associated reactions may occur—see SPCfor details.Caution is needed in patients who have received prioranthracycline therapy and dosage adjustment may be need-ed. Myelosuppression should be monitored by periodicblood counts during treatment with Caelyx. Caelyx is not recommended for use in pregnant women. Women ofchild-bearing potential should avoid pregnancy whilst theyor their male partners are receiving Caelyx.The most common undesirable effect reported inbreast/ovarian clinical trials palmar-plantar erythrodyses-thesia (PPE), characterised by painful, macular reddeningskin eruptions, mostly mild. PPE infrequently resulted inpermanent treatment discontinuation. Stomatitis/mucositisand nausea were also commonly reported in breast/ovari-an cancer patient populations, whereas myelosuppression(mostly leukopaenia) was the most common side effect inAIDS-KS patients.Clinically significant laboratory abnormalities were infre-quent, with elevated total bilirubin, AST and ALT reportedin 2.4%, 1.6% and < 1% of patients respectively. No clinical-ly significant increases in serum creatinine were reported.Most frequent side-effects are myelosuppression, leukopae-nia, anaemia, neutropaenia and thrombocytopaenia.

Adjustment of Caelyx dosing interval may be needed insuch cases.Other effects are nausea, asthenia, alopecia, fever,diarrhoea, infusion associated reactions, stomatitis, palmar-plantar syndrome, oral candidiasis, nausea and vomiting,weight loss, rash, mouth ulceration, dyspnoea, abdominalpain, allergic reaction, vasodilation, anorexia, glossitis, con-stipation, paresthesia, pain, skin decolouration, dry skin,pharyngitis, dyspepsia, somnolence and retinitis. Bullouseruption has been reported rarely in AIDS-KS patients.Undesirable effects reported for Caelyx-treated breastcancer patients, were breast pain, leg cramps, oedema, legoedema, peripheral neuropathy, oral pain, ventriculararrhythmia, folliculitis, bone pain, musculo-skeletal pain,thrombocythemia, cold sores (non-herpetic), fungal infec-tion, epistaxis, upper respiratory tract infection, bullouseruption, dermatitis, erythematous rash, nail disorder, scalyskin, lacrimation, and blurred vision.Overdosage worsens myelosuppression and patientsshould be hospitalised for symptomatic treatment of toxiceffects. Summary of Product Characteristics (SmPC) shouldbe consulted for further details.Presentations: 10ml vial containing 2mg/ml doxorubicinhydrochloride; 25ml vial containing 2mg/ml doxorubicinhydrochlorideLegal Category: Prescription Only Medicine;Marketing Authorisation Numbers: 10ml vial:EU/1/96/011/001; 25ml vial: EU/1/96/011/002.Marketing Authorisation Holder: S-P Europe, Rue deStalle 73, Brussels, Belgium.Date of Revision of text: February 2003

Schering-Plough

In platinum-sensitive recurrent ovarian cancerConfirmed: CAELYXTMsignificantly prolongs survival compared with topotecan1

*National Institute for Health and Clinical Excellence.

CAELYX™ is indicated as monotherapy for patients with metastatic breast cancer, wherethere is an increased cardiac risk; for treatment of advanced ovarian cancer in women whohave failed a first-line platinum-based chemotherapy regimen; and for treatment of AIDS-relatedKaposi’s sarcoma.

References: 1. Long-term survival advantage for recurrent ovarian cancer patients receivingpegylated liposomal doxorubicin. US Oncology Review 2004 (Business Briefing) 24-26.2. Overall survival advantage for pegylated liposomal doxorubicin compared to topotecanin recurrent epithelial ovarian cancer. Eur J Cancer (ECCO 12, Copenhagen, Denmark,Sept 21-25, 2003);1(5):Abstr 157. 3. NationaI Institute for Clinical Excellence, FinalAppraisal Determination, March 2005.

LONG - TERM ANALYSIS REINFORCES CAELYX™ SUPERIORITY1, 2

• 18% risk reduction in death for all patients withCAELYX™ vs topotecan: P=0.032 (N=474)

UPDATED NICE* GUIDELINES RECOMMEND EARLIER USE OF CAELYX™3

• The only single agent option for the newly recognized category of partial platinum sensitivity3– Tumor recurrence at 6 to 12 months following initial

platinum-based treatment

• Also recommended for platinum-resistant or platinum-refractory advanced disease

“…the only non-platinum agent to demonstrate a progression-free and overall survival advantagein platinum-sensitive disease…”1

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GCIC trial used gemcitabene as the second agent inthe combination. While the combination againshowed a significantly better response rate andprogression-free survival, there was no difference inoverall survival.

Does this mean that all patients with platinum-sensitive disease should be retreated withcombination platinum-based therapy? Although allof these trials were randomised, there aresignificant demographic differences that mayexplain some of the apparent differences in thestudy results (see Table 1).

The ICON 4 study had a greater number ofpatients who relapsed after 12 months relative tothe AGO-GCIC trial, which in turn was greaterthan that in the trial of PLD versus topotecan. Asimilar pattern was seen when looking at thenumber of patients who had not received prior

taxane in each study. A single agent wouldcertainly be expected to have a lower response ratethan a combination; however, the two-yearsurvival with single agent PLD was similar to thatof the platinum–taxane combination in ICON 4and the median survival was equivalent to thecombination (see Figure 1). The response rate ofsingle-agent PLD was equivalent to that of single-agent carboplatin in the AGO trial (see Figure 2).The progression-free survival was superior tosingle-agent carboplatin and similar to thegemcitabene combination and the median overallsurvival of single-agent PLD was superior to eitherarm of the AGO trial.

Those patients who have a prolonged platinum-free interval, will probably have a betterprogression-free and possibly overall survival withcombination therapy; however, for those patientswith early platinum-sensitive relapse, i.e. six to 12months, the data does not clearly indicate anadvantage for platinum-based therapy at this time.

In summary, no agent or combination has shownany significant improvement by any measure inplatinum-resistant disease. The ease ofadministration and low toxicity profile wouldfavour the use of PLD as the agent of choice inplatinum-resistant disease. PLD is the only non-platinum agent to demonstrate a progression-freeand overall survival advantage in platinum-sensitivedisease and should be the first choice wheneverresorting to a non-platinum agent.

Although combination therapy has shownimprovement on response rates and progression-free survival in platinum-sensitive patients, it is notclear at this time that equivalent results might notbe achieved with sequential single-agent therapy,without the added toxicity. ■

0

10

20

30

40

50

Response (%) PFS (%) Median Survival (months)

PLD

Carbo

G+C

2931

47

7.25.8

8.6

28

17.3 18

Figure 2: PLD Relative to GCIG

Table 2: Randomised Trials in Platinum-resistant Ovarian Cancer

Study Author/year N Conclusion

Paclitaxel versus Topotecan* ten Bokkel Huinink; 226 Equivalent activity

J. Clin. Oncol. 1997, Annals 2004

PLD versus Topotecan Gordon; J. Clin. Oncol. 2001, 255 Equivalent activity; less

Gynecol. Oncol. 2004 serious toxicity

PLD versus Paclitaxel O’Byrne; ASCO 2002 131 Equivalent activity;

alternative without alopecia,

neuropathy

Topotecan qd X 5 versus Hoskins; J. Clin. Oncol. 1998 63 Improved activity with daily

q wk* administration

Paclitaxel q 3 week versus Andersson; ASCO 2000 208 Equivalent activity; q wk

q wk* regimen has less toxicity

Paclitaxel/epirubicin Bolis; Gynecol. Oncol. 1999 81 Equivalent activity

versus paclitaxel

*Includes patients with platinum-sensitive disease.

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E S G O 1 4 I S T A N B U L 2 0 0 5

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