Other Options in the Recurrent Disease Setting

Despite the important data supporting the usefulness of carboplatin-based combination chemotherapy in recurrent ovarian cancer, it is not known whether the outcome of treatment (progression-free and overall survival) would be equivalent, but perhaps with less toxicity, if the agents were delivered in sequence rather than together.6,24 For example, patients could receive three cycles of carboplatin, followed by three cycles of paclitaxel (or gemcitabine, or liposomal doxorubicin). Unfortunately, without randomized phase III trial data, the answer to the usefulness of this rational alternative is simply unknown.

The delivery of non-platinum single-agent therapy in recurrent ovarian cancer is another option, particularly in a patient experiencing platinum hypersensitivity21 or who has preexisting toxicity from primary platinum-based therapy (e.g., persistent grade 2-3 neuropathy). Even in the setting of prior modestly severe (but disconcerting) toxicity (e.g., grade 2 emesis after each chemotherapy regimen lasting for several days), a patient may elect to be treated with a non-platinum strategy.

In addition, for patients whose treatment- or platinum-free interval minimally satisfies the definition of recurrent disease (e.g., 6 to 9 months), a reasonable case can be made to initiate treatment with an alternative drug.7-9 Of course, this argument is made stronger if the patient experienced difficulty tolerating the initial treatment program.

A number of cytotoxic agents have been shown to possess a sufficient level of biologic activity in phase II studies in recurrent or resistant ovarian cancer such that they may reasonably be considered to be used in this setting25 (Box 9-5). Unfortunately, very limited randomized phase III data exist to help in the selection of the best single agent to use in this patient population (Fig. 9-5).

One phase III study should be highlighted because the results appear to indicate the superiority (both an improvement in progression-free and overall survival) of single-agent liposomal doxorubicin, compared with single-agent topotecan, in recurrent ovarian cancer12,26 (Fig. 9-6). Although the data are of considerable interest and certainly document the clinical utility of liposomal doxorubicin in this setting, it must be noted that neither of these single agents has been compared with a platinum drug—either alone or as a component of a combination strategy.14

Furthermore, this trial is also notable for the fact that a rather modest improvement in progression-free survival in favor of the liposomal doxorubicin regimen (median: 5.6 weeks) translates to a substantial difference in overall survival (median:

Box 9-5. Antineoplastic Agents with Demonstated Activity in Recurrent or Platinum-Resistant Ovarian Cancer

Altretamine

Liposomal doxorubicin

Bevacizumab

Oxaliplatin

Docetaxel

Paclitaxel (q3 weeks, weekly)

Epirubicin

Pemetrexed

Etoposide (orally for 21 days)

Tamoxifen

Gemcitabine

Topotecan (q3 weeks, weekly)

Ifosfamide

Trabectedin (not FDA-approved)

Irinotecan

Vinorelbine

Extent of disease after cytoreductive surgery

Optimal stage III

( Suboptimal stage III-Ivj

Response to initial chemotherapy

Response Stable Progression Response

Stable

Progression

CR PR

Treatment-free interval

>6 months

<6 months

Recurrent disease, platinum sensitive

Recurrent disease, platinum resistant

Persistent disease

Refractory disease drug resistant

• Phase II trials Other second line*

Small-volume residual:

• IP platinum or paclitaxel

• Continue platinum ± paclitaxel

• Biological trials

Large-volume residual:

• Continue platinum ± paclitaxel

*Other second-line regimens include topotecan, prolonged oral etoposide, liposomal doxorubicin, weekly paclitaxel, and gemcitabine.

Figure 9-5. Decision map, based on extent of disease after cytoreductive surgery and response to chemotherapy. More precise definition of the treated population helps Inform the use of a particular regimen in routine clinical practice. Unfortunately, limited randomized phase III data exist to help in the selection of the "best" single agent. CR, complete response; IP, intraperitoneal; PR, partial response. (From Markman M, Bookman MA: Second-line treatment of ovarian cancer. Oncologist 5:26-35, 2000, Fig. 1.)

80 70 60 50 40 30 20

80 70 60 50 40 30 20

0 20 40 60 80 100 120 140 160 180 200 220 240 260

Weeks since first dose

0 20 40 60 80 100 120 140 160 180 200 220 240 260

Weeks since first dose

Pegylated liposomal doxorubicin (n = 239) Topotecan (n = 235)

100 120 140 160 180 200 220 240 260

Weeks since randomization

Pegylated liposomal doxorubicin (n = 240) Topotecan (n = 241)

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