Future Directions

As intraperitoneal (IP) chemotherapy has become a recommended option for advanced ovarian cancer, trials have also assessed the benefit of intraperitoneal therapy in early stages. Several of these trials have reported similar outcomes, that is, approximately a 15% to 20% cancer recurrence rate38-40 (Table 8-7). Since adjuvant regimens for early ovarian cancer essentially have been extrapolated from treatment of advanced disease, intraperitoneal therapy should be considered an alternative to intravenous chemotherapy for some subsets of early ovarian cancer. The National Comprehensive Cancer Network (NCCN) lists the following intraperitoneal regimen as an alternative for stage II: paclitaxel 135 mg/m2, IV 24-hour infusion on day 1; cisplatin 100 mg/m2, IP on day 2 after paclitaxel; paclitaxel 60 mg/m2, IP on day 8. Cycles are repeated every 3 weeks. Use of a venous catheter with a subcutaneous access port is shown in Figure 8-7.

A review of the various adjuvant treatments for early-stage epithelial ovarian cancer over the last two to three decades reveals surprisingly similar outcomes for radiation therapy techniques and chemotherapy agents of differing classes (Fig. 8-8). The risk of recurrent cancer in this patient population seems to have remained relatively unchanged over the years. Seemingly, some proportion of patients, perhaps 20% to 25%, has cancer that is resistant to various forms of adjuvant cytotoxic therapy. The door remains open for innovative research using combination chemotherapy, biologic modifiers, and molecular targeting agents.

The two major obstacles to finding a future therapy of greater benefit in early-stage disease are (1) defining true stage I cancers by accurate surgical staging and (2) the statistical design of the trials. The potential problem of including occult stage III patients in cohorts of nonoptimally staged patients has been previously discussed. In addition, the statistical design of these trials remains a challenge because the relatively small number of recurrent events or deaths occurring over fairly long intervals after treatment requires enormous sample sizes to detect clinically reasonable differences in outcomes.

Some researchers have suggested that biologic and molecular markers can either complement or replace surgical staging in apparent early-stage disease by predicting the outcome of treatment. The magnitude of research in molecular prognostic markers for ovarian cancer is beyond the scope of this chapter, but the future of adjuvant therapy in early disease could be defined by the identification of accurate prognostic markers. Table 8-8 gives a brief summary of some of the prognostic factors other than FIGO staging.41 Some investigators have developed models of prognostic markers. One such model in early ovarian cancer incorporated grade, p53, and EGFR.42 The model was applied to 226 patients with stage IA-IIC who had undergone a modified surgical staging operation followed by pelvic radiation, whole-abdomen

Table 8-7. Results of Intraperitoneal Chemotherapy in Early-Stage Ovarian Cancer

Trial Stage N IP Chemotherapy Outcome

Malmstrom (1994)38 I, II 47 Carboplatin x 4 cycles 23% relapse

Topuz (2001)39 IC 13 Cisplatin and mitoxantrone median 84% 5-year DFS

5 cycles

Fujiwara (2003)40 I 54 Carboplatin alone or with IV 81% 5-year DFS

cyclophosphamide or paclitaxel

DFS, disease-free survival; IP, intraperitoneal.

Huberpoint needle Self-sealing septum

Suture

Skin Pocket Sleeve

Suture

Catheter -

Muscle

Figure 8-7. A, Implanted peritoneal access catheter with subcutaneous self-sealing port providing a path for intraperitoneal therapy. B, Intraperitoneal chemotherapy. (From DiSaia PJ, Creasman WT (eds): Clinical Gynecologic Oncology, 7th ed. Philadelphia: Mosby, 2007, Fig. 11-25.)

Catheter -

Muscle

Intraperitoneal P-32 (GOG) Melphalan x 12 (GOG) Cisplatin/cytoxan x 3 (GOG) Carbo/paclitaxel x 3 (GOG)

Carbo/paclitaxel x 6 (GOG)

Cisplatin x 6 (Norwegian Hospital)

Platinum combo x 4 (EORTC)

72 73 74 75 76 77 78 79 80 Percent

Figure 8-8. Five-year recurrence-free rates for high-risk stage I ovarian cancer following various adjuvant therapies. Carbo, carboplatin.

Table 8-8. Nonstaging Factors That May Predict Outcome in Early-Stage Ovarian Cancer

Prognostic Factor Decreased Recurrence Increased Recurrence

Table 8-8. Nonstaging Factors That May Predict Outcome in Early-Stage Ovarian Cancer

Prognostic Factor Decreased Recurrence Increased Recurrence

Histology

Clear cell

Grade

Grade 1

Grade 3

DNA ploidy

Diploid

Aneuploid

HER2/neu

Normal expression

Overexpressed

Morphometry

Low volume

High volume

p53 mutation

Absent

Overexpressed

Bcl-2

Present

Absent

PDGF

Absent

Overexpressed

EGFR

Absent

Present

EGFR, epidermal growth factor receptor; PDGR, platelet-derived growth factor. Adapted from McGuire WP: Current aspects of adjuvant therapy of early stage ovarian cancer. Zentralbl Gynakol 120(3):93-97, 1998.

EGFR, epidermal growth factor receptor; PDGR, platelet-derived growth factor. Adapted from McGuire WP: Current aspects of adjuvant therapy of early stage ovarian cancer. Zentralbl Gynakol 120(3):93-97, 1998.

radiation, or four cycles of platinum-based chemotherapy. Patients with grade 1-2 tumors whose results were negative for p53 and EGFR had a 5-year disease-free survival of 89% compared with 39% for patients with grade 3 tumors that were also positive for p53 and EGFR (P = .00008). An intermediate risk model with any other combination of the three factors was associated with a 66% disease-free survival (P = .0006). In a regression analysis, FIGO substage was not significantly associated with disease-free survival, whereas grade, p53, and EGFR were. Since this study did not report what percentage of patients underwent the modified surgical staging operation and because lymph node dissection was not part of the operation, the model may apply only to incompletely staged patients.

Another confounding factor is the use of various adjuvant therapies. Nevertheless, it does show the potential value of combining molecular markers to better define prognosis, for example, as applied to the intermediate-risk group with grade 1 histology, positive p53, and positive EGFR. Such models may prove very useful in future trials whereby adjuvant therapy could be modified or tailored based on stratification into high- and low-risk groups. Such trials may also test molecular targeting for the high-risk groups as defined in Box 8-2. In addition, future strategy should include studies of prognostic factors applied to patients who are completely staged and receive no adjuvant therapy. This type of study could identify markers that are significantly associated with recurrence in true stage I disease.

Even if molecular markers were able to replace optimal surgical staging in gross stage I disease, until this happens future trials in early ovarian cancer are likely to require staging operations at least sufficient to separate stage I from stage II disease because of clinically significant different relapse rates between the two. In a recent GOG trial in which all patients received adjuvant chemotherapy, the recurrence rate for stage II was nearly twice that for stage I (33% versus 18%).29 This inferior prognosis of stage II patients has prompted the GOG to shift stage II patients to future protocols of advanced-stage disease. In addition, the NCCN recommendations for treatment of stage II are the same as for stages III and IV (Box 8-5 and Fig. 8-9).

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