**8. Recurrent ovarian cancer**

Recurrent ovarian cancer can be diagnosed by the appearance of new symptoms, radiologic evidence of recurrent disease or a rising CA-125 level in an asymptomatic patient.

In the past, treatment for recurrent ovarian cancer was given based on rising levels of tumor markers alone even without symptoms. However, a phase III randomized study (OV05- EORTC 55955) demonstrated no survival benefit of starting chemotherapy based on the increasing level of CA-125 alone and that quality of life may be improved by awaiting the appearance of symptoms or signs of ovarian cancer recurrence.

In this study treatment was delayed by a median of 4.8 months with no benefice on OS (HR 1.01; 95% CI 0.82–1.25; P = 0.91) [27]. Similarly, third-line treatment was started 4.6 months earlier in the patients who had regular CA 125 monitoring. Quality of life was lower in the early treatment group [27].

The choice of chemotherapy agents in recurrent disease is based on the response to first line treatment, the current symptoms; the time elapsed from last chemotherapy and the side effects of previous drugs administered.

The prognosis and the response to second-line therapy and subsequent lines depends in great part on the progression-free interval after the last dose of the preceding line of chemotherapy.

We define:

when intraperitoneal administration is performed compared with intravenous infusion [23]. Moreover, avascular tumors are more exposed to higher drug concentrations with intraperi-

A meta-analysis of five clinical trials confirmed a benefit in OS for intraperitoneal chemotherapy [25]. This led to a National Cancer Institute alert in 1996 recommending that intraperitoneal chemotherapy should be considered in patients with small volume (<1 cm) or no residual disease after surgery [16]. However, this has not been adopted as a standard care of

After surgery, there is still a risk that cancer cells remain and may return or spread to other organs of the body. Adjuvant chemotherapy is administered after surgery to destroy these cells and improve the chance of curing ovarian cancer and to decrease the risk of the death

A recent Cochrane meta-analyses of five prospective clinical trials (4 of 10 with platinumbased chemotherapy) demonstrated that chemotherapy is more beneficial than observation in patients with adequately staged early-stage ovarian cancer [26]. Patients who received adjuvant chemotherapy had better OS [hazard ratio (HR) 0.71; 95% confidence interval (CI) 0.53–0.93] and PFS (HR 0.67; 95% CI 0.53–0.84) than patients who did not receive adjuvant treatment [26]. Two-thirds of the patients included in the two major studies were suboptimally staged, in optimally staged patients, benefit for chemotherapy cannot be excluded, Long-term follow-up of the ICON 1 trial confirms the benefit of adjuvant chemotherapy, particularly in those patients at higher risk of recurrence (stage 1B/C grade 2/3, any grade 3 or clear-cell histology) [26].

Therefore, adjuvant chemotherapy should be recommended not only to suboptimally staged

Recurrent ovarian cancer can be diagnosed by the appearance of new symptoms, radiologic

In the past, treatment for recurrent ovarian cancer was given based on rising levels of tumor markers alone even without symptoms. However, a phase III randomized study (OV05- EORTC 55955) demonstrated no survival benefit of starting chemotherapy based on the increasing level of CA-125 alone and that quality of life may be improved by awaiting the

In this study treatment was delayed by a median of 4.8 months with no benefice on OS (HR 1.01; 95% CI 0.82–1.25; P = 0.91) [27]. Similarly, third-line treatment was started 4.6 months

evidence of recurrent disease or a rising CA-125 level in an asymptomatic patient.

appearance of symptoms or signs of ovarian cancer recurrence.

patients but also to those optimally staged at higher risk of recurrence [16].

in the majority of institutions and countries due to its great toxicity [16].

**7. Adjuvant chemotherapy in early stage disease**

due to ovarian cancer.

**8. Recurrent ovarian cancer**

toneal rather than intravenous administration [24].

302 Ovarian Cancer - From Pathogenesis to Treatment


A meta-analysis including four randomized trials confirmed an improvement in PFS with a HR of 0, 68 (95% CI 0.57–0.81) and OS with a HR of 0.8 (95% CI 0.64–1.0) [29].The phase III Calypso [30] trial compared two doublets, taxol and carboplatin vs. carboplatin with pegylated lipososmal doxorubicin (PLD). The PFS with the second regimen (11.3 months) was not inferior to the taxane-carboplatin (9.4 months, P < 0.001, HR = 0.82) [3]. However the PLD regimen was better tolerated because of the minimal incidence of neuropathy, alopecia, and arthralgia and with less hypersensitivity reactions [3].

Again, the selection between the different options of platinum-based doublets should be based on the previous toxicity profile and convenience of administration [16].

Bevacizumab (Avastin) has also been studied as a treatment option in patients with recurrent ovarian cancer. The phase III OCEANS [31], study performed in women with platinum-sensitive recurrent ovarian cancer compared gemcitabine plus carboplatin with or without bevacizumab for 10 cycles followed by bevacizumab alone until disease progression or toxicity as compared to placebo. Chemotherapy with bevacizumab improved PFS, 12 months with bevacizumab vs. 8 months in the placebo group, as well as the response rate (79 vs. 57%, P < 0.001) [31].

Regimens based on non-platinum combinations are another option for patients with platinum-sensitive disease. In a phase III randomized trial OVA 301 [32], PLD alone was compared with PLD combined with the Mariane-derived alkaloid trabectidin (Yondelis), this combination regimen improved the PFS [32], Median PFS was 7.3 months with trabectedin/PLD v 5.8 months with PLD (hazard ratio, 0.79; 95% CI, 0.65–0.96; P = 0.0190). Overall response rate (ORR) was 27.6% for trabectedin/PLD vs. 18.8% for PLD (P = 0.0080) [32].

It has been hypothesized that this benefit is due to the restoration of 'platinum-sensitivity' by prolonging the platinum- free interval. This is now being explored in two prospective randomized trials [16].

with platinum-sensitive disease, and PLD was found to be significantly superior to topotecan

Chemotherapy for Primary and Recurrent Epithelial Ovarian Cancer

http://dx.doi.org/10.5772/intechopen.80890

305

Compared with topotecan, PLD caused lower rates of neutropenia, thrombocytopenia and

Topotecan has similar efficacy to paclitaxel and PLD in the treatment of platinum-resistant recurrent ovarian cancer [36, 37]. Its use is usually associated with some degree of myelosup-

Monochemotherapy is therefore the standard of early "platinum-resistant" relapse of ovarian

The use of bevacizumab was demonstrated in the AURELIA trial that showed an improved PFS in patients with platinum-resistant ovarian cancer treated with bevacizumab in combination with single agent chemotherapy when compared to treatment with chemotherapy alone

Chemotherapy is the first systemic treatment of epithelial ovarian cancer at all disease stages. It is based on platinum with paclitaxel in the adjuvant and neoadjuvant setting. In advanced

Most cases of newly diagnosed ovarian cancer will respond to initial therapy, but 80% or more will ultimately relapse and further chemotherapy may be indicated. Newer strategies involving gene testing such as BRCA has proven to be an important addition to the treatment strategy. The choice of treatment for recurrent disease is based on the duration of response to

Department of Medical Oncology, Mohammed VI University Hospital of Marrakech,

[1] McGuire WP et al. Primary ovarian cancer chemotherapy: Current standards of care.

stage cases chemotherapy with bevacizumab improved the response.

prior therapy, previous treatment toxicity and quality of life.

Address all correspondence to: noura.naqos@gmail.com

British Journal of Cancer. 2003;**89**:S3-S8

was associated with higher rates of hand foot syndrome and stomatitis [36].

(P = 0.0.08) [36].

*8.2.1.3. Topotecan*

cancers [16].

(5.7 vs. 4 months) [38].

**9. Summary**

**Author details**

Nora Naqos

Morocco

**References**

pression especially neutropenia.

#### **8.1. Maintenance therapy in platinum-sensitive recurrent ovarian cancer**

Many clinical trials have evaluated the role of drugs aimed at prolonging the second remission. One of these is the OCEANS trial that demonstrated the role of bevacizumab as noted above in combination with chemotherapy and as maintenance therapy [31]. Chemotherapy with bevacizumab improved PFS, 12 months with bevacizumab vs. 8 months in the placebo group, as well as the response rate (79 vs. 57%, P < 0.001) [31].

In women with the BRCA mutation, the Poly-ADP ribose polymerase (PARP) inhibitor: rucaparib, olaparib is an active drug; a trial assessed olaparib in women with recurrent advanced ovarian cancer; the overall response rate was 34% (complete response, 2% and partial response, 32%) [33].

The FDA approved olaparib for patients with advanced ovarian cancer who have received treatment with 3 or more lines of chemotherapy and have germline BRCA mutation [34].

#### **8.2. Platinum-resistant recurrent ovarian cancer**

#### *8.2.1. Treatment selection*

In platinum-resistant recurrent cancer, patients should be treated with non-platinum based chemotherapy. The treatment aims to palliate symptoms, optimizing quality of life and prolonging life. In general in this case, response rates are low and the prognosis is poor.

We should use non cross-resistant agents and avoid toxicities based on side effects that have developed from previous therapies, in general higher response rates and PFS rates longer than 2–3 months are obtained with the use of combination regimens. But combination drugs is associated with higher toxicity without any improvement in OS compared with the use of single agent therapy [16]. In fact, for the platinum-resistant cancer, a treatment based on single agent is preferable since it may offer a balance between efficacy and toxicity.

#### *8.2.1.1. Taxane*

Many drugs have documented activity in platinum-resistant disease. In phase II and III trials, the use of single agent paclitaxel has permitted objective responses in 22–30% of patients [35].

#### *8.2.1.2. Pegylated liposomal doxorubicin*

A phase III trial compared PLD with topotecan [36] in women with recurrent ovarian cancer, patients were stratified prior to being randomized according to the platinum sensitivity of their tumor. Similar results were obtained for each of these regimens with respect to the overall RR (20 vs. 17%), time to progression (22 vs. 20 weeks) and median OS (60 vs. 56.7 weeks) [36]. PLD has resulted in a significant OS benefit with longer follow up, mainly for patients with platinum-sensitive disease, and PLD was found to be significantly superior to topotecan (P = 0.0.08) [36].

Compared with topotecan, PLD caused lower rates of neutropenia, thrombocytopenia and was associated with higher rates of hand foot syndrome and stomatitis [36].

#### *8.2.1.3. Topotecan*

It has been hypothesized that this benefit is due to the restoration of 'platinum-sensitivity' by prolonging the platinum- free interval. This is now being explored in two prospective

Many clinical trials have evaluated the role of drugs aimed at prolonging the second remission. One of these is the OCEANS trial that demonstrated the role of bevacizumab as noted above in combination with chemotherapy and as maintenance therapy [31]. Chemotherapy with bevacizumab improved PFS, 12 months with bevacizumab vs. 8 months in the placebo

In women with the BRCA mutation, the Poly-ADP ribose polymerase (PARP) inhibitor: rucaparib, olaparib is an active drug; a trial assessed olaparib in women with recurrent advanced ovarian cancer; the overall response rate was 34% (complete response, 2% and partial

The FDA approved olaparib for patients with advanced ovarian cancer who have received treatment with 3 or more lines of chemotherapy and have germline BRCA mutation [34].

In platinum-resistant recurrent cancer, patients should be treated with non-platinum based chemotherapy. The treatment aims to palliate symptoms, optimizing quality of life and pro-

We should use non cross-resistant agents and avoid toxicities based on side effects that have developed from previous therapies, in general higher response rates and PFS rates longer than 2–3 months are obtained with the use of combination regimens. But combination drugs is associated with higher toxicity without any improvement in OS compared with the use of single agent therapy [16]. In fact, for the platinum-resistant cancer, a treatment based on

Many drugs have documented activity in platinum-resistant disease. In phase II and III trials, the use of single agent paclitaxel has permitted objective responses in 22–30% of patients [35].

A phase III trial compared PLD with topotecan [36] in women with recurrent ovarian cancer, patients were stratified prior to being randomized according to the platinum sensitivity of their tumor. Similar results were obtained for each of these regimens with respect to the overall RR (20 vs. 17%), time to progression (22 vs. 20 weeks) and median OS (60 vs. 56.7 weeks) [36]. PLD has resulted in a significant OS benefit with longer follow up, mainly for patients

longing life. In general in this case, response rates are low and the prognosis is poor.

single agent is preferable since it may offer a balance between efficacy and toxicity.

**8.1. Maintenance therapy in platinum-sensitive recurrent ovarian cancer**

group, as well as the response rate (79 vs. 57%, P < 0.001) [31].

**8.2. Platinum-resistant recurrent ovarian cancer**

randomized trials [16].

304 Ovarian Cancer - From Pathogenesis to Treatment

response, 32%) [33].

*8.2.1. Treatment selection*

*8.2.1.1. Taxane*

*8.2.1.2. Pegylated liposomal doxorubicin*

Topotecan has similar efficacy to paclitaxel and PLD in the treatment of platinum-resistant recurrent ovarian cancer [36, 37]. Its use is usually associated with some degree of myelosuppression especially neutropenia.

Monochemotherapy is therefore the standard of early "platinum-resistant" relapse of ovarian cancers [16].

The use of bevacizumab was demonstrated in the AURELIA trial that showed an improved PFS in patients with platinum-resistant ovarian cancer treated with bevacizumab in combination with single agent chemotherapy when compared to treatment with chemotherapy alone (5.7 vs. 4 months) [38].
