Overview of treatment at relapse
Surgical debulking options at relapse
Despite the established value of cytoreduction in the primary setting, the value of tumour debulking surgery for recurrent epithelial ovarian cancer remains highly controversial.
A retrospective analysis of tumour resection in women in first ‘platinum-sensitive’ recurrence suggested that patients benefit if macroscopic clearance can be achieved. An ‘AGO score’ was developed, based on performance status, complete resection at primary surgery or early FIGO stage, and the absence of gross ascites at relapse, and it predicted a good outcome in the prospective DESKTOP II trial (56, 57). The scoring system has been used as a basis for the randomized phase III DESKTOP III trial comparing the addition of surgery to chemotherapy for ‘platinum-sensitive’ recurrent disease. A positive result from this trial could lead to a change in practice with more intensive follow-up to identify patients with potentially resectable disease. A surgical randomization was also included in the GOG 213 trial. There is little evidence to support the use of cytoreductive surgery in the ‘platinum-resistant’ setting, other than for palliation of bowel obstruction.Systemic regimens at relapse: current trials and novel/molecular approaches
Relapse of early-stage comprehensively staged FIGO stage I ovarian cancer is uncommon but for all other stages, it occurs in more than 75% of women. Since the 1980s, cisplatin and later carboplatin were the mainstay of therapy or recurrent disease, as these were the most active agents available. During the late 1980s, reports emerged that patients retreated with platinum-b ased therapy were likely to respond again, depending on the interval from primary therapy. Thus, the terms ‘platinum-sensitive’ and ‘platinum-resistant’ relapse were created, based on the probability of responding again if the relapse was less or more than 6 months after the end of primary treatment.
The definitions were later modified, somewhat arbitrarily, to subdivide the ‘platinum-s ensitive’ group into a ‘partially platinum-s ensitive’ (relapse interval 6-12 months) and fully ‘platinum-sensitive’ (relapse interval >12 months). Patients relapsing within 3 months were defined as having ‘platinum-refractory’ disease. These terms provided a convenient method of categorization for treatment design of clinical trials (58). Not only is much of the literature predicated on these groupings, but regulators and health funders have also often made decisions based on these categories. However, in reality it is clear that resistance is neither absolute in most patients, and is certainly not categorical. Furthermore, the definition was based on response at first relapse and it is less clear how these terms apply to patients who have had several lines of therapy and have been on maintenance regimens. Recently, there has been a move to classify patients according to the treatment interval, as some patients may not have received platinum-based therapy before the most recent relapse.For most patients the first recurrence will occur more than 6 months after the completion of first-line therapy. Clinical trials combining platinum with either paclitaxel, gemcitabine, or PLD have consistently shown a superior PFS with combination chemotherapy compared to single-agent platinum. It has been harder to demonstrate a benefit in overall survival, but a recent meta-analysis of combination therapy trials supports the use of combination therapy (59). The choice of combination therapy, summarized in Table 64.2, needs to take account of the relative toxicities of the regimen, the side effects experienced during recent treatment, and the likely choices for later-line therapy, particular when tumours become ‘platinum resistant’. It is not uncommon for women to receive several lines of therapy; the interval between treatments usually decreases as the degree of chemotherapy (and in particular platinum) resistance increases.
Use of non-platinum drugs increases as tumours become resistant, or unmanageable hypersensitivity to platinum occurs. Paclitaxel, PLD, and topotecan are all licensed for use as a single agent in recurrent ovarian cancer and combinations of non-platinum drugs have not been shown to be superior. Other drugs sometimes used are cyclophosphamide, often continuously in a low dose, etoposide, or gemcitabine. These are usually given as single agents but combinations with platinum (even in the ‘platinum-resistant’ setting) are sometimes used (Table 64.3). The median PFS following treatment for ‘platinum-resistant’ ovarian cancer is typically around 3 months and the median overall survival is about 12 months. There is a need to develop better treatments and also to evaluate current treatments carefully, taking account of the control of symptoms, time off chemotherapy, and the patient’s quality of life.Hormone therapy with tamoxifen or letrozole is sometimes used to treat late-stage disease when there are no further options for chemotherapy. Anecdotal and small series report responses to these drugs but for tamoxifen, a systematic review of the literature failed to show any benefit.
Antiangiogenic therapies
Bevacizumab is the antiangiogenic drug that has been most thoroughly explored in recurrent ovarian cancer. In the randomized OCEANS trial, a significant improvement in PFS was seen when bevacizumab was given in combination with carboplatin and gemcitabine, and then as maintenance until progression compared with chemotherapy alone. The median increased from 8.4 to 12.4 months (hazard ratio (HR) 0.484; P <0.0001) without any increase in overall survival (60, 61). A benefit in PFS was also seen in the GOG 213 trial using bevacizumab in combination with carboplatin and paclitaxel (62). In the ‘platinum-resistant’ setting, the randomized AURELIA trial used an investigator choice of weekly paclitaxel, PLD, or topotecan with or without bevacizumab.
Table 64.2 Randomized trials using drug combinations in 'platinum-sensitive' recurrent ovarian cancer
| Combination | Trial | Experimental arm (median PFS in months) | Control arm (median PFS in months) |
| CarboplatinZpacIitaxeI | ICON4 Compared to platinum alone | 13 | 10 |
| Carboplatin/gemcitabine | bgcolor=white>OVAR 2.58.6 | 5.8 | |
| CarboplatinZPLD | CALYPSO non-inferiority trial Comparison with GarboplatinZpaclitaxel | 11.3 | 9.4 |
| CarboplatinzgemcitabineZbevacizumab | OCEANS Addition of bevacizumab to chemotherapy and as maintenance compared to carboplatinZgemcitabine | 12.4 | 8.4 |
| CarboplatinzpaclitaxelZbevacizumab | GOG 213 Addition of bevacizumab to chemotherapy and as maintenance | 13.8 | 10.4 |
| Carboplatin-based combination (paclitaxel or gemcitabine) with cediranib | ICON6 Addition of cediranib to chemotherapy and as maintenance | 11.0 | 8.7 |
| Non-platinumι combination TrabectedinZPLD | OVA 301 Combination compared to PLD (partially platinum sensitive 6-12-month PFI) | 7.4 | 5.5 |
| Non-platinumι combination Weekly paclitaxel and trebananib | TRINOVA 1 Addition of AMG 386 (trebananib) to chemotherapy (includes a partially platinum-sensitive group 6-12-month PFI) | 7.4 | 5.2 |
PFI, platinum-free interval; PFS, progression-free survival; PLD, pegylated liposomal doxorubicin.
| Median progression- free survival (months) | |
| Pegylated liposomal doxorubicin (PLD) | 3.5 |
| Topotecan | 3.4 |
| Weekly paclitaxel | 3.9 |
| Weekly paclitaxel + bevacizumab | 10.4 |
| PLD + bevacizumab | 5.4 |
| Cisplatin and etoposide (<4 month platinum-free interval) | 5.0 |
| Weekly carboplatin and paclitaxel | 8.0 |
Entry was restricted to patients with no more than two prior lines of chemotherapy and excluded patients with refractory disease, a history of bowel obstruction, or significant serosal disease on the large bowel. Bevacizumab in conjunction with chemotherapy increased the median PFS from 3.4 to 6.7 months (HR 0.48; P <0.001).
Cross-over to bevacizumab on progression was permitted and there was no significant difference in overall survival (63). In this largely symptomatic group of women, bevacizumab increased the tumour response rate from 11.8% to 27.3%. This effect was most marked in patients receiving weekly paclitaxel. Furthermore, a greater number of patients receiving bevacizumab had a more than 15% benefit in abdominal/gastrointestinal symptoms (64). The use of bevacizumab in platinum-resistant ovarian cancer has now received widespread regulatory approval.Several trials have now reported on the activity of oral VEGF receptor tyrosine kinase inhibitors (VEGFR TKIs) in recurrent ovarian cancer. Trials have been performed with pazopanib, cediranib, and sorafenib in patients with either ‘platinum-sensitive’ or ‘platinum- resistant’ disease, and all bar one have shown a similar and significant difference in median PFS; the results are similar to those with bevacizumab, or the angiopoietin antagonist, trebananib (Table 64.2). The pattern of toxicity with oral VEGFR TKIs is different from bevacizumab. Hypertension is more pronounced with VEGFR TKIs and diarrhoea and fatigue are more common and troublesome. None of the oral VEGFR TKIs are currently licensed for use in ovarian cancer, but they are, nevertheless, a potent group of drugs that have considerable potential for further development.
Inhibition of DNA repair
The high response rate of ovarian cancer to platinum-based drugs is largely due to impaired mechanisms to repair cytotoxic-induced DNA damage. Poly(ADP ribose) polymerase (PARP) is activated in response to single-stranded breaks in DNA. Inhibitors of the pathway were initially developed to enhance the effectiveness of DNA-damaging cytotoxic drugs. However, it has been shown that PARP inhibitors are most active in cells that are homozygously deficient in the BRCA1 or BRCA2 genes. These gene products form an essential constituent of the repair proteins required to repair double-stranded breaks of DNA by a process known as homologous recombination repair (HRR) (65).
Phase I clinical trials with AZD2281 (olaparib) demonstrated antitumour activity and disease CHAPTER 64 Ovarian, fallopian tube, and peritoneal cancer control in tumours deficient in BRCA protein function. About 1520% of serous ovarian cancers have either a germline or somatic BRCA gene mutation (66, 67). Clinical trials with olaparib, given as maintenance therapy after platinum-based chemotherapy of recurrent high-grade ‘platinum-sensitive’ ovarian cancer, demonstrated a significant delay in tumour progression (68). This benefit was greatest in tumours with a germline or somatic BRCA mutation with extension of the median PFS following chemotherapy from 4.3 to 11.2 months (HR 0.18; P <0.OOO1) (69). Survival was extended and 15% of women with a BRCA mutation remained on the drug for more than 5 years without tumour progression (70). There is emerging evidence that the benefit of maintenance therapy with PARP inhibitors extends to a population without a BRCA mutation that has the phenotypic features of HRR deficiency. Randomized maintenance trials with niraparib and rucaparib, two other PARP inhibitors, in this setting will soon report. A BRCA mutation is the first (genetically determined) predictive marker for a response to a PARP inhibitor.Olaparib is the first PARP inhibitor to be licensed for maintenance therapy in ‘platinum-sensitive’ ovarian cancer with a BRCA mutation. Similar trials with niraparib and rucaparib have confirmed the benefit of maintenance therapy post platinum therapy in high grade ovarian cancers, with or without a BRCA mutation. This class of drugs is also active as monotherapy in BRCA mutated ovarian cancer (71). The implication from these results is that all women with high-grade ovarian cancer should undergo BRCA testing. The absence of a family history is not a good negative predictor of a BRCA mutation (72). ‘Second-g eneration’ PARP inhibitor studies are now underway, combining the drug with antiangiogenic drugs. There is evidence that this increases the degree of HRR deficiency, and initial trials with olaparib and cediranib have shown promising results, particularly in women without BRCA mutations (73).