1.51 Standard Treatment
Improvements in both 5 year survival, up from 42% to 46% since 1998 67 and median progression free survival, have been achieved over the past three decades. This has been achieved by, improvements in surgical techniques, the introduction of first cisplatin, in the 1980s and then paclitaxel in the 1990s. Currently the standard first line treatment is surgical debulking followed by combinational chemotherapy of a platinum agent, usually carboplatin, plus a taxol, usually paclitaxel. Carboplatin has largely replaced cisplatin due to its reduced toxicity. Platinum plus taxol is given regardless of stage at diagnosis. Two large studies have demonstrated the superiority of firstly platinum alone compared to no treatment after
cytoreductive surgery for stage I/II (5-YRS HR=0.67 95% CI 0.50-0.90 P =.008) 68, and both platinum alone and in combination with taxol in stages III/IV 69.
Despite these advances, improvements in overall survival have been less marked. One estimate suggests that 10 year survival before and after 1988 has increased from 32.2% to 34.4% 70. More significant gains in 10 year survival for those diagnosed with early stage tumours are overshadowed by the low proportion these cases constitute.
1.52 Surgery
Women presenting with invasive EOC cancer will generally undergo a complete hysterectomy, bilateral salpingo-oophorectomy with omentectomy, debulking of as much of the tumour mass as is reasonable. The success of cytoreductive surgery is strongly correlated with patient survival.
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Figure 4. Correlation between percentage of maximum of cytoreduction in debulking surgery, showing the importance of surgical quality and survival. Adapted from 71.
A large meta-analysis of over 6,000 patients who underwent debulking followed by chemotherapy found a linear correlation between the extent of residual disease and survival (P=0.001) 72. Changes in the recommendations regarding, extent and thoroughness of cytoreductive surgery contributed significantly to improved survival.
Figure 4 shows the relationship observed in the meta-analysis by Bristow et al in line
A. Line B shows the trend towards lower remaining residual disease, after debulking since 1987 and the associated increase in survival. In line B, each point relates to the average percentage of disease mass removed for the period shown.
1.53 Relapse and Resistance
Low overall survival in ovarian cancer is primarily due to relapse with platinum resistant disease after initial treatment. Initially response to combination chemotherapy after surgery is high. 80% of patients exhibit a significant reduction in tumour mass and in 40– 60% of cases the presence of tumour mass is undetectable after their first course of treatment 73. However the majority of patients will relapse. Median progression free survival of
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exclusively shorter. The duration of remission can also be used as a prognostic indicator of the probability of response to a second line of therapy.
Response rates of around 50% are seen with single-agent carboplatin treatment in tumours that relapse after more than 12 months following initial treatment. This figure falls to around 15% when the duration of remission is less than 6 months, at which point tumours are considered to be platinum resistant 75. Tumours that are unresponsive to platinum treatment or advance in stage during treatment are classified as platinum-refractory and in such cases patient care is essentially palliative.
1.54 Recent Novel Therapeutics
Various trials have examined the survival advantage associated with different cytotoxic drug combinations, doses, methods of administration and second bouts of
cytoreductive surgery. Improvements in survival have generally been either not observed or marginal especially in relation to overall survival.
A consistent beneficial effect has been demonstrated for intraperitoneal (IP)
compared to intravenous (IV) administration of chemotherapy. In one such study combining cisplatin and paclitaxel, PFS for IV administration was 18.3 months compared to 23.8 months for the IP group (log-rank test P=0.05) and median OS also increased from 49.7 and 65.6 months, (log rank test P=0.03) 76.
Two new targeted therapeutics have shown promise in recent trials. Bevacizumab is a humanised monoclonal antibody to vascular endothelial growth factor A (VEGFA). VEGFA is an important angiogenic factor released by hypoxic cells which simulates the growth of vascular endothelial cells providing blood flow to a tumour and facilitating its growth. Three trials have examined the benefit of combining bevacizumab with traditional chemotherapy in upfront treatment. Consistent increases in PFS have been observed, for example 10.3
compared to 14.1 months 77 and 8.4 versus 12.4 months 78 for control versus bevacizumab arms. However neither study was able to demonstrate a change in overall survival and increased toxicity in the combination treatment seems to make the introduction of bevacizumab as a standard treatment unlikely.
Olaparib is a small molecule inhibitor of poly-ADP ribose polymerase (PARP1), an important DNA repair enzyme that has been shown to exhibit synthetic lethality in
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inhibition of the function of either one of a pair of proteins has no effect in isolation but when both are inhibited together a cell cannot survive. Logic for the use of this drug is based on the high frequency of BRCA mutations seen in EOC, these concepts are described in more detail at the genetic level in section 1.77 - Molecular Characteristics of High Grade Serous
Tumours. The most comprehensive trial examining the effectiveness of olaparib was carried out in relapsed patients and compared to a placebo only arm. An increase in PFS in the treatment arm from 4.8 months to 8.4 months (HR 0.35 CI 0.25 – 0.49 P=0.001) was
observed, although there was no interim OS benefit 79. There is a clear rational behind using olaparib and these promising results warrant further study.
1.6 Monitoring and Screening
1.61 CA125
The most frequently used marker of EOC is the glycoprotein CA125 (also known as MUC16). CA125 was discovered via a screen of antibodies produced from hybridomas, created via the inoculation of mice with ovarian cancer cell lines 80. Originally termed OC125, as this was the 125th ovarian cancer hybridoma screened, latterly named CA125, for cancer antigen 125, antibodies produced from this hybridoma are now known to target mucin 16, MUC16 81. MUC16 is one of a family of cell surface or secreted glycoproteins expressed by epithelial cells that play a role in the lubrication of the epidermal membranes including the lungs, digestive system and uterus. Expression of the antigen was subsequently shown to be present in the serum of over 80% of patients with EOC and levels that correlated with disease progression and response to treatment 82. Since its discovery CA125 monitoring has become standard practice in the management of EOC and has been evaluated as the basis of a
population screen to detect early stage asymptomatic disease. Unfortunately these studies were unable to demonstrate sufficient specificity and as a consequence too many false positives were detected 83. This can partially be explained by the increased serum levels of CA125 in normal or benign conditions including endometriosis and menstruation 84.
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1.62 Screening, beyond Just CA125
Attempts to improve specificity and sensitivity of potential population screens have been made. A recent randomised trial of combination CA125/MUC16 monitoring and transvaginal ultrasound in nearly 80,000 women in the US hoped to demonstrate sufficient positive predictive value (PPV) by combining these two screening methods. A small but non- significant decrease in mortality was observed in the test group but the authors suggested was not justified by the unnecessary surgical intervention and associated complications due to false positives 85. Screening based on multiple serum markers may provide greater accuracy in the future however such tests are still in the early phase of development. For example Yurkovetsky et al. claim they were able to achieve a high enough specificity to use as a population screen by assaying serum levels of CA125, HE4, CEA and VCAM-1 86.
The low overall incidence of EOC makes the introduction of national screening programs unlikely until the PPV (the proportion of true positives to all positive results) of potential diagnostic techniques can be improved. The relatively low incidence of EOC increases the requirement of screening methods with very high specificity (the proportion of true negatives identified) in order to prevent an excess number of false positives. As such improving the efficacy of existing treatments may be the most viable method of increasing overall survival and progression free survival in cases of platinum resistant disease.