Abstract: A recent Japanese Gynecologic Oncology Group phase III clinical trial in patients with ovarian cancer receiving the conventional paclitaxel-carboplatin combination once every 3 weeks or "dose-dense" paclitaxel once a week with carboplatin once every 3 weeks has reported a large progression free survival advantage for the dose-dense therapy. Recent advances in the molecular understanding of ovarian cancer point to molecular differences between paclitaxel and carboplatin sensitivity which link to the status of BRCA genes -- so called familial and sporadic "BRCAness." It may be that the change in the way we use paclitaxel allows us to more effectively target the heterogeneity of such intrinsic sensitivity/resistance to these agents in the adjuvant therapy of ovarian cancer, leading to significant improvement in the management of the disease.

Introduction

The promise of the benefits of molecular targeted therapies has in no field of oncology been more eagerly anticipated than in ovarian cancer. This poor prognosis cancer has seen little substantive change in its standard of care since the introduction of the widespread use of platinum chemotherapy in the late 1980s as an adjuvant to high-effort, optimal debulking surgery (Aabo et al., 1998). Despite extensive subsequent research comparing different combinations of doublets (McGuire et al., 1996) and triplets of chemotherapy (Bookman et al., 2009), and intraperitoneal approaches to chemotherapy (Armstrong et al., 2006) it seemed that we had reached the ceiling of benefit from chemotherapy in the form of a consensus gold standard: paclitaxel-carboplatin 3 weekly combination chemotherapy. Even this consensus is controversial with evidence and strong arguments made that it represents a standard of care no better than single agent platinum chemotherapy (Sandercock et al., 2002). This ceiling of around 16-19 months median progression free survival has remained essentially static since the introduction of platinum chemotherapy, with most overall survival gains since then made as a result of increased research effort in the incurable recurrent ovarian cancer situation. The most eagerly anticipated molecular targeted therapies (antiangiogenics, PARP inhibitors, PI3 Kinase pathway inhibitors) will therefore be tested in the context of this paclitaxel-carboplatin doublet.

Dose-dense Chemotherapy in Recurrent Ovarian Cancer

Recurrent ovarian cancer signifies incurable disease, but research in this clinical setting has defined that combination platinum-based chemotherapy can improve survival in disease which recurs more than 6 months after last platinum therapy. However, with the onset of platinum resistant disease (relapsing less than 6 months after last platinum chemotherapy) comes a profound decline in the activity of conventional chemotherapy agents (particularly platinum), an increased event rate for clinical episodes, and shortened survival. However, there have been some interesting developments over the last 8 years in this difficult clinical scenario that demonstrate clinical benefit from chemotherapy.

Two clinical reports showed that giving dose-dense cisplatin weekly with dose intensities substantially more than for conventional chemotherapy resulted in response rates of nearly 50% compared with expectations of <10% response rate for conventional platinum based chemotherapy in this context (van der Burg et al., 2002). However these regimes were fairly toxic. Several groups had also explored weekly paclitaxel 80mg/m² in recurrent ovarian cancer and found approximately 25-40% response rates (Linch et al., 2008; Markman et al., 2002).

It was subsequently realized that weekly paclitaxel could be used with carboplatin to enhance activity and protect against thrombocytopenia, and van der Burg demonstrated she could adapt her cisplatin/etoposide regime such that a similarly organized regimen consisting of AUC4 (AUC: target area under the concentration-time curve) carboplatin and 90 mg/m² taxol could be delivered weekly in the induction phase followed by conventional paclitaxel-carboplatin. Our group adapted and extended the induction phase from this regime resulting in a regime consisting of 18 weekly cycles of AUC3 carboplatin and 70mg/m² paclitaxel and demonstrated 60% response rate in platinum resistant/refractory ovarian cancer with an 8 month median progression free survival (Sharma et al., 2009). These exciting findings in recurrent disease have recently begun to be explored in the adjuvant setting.

Exploring Dose Density in Adjuvant Therapy of Ovarian Cancer

A fascinating and exciting result was recently reported by the Japanese Gynecological Oncology Group (JGOG) in a convincing clinical trial that appears to have propelled the median progression free survival strikingly through the 17 month “barrier” (Katsumata et al., 2009). The JGOG trial randomized untreated stage II-IV ovarian cancer patients to either standard postoperative paclitaxel-carboplatin 3 weekly or weekly dose-dense paclitaxel with 3 weekly standard carboplatin. Patients in the dose-dense test arm had a median progression free survival of 28 months, an 11 month improvement, with a HR of 0.71. This result, if confirmed, delivers the first real step-change in the treatment of ovarian cancer for 20 years in terms of impact on progression free survival. In the accompanying editorial (Bookman, 2009) we are reminded that paclitaxel scheduling changes in front line therapy are also to be found with intraperitoneal chemotherapy regimens where a survival advantage for the intraperitoneal arm has been reported. Despite this extremely encouraging result, a slight note of caution does need to be sounded, that in a non-randomized phase II study in elderly patients (with co-morbidities) of non-dose dense but schedule-altered carboplatin (AUC2) and paclitaxel 60mg/m² weekly the median progression free survival was only 13.6 months with a median overall survival of 32 months (Pignata et al., 2008), hinting that dose density or any form of break in the weekly cycle length might be important for the improvement seen in the Japanese study rather than just scheduling alteration. Furthermore, a randomized study testing the van der Burg paclitaxel 90mg/m²-carboplatin AUC4 weekly induction regimen with subsequent standard paclitaxel-carboplatin has been reported in abstract form as showing no benefit compared with standard paclitaxel-carboplatin (Burg et al., 2009), suggesting that either a short 2 cycle induction of dose-dense therapy is insufficient to deliver benefit, or that any gap in weekly delivery during this period may negate the observed benefits seen in the Japanese study.

What Are the Potential Factors Underlying These Striking Clinical Data?

The prediction from mathematical models of gompertzian tumor growth are that reducing the interval between chemotherapy cycles should result in greater efficacy by minimizing regrowth of cells between cycles of treatment. The impact of accelerating chemotherapy is predicted to be an effect that is maximal in the early (faster growing) part of the growth curve, and conversely delays or interruptions in chemotherapy result in lesser efficacy as the drugs act in the later (flat) part of the gompertzian growth curve (Norton, 2001). Minimization of regrowth will have contributions from both the intrinsic kinetics of cancer cell growth as well as potential effects on tumor vasculature, that summate as an overall impact on tumor regrowth. In addition to this mathematical prediction, an important factor will be heterogeneity of chemotherapy sensitivity of cancer clones reflecting the evolutionary diversity of any individual cancer. This heterogeneity predicts that resistant cancer clones are growing even as sensitive clones are responding to chemotherapy. The result of the JGOG study does demonstrate that the use of schedule optimization in combination with the use of non-cross-resistant drugs is capable in practice of substantial step-change clinical benefit. In addition to the biological basis of scheduling, the biology of intrinsic and acquired clinical drug resistance can explain the importance of these drugs and how to improve further their utility.

Molecular Mechanisms Underlying Schedule Change Effects

Separately from the mathematical basis of cell death kinetics and gompertzian growth, cell culture models have shown that low dose taxol exposure results in intracellular sequestration of taxol and subsequent cell death (Jordan et al., 1996). Longer exposure rather than higher dose appeared to be a more important factor (Lopes et al., 1993). Furthermore there is evidence from preclinical models that taxol has an antiangiogenic effect, with inhibition of bFGF and VEGF induced neovascularization (Klauber et al., 1997) and inhibition of endothelial migration (Belotti et al., 1996). The metronomic nature of weekly therapy adds to this intrinsic antiangiogenic effect of taxol. Experimentally, it is known that metronomic administration of conventional chemotherapy is further enhanced by the addition of an antiangiogenic therapy, and therefore it is logical that the JGOG schedule be tested with antiangiogenics such as bevacizumab in clinical trials.

Molecular Factors in Clinical Platinum and Taxol Sensitivity/Resistance: BRCA1

Molecular mechanisms that may regulate sensitivity/intrinsic resistance to either platinum or paclitaxel represent major factors in the optimization of the ovarian cancer chemotherapy standard. These factors may share some similarities but have many differences to the process of acquired drug resistance (that is not considered here). Almost no predictive biomarkers for chemotherapy response have found their way to the clinic in ovarian cancer. Several proposed biomarkers exist that may predict response to platinum or taxanes. These include molecules such as beta-tubulin, p53, bcl2, MMR, and ERCC1, and many have not been validated. However, p53 and ERCC1 have been subject to validation studies and in these studies the correlation with response has not been proven.

Despite this lack of success it does look like at least one predictive surrogate, BRCA1, is beginning to emerge as a strong candidate, and both the biology of this molecule and its clinical validation appear to be lending credence to this idea. BRCA1 is a gene central to the maintenance of genome stability and DNA repair via homologous recombination, and its germline mutation results in a high probability of breast/ovarian cancer, transmitted as a Mendelian dominant trait.

BRCA1 is involved in DNA damage response, in cell cycle checkpoint control, in apoptosis, and in both transcriptional control and post-translational control (via ubiquitination). These pleiotropic effects help to explain the profound impact of BRCA1 dysfunction in the cell.

There is accumulation of data that BRCA1 deficient cells are very sensitive to platinum and relatively resistant to taxol, and the converse, BRCA1 competent cells are more likely to be platinum resistant and taxol sensitive; the correlative clinical studies largely confirm these laboratory observations, and these data have been summarized in an excellent previous review (Quinn et al., 2009).

“BRCA Syndrome”

Mutant BRCA1 inherited ovarian cancers have a characteristic “BRCA syndrome” with a constellation of clinicopathological features, these being younger age at onset and of serous high grade type with very frequent p53 mutation (Turner et al., 2004). These patients are very responsive to platinum chemotherapy from which they achieve long term or very durable remissions, generally having a better prognosis, and if they do relapse they have a high probability of durable subsequent remissions.

BRCA1 somatic mutations are rare; however, epigenetic silencing of BRCA1 occurs in a significant proportion (15-60%) of ovarian cancers and identifies a very similar presentation of serous high-grade ovarian cancer. With the somatic correlate of the above syndrome (called “somatic BRCAness”) comes the same high probability of durable remission with platinum, and a better prognosis again (Tan et al., 2008). Analysis of sporadic ovarian cancer populations in several studies has shown that low BRCA1 mRNA (Quinn et al., 2007) or low BRCA1 IHC score (Thrall et al., 2006) was associated with significantly better survival where patients received platinum alone (57 vs. 18 month median overall survival). Furthermore, one of these studies reveals that patients with high BRCA1 mRNA expression are more resistant to platinum and more sensitive to taxol, with survival being better for those receiving combination taxol/platinum than for those receiving platinum alone.

Where Do We Go From Here?

There are many emerging concepts relating to this important advance for patients both in the context of understanding chemotherapy better and also from the perspective of enriched molecular understanding of chemotherapy response.

At least for sporadic common epithelial ovarian cancer there is likely to be a continuum of sensitivity and resistance to both platinum and paclitaxel as determined by intra-patient tumoral heterogeneity and its evolution.

Much is currently discussed relating to the potential frequency of somatic BRCAness in the serous/endometrioid population, and this figure is variously placed somewhere between 30 and 60% of patients based largely on the sensitivity and accuracy of technologies used, e.g., measuring CpG island methylation at the BRCA1 promoter.

However the idea of heterogeneity and the concept of a continuum of sensitivity imply that most serous/endometrioid tumors may have a degree of functional BRCAness, but that solely targeting this may be ultimately ineffective as it does not tackle scenarios that escape from the BRCAness state. Such scenarios include (in BRCA mutant patients) mutation reversion to BRCA functionality of inherited BRCA mutation leading to platinum resistance; or the possibility that BRCA1 can reactivate expression under selective pressure by demethylating the BRCA1 promoter. This latter scenario would allow a somatic BRCAness state to rapidly evolve to platinum resistance (and possibly simultaneous relative taxane sensitivity).

A further question is whether the anti-angiogenic effects of the more metronomic scheduling of taxol are significant to such an extent that there would be no role for an additional antiangiogenic such as bevacizumab as the impact might be directly overlapping. In-vitro data would suggest that taxol and bevacizumab might be additive, however the question in this context is an empirical one and will be tested in forthcoming clinical trials.

Unanswered questions remain: what is the additional impact if any of giving dose-dense carboplatin (e.g., AUC3-4 weekly) or simply schedule-altered non-dose-dense (AUC2 weekly) carboplatin? Although the evidence for benefit of dose dense carboplatin is sparse at the moment, it is nevertheless a very important question. What is the impact of addition of a PARP inhibitor to this regimen for somatic or familial BRCAness patients? Also, no great benefit was observed in clear cell or mucinous ovarian cancers so it is important that alternative ways of managing these are found; they are in any case directed to different trials currently.

Conclusion

It is in the context of the above discussion that the JGOG weekly dose-dense paclitaxel trial result is so startling (if confirmed), because this disease appears to be coming under better control with dose-dense weekly paclitaxel to such an extent that it has resulted in the biggest advance in the standard of care for ovarian cancer since the introduction of platinum. Analysis of tumor tissue exposed to this regime will help to clarify the pharmacodynamic impact of this schedule and the underlying molecular processes that will no doubt be altered in this setting.

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