Even though HDC plus HSCS cannot be considered as a standard of care for all AOC patients, results from this monocentric comparative retrospective study including 163 patients suggest that it may be beneficial to young patients. In women under 50 years of age, addition of HDC to platinum/taxane-based chemotherapy improves not only PFS (p=0.02), but also OS (median of 54.6 months versus 36 months with conventional therapy alone, p=0.05).
Despite advances in chemotherapy and multidisciplinary management of ovarian carcinomas, the prognosis of patients with advanced stages (FIGO III/IV) remains poor. Median PFS and OS of our cohort treated with a platinum/taxane combination alone (18.1 and 41.3 months, respectively) were similar to those of phase III pivotal studies: 18 and 38 months, and 19.4 and 48.7 months with cisplatin and paclitaxel; 20.7 and 57.4 months for carboplatin and paclitaxel. Our population was thus similar to previously described cohorts. Prognosis is known to be dramatically influenced by cytoreductive surgery and response to adjuvant platinum/taxane-based chemotherapy. However, even good responders to initial treatment often have a poor prognosis due to secondary relapse. Such relapses are generally chemoresistant and remain the major cause of death. Thus, it may be useful to treat chemosensitive patients in order to kill residual clones and avoid the chemoresistant relapse. Different consolidation therapies have been considered: conventional maintenance chemotherapy, intraperitoneal treatment with chemotherapy and/or hyperthermia, and HDC with HSCS. The latter has been widely used in the context of poor risk hematological malignancies and sometimes in chemosensitive solid tumors such as metastatic breast cancer[21–25] or germ cell tumors with controversial results.
The main toxicity of high-dose alkylating agents is hematological. Stem cell transplantation is needed in such treatment strategies to limit the duration and consequences of aplasia. Nevertheless, severe infection can always occur during grade 4 neutropenia and remains the major potential risk during severe aplasia. However we observed no toxic death after HDC in this study.
Several promising but preliminary studies have reported that HDS plus HSCS may improve ovarian cancer outcome in first-line therapy. These results were observed when HDC was used either as front-line treatment[19, 27], or as consolidation therapy[17, 28–32]. However published randomized phase III trials did not confirm these results. In a single center small-sized study from Papadimitriou et al., although PFS was numerically improved by HDC (85.2 months versus 18 months), the difference was not significant (p=0.059). Moreover, no significant difference was observed in OS (not reached after 75 months of follow-up versus 75 months, p=0.38). The authors attributed PFS gain to the higher rates of stages IV (14% vs. 8.1%) and larger post-operative residue (32.6% vs. 21.6%) in the conventional therapy arm. Mobus et al. reported similar findings in their relatively large phase III trial published in 2007. Median PFS was 29.5 months in the HDC arm versus 20.5 in the control arm (p=0.40). There was also no difference regarding OS (54.4 vs. 62.8 months, p=0.54). Conclusions of these studies were that HDC does not improve outcome in advanced ovarian cancer.
Nevertheless a question that could be asked is: are these conclusions relevant for all patients or is there a subset of patients who may benefit from HDC? In this retrospective study, we tried to address this issue using a subgroup analysis approach in a large population of more than 160 patients. We have explored prognostic value of the different histoclinical features used in ovarian cancer evaluation: age, performance status, FIGO stage, histological subtype, histological grade, debulking status and response to conventional chemotherapy. Age was the only parameter correlated to HDC efficacy, both in PFS and OS. Intriguingly, patients under 50 years of age had a gain in survival when HDC was performed after platinum/taxane-based chemotherapy: median OS of 54.6 months vs. 36 months with standard treatment (p=0.05). This benefit was observed independently of the response after standard treatment. A possible hypothesis is that, in young patients known to have a better prognosis than older women, HDC may be more efficient regardless of the persistence of residual disease after conventional therapy. A hypothesis to explain these results could be the higher prevalence of BRCA-related tumors in younger patients compared to sporadic forms[33, 34]. Indeed, BRCA-related ovarian cancers display distinctive biological and clinical characteristics including genomic instability, dysfunction in DNA repair processes especially homologous recombination and thereby higher sensitivity to platinum-based chemotherapy and better outcome[35, 36]. Of note, recent data have shown that this phenotype could be extended to a larger group of tumors without germline BRCA mutations, the so-called “BRCAness” phenotype[37, 38]. Thus, the benefit of alkylating agents-based HDC in younger patients observed in this study may reflect the enrichment in BRCA-related or BRCAness-associated forms in this subgroup and therefore a higher sensitivity of ovarian cancer cells to DNA damages that can be induced by alkylating agents. As suggested by the dose-effect concept, more chemotherapy –and thus more DNA lesions- may lead to an increase in tumor cells death.
A similar exploitation of this Achilles’ heel of the BRCAness-related phenotype was recently demonstrated with the new therapeutic class of PARP1 inhibitors, which also target DNA repair processes. PARP1 inhibitors are able to induce DNA single-strand breaks that will accumulate and degenerate to DNA double-strand breaks, which are not appropriately repaired if the BRCA pathway is deficient or dysfunctional, the so-called synthetic lethality concept. Olaparib has been shown to induce relevant and promising rates of response when used as single agent in AOC. Interestingly, its activity was documented not only in patients carrying BRCA mutations[40, 41], but also in patients without constitutive mutations, further validating the BRCAness concept.
This phenomenon may be increased with the association of PARP inhibitor and alkylating drugs. Such an additive activity may not be necessary in case of complete remission after standard treatment, but may have a positive effect when the tumor burden has been decreased but not eliminated by the initial treatment.
Our observations show that more treatment may be more effective in young patients. Addition of HDC after platinum/taxane-based chemotherapy in this population should be compared to other ways to enhance treatment exposure. Intra-peritoneal chemotherapy may be an option to increase the doses of platinum and/or taxane administered to cancer cells, with less hematological adverse events. Another issue is the lack of studies comparing consolidation (such as HDC) and maintenance therapy, which could be based on cytotoxic treatments as well as angiogenesis inhibitors. Nevertheless it is of note that, except angiogenesis inhibiting agents, none of the treatments cited above has shown his superiority in randomized trials versus observation alone, but without age consideration as we have done in this analysis. These new findings must be balanced with the fact that this study was retrospective, and that HDC regimens were heterogeneous. Nevertheless, despite its retrospective nature, this study, based on a large population, used a comparative design and included subgroup analyses with traditional clinical and pathological prognostic factors. Another limitation of this work is the absence of relevant information about the BRCA status of our patients. Unfortunately, this data was available only for few patients in our retrospective cohort (21 of 163), with only six BRCA1 and two BRCA2 mutations identified.