decision - making strategies for optimal treatment of recurrent ovarian cancer ( roc ) are complex as new cytotoxic drugs and an increasing number of biological agents become available .
this presents challenges in defining the optimal timing and sequencing of the drugs or treatment regimen . a controversial issue of roc treatment concerns the lack of an os advantage observed with a number of investigational compounds and regimens , and they can be often associated with increased toxicity and no improvements in patients ' qol . therefore , current treatment options for patients with roc are frequently guided by safety considerations and convenience .
a sub - analysis of the ova-301 study showed that for platinum - sensitive patients ( pfi > 6 months ) , median progression - free survival was 9.2 months with the trabectedin + pld combination vs 7.5 months with pld monotherapy ( hazard ratio , 0.73 ; 95% ci , 0.56 to 0.95 ; p=0.0170 ) .
in fact , the median overall survival in the patient subgroup with a platinum - free interval in excess of 12 months ( considered to have very ps disease ) was 36.5 months with the combination , which was in the range of that obtained with platinum combinations .
although therapeutic regimens that combine platinum - based therapy with other cytotoxic agents are the current standard of care for advanced ovarian cancer patients , the cumulative toxicities of cisplatin and carboplatin can present barriers for the long - term use of these agents [ 2 , 3 ] .
as previously discussed , there are women with relapsing disease ( particularly the pps subgroup ) who would benefit from a delay in platinum retreatment to possibly enhance their response to platinum in a future application , or who are not ideal candidates for platinum - based therapy due to the toxicity profile of platinum or due to platinum - induced toxicity .
there appear to be three main limitations to using carboplatin combinations , including allergy to carboplatin ( hypersensitivity ) , renal toxicity , and ototoxicity .
hypersensitivity reactions ( hsrs ) to carboplatin are a particular concern , and have been reported in approximately 15 - 20% of women .
symptoms of carboplatin hsrs are highly variable and can be mistakenly attributed to other agents , particularly when they are used in combination .
they include itching , rash , chest tightness , emesis , blood pressure changes and facial swelling .
the onset of the carboplatin - associated hsr is also highly variable , occurring either as soon as the infusion starts or after it is completed .
when expectations for a positive outcome with platinum are good , then desensitisation protocols may be useful to continue platinum - based therapy , and success rates in excess of 50% have been reported .
however , for example a 12-step desensitization protocol that administers the total dosage of carboplatin at increasing doses and faster rates over an extended period of time , requires adequate support in an intensive care unit or allergy department .
all with the attendant burden on staffing and resources , and of course patient preference [ 1 , 2 ] .
other clinically significant sequelae such as neurotoxicity , severe cumulative myelosuppression , renal toxicity and ototoxicity are commonly caused by platinum - based chemotherapy .
indeed neurotoxicity , which influences patient 's quality of life , is a dose - limiting adverse effect for all platinum compounds , and there is a high probability of persistent neurotoxicity including residual neuropathy ( ~20% of oc patients ) associated with carboplatin plus paclitaxel treatment .
carboplatin causes dose - limiting and cumulative myelosuppression , characterised by frequent and severe thrombocytopenia , granulocytopenia and anaemia .
likewise , cisplatin is associated with several cumulative and irreversible toxicities , including dose - dependent renal tubule toxicity and neurotoxicity .
cumulative doxorubicin and paclitaxel exposure must also be monitored to minimize the risk of patient morbidity due to cardiotoxicity and neuropathy .
gemcitabine has many overlapping toxicities with other agents , and care must be taken with combination regimens to avoid synergy of these adverse effects .
toxicity issues should be carefully taken into account before considering platinum re - treatment , as the platinum - associated cumulative and irreversible toxicities may jeopardise its long - term intervention on subsequent relapses .
consideration of platinum - induced cumulative toxicity takes on greater significance as the number of salvage regimens increase , as it can be given only to those patients for whom the toxicities would be acceptable .
this underscores the need for alternative therapeutic options , including an efficacious non - platinum regimen with an acceptable toxicity profile .
other factors that influence treatment decisions in this heavily - treated patient population have to be taken into account . for example , efficacy ( clinical or symptom benefit ) , safety ( specifically limitations with carboplatin due to hypersensitivity or residual toxicities ) and qol need to be considered .
this could include health - related qol , patient - reported outcomes regarding symptoms , and time without symptoms or toxicity .
for example , although temporary in nature , alopecia is a visible reminder of cancer treatment and is extremely upsetting for many women . a recent pan - european survey into the qol of 1743 patients with ovarian cancer by oskay - ozcelik et al .
reported that alopecia was the single most troublesome side effect , with 42% patients reporting being bothered by alopecia .
furthermore , there is now an increasing body of evidence which shows that extending the platinum - free interval in relapsing patients with partially platinum sensitive ovarian cancer , also improves their response rate to platinum re - treatment at a later time point .
clinical evidence from ova-301 shows that the toxicity related to the trabectedin + pld combination was acceptable .
the most common adverse events with the trabectedin + pld combination were neutropenia and transient increased transaminase levels ( box 1 and table 1 ) .
the results show that neutropenia followed a predictable pattern of rapid onset and reversibility and , similarly , transaminase increases appear early after administration ( during treatment cycles one and two ) , then generally decrease in incidence and severity with subsequent treatment cycles ( fig .
1 ) . hence the clinician can assess the impact of the combination therapy on the patient from the first 2 cycles .
the impact of the trabectedin + pld combination was also assessed on patients ' qol via qlq - c30 , a standardised qol instrument developed by the eortc to assess the quality of life of cancer patients .
results from ova-301 showed no difference in patients ' qol between the 2 study arms ( fig .
during the course of their illness , patients with ovarian cancer may undergo multiple cycles of treatment , with alternating multiple episodes of remission and relapse .
therefore roc patients are treated over a continuum in which therapeutic choices and strategies may impact the efficacy and safety of future therapies .
platinum rechallenge in combination or monotherapy regimes are often limited by hypersensitivity reactions and cumulative long - term toxicities , regardless of the regimen .
desensitisation protocols may be useful so as to allow treatment to continue , albeit with significant burden on staffing and resources and with varying outcomes .
the safety data from ova-301 show that trabectedin + pld can be considered as a treatment option at any relapse of ovarian cancer , including fully platinum - sensitive patients unsuited to receive subsequent platinum , with a manageable safety profile and equivalent efficacy .
therefore , trabectedin + pld is a non - platinum alternative that is well tolerated .
furthermore , increasing evidence indicates that by extending the platinum - free interval with effective non - platinum agents such as trabectedin + pld , patients are given some extra time to recover from any of the adverse effects of their prior platinum - based therapy with no detriment in qol ; and with even potential induction of their response to any subsequent platinum application , hence preserving their future treatment options .
professor fotopoulou received speaker fees from pharmamar for her participation at the bgcs 2014 symposium .
 most patients with recurrent ovarian cancer ( roc ) undergo a series of remissions and recurrences , therefore the additive or cumulative toxicity of chemotherapy must be factored into their treatment plan . 
 there are challenges in defining tailored therapeutic approaches , including optimal timing and drug sequencing management strategies to treat patients with roc . 
 this is particularly relevant as new cytotoxic drugs and biological agents become available . 
 many of these drugs are associated with increased toxicity and with no observable survival advantage . 
 therefore current treatment options for the heavily - pretreated relapsing oc patient population are frequently guided by safety considerations and convenience . 
 rechallenge with platinum - based combination regimes is commonly limited by the risk of cumulative long - term toxicities . 
 not all patients can continue with platinum at second - line or , indeed , further relapses due to loss of activity or toxicity - related issues including hypersensitivity , neurotoxicity , alopecia and ototoxicity 
 . in particular , hypersensitivity reactions are a concern and have been reported in approximately 15 - 20% of women receiving the drug . 
 trabectedin + pld is a non - platinum combination that is well tolerated , with a manageable safety profile , which is independent of age . 
Factors influencing treatment decisions in this heavily-treated patient population in the UK
Limitations to rechallenging with platinum-based therapy
Trabectedin plus PLD is a non-platinum combination that is well tolerated with a manageable safety profile
The impact of trabectedin plus PLD combination on patients' QoL
Conclusions
Conflict of Interest Statement