Thank you, Dr. Jitendra. So Dr. Rajiv will be presenting. So thank you, Dr. Jitendra. And also, I'd like to thank IGCS Eco-Nepal Project for giving me this opportunity. So I'll be discussing briefly on management of recurrent epithelial ovarian cancer. And I'd like to apologize if power cut happens, because it is most frequent in Dharan also, in between. Is my screen visible to all? Yes, thank you. So today, I'll be discussing regarding the platinum sensitivity and its various options in platinum-sensitive and resistant disease and management of recurrent ovarian cancer, SSTD, BRCA, and other genetic mutations. And regarding secondary cycle reduction, it is the second. I'll not be discussing that, because it is our second presentation. So basically, focusing on chemotherapy options. So as we all know, we have a definition for platinum sensitivity. So if the recurrence occurs within the six months after completion of first-line platinum-based therapy, that is, if the platinum-free interval or disease-free interval is less than six months, that we define this as platinum resistance. And if it is between six months and 12 months, it is partially platinum-sensitive. And if it is more than 12 months, it is platinum-sensitive disease. And we also have a term known as platinum refractory disease. Those patients that are progressing on ongoing platinum-based therapy, evident by increasing CA125 level with worsening of symptoms or any other new metastatic tumor deposits. And general management scheme for this group of patients is, for platinum-sensitive disease, we basically prefer re-induction of platinum-based chemotherapy. And for resistance disease, as we all know, these conventional therapies are probably ineffective. And basically, they are treated with sequential single-use. I'll be discussing in later slides. And in case of platinum refractory disease, they are even associated with poor prognosis. And available therapies are basically ineffective. And basically, they should be enrolled in clinical trials with newer agents. So this is the basic management scheme. So for platinum-sensitive recurrent disease, we have various options. So there are paclitaxel in combination with chiroplatin, or chiroplatin with docetaxel, chiroplatin with liposomal doxorubicin, or zemcitabine with chiroplatin, or liposomal doxorubicin with tribenicidin. And bevacizumab can be added to either paclitaxel or chiroplatin, or zemcitabine or chiroplatin resamin. So this is the landmark trial, which demonstrated the efficacy of paclitaxel with platinum-based chemotherapy, versus conventional platinum-based chemotherapy in women with relapsed platinum-sensitive ovarian cancer. So basically, 802 patients were randomized. And primary outcome measure was overall survival. And secondary outcomes were progression, survival, and quality of life. So these were the results. So as we can see, in paclitaxel and platinum-based combination, it has better overall survival, as compared to conventional treatment, as well as better PFS, as compared to conventional treatment. And also, in subgroup analysis, this combination of paclitaxel and platinum had better outcomes, as compared to conventional treatment, in overall survival, as well as in progressive survival. So with this multilateral phase 3 study, basically, this paclitaxel and platinum-based chemotherapy doperate is considered a standard for platinum-sensitive recurrent disease. But however, so basically, in recurrent setting, most of the patient basically receives this therapy in first-line setting. So toxicities were a major concern. So in paclitaxel and platinum-based combination, neurological toxicity was seen in about 20%, as well as allopatia in 86%. But however, in conventional platinum, neurological and allopatia were lesser. But however, hematological toxicity were more than the paclitaxel and platinum-based combination. So for that, there were non-neurotoxic alternatives too. So this was studied on at least 56 patients that compared chiroplatin and gemcitabine. And then the primary objective was measure of progressive survival. And also, we can see that median PFS was better with hazard of 0.72 in combination group. And also, response rate in gemcitabine and chiroplatin group was also better than chiroplatin alone. And in cases of toxicity, though in combination group, we have more grade 3 or 4 hematological toxicity. But however, the neutropenia with infections were very much less. And also, the neuropathy, both motor and sensory neuropathy, were also very much less in gemcitabine and chiroplatin. So with this, another trial, that is calypso trial, that basically compared chiroplatin and liposomal doxorubicin combination. So this is also phase 3 randomized trial. And we missed 976 women with recurrence of more than six months were enrolled. And here we can see in chiroplatin and liposomal doxorubicin combination, they have better median PFS than as compared to chiroplatin and paclitaxel of 11.3 versus 9.4 months. So with this improved PFS and superior therapeutic index of chiroplatin and liposomal doxorubicin, this regimen is an excellent alternative to conventional paclitaxel for platinum-sensitive recurrent ovarian cancer, who basically had toxicity issues with tags and groups. Another is GOG213, an OCS study, which basically studied the addition of bevacizumab, that is anti-BHGF, so in platinum-sensitive recurrent EOC. So in this, chiroplatin and paclitaxel were combined with bevacizumab, and they were compared without bevacizumab 2. So in both the PFS and OS, they favored combination with bevacizumab, and followed by maintenance bevacizumab. And similarly, in OCS study, it also had favorable results with bevacizumab addition. So with this, the FDA has approved the combination of bevacizumab with either chiroplatin or paclitaxel, or chiroplatin plus zamzidebin, followed by maintenance bevacizumab in this group of patients. And for those patients who are intolerable to platinum, so meaning who demonstrated hypersensitivity to platinum, or who have comorbidities that lead to ineligibility for platinum administration. So for those patients also, in platinum-sensitive disease, we can also consider for single-use bevacizumab. In platinum-sensitive disease, we can also consider for single-agent therapy. So these are the single-agent therapy options. So it can be used based upon the patient's preference and the comorbidity status. Now for the platinum-resistant disease, so there are various, basically, for platinum-resistant, it is basically recommended as single-agent sequential therapy, rather than combination, due to toxicity issues. So with all these agents, any of the agents can be considered, differing with patient's preference and also the patient's comorbidity status. So with all these agents can be used as single-agent and also as sequential therapies in platinum-resistant patient. And there is OVA-301 trial, which randomized 672 patients with liposomal doxorubicin follow in combination with trabenicidin versus liposomal doxorubicin alone. And it favored the combination group with trabenicidin in PFS as well as overall response rate. And there is Aurelia trial. So it is, again, the bevacizumab combination trial in platinum-resistant group of patients. It is phase 3 trial. And the chemotherapy is selected where physician's choice, either of liposomal doxorubicin or weekly packed reaction or 2-protecan. So it also favored with addition of bevacizumab, with PFS of almost double in bevacizumab addition group. And now the question arises whether to consider treatment if there is only rising CA-125 with no clinical symptoms or radiological progression. So this is a trial which showed there was no difference in early treatment versus delayed treatment in a patient with rising CA-125. So there were no difference in overall survival. So in cases of only rising CA-125, we can basically observe the patient for further progression. Or if the systemic therapy is indicated, we can consider for hormonal therapy as it has shown lesser toxicity as compared to chemotherapy. And with BRCA-positive tumors. So for platinum-sensitive relapse, so basically for patients with BRCA-1 or 2-associated platinum-sensitive relapse, re-treatment with platinum-based chemotherapy is preferred. And for patients who experience a complete or partial response to platinum-based therapy and who did not receive PARP inhibitor maintenance in the front-line setting, maintenance with PARP inhibitor rather than bevacizumab is recommended. And there are no data to inform the use of PARP inhibitor either as a treatment or maintenance after platinum-sensitive relapse after exposure with previous PARP. And for BRCA carriers with platinum-sensitive disease who did not undergo maintenance with PARP therapy in the front-line or adjuvant setting, PARP inhibitor is an appropriate alternative to chemotherapy. And these are the FDA-approved drugs in PARP inhibitor. So niraparib, olaparib, and rucaparib can be considered. For niraparib, it is basically for maintenance recommendation for more than two lines of prior chemotherapy in recurrent ovarian cancer with complete or partial response to platinum. And olaparib has both maintenance and treatment indications in zone-line BRCA-mutated patients. And similarly, rucaparib, it also has both maintenance and treatment indication in both zone-line or somatic BRCA-mutated patients. And for platinum-resistant relapse, basically the treatment approach is similar to that with wild-type for BRCA carriers. But however, PARP inhibitors are no longer used in these settings. And as you all know, immunotherapy is also transferred and transfer immunotherapy are also ongoing. But however, the results are not satisfying. So one could be pembrolizumab, which can be used in patients with micro-satellite high MSI patients, where other alternative options are not available. So pembrolizumab can be used with overall response of 34%. And similarly, endocrine therapy for patients with radiological evidence of disease progression, but with little or no symptoms associated with recurrent epithelial ovarian cancer. Endocrine therapy can be a reasonable option. These are all based on phase two trials with response rate of 10 to 12%. And available options could be Tamoxifen, Letrozole, or Fulvestrin. And as we all know, Nepal is basically a resource stratified country. So ESCO has also given a resource stratified guideline with the framework resource stratification as basic, limited, and enhanced. So this guideline is available in ESCO guideline. So for resource stratified in a country like Nepal, so we can use these guidelines for the management of the patients in our context. And also, there is one paper that basically has compared weekly cisplatin and daily oral etoposide in platinum-PTTed ovarian cancer. And this has shown a very promising result that weekly cisplatin and daily etoposide can be highly effective as well as very tolerable in patients with ovarian relapsing after conventional platinum-based chemotherapy, including patients who have progressed during or within four months of platinum treatment. So cisplatin was used as 50 mg per mL square, six weekly doses, and etoposide was oral 50 mg daily. So for our patients, we can also consider this combination in platinum-resistant cases. So in summary, so we have, if only rising CM125 with no radiological or symptomatic progression, we can consider for observation or consider hormonal therapy. And if there are symptoms and also definite radiological evidence, so based upon the time of the previous platinum duration, so we can consider either as platinum-sensitive, resistant, so with that, if the progression is more than six months, we can re-challenge with the platinum-based chemotherapy. Or if the progression is less than six months, so for platinum-resistant cases, so either a single agent-sequential chemotherapy can be considered. So with this, I'd like to end my presentation, and I'd like to thank all of you for giving me this opportunity to present in this forum. Thank you very much.

recurrent epithelial ovarian cancer

platinum sensitivity

platinum resistance

chemotherapy options

PARP inhibitors