Yes. Yes. So, namaste everyone. So, I'm Dr. Amila Shilpakar and today I'll be talking in brief about systemic therapies in management of cervical carcinoma. So as we all know, cervical cancer is a major public health problem worldwide and it is second most commonly diagnosed cancer and the third leading cause of cancer related deaths among females, especially in underdeveloped countries, and it accounts for more than 85% of cervical cancer, of course, more than 85% in less developed countries. And it requires multimodality treatment with surgery and radiation in the form of local treatment, whereas a systemic treatment comprises of chemotherapy, targeted therapies, and immunotherapy. So chemotherapy in a systemic use can be done at various settings in case of cervical cancer. We can use it in concurrent chemotherapy with radiation as a part of definitive treatment. There are studies with adjuvant therapy in cervical cancer, in neoadjuvant setting, and in advanced metastatic or recurrent setting. So going to the concurrent chemo-radiation scheme, there has been definite survival benefit with chemotherapy and radiation for cervical, different stages of cervical cancer, especially with 1b, 2b, and 4b. And chemotherapy, there are various regimes being used, like weekly cisplatin in a dose of 40 milligram per meter square, along with radiation is the commonly used regime, because it has shown that it has similar outcome as with other combination regime, and it's least toxic in comparison to the combination therapies. For patients who are frail or who are deemed, suppose, not to tolerate cisplatin, carboplatin can be replaced for cisplatin. There has been various studies with other combination regimes, like cisplatin and 5-fluorouracil, mitomycin, cisplatin, along with gemcitabine, but all these trials have shown greater toxicities, especially with cisplatin and gemcitabine combination. So most of the guidelines now currently recommend concurrent cisplatin containing chemotherapy in a dose of 40 milligram per meter square, when we are using it for definitive concurrent chemoradiation. So it can also be used in adjuvant setting, and in locally advanced cervical cancers, what are the benefit of adjuvant chemotherapies? This has been answered by one of the major Outback trial, which was published in 2021, and it randomized patients undergoing definitive concurrent chemoradiation to either concurrent cisplatin-based chemoradiation or concurrent cisplatin-based chemoradiation, followed by four cycles of adjuvant chemotherapy with carboplatin and cisplatin, carboplatin and paclitaxel combination, and the results showed that there was no difference in PFS or overall survival, and there were similar pattern of disease recurrence. So based on this trial, now we recommend definitive concurrent chemoradiation only in case of locally advanced cervical cancer. There was also another phase three randomized control trial using gemcitabine and cisplatin concurrent chemoradiation, followed by adjuvant radiation with cisplatin and gemcitabine for two more cycles, following completion of concurrent chemoradiation, and this trial showed that there was significant improvement in PFS and OS, however, there was so much of toxicity in the gem-cis arm, and since it was done, there were unclear benefits. It was not sure that whether this benefit was due to concurrent chemoradiation only or addition of adjuvant chemotherapies, and on further analysis of the trial, it was found that probably side effect monitoring was not done very perfectly, so because of that and increased toxicity with gemcitabine and cisplatin, we still use concurrent chemoradiation with only cisplatin, and no adjuvant chemotherapy is recommended as of now. So then what is the role of neoadjuvant chemotherapy in case of cervical cancer? Again there has been a lot of trials with studies of neoadjuvant chemotherapy, and there was this trial which evaluated three cycles of neoadjuvant chemotherapy with paclitaxel and carboplatin for every three weeks, followed by radical hysterectomy versus standard concurrent chemoradiation with 40 mg per m2 of cisplatin for five weeks, and the trial showed that five-year disease-free survival was actually better with the concurrent chemoradiation arm, however, the five-year overall survival was similar between the two groups. So it's still debatable. The benefit is clearly with concurrent chemoradiation, but there are certain conditions we have to think about when we consider neoadjuvant chemotherapy, which I'll be coming in next slide. So this was another URTC trial which compared neoadjuvant chemotherapy followed by radical hysterectomy versus concurrent chemoradiation, and this trial also showed similar results. The overall survival was similar in both the arms, however, there was trend for better results in neoadjuvant chemotherapy followed by surgery for stage 1b2, and trend for better results for concurrent chemotherapy arm for stage 2b onwards with patients of BMI less than 25 and age of more than 50 years. So these are probably the patients who had risk for surgery, and subgroup analysis showed better results in this subgroup. Short-term grade 3 and 4 toxicity were higher with neoadjuvant chemotherapy arm, especially the toxicity of chemotherapy, whereas long-term toxicity were higher in the concurrent chemoradiation arm. So based on this, who are the patients who might be benefited from neoadjuvant chemotherapy? Basically if the patient has stage 1b and patient is without any comorbidities, young patient whom we are thinking about, you know, other bladder and other long-term toxicity of radiation, probably these patients might be the candidate to undergo surgery with neoadjuvant chemotherapy. And especially in our setup, like in Nepal or other areas where the access to radiation or brachytherapy expertise is very limited, probably where the wait list of radiation is quite a few months in our country. In locally advanced carcinoma of cervix, we can start with neoadjuvant chemotherapy and then possibly undergo surgery if possible, and if not possible, we go for definitive concurrent radiation. So we can use it as a bridge to definitive therapy. And again, expertise for surgical approach is very important. If the surgeons are not experienced, if the surgeons are not trained gynecological surgeons, which is very prevalent in low-middle-income countries like ours, there is very limited expertise manpower in gyneco-oncological surgeries, probably concurrent chemo-radiation would be better in those scenarios. And again, patient's comorbidity profile is very important, risk of surgery versus long-term risk of radiation therapy should be balanced. So again, in metastatic or recurrent cervical cancer settings, what are the role of systemic therapy? First of all, let's discuss about what is the role of chemotherapy. So there has been a lot of trials. We needed quite a few time to identify which chemotherapy was better, whether cisplatin is better or carboplatin is better, and whether there are any further treatment that can improve the overall survival in these patients with respect to chemotherapy. So this which chemotherapy question was answered by this GOG-204 trial, in which there were four arms which compared paclitaxel cisplatin with vinerolbin cisplatin, gemcitabine cisplatin, and topotecan cisplatin. And this trial gave us the answer that taxol with cisplatin was better tolerated and had better improved overall survival for recurrent or metastatic carcinoma cervix. After this, we changed our standard of care to taxol and cisplatin. And there are patients in which probably in metastatic setting with comorbidities and cisplatin may not be, the patients may not be cisplatin eligible. So this JCOG trial answered the question about probably whether we can use carboplatin in those subset of patients who might be intolerable to cisplatin. And this trial showed that substituting carboplatin for cisplatin in metastatic setting was non, it is non-inferior, and it can be used safely in patients. So after this, probably cisplatin carboplatin, paclitaxel regime was changed to carboplatin paclitaxel in patients whom we might think that it's not tolerable as cisplatin. And the quest for improvement in overall survival continued. So this is just a summary that 204 gave us cisplatin and taxol were favorable. So whether there was, there can be improvement in overall survival in this metastatic recurrence setting or not. And this was answered by the pivotal GOG 240 trial in which chemotherapy arm was compared with Bevacizumab. And we can see that there was improvement in survival by 13.3 months versus 17 months in Bevacizumab arm. So after a long gap, this GOG 240 trial, cisplatin, paclitaxel, and Bevacizumab arm was something that showed significant benefit in overall survival. And this became standard of care in patients who can afford, unfortunately in Nepal, most of our patients cannot afford Bevacizumab due to financial constraint, but they should be offered due to those patients who can afford this treatment. So coming to what might be the role of immunotherapy in carcinoma cervix. So there has been a study now upfront chemotherapy combined with immunotherapy in case of persistent recurrent or metastatic cervical cancer. So this was a keynote 826 trial in which it was a phase three double-binded randomized control trial and pembrolizumab with placebo was compared in advanced cervical cancer to the patient who were receiving platinum-based chemotherapy with or without Bevacizumab. So this trial showed improved overall survival at two years, 40.4% versus 40.4%. And we can see this Kaplan-Meier curve in which we can clearly see the benefit in patients whose combined proportion score was positive. So it was more than 1%. So CPS score is a ratio of PD-L1 positive cells combining lymphocyte, macrophages or tumor cells divided by total number of tumor cells into 100. So it's a percentage. And if we can clearly see if CPS score was more than or equal to one, there was definite benefit of pembrolizumab and it can also be seen in this forest plot. And for CPS score more than or equal to 10, the benefit was even higher. And we can see the separation of this curve after two years and which tells that if the patient responds to immunotherapy, there are few patients who have very durable responses. So this is very promising to those patients who like if they respond, it can be durable responses. Coming to second line chemotherapy, there are a number of drugs active in second line treatment of cervical cancer. However, the response rates for most of the second line treatments are around 15 to 29%. NAP-paclitaxel is something we can consider with response rate of around 29%. We can use I-phosphamide, irontican, topotican. Imetrexate can be used. Vinorbin can be used. Gemcitamine, 5-FU and docetaxel. These are the drugs that are active in second line treatment. But we know that there is no durable responses in second line settings. So there has been studies initially with immunotherapy now in second line treatment of recurrent or advanced metastatic carcinoma cervix. And this keynote 158 trial evaluated the use of single agent pembrolizumab in advanced carcinoma cervix. The patients progressed after first line chemotherapy. And we can see that the overall response rate was 12.2%. However, the point to be noted is there were three complete responses, nine partial responses, and all were PD-L1 positive patients. However, the overall response rate was higher with PD-L1 positive patients, which was 14.6%. So again, the beauty of immunotherapy is that those patients who respond to this treatment may have durable response. And there are case reports of even no evidence of disease as well. The only constraint is financial and availability of these drugs in our setup. And so there was, again, nivolumab can be used in the second line setting, in which overall response rate is around 26%. So now coming to this semiplimab. This is the trial, phase three randomized trial, which compared semiplimab with chemotherapy in recurrent carcinoma of cervix after first line chemotherapy. And we can see that there was a good response with semiplimab, 16.4% versus 6.3% with chemotherapy. And there has been median overall survival of 12 months versus 8.5 months with this drug. So this has been FDA approved in treatment of metastatic or recurrent carcinoma cervix in second line and beyond. So the newer drug that is coming is Tissotumab Vedontin. It is an antibody drug conjugate. The antibody is directed against the tissue factor, which is present in the tumor microenvironment, whereas the microtubule drug conjugate acts upon the tumor cells by binding to the tissue factor. And this single arm trial showed that the response with this drug was 24% with 7% complete response rate. However, this drug has significant toxicity, especially ocular, like uveitis and keratitis. So this is something coming up in newer treatment of metastatic cervical cancer. There are a lot of ongoing trials, like there are vaccine trials undergoing adoptive cell transfer therapies, like tumor infiltrating lymphocytes therapy is something that has shown some promising result in preliminary studies. And combination immunotherapies are something which are underway, like Nivolumab with Ipilimumab and Atelizumab with other combinations. There are a lot of trials going on. There has been newer targeted treatment with the onset of precision oncology in treatment of cancers. So Nexin sequencing has revealed a lot of targetable driver mutations in most of the solid tumors. And depending on that, if there is red gene fusion positive tumors in metastatic carcinoma cervix, cell percatinib can be used. And for entract gene fusion positive tumors, ladeptinib or entrectinib has been approved by USFDA for treatment of this metastatic cancers. So there has been a quite evolving landscape of treatment of cervical cancer over the last few years. We hope there will be much more development in the future. And apart from this, we should always think about palliative treatment right from the diagnosis of the patient for symptomatic management, because what we aim is not only disease control, but also improvement in quality of life of our patients. Thank you. I'm happy to answer any questions.

systemic therapies

cervical carcinoma

chemotherapy

targeted therapies

immunotherapy