Friday, February 26, 2021

Immunotherapy Clinical Trials with Dr. Ezra Cohen at the 2020 CRI Virtual Immunotherapy Patient Summit

 


Although this video is not specific to ovarian cancer, it does address common questions about who should participate in these immunotherapy trials and how to go about doing this. 

Tuesday, February 23, 2021

Astonishing Podcast: 3-D Model To Be Used for Testing of New Treatments for OC

This is quite an astonishing use of 3-D technology that I had to read several times and it still caused me to shake my head in wonder and amazement.

Joanna Burdette, PhD and her team developed Evatar, a model of the female reproductive tract that uses cultured tissue of the ovaries and oviduct that can be used in the Evatar device to study the effects of new drugs on high grade serous ovarian cancer. 

What makes this model unique is that in basic research, cells are often kept in petri dishes, isolated from the tissue from which it came and stew in their own waste. In the body, cells interact and respond to neighboring cells and cellular waste is carried away by the vascular system. Evatar replicates the reproductive environment and is therefore able to recreate a more natural environment in which to study novel drugs.

To listen to a relatively short podcast about this research, follow this link.


Friday, February 19, 2021

How the Immune System Fights Ovarian Cancer


 Dr. Sarah Spear is an immunologist who is doing research in England about the role of this system to OC. The first minute or so of the video is presented by the host and the audio isn't great BUT once Dr. Spear starts, the audio and video quality is great and her explanations are incredibly accessible! She covers everything from checkpoint inhibitors to vaccines. Overall, a worthy video to watch!

Tuesday, February 16, 2021

Are You Interested in Helping to Decide Which OC Research Gets Funded?

 

I've been a consumer advocate for ovarian cancer with CDRMP. This stands for "congressionally directed medical research program". 

As a consumer advocate, my role is to keep the needs of the "consumer" (ie, those of us who have been diagnosed w/ovarian cancer) in the forefront of the scientific discussions about the research that is looking for funding from the government.

The Department of Defense is the second largest funder of ovarian cancer research (the first is the NIH which apparently is too snobbish to have consumer advocates on their panels). Approximately $20 million is allocated by the DoD for OC research. As a consumer, I have full voting privileges on which research projects get funded. 

Are you interested in being a consumer to do this very important work? I am including a link to the most frequently asked questions. The ONLY requirement to participant on this panel, is to be a survivor or a person living with ovarian cancer. The second link I'm including, is specific to the OC research.

For ovarian cancer, the panel generally meets in September, although sometimes it's early October. We gather just outside of DC and spend anywhere from 1-2 days depending upon the panel you are on, reviewing each of the research proposals. I am NOT required to have ANY medical background - that is not my role on the panel so don't let that stop you from participation. Remember you are only representing the needs of OC patients. You are required to read each proposals impact statement which is only about a page, but I find that it's helpful for me to read the body of the proposal to get a better understanding.

If you're interested in looking into this, contact me at mastrangelo.margaret@gmail.com


Friday, February 12, 2021

New Hope for OC


 What I like about this video is that Dr. Wahner Hendrikson out of Mayo, talks about 4 new options in the treatment of OC.

Tuesday, February 9, 2021

Dana Farber Covid-19 Vaccinations are Underway

 

I found this article particularly useful because so many of our members are seen at Dana Farber or else have had consults with them. In addition, they provide links to other states in New England that give information about the Covid-19 vaccine.

February 8 Update: COVID-19 Patient Vaccinations Now Underway

We are now vaccinating and scheduling vaccinations for our patients who are eligible for the COVID-19 vaccine. For Dana-Farber, this includes patients who are age 75 and older. We will move to the next phase of patients when the state of Massachusetts allows, and when we have supply of vaccine.

If you are currently eligible for a COVID-19 vaccine, please watch for messages that may come to you this week via text, email, phone call, or Patient Gateway with details on how to schedule your vaccine appointment.

  • If you are scheduled for a vaccination at Dana-Farber, your care team will not be present at your vaccination appointment. Our vaccine clinic is operated by trained vaccine personnel. 

  • Please do not call your Dana-Farber doctor's office to ask about the COVID-19 vaccine, as they cannot schedule vaccinations at this time.

We will frequently update this page with the latest vaccine news, which is rapidly changing.

Please Sign Up for Patient Gateway

If you are not already signed up, we urge you to take a few minutes to enroll in Patient Gateway (at www.patientgateway.org). Having a free account on Patient Gateway will make it easier for you to schedule a COVID-19 vaccine appointment when you are eligible to get one.

To get started, visit Patient Gateway and click Enroll Now. For step-by-step instructions, download our How to Enroll in Patient Gateway guide.

For more details about the site, check Dana-Farber's Patient Gateway overview.

COVID-19 Vaccine FAQ for Cancer Patients

When will I be able to get the vaccine?

  • We are now scheduling vaccinations for patients who are age 75 and older. We will move to the next phase of patients when the state of Massachusetts allows, and when we have supply of vaccine.

  • Our ability to offer vaccines to patients depends on the amount of vaccine we get from Massachusetts and the state’s direction on who is eligible.

  • If you are able to schedule a COVID-19 vaccination outside of Dana-Farber before you hear from us, we encourage you to get the vaccine at that other site. Learn more at www.mass.gov/COVIDvaccine.

What if I don’t live in Massachusetts?

Check with your state’s COVID-19 vaccine effort. New England state websites include:

How are you prioritizing vaccinations for patients?

Dana-Farber must follow the rules set out by the state of Massachusetts for phases of the vaccine rollout. We will follow state guidelines and prioritize those patients who are most at risk from COVID-19. To learn more about the state's phases, visit www.mass.gov/COVIDvaccine.

Will you be giving the vaccine during infusion when I visit Dana-Farber?

No. Our vaccination clinic will be held separate from your cancer care. This is to ensure that we can safely give the vaccine to a large number of patients without wasting any of the supply.

  • If you are scheduled for a vaccination at Dana-Farber, your care team will not be present at your vaccination appointment. Our vaccine clinic is operated by trained vaccine personnel.
  • Please do not call your Dana-Farber doctor's office to ask about the COVID-19 vaccine, as they cannot schedule vaccinations at this time.

What if I don’t live near Dana-Farber's vaccination location?

If you are unable to travel to Dana-Farber's vaccination clinic when you are eligible for a COVID-19 vaccine, visit your state’s vaccine website to determine where a COVID-19 vaccine may be available near you. If you are in Massachusetts, visit www.mass.gov/COVIDvaccine.

I am no longer in active treatment at Dana-Farber, but I still have active disease and am seen regularly at Dana-Farber. Can I get the vaccine from Dana-Farber?

Not at this time. Based on our allotment of vaccines, we will follow state guidelines and prioritize those cancer patients who are most at risk from COVID-19. For many cancer patients and survivors, vaccines may be available to you in your community before they are available at Dana-Farber. To learn more about when you might be eligible, visit www.mass.gov/COVIDvaccine.

Can I choose which vaccine I get?

No. Dana-Farber and other vaccination sites do not have a choice in which vaccine they receive. The COVID-19 vaccines that have now been authorized for Emergency Use Authorization by the FDA are nearly identical in their efficacy and safety.

Can my cancer caregiver (a person who is helping me and with me often during my treatment) get the vaccine from Dana-Farber?

No, because Dana-Farber must follow the rules set out by the state of Massachusetts for phases of the vaccine rollout. Learn more about the vaccine phases and where to get a vaccine outside of Dana-Farber at www.mass.gov/COVIDvaccine.

Should I get a COVID-19 vaccine if I've recently had cellular therapy (such as CAR T-cell therapy) or a stem cell transplant?

Yes, but only after 100 days has passed since your transplant or cellular therapy. In fact, we recommend that all transplant and cellular therapy patients strongly consider a COVID-19 vaccine when 100 days have elapsed from their transplant or cellular therapy. We anticipate that some transplant and cellular therapy patients may be able to receive the vaccine at Dana-Farber, depending on your time from transplant or cellular therapy. Please continue to check this Dana-Farber COVID-19 vaccine page for updates.

How can I get a list of my comorbidities?

The after-visit summary that you get after each Dana-Farber appointment should list any health issues that you may have. If you don't have this form handy or haven't visited Dana-Farber in a while, you can also get this information by logging into your Patient Gateway account at www.patientgateway.org.

Can I go back to normal after I get the vaccine (no masks, etc.)?

No. Even after you are vaccinated, it will still be important to follow best practices for preventing spread of the virus as we learn more about how the vaccines protect us under real-life conditions. This includes wearing a facemask, washing hands often, physical distancing, and complying with the Massachusetts COVID-19 travel order, as well as its testing and quarantine requirements.

Is the vaccine safe?

As with any medication, we follow guidance from the U.S. Food and Drug Administration, which has a strong vaccine safety system to ensure that all vaccines are as safe as possible. Many clinical trials are currently evaluating the COVID-19 vaccines to best determine their safety and effectiveness.

If I've had an allergic reaction to chemotherapy in the past, should I worry about reactions to the vaccine?

Talk with your care team if you've had an allergic reaction to certain chemotherapy drugs, such as those that contain polyethylene glycol (PEG), which is a compound that is part of the current COVID-19 vaccines. Learn more at www.cdc.gov/vaccines/covid-19.

Who should not get the vaccine?

According to the Centers for Disease Control, you should not get a COVID-19 vaccine if you have had an immediate allergic reaction to any ingredient in either of the two available COVID-19 vaccines. This includes polyethylene glycol (PEG), a compound found in some chemotherapy treatments. Talk with your care team or healthcare provider if you have questions. Learn more at www.cdc.gov/vaccines/covid-19.

Can I get one vaccine dose at Dana-Farber, and the other dose at another location?

No. Both of the currently approved vaccines require two doses and you must receive both doses at the same location. You must receive the same vaccine for doses one and two.

Is it OK to mix the vaccines (i.e., get a different vaccine for each dose)?

No. You must receive the same vaccine for doses one and two.

Is there a cost to receive a COVID-19 vaccine at Dana-Farber?

No. Per federal rules, there is no cost to you to receive a COVID-19 vaccine. Your health insurance plan may be charged a modest administration fee, but there will be no cost to you.

What if I experience side effects after getting a COVID-19 vaccine?

No matter where you are given a COVID-19 vaccine, you will be given clear instructions on what to do if you experience side effects (which are typically mild). For answers to some of the more common questions about getting the COVID-19 vaccine, please visit www.mass.gov/COVIDvaccine and click on "Frequently Asked Questions" or go directly to www.mass.gov/info-details/covid-19-vaccine-frequently-asked-questions.

My child is younger than age 16. When will he or she be able to get the vaccine?

We do not know, but experts are optimistic that a vaccine for children and young adults may be available by late 2021. Keep in mind that kids and young adults are not typically at high risk for severe illness from COVID-19.

As a parent of a cancer patient, will I be eligible to get a vaccine from Dana-Farber?

No, because Dana-Farber must follow the rules set out by the state of Massachusetts for phases of the vaccine rollout. Learn more about the vaccine phases and where to get a vaccine outside of Dana-Farber at www.mass.gov/COVIDvaccine.

Additional Information on Vaccines

Early clearance of serum HE4 and CA125 in predicting platinum sensitivity and prognosis in epithelial ovarian cancer


 Wouldn't it be nice to know if we could predict how we would respond to platinum therapy and what are chances are of having a relapse? 

This article, published Jan. 2021 in the Journal of Ovarian Research might move us a step closer in this direction. This article shows that if these two biomarkers are lowered quickly during treatment, HE4 (human epididymis protein 4) and CA125, may be good predictors of sensitivity to platinum therapy.  Although we are quick to know our CA 125 markers, many of us have no idea what our HE4 numbers are. Essentially, this article states that in epithelial ovarian cancer, these two biomarkers used jointly, may have good predictive value.

Abstract

Objectives

To assess the clinical value of early clearance of HE4 and CA125 for platinum sensitivity and prognosis in patients with ovarian cancer.

Method

HE4 and CA125 value including clinical data of 89 patients with ovarian cancer were collected. The clearance of HE4 and CA125 were assessed base on the platinum sensitivity, two-year PFS, PFS and OS.

Results

Sixteen patients were classified as platinum resistant and 73 as platinum sensitive according to the response to platinum-base chemotherapy. When HE4 clearance after 3rd cycle chemotherapy or CA125 clearance after 1st cycle chemotherapy, it gave the highest AUC of 0.788, with 100% of sensitivity and 57.5% of specificity respectively between platinum resistant and platinum sensitive group. In addition, 59 patients were classified as two-year PFS group and 30 as not achieved two-year PFS group according to obtaining two-year PFS or not. It gave the highest AUC of 0.730, with 83.3% of sensitivity and 62.7% of specificity respectively when HE4 clearance after 3rd cycle chemotherapy or CA125 clearance after 1st cycle. The prolonged PFS and OS were significantly associated by the clearance of HE4 after 3rd cycle chemotherapy (p< 0.0001, p< 0.0001) as well as CA125 after 1st cycle chemotherapy (p< 0.0001, p< 0.0001).

Conclusions

Our data suggested that the early clearance of HE4 and CA125 could predict platinum response and prognosis in patients with ovarian cancer. Monitoring the HE4 and CA125 during first-line chemotherapy might be helpful in predicting platinum sensitivity and risk to progress and relapse.

Introduction

Epithelial ovarian cancer (EOC) is the leading cause of mortality among gynecological cancer [2]. Due to the lack of typical clinical performance and reliable screening methods, approximately 75% of patients were diagnosed at advance disease with a poor prognosis. 30–50% of advanced patients will relapse within 5 years after standard surgery and platinum-based chemotherapy. Although the inhibition of the poly ADP-ribose polymerase has become an attractive therapeutic strategy in patients of epithelial ovarian cancer, early identification of drug-resistant or high-risk patients and taking hierarchical management is still crucial for improving prognosis.

Since patients with EOC have no measurable target lesion after initial surgery, it is difficult to assess the treatment response with gynecological examination and image. Effort has been made to find out reliable biomarker for monitoring therapeutic response and detecting relapse in EOC. Cancer antigen 125 (CA125) is the most common serum biomarker for judging treatment response and monitoring recurrent in EOC. Our previous study demonstrated that the median PFS and OS of patients with serum CA125 who had a logarithmic decrease or a decrease to normal within 1 month after treatment were better than those of with a non-logarithmic decrease or a decrease to normal that took longer than 1 month [25]. However, the single role of serum CA125 in predicting prognosis and platinum sensitivity still remains controversial [71722]. Therefore, there is still an urgent need to find more promising biomarkers for monitoring the prognosis of ovarian cancer.

Human epididymis protein 4 (HE4), has been proved to be a reliable biomarker for detecting ovarian cancer with a sensitivity of 76% (95%CI, 0.72–0.80) and a specificity of 94% (95%CI, 0.90–0.96) [29] and approved by the Food and Drug Administration in Unite State as a novel tumor biomarker for the diagnosis of ovarian cancer. The exploration of the value of this glycoprotein in predicting prognosis in ovarian cancer is still ongoing [6101516]. But there are seldom study concern with the correlation of early clearance of serum HE4 combined with CA125 during first-line treatment with platinum sensitivity and prognosis. The aim of this study is to evaluate the role of early clearance of HE4 and CA125 in predicting platinum sensitivity and prognosis in epithelial ovarian cancer.

Materials and methods

Patients and clinical data

The retrospective study was conducted in the Guangxi Medical University Cancer Hospital of china from July 2012 to December 2018. Patients diagnosed with epithelial ovarian cancer by histopathology with full serum HE4 and CA125 value and clinical record were available for review. Inclusion criteria were: 1) Initially treated with staging surgery or optimal cytoreductive surgery, including total hysterectomy, bilateral oophorectomy and salpingectomy, peritoneal washing, omentectomy, pelvic/para-aortic nodal dissection, and multiple peritoneal biopsies (multivisceral resection including en bloc resections with bowel resection, upper abdominal procedures, and extensive peritonectomy are required to achieve optimal tumor debulking when necessary). 2) Patients with stage IC and higher stage received platinum-based combined chemotherapy for 6–8 cycles after surgery. 3) Good nutritional status without other cancer. Exclusion criteria were:1) Death due to non-oncological reasons. 2) Lacking of follow-up after treatment.

Responds to treatment and progression were evaluated according to the guidelines of the Gynecology Cancer Intergroup (GCIG) [23] and the Response Evaluation Criteria in Solid Tumors (RECIST) criteria [11]. PFS was defined as the length of time between the initial treatment to the occurrence of the progress or relapse. OS was defined as the length of time between the initial treatment to death. According to the respond to chemotherapy, patients with recurrence within 6 months after the completion of first-line platinum chemotherapy were defined as platinum resistant. Patients who developed recurrence with an interval > 6 months were defined as platinum sensitive patients [8].

The study was compliant with the Declaration of Helsinki, and approved by the Ethics Committee of Guangxi Medical University Cancer Hospital. Informed consents of all treatments and examinations have been obtained from patients or their families.

Test of HE4 and CA125 value

Serum HE4 and CA125 concentration of each patient were measured at the time of pretreatment, each post-chemotherapy and recurrence. The tests were performed using an electro-chemiluminescence immunoassay (Roche, Diagnostics, Inc., Mannheim, Germany, performed according to the manufacturer’s specifications) at the departmental laboratory of Guangxi Medical University Cancer Hospital. The normal value range of HE4 is less than or equal to 70 pmol/L as suggested by Moore et al. [19], and the normal value of CA125 is less than or equal to 35 U/ml.

Statistical analyses

All the statistical analyses were conducted by SPSS 25.0 Software. T-test was used for the comparison between groups. The area under the curve (AUC) was used to calculate with a receiver operating characteristics (ROC) in predicting platinum sensitivity and two-year survival. The Kaplan-Meier survival curve and long rank test were used to assess the influence of HE4 and CA125 on PFS and OS. Cox regression models was used to conduct the univariate and multivariate analyses. A two-tailed probability of p< 0.05 was defined as a statistically significant.

Results

Patients’ characteristics

A total of 89 patients with EOC were included in the study. All patients were followed up to December 31, 2019. At the end of follow-up period, 36 patients were progress, 19 patients were dead and 70 patients were still alive. The median follow-up time was 35 months. Patients’ clinicopathological characteristics and the mean pretreatment level of HE4 and CA125 were presented in Table 1. The mean HE4 value of pretreatment was significantly increased with FIGO stage (p=0.008) and tumor grade (p=0.000). While the mean CA125 level of pretreatment was only significant increased with FIGO stage (p=0.008) and histology types (p=0.040). However, there were no significant differences in menopausal, platinum response and two-year PFS with pretreatment HE4 or CA125.

Table 1 Characteristics of patients with ovarian cancer and comparison with pretreatment HE4 and CA125 level

The predictive value of HE4 and CA125 in platinum sensitivity

In the analyzed patients, 16 were defined as platinum resistant and 73 as platinum sensitive. The capability of HE4 and CA125 clearance after 1st, 3rd, 6th cycle chemotherapy to predict platinum sensitivity were assessed by ROC and AUC. The clearance was defined as the level of HE4/CA125 reduced to normal value or had a reduction rate of 90% at least. The early clearance was defined as the clearance of HE4/CA125 before the 4th cycle of adjuvant chemotherapy. According to the definition, we found in platinum sensitive group that the clearance of HE4 in 55 of 73 (75.3%) cases after 1st cycle chemotherapy, in 59 of 73 (80.8%) cases after 3rd cycle chemotherapy, and in 61 of 73 (83.6%) cases after 6th cycle chemotherapy. The HE4 non-clearance patients of platinum resistant were found in 10 of 16 (62.5%) cases after 1st cycle chemotherapy, in 12 of 16 (75.0%) cases after 3rd cycle chemotherapy, and in 10 of 16 (62.5%) cases after 6th cycle chemotherapy. The maximum AUC was 0.779 for HE4 after 3rd cycle chemotherapy, with 75.0% of sensitivity, 80.8% of specificity, and a p value of 0.000. The maximum AUC was 0.731 for CA125 after 1st cycle chemotherapy, reporting 75.0% of sensitivity, 71.2% of specificity, and a p value of 0.004. When the two biomarkers were combined, the result showed that when HE4 clearance after 3rd cycle chemotherapy or CA125 clearance after 1st cycle chemotherapy, it gave the highest AUC of 0.788, with 100% of sensitivity and 57.5% of specificity respectively. When HE4 clearance after 3rd cycle chemotherapy and CA125 clearance after 1st cycle chemotherapy were used at the same time, the AUC, sensitivity, and specificity were 0.723, 50, and 94.5% respectively. The AUC, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), accuracy and p-value base on each parameter were shown in Table 2.

Table 2 Classification base on the platinum response and the AUC value using the clearance of HE4 and CA125

The clearance of serum HE4 and CA125 in predicting two-year PFS

In this part (Table 3), 59 patients were classified as two-year PFS group and 30 as not achieved two-year PFS group according to obtaining two-year PFS or not. Using the predefined standard with the clearance of HE4 and CA125, we found in two-year PFS group that the clearance of HE4 in 45 of 59 (76.3%) cases after 1st cycle chemotherapy, in 50 of 59 (84.7%) cases after third cycle chemotherapy, and in 51 of 59 (86.4%) cases after sixth cycle chemotherapy. The HE4 non-clearance patients of not achieved two-year PFS were found in 14 of 30 (46.7%) cases after 1st cycle chemotherapy, in 17 of 30 (56.7%) cases after 3rd cycle chemotherapy, and in 14 of 30 (46.7%) cases after 6th cycle chemotherapy. We found a statistically significant difference in predicting two-year PFS between patients with HE4 clearance and non-clearance at the period of after the 3rd and 6th cycle chemotherapy (p=0.001, 0.011), and the AUC of 0.707, 0.666 respectively (Table 3). The early clearance of HE4 after 3rd cycle chemotherapy demonstrated the optimal accuracy of 75.3%, with a corresponding 56.7% of sensitivity and 84.7% of specificity (PPV=65.4%, NPV=79.4%). The CA125 clearance profile in two-year PFS group were found in 43 of 59 (72.9%) cases after 1st cycle chemotherapy, in 56 of 59 (94.9%) cases after 3rd cycle chemotherapy, and in 57 of 59 (96.6%) cases after 6th cycle chemotherapy. The CA125 non-clearance patients of not achieved two-year PFS group were found in 17 of 30 (56.7%) cases after 1st cycle chemotherapy, in 7 of 30 (23.3%) cases after 3rd cycle chemotherapy, and in 7 of 30 (23.3%) cases after 6th cycle chemotherapy. Significant differences in predicting two-year PFS was only found in patients with CA125 clearance after the 1st cycle chemotherapy (p=0.023), with the AUC of 0.648, and a corresponding 56.7% of sensitivity and 72.9% of specificity (PPV=51.5%, NPV=76.8%). When HE4 and CA125 were combined, it was shown that the AUC reached 0.730 when the HE4 value after 3rd cycle chemotherapy or the CA125 after 1st cycle chemotherapy that declined above 90% or normalized (p=0.000). However, when both of the HE4 after 3rd cycle chemotherapy and the CA125 after 1st cycle chemotherapy declined above 90% or normalization, the AUC was 0.625 with p=0.056.

Table 3 Classification base on the two-year PFS and the AUC value using the clearance of HE4 and CA125

The relationship between prognosis and the serum HE4 and CA125

The Kaplan-Meier survival curve and a log rank test were conducted to analyze the relationship between patient’s PFS/OS and the value of HE4 and CA125 (Fig. 1). The result showed that the prolonged PFS and OS were significantly associated with the clearance of HE4 after 3rd cycle chemotherapy (p< 0.0001, p< 0.0001) and CA125 after 1st cycle chemotherapy (p< 0.0001, p< 0.0001). The pretreatment levels of HE4 had an impact on the PFS (p=0.014). However, there were no statistical significance between pretreatment levels of CA125 with PFS (p=0.694) and also no statistical significance between pretreatment HE4 and CA125 with OS (p=0.172, p=0.341).

Fig. 1
figure1

Correlation between the HE4 and CA125 level and OS/PFS. Kaplan-meier curve presenting the OS/PFS with different stratification of HE4 and CA125, including a The median of pretreatment HE4. b The median of pretreatment CA125. c The clearance of 3rd cycle chemotherapy. d The clearance of 1st cycle chemotherapy. e The median of pretreatment HE4. f The median of pretreatment CA125. g The clearance of 3rd cycle chemotherapy. h The clearance of 1st cycle chemotherapy

Univariate and multivariate cox regress analysis were explored to analyze the widely recognized prognostic of EOC, as well as the early clearance of HE4 and CA125 (Table 4). The univariate analysis demonstrated a significant influence of stage, HE4-clearance after 3rd cycle of chemotherapy, and CA125-clearance after 1st cycle of chemotherapy with respect to both OS and PFS in patients. Multivariate analysis revealed that only the HE4-clearance after 3rd cycle of chemotherapy and CA125-clearance after 1st cycle of chemotherapy were significantly independently associated with OS. The prolongation of PFS was significantly influenced by the stage, HE4-median pretreatment, HE4-clearance after 3rd cycle of chemotherapy, and CA125-clearance after 1st cycle of chemotherapy.

Table 4 Univariate and multivariate analyses for OS and PFS

Discussion

To our knowledge, optimal tumor debulking and platinum response have been proven to be the most powerful prognostic factor for both overall survival and progression-free survival of ovarian cancer patients. To acquire optimal tumor debulking, multivisceral resection including en bloc resections with bowel resection, upper abdominal procedures, and extensive peritonectomy are required when necessary. Despite improvement in surgical techniques, there are still patients who are not obtain radical resection will develop platinum-resistance with poor prognosis. At present, CA125 are conventionally used in monitoring responds to surgery and chemotherapy for ovarian cancer patients. Data from GOG-182 showed that the median OS for patients whose CA125 value declined to normal level after 2nd cycle chemotherapy was 77.7 months, compared with 23.0 months for those who did not normalized, and improved PFS was observed in patients with CA125 value declined to normal level after 1st, 2nd or 3rd cycle chemotherapy compared to those who never normalized before 4th cycle chemotherapy [12].

HE4 is a novel tumor biomarker in EOC patients. The assessment of the prognostic significance of pretreatment HE4 has been described in many papers. However, few studies focused on the early clearance of HE4 after treatment in predicting prognosis of epithelial ovarian cancer. There were several results suggested that HE4 was mainly secreted by malignant ovarian cancer cell and tumor micro-environment [1318]. Therefore, the removal of the tumor and the response to treatment should correlate with the clearance of HE4.

A prospective study of Roberto Angioli suggested that HE4 reduction with above 47% at the third cycle of chemotherapy were more likely to be platinum sensitive. On the contrary, CA125 value did not correlate with platinum response [1]. In our recent study, we have demonstrated that single HE4 superior to CA125 in predicting platinum sensitivity. Our data showed that the maximum AUC value of HE4 alone was 0.779 (p=0.000) in predicting platinum sensitivity after the third cycle chemotherapy compared to the maximum AUC=0.731 of CA125 (p=0.004) after 1st cycle chemotherapy respectively. When the two biomarkers were combined, the result showed that when HE4 clearance after 3rd cycle chemotherapy or CA125 clearance after 1st cycle chemotherapy, the AUC, sensitivity and specificity were 0.788, 100 and 57.5% respectively. It means that 100% patients with platinum resistant could be identified through the both non-clearance of HE4 after 3rd cycle chemotherapy and CA125 after 1st cycle chemotherapy. When HE4 after 3rd cycle chemotherapy and CA125 after 1st cycle chemotherapy were both clearance, 94.5% individual with platinum sensitive could be recognized. Previous publications on the application of HE4 and CA125 as a method of predicting chemotherapy response have mainly focused on the pretreatment biomarker value [14520]. Anita et al. have reported that the predictive abilities with regard to platinum sensitivity for pretreatment HE4 was excellent with an AUC of 0.627, and poor for pretreatment CA125 with an AUC of 0.547 respectively [4]. Nassir et al. showed that high level of pretreatment HE4 and CA125 correlated significantly with a poor response to platinum based chemotherapy [20]. Few studies pay attention to the dynamic change of biomarker corresponding to treatment response during first-line treatment. Chen et al. concluded that the change of HE4 was more closely related to the chemotherapy response compared to the change of CA125 individually [3]. Vallius et al. presented their result that HE4 was a reliable serum tumor marker for monitoring treatment response in advanced EOC patients [27]. They focused on the postoperative level and the nadir value during postoperative chemotherapy with serum HE4 and CA125. Their result suggested that the single postoperative HE4 was associated to residual tumor after surgery, primary therapy outcome and PFS in both primary debulking surgery (PDS) and interval debulking surgery (IDS) patients. The single postoperative CA125 was associated to PFS after IDS but not for PDS. They also demonstrated that the combination of HE4 and CA125 nadir level predicted primary treatment outcome and PFS better than either alone. However, they didn’t refer the combination of the clearance speed of HE4 and CA125 in predicting treatment response and prognosis. In Pelissier’ report, the cut-off for CA125 of 35 UI/ml and combined with HE4 of 115 pmol/L after the 3rd cycle of neoadjuvant chemotherapy (NACT) has a sensitivity of 92.9% and a specificity of 68.7% (PPV=72.2% and NPV=91.7%) in predicting platinum sensitivity in a small cohort of 30 patients deemed inoperable with advanced EOC [21]. Our study is the first to evaluate the predicting effect of treatment response and platinum sensitivity with the combination of early clearance of HE4 and CA125 during first-line chemotherapy. Our results suggest that monitoring HE4 and CA125 during first-line chemotherapy should be recommended. It may help early identifying high-risk patients with platinum-resistant in EOC patients. In other words, for this part of high-risk patients with a slow decline in HE4 and CA125, the corresponding imaging evaluation or individualized treatment should be developed. At present, there are no clinical trials showing that modifying the treatment based on the unsatisfactory decline of serological tumor biomarkers after treatment can improve the outcome of patients. HE4 and CA125 appear to be able to select high-risk patients who demand further treatment base on their adverse features, but still need to be confirmed in larger studies.

Olivier Colomban et al. used a Kelim model [26], which characterize the CA125 elimination rate during the first 100 days of NACT and adjuvant chemotherapy, to assess the benefit in survival with bevacizumab addition for high-risk ovarian cancer patients in ICON-7 [9]. The result showed that only those high-risk patients with an unfavorable KELIM parameter less than 1.0 might have derived a benefit from bevacizumab when considering non-censored median survivals. With respect to HE4, previous study showed that patients with HE4 change of > 80% during NACT in advance high-grade serous ovarian cancer correlated with prolonged OS compared to change < 80% [28]. However, serum CA125 decline of > 80 and < 80% during NACT had no statistical significance in OS. Patients with CA125 logarithmic decrease or normalization within 1 month post-operative were correlated with better PFS and OS [25]. Our data also demonstrated that serum HE4 is a more promising biomarker in prognosis of EOC compared to CA125. In the ROC curve analysis, patients with HE4 level normalization or reduction above 90% after 3rd and 6th cycle chemotherapy significantly correlated with two-year PFS (AUC=0.707, p=0.001, and AUC=0.666, p=0.011). CA125 level normalization or reduction above 90% after 1st cycle chemotherapy correlated with two-year PFS, with a lower AUC of 0.648, p=0.023. When combination of the HE4 after 3rd cycle chemotherapy and CA125 after 1st cycle chemotherapy, it was shown that the AUC reached to 0.730 when one of them declined above 90% or normalized (p=0.000), reporting an 83.3% of sensitivity and a 62.7% of specificity. Approximately 83.3% of patient who relapsed or progressed in 2 years could be identified during first-line chemotherapy with a 62.7% of specificity based on the combination of HE4 and CA125 non-early clearance. Using biomarkers to identify high-risk patients was a simple and non-invasive way and may complement the current definition of high-risk patients.

The result of Kaplan-Meier survival curve and long rank test also demonstrated that both the clearance of HE4 after 3rd cycle chemotherapy and CA125 after 1st cycle chemotherapy were significantly correlation with the PFS and OS. Prolonged PFS was significantly impacted by the pretreatment HE4 value but not pretreatment CA125. As respected to OS, there were no significant correlation between pretreatment value of HE4 and CA125 in our results. Similar results were obtained in other research which analyzed the influence of the pretreatment HE4 on PFS [12141524]. Amanda Fader et al. analyzed a group of 3686 patients with ovarian cancer and demonstrated that there was no difference in pretreatment CA125 with outcome [12]. However, patients with CA125 that normalized after 1st, 2nd, 3rd cycle of chemotherapy treatment were less likely to experience disease progression as compared to those of not normalization ones in Fader’ study. Anita et al. analyzed a group of 48 EOC patients treated with PDS and demonstrated that the prolongation of PFS and OS was significantly correlated with the pre-operative HE4 value [4]. Their result also concluded that the duration of OS was significantly influenced by the HE4 value after the third course of chemotherapy but not CA125, and the prolonged PFS was influenced by the CA125 value after the third course of chemotherapy treatment bot not the HE4. This result was different from ours. The reason for this problem may be due to its small sample size and selection bias.

This study was a retrospective character, single-center setting, relatively small number of patients, and lack of external validation, which may bias the results. A bigger prospective cohort or including more clinical covariate such as ECOG score, oncogene expression might be helpful to validate the result and provide more information. Therefore, further studies are needed to confirm these results.

Conclusions

In conclusions, our findings revealed that the early clearance of HE4 and CA125 during first-line platinum chemotherapy were significantly associated with the platinum sensitivity and prognosis. Monitoring the dynamic value of both HE4 and CA125 during treatment might be helpful in future clinical practice.

Availability of data and materials

The data and materials which were analyzed and generated at the study are available from the corresponding author on reasonable request.

Abbreviations

HE4:

Human epididymis protein 4

CA125:

Cancer antigen 125

EOC:

Epithelial ovarian cancer

ADP:

Adenosine Diphosphate

FIGO:

The International Federation of Obstetrics and Gynecology Staging System

PFS:

Progression-free survival

OS:

Overall survival

CI:

Confidence interval

GCIG:

The Gynecology Cancer Intergroup

RECIST:

The Response Evaluation Criteria in Solid Tumors

AUC:

Area under the curve

ROC:

Receive operator characteristics

PPV:

Positive predictive value

NPV:

Negative predictive value

PDS:

Primary debulking surgery

IDS:

Interval debulking surgery

NACT:

Neoadjuvant chemotherapy

ECOG:

Eastern Cooperative Oncology Group

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Acknowledgements

Not applicable.

Funding

This work was supported by grants from the Key Laboratory of Early Prevention & Treatment of Regional High-Incidence-Tumor, Ministry of Education of China, the Innovation Project of Guangxi Graduate Education (Grant No. YCBZ2020051), and Guangxi zhuang autonomous region clinical key specialized subject construction project funds. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.