DOI: https://doi.org/10.21203/rs.3.rs-1614408/v1
Gastric cancer remains one of the leading causes of cancer-related morbidity and mortality. It requires combination of chemotherapy and surgery to achieve the longest overall survival and disease-free survival. However, chemotherapy regimens have a significant toxicity level that prevents patients from completing the entire treatment protocol.
This is a prospective randomized clinical trial aiming to assess an intolerance of chemotherapy related adverse effects in patients with resectable gastric cancer receiving perioperative XELOX and FLOT regimen. The primary endpoint is a quantity of patients who complete all the protocol treatment without any deviations. Secondary endpoints are pathological regression rate, chemotherapy toxicity profile, disease-free survival rate and overall survival rate.
The results of the trial will demonstrate the proportion of patients who are able to complete protocol treatment without any deviations in real world settings and its impact on overall survival and disease-free survival rates.
The protocol compliance is one the main factors in successful treatment of gastric cancer. In case the compliance of chemotherapy regimen with potentially lower toxicity has bigger impact than application of three-drug scheme, it can play a significant role in real-world settings.
Gastric cancer remains one of the leading causes of cancer morbidity and mortality. According to the GLOBOCAN Cancer Network the incidence of gastric cancer in Ukraine in 2020 comprised 5.6–8.2 among women and ≥ 16.4 among men per 100,000 people [1]. According to the data of the Cancer Registry of Ukraine there were 26,536 patients suffered from gastric cancer in 2018 [2]. The incidence of gastric cancer has steadily declined worldwide over the past 50 years. These declines preceded the successful reduction of H. pylori infection, and are likely attributable to changes in food preservation, such as less pickling of vegetables, and less smoking and processing of meat. The decline has also been elicited by the greater availability of fresh fruits and vegetables [3]. However, long-term treatment outcomes even after implementation of combined treatment are still poor.
Nowadays, the main method of treatment of resectable gastric cancer is surgery [4, 5]. However, surgery alone does not allow achieving optimal treatment results, so it is necessary to combine surgical treatment with chemotherapy or radiation therapy. Perioperative chemotherapy is the method of choice in the recommendations of the National Comprehensive Cancer Network and the European Society of Clinical Oncology. Treatment regimen should be chosen taking into account the patient's functional status, comorbidities and chemotherapy toxicity profiles [4, 5]. Therefore, the balance between effectiveness and tolerability of chemotherapy is important. Chemotherapy has quite toxic compounds that often do not allow completing the prescribed course of chemotherapy.
Both two- and three-component chemotherapy regimens are recommended for patients with resectable ≥ IB stage gastric cancer and there is currently no evidence to suggest a significant difference in efficacy between these regimens.
The MAGIC study became the evidence base for prescribing perioperative chemotherapy to patients with resectable locally advanced gastric cancer, as this approach improves 5-year survival to 40% [6]. However, only 91% of the patients enrolled in this study completed all of the ECF / ECX neoadjuvant chemotherapy. Only 37% of the patients received 3 courses of adjuvant chemotherapy.
In another randomized prospective study TOPGEAR, which compared perioperative ECF chemotherapy with preoperative chemoradiation, not all patients completed the full course of treatment in two cohorts [7]. The proportion of patients who received all two planned cycles of preoperative ECF was 98% in the group of patients who received chemoradiation and 93% in the group of patients who received only chemotherapy (3 cycles). At the same time, the proportion of patients who received at least 80% of the planned treatment volume was 98% in the chemoradiation group and 92% in the chemotherapy group. Among patients who underwent surgery, 53% of patients in the chemoradiation group and 65% of patients in the chemotherapy group completed postoperative ECF protocol.
Study ST03 also demonstrated that chemotherapy with the ECX regimen also has pronounced side effects [8]. 472 (89%) of the 529 patients who were randomized to the chemotherapy-only group received all three preoperative cycles. 457 [86%] of the 533 in the chemotherapy group alone received surgical treatment. Only 215 patients in the chemotherapy group received all three postoperative cycles.
According to another study, more patients treated with FOLFOX had metastatic lymph nodes in 67.8% after neoadjuvant chemotherapy in contrast to those treated with EOX (57.7%) [9]. In the FOLFOX and EOX groups there were 4 (4.6%) and 3 (11.5%) cases of complete tumor regression, respectively. Instead, all patients received "approximately 4 courses of neoadjuvant chemotherapy" without indication of dose reduction and delay schedule. Therefore, this study cannot be of high quality.
The NEO-CLASSIC study was designed to prove the efficacy and safety of the XELOX regimen in perioperative mode [10]. Grade 3–4 toxicity was recorded in 8.5% of patients. The main types of toxicity were neutropenia and leukopenia, and no toxicity-related deaths were reported. 62% of patients completed the treatment protocol.
If we analyze the NCCN recommendations more meticulously we can find out that the basis for application of this scheme in the perioperative mode was a study conducted in South Korea [11]. Investigators compared XELOX with SOX scheme in the study. XELOX showed the same toxicity profile and the same time to disease progression as SOX [10]. The mean number of cycles for XELOX was 8 (range 1–28 cycles). Dose reduction and treatment delays occurred in 33 patients (51.6%) and 41 patients (64.1%) experienced treatment delays of more than 7 days.
According to a randomized CLASSIC study in which XELOX was used as an adjuvant treatment after radical surgery 3-year recurrence-free survival was 74%, compared with patients who receivied only surgery (59%) [11]. As to chemotherapy, 346 patients (67%) assigned to the chemotherapy group received eight cycles as planned. 167 patients had capecitabine dose reductions, 147 patients had cycle interruptions, and 369 had cycle delays, and 163 patients needed oxaliplatin dose reductions.
The Phase 2 study FLOT-AIO compared FLOT chemotherapy regimen (4 preoperative and 4 postoperative cycles) and a combination of epirubicin, cisplatin, and fluorouracil [12]. According to the study design, 300 patients with gastric or esophago-gastric cancer were involved. The FLOT regimen was associated with a more numbers of cases of complete pathohistological tumor response to chemotherapy (16% and 8%, respectively). 91% of patients in the ECF group and 90% of patients in the FLOT group completed chemotherapy protocol. For various reasons 63% of patients in the ECF group and 54% in the FLOT group did not complete the treatment. Toxicity of chemotherapy caused discontinuation in 13% of patients in the ECF group and 10% in the FLOT group. 3–4 levels of toxicity developed in 16% of patients in the ECF group and up to 7% of patients in the FLOT group, with neutropenia and infectious complications more often developed in the group of patients receiving FLOT (9% vs. 18% and 39% vs. 51%, respectively). The number of deaths due to toxic complications did not differ and was less than 1% in both groups. In addition, disease progression, early death, or loss of efficacy resulted in discontinuation of chemotherapy in 21% of the ECF group and 13% of patients in the FLOT group. The most common complications, according to the study, were neutropenia (52 [38%] of 137 patients in the ECF / ECX group vs. 67 [52%] of 128 patients in the FLOT group), leukopenia (28 [20%] vs. 36 [28%] ), nausea (23 [17%] vs 12 [9%]), infectious complications (16 [12%] vs 15 [12%]), nausea and vomiting (13 [10%] vs. 4 [3%]).
S-1 chemotherapy regimen widely used in Asian countries also showed pronounced side effects that sometimes make chemotherapy impossible. The POST trial included 153 patients who were randomized to receive S-1 + docetaxel (DS) or S-1 + cisplatin (SP) adjuvant chemotherapy [13]. The mean number of treatment cycles in each group was 8. The number of patients who failed to complete the full eight cycles of chemotherapy was 24 (32.0%) in the DS group and 26 (33.3%) in the SP group. Discontinuation of treatment occurred among 24 patients in the DS group and 26 patients in the SP group. The main reason for discontinuation of treatment was overall toxicity (12 [50.0%] in the DS group and 13 [50.0%] in the SP group).
Another study, KDOG1001 in Japan, included patients receiving DCS chemotherapy followed by surgery and D2 lymph dissection [14]. S-1 chemotherapy was prescribed for a period of 1 year after surgery. 32 (80%) of 40 patients started postoperative chemotherapy according to the protocol. Of the 32 patients, only 25 (78.1%) completed postoperative S-1 chemotherapy within 1 year. In general, only 62.5% (25/40) of patients received protocol treatment (DCS as neoadjuvant treatment, surgical treatment and postoperative S1 chemotherapy).
The main reasons for this study are:
the lack of any randomized clinical trials to determine a perioperative treatment regimen for gastric cancer within the Ukrainian population
necessity of identification of complications levels and deviations from the treatment protocol;
significant popularity of XELOX regimen, for which there is no evidence-based reason for use; and FLOT regimen, which having greater toxicity can lead to dose reduction and paradoxical deterioration of treatment quality and prognosis.
Aims and endpoints
Aim of the study: To determine whether patients receiving XELOX chemotherapy are supposed to complete treatment protocol compared with patients receiving FLOT chemotherapy. Patients receiving FLOT chemotherapy regimen has lower protocol compliance than XELOX regimen.
Primary endpoint: proportion of patients who complete treatment protocol of perioperative FLOT and XELOX regimen.
Secondary endpoints: Pathological regression rate, chemotherapy toxicity profile, surgical complications rate, disease-free survival and median overall survival.
Statistical analysis: According to the literature, 46% of those patients receiving the FLOT-4 regimen do not complete the treatment protocol [12]. To prove that, to increase the number of patients who complete the entire treatment protocol from 46–62% [10] when changing the scheme to XELOX with a unilateral confidence level of 5% and a power 80%, it requires 328 patients with 10% loss. The theoretical level of conversion is 5%. This will require the recruitment of 164 patients to each group.
This study is a prospective randomized phase II study to evaluate the difference in tolerance between perioperative XELOX and FLOT chemotherapy.
Patients who meet the inclusion criteria be included in the study after reviewing and signing an informed consent.
Randomization will be performed in 1:1 ratio dividing patients into one of the two study groups.
Patients who will be randomized to the first (control) group will receive XELOX perioperative regimen. Patients who will be randomized to the second (study) group will receive FLOT perioperative chemotherapy regimen.
Evaluation of pathomorphological response will be performed according to Becker's criteria [15]. All patients will be involved in 5-year follow-up period.
Algorithm for patients registration and inclusion in the study
Patients are enrolled by investigating physicians. Physicians explain all the necessary points about the clinical trial to patients and familiarize patients with informed consent. Patient’s consent is confirmed with the signature. After signing the informed consent, every patient will be assigned a unique number, which will be entered into a paper CRF-form and duplicated in electronic database. The paper form and electronic database completely duplicate each other. The electronic and paper forms will be completed by the researcher as soon as the patient signs an informed consent to participate in the study. The electronic form is based on REDCap data base [16].
Randomization
The randomization process will be performed by Randomization module of REDCap software [16]. Initially we input the patient’s data into the REDCap program. After the approval for the patient to be included in the study, the randomization module will randomize patient into one of the two (FLOT arm and XELOX arm) groups. Patients will further receive 3 or 4 cycles of chemotherapy following by surgery and postoperative chemotherapy.
Inclusion criteria
cT1b, cT2, cT3, cT4a, cT4b (except invasion of the common hepatic artery, proper hepatic artery, celiac trunk, proximal part of the splenic artery)
cN0, cN1, cN2, cN3
M0
Age: 18–80
Gender: men and women
ECOG: 0–1
Histological type of tumor: Papillary adenocarcinoma; tubular adenocarcinoma - highly differentiated or moderately differentiated; low-grade adenocarcinoma; mucinous adenocarcinoma; squamous cell adenocarcinoma; glandular squamous cell carcinoma.
Degree of differentiation: G0 - G4
Tumor localization: cardio-esophageal junction (Siwert 2, 3), cardiac stomach, gastric body, antral stomach, pyloric stomach;
Tumor spread: esophagus, diaphragm, liver, pancreas, spleen, anterior abdominal wall, small and large intestine, distal splenic artery, spleen)
No history of cancer in the last 5 years
Absence of prior chemotherapy, surgery or radiation therapy for cancer
Absence of significant comorbidity
Exclusion criteria
M 1 (distant metastases)
ECOG 2–4
Age > 80 and under 18
The presence of significant comorbidity
The patient's refusal to participate in the study
Statistics
According to the literature, 46% of patients who receive FLOT-4 regimen do not complete the treatment protocol. In order to increase the number of cycles that complete the entire treatment protocol from 46–62% when changing regimens to XELOX with a unilateral confidence level of 5% and a power 80%, it requires 328 patients with 10% losses. The theoretical level that patients change randomization group is 5%. This will require enrollment in each group 164 patients. Recruiting of patients is planned for three years. Further follow-up period will comprise 5 years. It is planned to include 55 − 50 patients to each group annually.
Analysis
The modified intention-to-treat analysis of the primary point is planned. It provides data analysis of only those patients who will have the tumor removed during surgery, except of those patients whose surgery will not be performed due to progression or other factors ( eg, cardiac events at the beginning of surgery). The difference in quantity of patients who tolerates chemotherapy regimen will be checked using one-sided Pearson's criteria, for values less than 5 - using Fisher's exact test. Logistic regression will be used to analyze the correlation between histopathological response rate and recurrence-free survival.
Univariate analysis for each clinical factor and its relationship to the development of the main types of complications will be used to analyze treatment-related complications. Continuous data will be analyzed using an odd t-test. The comparison of toxic profile between the two groups will be performed using the bilateral Pearson agreement criterion, with values less than 5 - Fisher's exact criterion. Multivariative analysis to determine the correlation between clinical variables and complications will be performed using a logistic regression model.
Quality of life will be analyzed using the ANOVA method for correlated data.
Disease-free survival and overall survival as a secondary endpoints, will be calculated from the date of randomization until clinical or radiological signs of recurrence or death occur, whichever occurs first. The Kaplan-Meier procedure based on the intention-to-treat position will be used for the analysis.
Pathomorphological protocol
Histological examination is performed according to the adapted pathohistological protocol of the College of American Pathologists: Gastric Cancer v4.0.0.0 2017 [17]. The pathology assessment of pCR is not blinded to treatment allocation. Marking of groups of lymph nodes is not mandatory in this trial.
Staging laparoscopy
Staging laparoscopy is a mandatory stage before randomization. It is performed to evaluate the presence of tumor invasion and peritonial carcinomatosis. During the procedure, the surgeon should take a biopsy of parietal peritoneum and great omentum to exclude distant metastases. We also obtain peritoneal washings to exclude cyt + status.
Centre registration
Any hospital that performs more than 30 gastrectomies for gastric cancer annually are able to be joined to the clinical trial. Primary investigators should guarantee following all staging, treatment, morphological assessment and follow-up pipelines according to current protocol. Local ethical committee approval is needed.
Perioperative chemotherapy
This trial includes FLOT and XELOX chemotherapy regimen. FLOT regimen includes docetaxel 50 mg/m2 on day 1, oxaliplatin 85 mg/m2 on day 1, leucovorin 200 mg/m2 on day 1 and continuous infusion of fluorouracil 2600 mg/m2 on day 1 and 2; cycle each 14 day. XELOX regimen includes oxaliplatin 130 mg/m2 on day 1 and capecitabine 1000 mg/m2 2 times per day on days 1–14; cycle each 21 day. Patients receive 4 preoperative cycles and 4 postoperative cycles within each of the regimen.
Preoperative care
Patients with comorbidities are treated according to national or local guidelines before starting treatment. It is required for patients to visit an appropriate consultant prior to the beginning of chemotherapy and surgery. Before preoperative chemotherapy patients are obliged to have histologically confirmed gastric cancer, CT chest, abdomen and pelvis with intravenous contrast and gastroscopy.
Surgery
Surgery is performed under general anaesthesia with spinal or epidural analgesia supplement. Date of surgery, time of start and end of surgery, blood loss, blood transfusions and approach are registered. In case of conversion, reason of conversion is noted: “tactical” conversion is performed after laparoscopic revision in case of new data, complicating laparoscopic procedure (adhesions, tumour size etc.), “reactive” conversion is a change in approach because of intraoperative
events (bleeding, perforation etc.). Intraoperative findings, main steps and type of surgery are registered in operative notes and in electronic CRF (eCRF). In case of multivisceral resections the extent and details of other organ resections are documented.
Quality control of surgery
Before and after the specimen are removed taking photos of the operating field will be mandatory The following stages are fixed:
a stomach with a tumor before the beginning of mobilization of a stomach;
operating field after stomach removal and lymph nodes dissection;
removed stomach in longitudinal section; removed lymph nodes.
Postoperative care
Postoperative treatment is given according to local guidelines. Main parameters of postoperative period are registered in patient’s eCRF: admission and discharge
dates (if the discharge is postponed for social reasons - date, when patient was medically fit for discharge is documented), day of abdominal drainage withdrawal, start of fluids, patients movement activity, blood transfusions. Surgical complications are registered according to Clavien–Dindo classification. Treatment of complications is given according to local guidelines. Data on beginning, duration and treatment for complications is documented in patients eCRF (CRF).
Follow-up
Postoperative follow-up includes investigations (CT chest and abdomen, upper GI endoscopy) in 4, 8 and 12 month, than 2 times on 2nd year after surgery, afterwards annually during the follow-up period. Complications, adjuvant treatment and recurrence are registered during follow-up period. Recurrence is registered when local recurrence or distant metastases are found during investigation (upper GI endoscopy, CT, MRI); Quality of life will be assessed with validated questionnaires EORTC QLQ-C30 and EORTC QLQ-C25. Patients rejecting surgery after randomization or patients receiving different to randomization group treatment will be analysed in primary randomization groups. For patients rejecting treatment and follow-up continuation of data collection without treatment is offered.
Efficacy and safety
Postoperative period data will be assessed based on morbidity and mortality rates. Safety analysis will be performed each year and finally after all the patients will be enrolled. Surgery risks and preferable approach is under the surgeon’s responsibility. Adverse event is understood as any unwanted medical deviation in any kind of treatment and not necessarily associated with such treatment. In current study, adverse event is any unfavorable or unwanted deviation including laboratory tests or conditions not necessarily associated with the chemotherapy or surgery. Adverse event is any change from preoperative state of a patient, including exacerbation of comorbidities.
Adverse events classification is performed in accordance with CTCAE ver. 5.0 terminology for chemotherapy adverse effects [18]. Any treatment or observation in case of adverse event is prescribed by attending doctor, who is responsible for it.
Follow-up
Schedule of necessary investigations and follow-up visits is established according to clinical guidelines. Date deviation can probably happen. However, it has to be written in eCRF. Data on completed visits is transferred to eCRF in 5 working days. Quality of life is assessed via questionnaires after surgery, on day 30, 3-month visit, 1, 3 and 5-year visits.
To minimize number of patients lost during follow-up, patients are able to provide results of their routine follow-up investigations and get a consult of their physicians, which will facilitate patients’ adherence to follow-up.
Russian full-scale invasion
We suspended recruitment of patients into the study on February 24, on a day when a Russian full-scale aggression began. Main reasons for such decision were:
inability of precision selection of the patients that may be included in the study;
stochastic interruption in performing of diagnostic procedures, such as endoscopy, computed tomography and staging laparoscopy;
lack of medications, especially chemotherapeutic agents;
inability to follow timeframes and recommendations (time gap between cycles and lab tests may be longer).
Recruitment process will be continued if investigators are able to provide all patients needs per protocol.
The trial results will demonstrate the proportion of patients who can complete protocol treatment without any deviations in real-world settings and its impact on pathological regression rate, overall survival and disease-free survival of such group of patients.
Despite using novel protocols and a significant improvement in disease-free and overall survival in patients with gastric cancer perioperative chemotherapy remains treatment of high toxicity burden and has an impact on tolerability and protocol compliance [6, 8, 12].
Patient selection, acute preoperative staging and perioperative intensive care and surgical technique had a great influence on treatment such cohorts of patients suffering from gastric cancer. In addition, multimodal treatment protocols became available to use in different countries. Since the publication of the MAGIC, CLASSIC, FLOT-4 and NEO-CLASSIC trials these protocols were widely implicated in clinical practice all around the world and have been integrated in national and international guidelines for the treatment of locally-advanced gastric adenocarcinoma [6, 10, 12, 19]. However, different chemotherapy regimens show a significant level of adverse effects, thus failing in tolerance to such treatments and protocol compliance.
This study compares two perioperative chemotherapy regimen, XELOX and FLOT. The last one goes as a control. XELOX regimen is a widely-use protocol for treatment of gastric cancer in Ukraine because of relatively comfortable administration route. There are not any clinical studies in Ukraine investigating any chemotherapy regimen in treatment of gastric cancer.
FLOT regimen is well-known by European physicians after the publication of final results of FLOT-4 clinical trial [12]. FLOT regimen offers the chance for achieving higher R0 resection rates and better control of occult distant metastases. However, it shows higher level of adverse effects and lower protocol compliance comparing to XELOX regimen.
The PECORINO trial is a prospective randomized clinical trial aiming to assess an intolerance of chemotherapy related to adverse effects in patients with resectable gastric cancer receiving perioperative XELOX and FLOT regimens. It is hypothesized that more patients who receive perioperative XELOX chemotherapy tend to complete all the protocol treatment then patients who receive FLOT regimen.
Not applicable
Ethics approval and consent to participate: The study was approved by National Cancer Institute ethics committee in 4 of June, 2020. Unique Protocol ID: 275
Consent for publication
Consent for publication was obtained from all investigators and participants involved in the study.
Availability of data and materials
All the data and materials related to the study will be available after publication of study results.
Competing interests
The authors declare that they have no competing interests.
Funding
The clinical trial is a non-commercial funding. Participation in the trials is on the volunteer basis. The study is conducting on a governmental policy basis (https://zakon.rada.gov.ua/laws/show/z1236-12)
Authors' contributions
Y.K. developed the concept of the study, study design and critical review of protocol drafts.
O.D. developed concept of the study and its design, responsible for development of the protocol and literature review.
V.K. performed review of the protocol draft, developed the concept of the study, performed calculation of sample size and primary statistical expertise and is responsible for conducting of primary data analysis.
All authors read and approved the final manuscript.
Acknowledgements
Not applicable.