scholarly journals Impact of Provider Imaging Practices on Survival Outcomes in Advanced Ovarian Cancer

2020 ◽  
Vol 18 (4) ◽  
pp. 414-419 ◽  
Author(s):  
Angela K. Green ◽  
Deborah Korenstein ◽  
Carol Aghajanian ◽  
Brooke Barrow ◽  
Michael Curry ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Epithelial Ovarian Cancer ◽  
Advanced Ovarian Cancer ◽  
Ca 125 ◽  
Study Cohort ◽  
Median Frequency ◽  
Time To Recurrence ◽  
Surveillance Imaging ◽  
Platinum Based Chemotherapy ◽  
Significant Difference

Background: This study sought to describe how high- versus low-frequency surveillance imaging practices among providers at Memorial Sloan Kettering Cancer Center (MSKCC) impact overall survival (OS) and time to recurrence of patients with advanced epithelial ovarian cancer in first remission. Methods: The study cohort included patients with stage II–IV high-grade epithelial ovarian cancer diagnosed in January 2001 through January 2017 who experienced recurrence after initial platinum-based chemotherapy. To determine usual imaging practices for providers at MSKCC, median frequency of CT or MRI of the abdomen/pelvis was calculated among patients with a long-term remission (defined as at least 1 year) treated by each provider. Cox proportional hazards models were used to examine differences in OS and time to recurrence among patients treated by providers with high versus low imaging frequency practices, with additional subgroup analysis among patients with elevated CA-125 levels >35 U/mL at diagnosis. Chi-square tests were used to examine differences in the proportion of patients who enrolled in clinical trials or underwent secondary cytoreductive surgery (SCS) by imaging frequency. Results: A total of 543 patients were treated by providers with high imaging frequency (>1 scan every 12 months) and 141 were treated by providers with low imaging frequency (≤1 scan every 12 months). Time to recurrence was shorter among patients treated by providers with high versus low imaging frequency (18.0 vs 19.2 months; hazard ratio, 1.33; P=.003). Results were similar when restricted to patients with elevated CA-125 levels at diagnosis. There was no significant difference in OS, clinical trial enrollment, or SCS by imaging practice. Conclusions: Within the limitations of this retrospective analysis, patients with advanced ovarian cancer treated by high-frequency-imaging providers had earlier detection of recurrence. Future analyses in a larger population are warranted to elucidate the risks versus benefits of surveillance imaging.

scholarly journals Development and Validation for Prognostic Nomogram of Epithelial Ovarian Cancer Recurrence based on Circulating Tumor Cells and Epithelial–Mesenchymal Transition

2020 ◽  
Author(s):  
Jiani Yang ◽  
Jun Ma ◽  
Yue Jin ◽  
Shanshan Cheng ◽  
Shan Huang ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Risk Stratification ◽  
Epithelial Ovarian Cancer ◽  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Epithelial Mesenchymal Transition ◽  
Ca 125 ◽  
Mesenchymal Transition ◽  
Cox Regression Analysis ◽  
Significant Difference

Abstract We aimed to determine prognosis value of circulating tumor cells(CTCs) undergoing epithelial–mesenchymal transition(EMT) in epithelial ovarian cancer(EOC) recurrence. We used CanPatrol CTC-enrichment technique to detect CTCs from blood samples and classify subpopulations into epithelial, mesenchymal and hybrids. To construct nomogram, prognostic factors were selected by Cox regression analysis. Risk stratification was performed through Kaplan–Meier analysis among training group(n=114) and validation group(n=38). By regression screening, both CTC counts(HR 1.187; 95%CI 1.098-1.752; p=0.012) and M-CTC(HR 1.098; 95%CI 1.047-1.320; p=0.009) were demonstrated as independent factors for recurrence. Other variables including pathological grade, FIGO stage, lymph node metastasis, ascites and CA-125 were also collected(p < 0.005) to construct nomogram. The C-index of internal and external validation for nomogram was 0.913 and 0.874. We found significant predictive value for nomogram with/without CTCs (AUC 0.8705 and 0.8097). Taking CTC counts and M-CTC into separation, the values were 0.8075 and 0.8262. Finally, survival curves of risk stratification based on CTC counts(p=0.0241), M-CTC(p=0.0107) and the nomogram(p=0.0021) were drawn with significant difference. In conclusion, CTCs could serve as a novel factor for EOC prognosis. Nomogram model constructed by CTCs and other clinical parameters could predict EOC recurrence and perform risk stratification for clinical decision-making.Trial registration: Chinese Clinical Trial Registry, ChiCTR-DDD-16009601, October 25, 2016

Oral Topotecan as Single-Agent Second-Line Chemotherapy in Patients With Advanced Ovarian Cancer

2001 ◽  
Vol 19 (19) ◽  
pp. 3967-3975 ◽  
Author(s):  
D. L. Clarke-Pearson ◽  
L. Van Le ◽  
T. Iveson ◽  
C. W. Whitney ◽  
P. Hanjani ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Epithelial Ovarian Cancer ◽  
Median Time ◽  
Single Agent ◽  
Advanced Ovarian Cancer ◽  
Prolonged Treatment ◽  
Second Line ◽  
Gynecology And Obstetrics ◽  
Platinum Based Chemotherapy ◽  
Oral Topotecan

PURPOSE: To evaluate oral topotecan as single-agent, second-line therapy in patients with ovarian cancer previously treated with a platinum-based regimen. PATIENTS AND METHODS: Patients (N = 116) received oral topotecan 2.3 mg/m2 daily for 5 days every 21 days. Eligibility criteria included histologic diagnosis of International Federation of Gynecology and Obstetrics stage III or IV epithelial ovarian cancer, bidimensionally measurable disease, prior platinum-containing chemotherapy, age ≥ 18 years, performance status ≤ 2, and life expectancy ≥ 12 weeks. RESULTS: Overall response rate was 21.6% (25 of 116 patients). Median duration of response was 25.0 weeks; median time to response was 8.4 weeks. Median time to progression was 14.1 weeks; median survival was 62.2 weeks. Grade 4 neutropenia was experienced by 50.4% of patients in 13.4% of courses administered. Grade 4 thrombocytopenia was experienced by 22.1% of patients in 5.1% of courses. Grade 3 or 4 anemia was experienced by 29.2% of patients in 8.5% of courses. Most frequent nonhematologic toxicities were predominantly (> 90%) grade 1 or 2 and included nausea, alopecia, diarrhea, and vomiting. CONCLUSION: Second-line oral topotecan administered at 2.3 mg/m2 for 5 days every 21 days demonstrated activity in patients with progressive or recurrent ovarian cancer after first-line platinum-based chemotherapy. This activity was comparable to that seen in previous studies with intravenous topotecan. Grade 4 neutropenia was less frequent with oral topotecan than previously reported for intravenous topotecan. Oral topotecan is an active, tolerable, and convenient formulation of an established agent for the second-line treatment of advanced epithelial ovarian cancer and may also facilitate exploring prolonged treatment schedules.

DUETTE: A randomized phase II study to assess a second maintenance treatment with olaparib (ola) or ola+ceralasertib (cer), in patients (pts) with platinum-sensitive relapsed (PSR) epithelial ovarian cancer who have previously received PARP inhibitor maintenance treatment (NCT04239014).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS6104-TPS6104 ◽  
Author(s):  
Amit M. Oza ◽  
Andrew Pierce ◽  
Alan Lau ◽  
Nisha Kurian ◽  
Graeme Parr ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Epithelial Ovarian Cancer ◽  
Phase Ii ◽  
Maintenance Treatment ◽  
Phase Ii Study ◽  
Brca Mutation ◽  
Unmet Need ◽  
Advanced Ovarian Cancer ◽  
Resistance Mechanisms ◽  
Platinum Based Chemotherapy

TPS6104 Background: Ovarian cancer is the leading cause of death from gynecological cancers in the USA, and the fifth most common cause of cancer death in women. Ola is a PARPi approved for first-line maintenance treatment of BRCA-mutated advanced ovarian cancer in women who achieve a complete or partial response to platinum-based chemotherapy. Ola is also efficacious in combination with bevacizumab in the same population, independent of BRCA mutation status. Cer is a potent, oral, selective inhibitor of ATR. ATR is a critical DDR kinase that is activated in response to replication stress and stalled replication forks. There is no second maintenance standard of care for patients with PSR ovarian cancer who have previously received a PARPi in the maintenance setting. Pre-clinical models have shown that several mechanisms of PARPi resistance may be overcome by ATR inhibition, such as BRCA reversion, replication fork protection and DDR rewiring. DUETTE will select pts with tumor response or stable disease after second or third-line platinum-based treatment, with the expectation to enrich for non-BRCA reversion PARPi resistance mechanisms. The study will address the role of a second maintenance treatment following prior 1L or 2L maintenance, an emerging population of unmet need, and includes translational studies that aim to further our knowledge of clinical PARPi resistance mechanisms and predictors of treatment response. Methods: DUETTE is a global, multi-center, phase II study. 192 pts with PSR epithelial ovarian cancer who have previously received PARPi maintenance treatment, will be retreated with platinum and those who have not progressed after ≥ 4 cycles will be randomized (1:1:1) to 3 treatment arms: Arm 1, open-label: cer 160 mg once daily (qd) days 1 to 7 plus ola 300 mg twice daily (bd); Arm 2, blinded: ola monotherapy 300 mg bd and Arm 3, blinded: ola-placebo. Treatment is administered in 28-day cycles. All pts will be stratified by BRCA status (mutation or wildtype) and response to most recent line of platinum-based chemotherapy (CR/PR or SD). The primary endpoint is to assess the efficacy of maintenance ola monotherapy and cer+ola combination therapy compared with placebo by PFS using blinded, independent central review. Secondary endpoints are overall survival, PFS2, ORR, DoR, safety and tolerability. Enrolment is planned to start in April 2020.

A retrospective analysis of neoadjuvant platinum-based chemotherapy versus up-front surgery in advanced ovarian cancer

2006 ◽  
Vol 16 (Suppl 1) ◽  
pp. 47-53 ◽  
Author(s):  
H. Steed ◽  
A. M. Oza ◽  
J. Murphy ◽  
S. Laframboise ◽  
G. Lockwood ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Neoadjuvant Chemotherapy ◽  
Retrospective Analysis ◽  
Advanced Ovarian Cancer ◽  
Progression Free Survival ◽  
Postoperative Chemotherapy ◽  
Pleural Effusions ◽  
Primary Surgery ◽  
Platinum Based Chemotherapy ◽  
Significant Difference

The objective of this study is to compare progression-free survival (PFS) and overall survival (OS) of ovarian cancer patients treated with neoadjuvant chemotherapy and surgery to primary surgery and postoperative chemotherapy. Retrospective analysis from 1998 to 2003 of 116 patients with ovarian cancer was performed. Fifty women diagnosed by positive cytology received three cycles of carboplatin and paclitaxel. Thirty-six patients subsequently underwent cytoreductive surgery and completed three further cycles postoperatively. The OS and PFS were compared in 66 women treated with primary surgery and postoperative chemotherapy. A statistically significant difference was observed for OS (P= 0.03, HR = 1.85, CI = 1.06–3.23) and PFS (P= 0.04, HR = 1.61, CI = 1.03–2.53) favoring the primary surgery group. Due to the small numbers, age, grade, stage, pleural effusions, and histologic cell type were controlled for separately in the bivariate analyses. Controlling for stage made the results weaker. A matched subgroup survival analysis was performed on patients who had surgery following neoadjuvant chemotherapy. After matching for stage and grade and controlling age and pleural effusions (N= 28 matched pairs), there was no statistical difference for OS (P= 0.95, HR = 1.04, CI = 0.33–3.30) or PFS (P= 0.79, HR = 1.11, CI = 0.98–1.04). It is concluded that primary surgery should be considered in all patients. Neoadjuvant chemotherapy may be an alternative in a subset of women with the intent to also perform interval debulking.

Venous thromboembolism in advanced ovarian cancer patients undergoing front-line adjuvant chemotherapy.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 5570-5570
Author(s):  
Alok Pant ◽  
Julian C. Schink
Keyword(s):  
Ovarian Cancer ◽  
Venous Thromboembolism ◽  
Adjuvant Chemotherapy ◽  
Epithelial Ovarian Cancer ◽  
Bowel Resection ◽  
Prognostic Significance ◽  
Advanced Ovarian Cancer ◽  
Ca 125 ◽  
Front Line ◽  
Advanced Epithelial Ovarian Cancer

5570 Background: To define the incidence and prognostic significance of venous thromboembolism (VTE) in patients with advanced, epithelial ovarian cancer undergoing front-line adjuvant chemotherapy after extended period (28 day) post-operative prophylaxis. Methods: A retrospective analysis of patients with advanced, epithelial ovarian cancer who underwent surgery and chemotherapy at a single institution from January 2008 through December 2011 was performed. Exclusion criteria were prior history of VTE, VTE during the post-operative period, clear cell histology, use of anti-coagulation for a different indication, and lack of compliance with 28 days of post-operative prophylaxis with a low molecular weight heparin. Results: 128 patients met criteria for inclusion. Sixteen patients had a reported VTE during the time they were on front line chemotherapy (12.5%). Nine patients (7%) had a pulmonary embolus (PE) and 8 (6.3%) had a deep vein thrombus (DVT). The average BMI in the group that developed VTE was 28 and in the group without VTE was 26.5 (p = 0.23). Three out of 16 (23%) patients who developed VTE had undergone a suboptimal cytoreduction compared to 12/112 (11%) in the group with no VTE (p = 0.4). Six of the 16 (37%) patients who developed VTE during chemotherapy underwent a bowel resection and/or splenectomy during their cytoreductive surgery compared to 18 of 112 (16%) patients who did not develop VTE (p=0.079). Eight of the patients in the VTE group had indwelling venous catheters during chemotherapy (50%) compared to 39 (35%) in the group with no VTE (p = 0.27). In the group that developed VTE, there was a trend towards increased pre-operative CA-125, higher rates of bowel resection and/or splenectomy during surgery, decreased use of aspirin, and inferior survival. On multivariate analysis, patients who developed VTE had significantly longer post-operative hospital stays (7 vs 5 days [p = 0.009]) and lower rates of complete response (p = 0.01). Conclusions: A 12.5% risk of VTE merits consideration of prophylaxis during chemotherapy in this cohort. A randomized, controlled trial is needed to clarify whether the benefits of long term prophylaxis outweigh the risks and costs of such therapy.

Impact of BRCA mutation status and time to platinum resistance on patients with advanced ovarian cancer.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 5561-5561
Author(s):  
Alexandra Tyulyandina ◽  
Maxim Filipenko ◽  
Alexey Rumyantsev ◽  
Ilya Pokataev ◽  
Valentina Nechushkina ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Brca Mutation ◽  
Advanced Ovarian Cancer ◽  
Progression Free Survival ◽  
Platinum Resistance ◽  
Term Survival ◽  
Mutation Status ◽  
Platinum Based Chemotherapy ◽  
Significant Difference

5561 Background: The influence of germline BRCA1/2 mutations (gBRCAmt) on ovarian cancer patients (pts) long-term survival remains controversial. Methods: 228 pts with serous and endometrial ovarian cancer stage Ic-IV were enrolled in the retrospective study. Next-generation sequencing testing of BRCA1/2 in blood was employed. Progression-free survival (PFS), overall survival (OS) and time to platinum resistance (TPR) were analyzed. TPR was defined as time from first line chemotherapy to registration of platinum resistance relapse. Results: The rate of pathogenic gBRCAmt was defined in 29.4% (67/228) pts. There was no any significant difference between BRCA1/2 mutation carries and non-carries in both PFS (18.3 and 16.7 months, p = 0.27, HR 0.79, 95%CI 0.52-1.20) and OS (71.9 and 79.1 months, p = 0.69, HR 0.88, 95%CI 0.46-1.68). However, TPR was significantly longer in pts with gBRCAmt than in germline BRCA wild type (gBRCAwt) pts (51.4 and 34.4 months, p = 0.05, HR 0.60, 95% CI 0.36-0.98). Pts with gBRCAmt had poor prognosis after registration of platinum resistance. gBRCAwt pts had longer survival than gBRCAmt after platinum-resistance relapse: 33.7 and 16.9 months respectively (p = 0.05; HR 1.85, 95%CI 1.02-4.08). Conclusions: Our finding provided possible explanation of equal survival of pts with or without BRCA1/2 mutations. Long-term sensitivity to platinum-based chemotherapy allowed pts with gBRCA1/2mt to control the disease for a long period of time. However the non-platinum regimens had less efficacy in pts with gBRCAmt than gBRCAwt after platinum resistance.

scholarly journals The Value of CA 125 and CA72-4 in Management of Patients with Epithelial Ovarian Cancer

1998 ◽  
Vol 14 (3) ◽  
pp. 155-160 ◽  
Author(s):  
Salah T. Fayed ◽  
Samira M. Ahmad ◽  
Samar K. Kassim ◽  
Ali Khalifa
Keyword(s):  
Ovarian Cancer ◽  
Epithelial Ovarian Cancer ◽  
Residual Disease ◽  
Ca 125 ◽  
Platinum Based Chemotherapy ◽  
Pelvic Masses ◽  
Radiometric Assay ◽  
Normal Women

The role of the tumor markers CA125 and CA72-4 has been evaluated in the diagnosis and management of ovarian cancer. Both markers were measured in 30 patients with proven epithelial ovarian cancer, 30 patients with benign pelvic masses and 30 normal women. CA125 and CA72-4 were measured using the luminometric immunoassay and immuno-radiometric assay respectively. All patients with ovarian cancer were submitted to surgical staging and cytoreduction followed by adjuvant platinum based chemotherapy for 3–6 courses. Fixing the specificity at 95%, CA125 had a sensitivity of 76.7% at a cut-off 85u/ml while CA72-4 had a sensitivity of 70% at a cut-off 8.5 u/ml. The combination of CA72-4 with CA125 increased the sensitivity to 95% while fixing the specificity at 95%. Among seven cases with stage I and II ovarian cancer five cases had CA125 level below 85 U/ml, three patients out of them had CA72-4 above 8.5 U/ml. CA 72-4 could reflect the residual disease following cytoreduction and could improve the detection of relapse by CA125.Conclusion: CA72-4 could complement the standard tumor marker CA125 both in diagnosis and follow up of patients with epithelial ovarian cancer.

scholarly journals The clinical and pathological characteristics and survival of patients with advanced ovarian cancer

2021 ◽  
Vol 52 (3) ◽  
pp. 205-210
Author(s):  
Miroslav Popović ◽  
Tanja Milić-Radić ◽  
Arnela Cerić-Banićević
Keyword(s):  
Ovarian Cancer ◽  
Residual Disease ◽  
Advanced Ovarian Cancer ◽  
Figo Stage ◽  
Ovarian Tumour ◽  
Ca 125 ◽  
Optimal Cytoreduction ◽  
Chi Square ◽  
Pathological Characteristics ◽  
Significant Difference

Introduction: Ovarian cancer has the highest mortality rate of all gynaecologic malignancies. The aim of this study was the evaluation of the clinical pathological characteristics and survival analysis of primarily operated patients with advanced stages of malignant epithelial ovarian tumour. Methods: The research was conducted as a cohort study with 59 patients with FIGO stage III and IV, which were primarily operated between 1 January 2008 and 31 December 2010 (three years). Age, comorbidities, BMI, presence of ascites, the level of the marker CA-125, histopathology and FIGO stage were analysed. The survival rate was estimated at the level of 1, 3 and 5 years. Results: The median age was 53 years (range 29-86). The most common histopathological type was serous (66.1 %) and the most common FIGO stage was 3a (49.2 %). Optimal cytoreduction was performed in 35.5 % of patients, 84.7 % of patients survived for one year, 44.1 % three years and 37.3 % for five years. The median survival was 26.25 months (range 0-91). Chi-square test showed significant difference between the number of months of survival and: the value of CA125 (t = 2.004, p = 0.050), cytoreduction (p < 0.001) and FIGO stage (p < 0.01). Conclusion: According to the results of this study, optimal cytoreduction and FIGO stage significantly influence survival (p < 0.001). Optimal cytoreduction (< 2 cm of residual disease) had the highest prognostic value for survival. A total five-year survival in this study was 37.3 %.

Second-line therapy of advanced ovarian cancer with GnRH analogs

2004 ◽  
Vol 14 (5) ◽  
pp. 799-803 ◽  
Author(s):  
G. Balbi ◽  
L. D. Piano ◽  
A. Cardone ◽  
G. Cirelli
Keyword(s):  
Ovarian Cancer ◽  
Advanced Ovarian Cancer ◽  
Progression Free Survival ◽  
Ca 125 ◽  
Second Line ◽  
Second Line Therapy ◽  
Gnrh Analogs ◽  
Line Therapy ◽  
Platinum Based Chemotherapy ◽  
Previously Treated

Ovarian cancer is still the first cause of death among female malignancies. The standard treatment adopted in ovarian cancer is a radical surgical treatment or cytoreduction, followed by six courses of platinum-based chemotherapy; second-line regimens are associated with severe side effects. GnRH analogs could represent an alternative therapeutical approach. The aim of our study was to evaluate the role of GnRH analogs in the management of platinum-resistant ovarian cancers. We enrolled 12 patients affected by advanced ovarian cancer, previously treated with six courses of platinum–paclitaxel. In second-line therapy, we used leuprolide on 1, 8, and 28 days of treatment. CA 125 levels were recorded for each patient. One case of clinical partial response was obtained (8.3%). Stable disease was diagnosed in three patients (25%). Progression was recorded in eight cases (66.7%). Progression-free survival was 6 months. The treatment was well tolerated by patients. The high tolerability and the results obtained with leuprolide versus platinum in second-line therapy might permit a better use of the analogs for advanced ovarian cancer.

Neoadjuvant Chemotherapy Is Associated With Prolonged Primary Treatment Intervals in Patients With Advanced Epithelial Ovarian Cancer

2011 ◽  
Vol 21 (1) ◽  
pp. 66-71 ◽  
Author(s):  
Michael R. Milam ◽  
Xia Tao ◽  
Robert L. Coleman ◽  
Robyn Harrell ◽  
Roland Bassett ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Neoadjuvant Chemotherapy ◽  
Epithelial Ovarian Cancer ◽  
Advanced Ovarian Cancer ◽  
Disease Stage ◽  
Perioperative Outcomes ◽  
Cycle Number ◽  
Significant Difference ◽  
Advanced Epithelial Ovarian Cancer ◽  
The Impact

Background:We evaluated the impact of neoadjuvant chemotherapy (NC) relative to primary surgery (PS) to determine if there was a difference in the total time and number of chemotherapy cycles given in patients with advanced epithelial ovarian cancer.Methods:We identified 263 consecutive women meeting eligibility from 1993 to 2005 for this institutional review board-approved study. Eligible patients in this analysis were those women with advanced disease (stage IIIC-IV) in whom a maximal cytoreductive effort was planned either at PS or after NC. Time to start chemotherapy was defined as follows: (1) NC group: confirmation of diagnosis through biopsy, cytological diagnosis from ascites, and pleural effusion; (2) PS group: confirmation of diagnosis from the date of surgery that confirmed the diagnosis of epithelial ovarian cancer. Total chemotherapy cycles: (1) NC group: NC chemotherapy cycles plus postoperative cycles; (2) PS group: chemotherapy after primary tumor debulking surgery. Clinical information evaluated included chemotherapy type, chemotherapy cycle number, total time to administer frontline chemotherapy, and survival.Results:Median chemotherapy cycles were greater in the NC group compared with the PS group (9 [range, 4-30] vs 6 [range, 3-19];P< 0.01). The PS group was also more likely to undergo chemotherapy regimens involving platinum and taxane treatment compared with the NC group (79% vs 65%;P= 0.017). Total time undergoing primary chemotherapy from initial diagnosis was greater in the NC group compared with PS (223 vs 151 days;P< 0.01). No significant difference was observed in overall survival and progression-free survival in the 2 groups.Conclusions:In patients with advanced ovarian cancer, NC followed by abdominal hysterectomy is associated with improved perioperative outcomes including optimal cytoreduction, decreased blood loss, and decreased inpatient hospitalization. In this cohort, NC was also associated with prolonged chemotherapy treatment intervals and increased chemotherapy cycles without improvement in survival.

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