Prognostic significance of the relative dose intensity of chemotherapy in primary treatment of epithelial ovarian cancer

doi:10.1016/j.ygyno.2011.05.023

Gynecologic Oncology

Volume 122, Issue 3, September 2011, Pages 532-535

https://doi.org/10.1016/j.ygyno.2011.05.023 Get rights and content

Abstract

Objective

Relative dose intensity (RDI) is the ratio of delivered dose intensity of chemotherapy to standard dose intensity. In this study, we sought to determine the prognostic significance of RDI in patients with epithelial ovarian cancer (EOC).

Methods

A retrospective analysis of chemotherapy naïve patients treated between 2001 and 2008 with intravenous taxane and platinum was performed. RDI was calculated as the delivered dose intensity (total dose delivered/total time of therapy) divided by standard dose intensity calculated for each regimen and compared to progression-free survival (PFS). Multivariate recursive partitioning survival analysis was utilized.

Results

138 EOC patients completed initial taxane/platinum-based chemotherapy following surgical cytoreduction. The most common reasons for dose delays and reductions were thrombocytopenia (38%) and neutropenia (31%). 24% of treatment delays were due to social reasons such as transportation constraints or scheduling conflicts. The average RDI was 90% (range, 24–126%). The mean PFS was 31 months (range, 3–117). Patients that achieved an RDI between 70% and 110% had a mean PFS of 32 months compared to 20 months in patients with an RDI of < 70% or > 110% (p = 0.046). 14 patients (10%) had a RDI of < 70%.

Conclusions

RDI is a significant predictor of survival in patients with EOC. Effort should be made to achieve an RDI of at least 70%. Dose reductions and treatment delays could be minimized by utilizing prophylactic colony stimulating factors and educating patients about the importance of adhering to their treatment schedule.

Research highlights

► Chemotherapeutic relative dose intensity (RDI) is related to outcome in the treatment of ovarian cancer. ► Attempts should be made to achieve RDI between 70 and 110% when treating with intravenous taxol and platinum based chemotherapy.

Introduction

It is predicted that 21,880 women will be diagnosed with epithelial ovarian cancer (EOC) in 2011, the vast majority of whom will be diagnosed with advanced stage disease [1]. Surgical cytoreduction is considered the primary treatment for patients with EOC, and optimal debulking (< 1 cm residual disease) markedly improves survival [2]. In the United States, adjuvant treatment regimens with platinum-based chemotherapy have evolved as a result of randomized trials by the Gynecology Oncology Group (GOG). Cisplatin and paclitaxel were established as a superior regimen because of improved response rates, overall survival, and progression-free survival [3]. Noninferiority trials have demonstrated carboplatin to have similar efficacy as cisplatin when used in combination with a taxane agent with decreased toxicity[4]. Currently, combination therapy with carboplatin and a taxane is the standard of care for patients with EOC.

Even with appropriate adjuvant therapy, approximately two-thirds of patients will experience recurrence, with a median time to progression of less than 2 years [4]. Prognostic factors that have been shown to influence survival include age at diagnosis, stage, and amount of residual disease[5]. It is postulated that on-time, full dose chemotherapy administration is also important to prolonging progression-free and overall survival. Dose-limiting toxicity is a known risk of therapy; however, there are limited data investigating the impact of dose reductions and treatment delays during chemotherapy administration on prognosis in EOC patients.

Relative dose intensity (RDI) is a measure of the delivered dose intensity compared to the standard dose intensity, and accounts for treatment over time [6]. There is well-established evidence supporting the significance of RDI and its impact on survival in patients with breast cancer and non-Hodgkin's lymphoma (NHL) [7], [8]; however data in patients with EOC are limited. Select studies have established an association between RDI and mean survival time in the treatment of EOC using previous regimens[9]; however, considerable controversy exists regarding the importance of dose intensity versus total dose delivered[10]. Additionally, there is a paucity of data regarding the effects of reduced dose intensity of current EOC treatment regimens and its effect on survival. This study was designed to evaluate the prognostic significance of RDI in patients with EOC undergoing primary adjuvant treatment with intravenous paclitaxel or docetaxel in combination with carboplatin.

Section snippets

Methods

A computerized database was utilized to retrospectively identify patients with EOC who underwent primary chemotherapy at the University of Alabama at Birmingham between 2001 and 2008. Inclusion criteria included all patients (Stages I–IV) scheduled to undergo treatment with six cycles of paclitaxel or docetaxel in combination with carboplatin. Patients treated with intraperitoneal chemotherapy, or patients who received both paclitaxel and docetaxel during their treatment course were excluded.

Results

One hundred thirty-eight eligible patients with EOC who received initial therapy with paclitaxel or docetaxel in combination with carboplatin were identified. Patient demographics are outlined in Table 1. The median age was 63 (range, 29–84). The majority of patients were stage III or stage IV (72%), had papillary serous histology, and were Caucasian. 71% were optimally debulked (residual disease < 1 cm). Forty-seven patients (34%) received docetaxel/carboplatin, 89 (64%) received

Discussion

It is well accepted that RDI has an impact on survival in patients with breast cancer and lymphoma; however, its role in ovarian cancer using current treatment regimens remains less clear [11], [12], [13], [14], [15]. Bonadonna et al. showed that an RDI of less than 85% was clinically significant for patients with early stage breast cancer (ESBC) [16]. In the group of patients who received < 65% of planned therapy, only 29.6% of patients were disease-free at 20 years, which was similar to the

Conflict of interest

We have no conflicts of interest to disclose.

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Cited by (38)

Results of TRIO-14, a phase II, multicenter, randomized, placebo-controlled trial of carboplatin-paclitaxel versus carboplatin-paclitaxel-ganitumab in newly diagnosed epithelial ovarian cancer
2021, Gynecologic Oncology
Citation Excerpt :
The increase in hematologic toxicities in our study in the ganitumab arm was associated with more frequent dose reductions and dose delays. It is known that the ratio of delivered dose intensity of chemotherapy to standard dose intensity (RDI) is a significant predictor of survival in patients with OC [33]. Patients in the ganitumab arm required lower RDI and this may have in part affected the observed adverse outcome.
Insulin-like growth factor (IGF) signaling is implicated in pathogenesis and chemotherapy resistance of epithelial ovarian cancer (EOC). We explored efficacy and safety of adding ganitumab, a monoclonal antibody targeting IGF-1R, to carboplatin/paclitaxel (CP) chemotherapy in patients with primary EOC.
Patients were randomly assigned to receive CP/ganitumab (18 mg/kg q3w) or CP/placebo for 6 cycles followed by 6 cycles of single agent ganitumab/placebo maintenance therapy as front-line therapy. Primary endpoint was progression free survival. Secondary endpoints were time to progression and overall survival. Pretreatment samples were prospectively collected for retrospective biomarker analyses.
170 patients enrolled. 165 patients assessable for toxicity. Median PFS was 15.7 months with CP/ganitumab and 16.7 months with CP/placebo (HR 1.23; 95% CI 0.82–1.83, P = 0.313). All grade neutropenia (84.1% vs 71.4%), thrombocytopenia (75.3% vs 57.1%) and hyperglycemia (15.9% vs 2.6%) were more common in the ganitumab group compared to the placebo group. Ganitumab/placebo related serious adverse events were reported in 26.1% of the patients with ganitumab and in 6.5% with placebo. Non-progression related fatal events were more common with ganitumab (5 versus 2 patients). The ganitumab group experienced more dose delays which resulted in lower relative dose intensity of chemotherapy in the experimental group. In an exploratory model IGFBP2 expression was predictive of ganitumab response (treatment interaction; PFS, P = 0.03; OS, P = 0.01).
Addition of ganitumab to CP chemotherapy in primary EOC did not improve PFS. Our results do not support further study of ganitumab in unselected EOC patients.
Frailty is a determinant of suboptimal chemotherapy in women with advanced ovarian cancer
2020, Gynecologic Oncology
To evaluate the relationship between frailty and chemotherapy delivery among women with epithelial ovarian cancer (EOC).
We included women who underwent primary debulking surgery (PDS) for stage IIIC/IV EOC between 1/2/2003 and 12/30/2011, received adjuvant chemotherapy at our institution, and had data available to calculate a frailty deficit index. Frailty was defined as a frailty deficit index ≥0.15. Relative dose intensity (RDI) of chemotherapy was calculated as the percentage of the standard dose that was administered, and compared between frail and non-frail using the Wilcoxon rank-sum test.
Failure to receive chemotherapy following PDS was twice as common among frail vs. non-frail women (26.7% vs 14.2%, p = 0.001). Of the 169 women who received chemotherapy at our institution, 17.2% (29/169) were frail. Frail women were older (mean, 67.9 vs 62.3 years, p = 0.01), had higher BMI (mean, 29.6 vs 25.7 kg/m², p = 0.003), and were less likely to complete 6 cycles of chemotherapy (75.9 vs. 93.6%, p = 0.008). Using an RDI cutoff of 85%, frail women were less likely to have adequate doses of carboplatin (15.8 vs. 66.2%, p < 0.001) and paclitaxel (57.9 vs. 80.5%, p = 0.07) despite no differences in dose delays (34.5 vs. 42.1%), dose reductions (65.5 vs. 68.6%), and severe neutropenia (44.8 vs. 39.3%). After adjusting for age, frailty was associated with shorter progression-free (HR 1.58, 95% CI: 0.99–2.50) and overall survival (HR 2.14, 95% CI: 1.35–3.41).
Frail women with EOC were less likely to receive chemotherapy or the optimal dose of chemotherapy after PDS despite no evidence of treatment-related toxicity. Frail EOC patients demonstrated shorter progression-free and overall survival. Further studies are needed to explore the association between frailty, chemotherapy, and survival.
Impact of Second-Line Targeted Therapy Dose Intensity on Patients With Metastatic Renal Cell Carcinoma
2016, Clinical Genitourinary Cancer
Citation Excerpt :
RDI may play an important role for the feasibility of a drug therapy at a given strength. Some reports have demonstrated a correlation between RDI and survival prognosis of various malignancies, including mRCC.14-17 One retrospective study reported that a 1-month RDI greater than 50% predicted favorable PFS, but not OS, in sorafenib therapy for patients with advanced RCC who had received prior cytokine treatment.7
Relative dose intensity (RDI) is a simple index for evaluation of the amount of drug administered per unit time. We retrospectively investigated the prognostic impact of RDI for patients with metastatic renal cell carcinoma (mRCC) treated with second-line targeted therapy.
We enrolled 168 patients with mRCC. We assessed RDI at 4 weeks after second-line targeted therapy induction.
The median follow-up after second-line targeted therapy was 18.1 months. The median time-to-treatment-failure (TTF) and overall survival (OS) were 4.9 and 25.4 months, respectively. In the Kaplan-Meier analysis, the median OS of patients with second-line RDI < 0.7 was significantly shorter than those with RDI ≥ 0.7 (12.1 vs. 31.3 months; P = .030). In the subgroup analysis, second-line RDI was definitely prognostic in the poor-risk group of the International Metastatic Renal Cell Carcinoma Database Consortium criteria, showing second-line RDI was an independent predictor for both TTF (hazard ratio [HR], 3.6; 95% confidence interval [CI], 1.6-8.0; P = .002) and OS (HR, 3.1; 95% CI, 1.1-8.4; P = .026). Also, assessing the type of second-line regimen, the multivariate analysis showed that second-line RDI was an independent prognostic indicator of TTF (HR, 1.7; 95% CI, 1.0-2.9; P = .040) and OS (HR, 2.7; 95% CI, 1.3-5.7; P = .009) in patients treated with everolimus. In this group, the median TTF and OS of patients with RDI < 0.7 were 2.4 and 11.1 months, and those with RDI ≥ 0.7 were 5.3 and 25.9 months, respectively.
The results suggest that second-line RDI may be a prognostic predictor for patients with mRCC treated with second-line targeted therapy, particularly in both the International Metastatic Renal Cell Carcinoma Database Consortium poor-risk group and everolimus-treated group.
Chemotherapy dose intensity predicted by baseline nutrition assessment in gastrointestinal malignancies: A multicentre analysis
2016, European Journal of Cancer
Citation Excerpt :
Despite being more likely to receive attenuated doses at the start of chemotherapy, malnourished patients were also more likely to require continued and larger dose reductions than well-nourished patients, most likely due to chemotherapy-related toxicity. Chemotherapy toxicities often lead to dose-reductions and treatment delays, which are associated with inferior outcomes in several malignancies [19–22]. For example, patients with colorectal cancer who received relative chemotherapy dose-intensity >80% and >79% of irinotecan and oxaliplatin in FOLFIRI and mFOLFOX6 had longer progression free survival (9.9 versus 5.6 months, p < 0.01) and OS (26.7 versus 12.9 months, p = 0.01) [23].
Malnutrition is prevalent in cancer patients and is associated with inferior outcomes. We examined the association between malnutrition, as measured by the Subjective Global Assessment (SGA), and chemotherapy dose reduction in patients with gastrointestinal malignancies. We hypothesised that malnutrition, defined by a patient's baseline SGA, would be associated with a greater degree of chemotherapy dose-reduction, with the implication of greater chemotherapy related toxicity.
We reviewed chemotherapy dosing and treatment related toxicity for patients enrolled in a prospective Gastrointestinal Cancer Registry over their first 8 weeks of treatment. We compared results between well-nourished and malnourished patients.
Malnourished patients were more likely than well-nourished patients to have their starting chemotherapy dose reduced from standard published dosing (67% versus 35%, p = 0.0001). Despite attenuated initial dosing, malnourished patients received a smaller fraction of planned chemotherapy (mean 80 ± 23% versus 90 ± 15% of cycle 1, p = 0.005), primarily due to toxicity-related dose reductions. After controlling for age, gender, Eastern Cooperative Oncology Group performance status (ECOG), albumin, smoking status, body habitus, and weight loss, malnutrition remained the strongest independent predictor of the magnitude of chemotherapy dose reduction (estimate –10.3%, 95% confidence interval –19.0 to –0.1.6%, p = 0.020).
Malnutrition is an independent predictor of chemotherapy dose-reduction for toxicity. This study highlights the practical significance of malnutrition in gastrointestinal malignancies and provides a baseline for future nutrition intervention studies to improve chemotherapy tolerability in malnourished patients.
Delay in chemotherapy administration impacts survival in elderly patients with epithelial ovarian cancer
2015, Gynecologic Oncology
The objective of this study was to characterize chemotherapy treatment patterns in elderly patients with epithelial ovarian cancer (EOC) and their impact on overall survival (OS).
We identified patients age ≥ 65 years with stage II–IV EOC who underwent cytoreduction from 2003 to 2011. Relevant clinical variables were extracted and correlated with OS. Statistical analyses were performed using logistic regression, Kaplan–Meier methods, and multivariable Cox proportional hazard models.
One hundred and eighty-four patients were included in the analysis. The average age was 73 years with American Society of Anesthesiology Physical Status Class 2 or 3. Approximately 78% underwent primary debulking surgery (PDS). OS for the entire cohort was 3.3 years. One hundred and fifty-seven patients received adjuvant chemotherapy, of which 70% received initial platinum-based doublet therapy; 67.5% of patients were able to complete the intended six cycles of chemotherapy; of these, 34% experienced a dose reduction and 45% experienced one or more dose delays. Any dose delay was associated with a decrease in overall survival (p = 0.02) and remained significant even after controlling for age, stage, and residual disease and number of chemotherapy cycles received (p = 0.029).
Elderly EOC patients frequently required chemotherapy dose reductions and delays in chemotherapy administration. Multivariate analysis confirmed that dose delays are an independent factor associated with decreased OS.
Cost-effectiveness of prophylaxis treatment strategies for febrile neutropenia in patients with recurrent ovarian cancer
2014, Gynecologic Oncology
Citation Excerpt :
Depending on the willingness-to-pay threshold, the percentage of FN events assumed to be managed in an outpatient setting may impact whether PP with pegfilgrastim is considered cost effective compared to SP for docetaxel. Second, maintaining high RDI is associated with improved overall survival in non-Hodgkin's lymphoma (NHL) and early-stage breast cancer [3], but conflicting results have been reported for ovarian cancer [2,4,33]. To account for this uncertainty, we performed an alternative analysis assuming that RDI < 85% was associated with lower survival rates; results were similar to the base-case analysis.
Evaluate the cost-effectiveness of primary prophylaxis (PP) or secondary prophylaxis (SP) with pegfilgrastim, filgrastim (6-day and 11-day), or no prophylaxis to reduce the risk of febrile neutropenia (FN) in patients with recurrent ovarian cancer receiving docetaxel or topotecan.
A Markov model was used to evaluate the cost-effectiveness of PP vs SP from a US payer perspective. Model inputs, including the efficacy of each strategy (relative risk of FN with prophylaxis compared to no prophylaxis) and mortality, costs, and utility values were estimated from public sources and peer-reviewed publications. Incremental cost-effectiveness was evaluated in terms of net cost per FN event avoided, incremental cost per life-year saved (LYS), and incremental cost per quality-adjusted life-year (QALY) gained over a lifetime horizon. Deterministic and probabilistic sensitivity analyses (DSA and PSA) were conducted.
For patients receiving docetaxel, the incremental cost-effectiveness ratio (ICER) for PP vs SP with pegfilgrastim was $7900 per QALY gained, and PP with pegfilgrastim dominated all other comparators. For patients receiving topotecan, PP with pegfilgrastim dominated all comparators. Model results were most sensitive to baseline FN risk. PP vs SP with pegfilgrastim was cost effective in 68% and 83% of simulations for docetaxel and in > 99% of simulations for topotecan at willingness-to-pay thresholds of $50,000 and $100,000 per QALY.
PP with pegfilgrastim should be considered cost effective compared to other prophylaxis strategies in patients with recurrent ovarian cancer receiving docetaxel or topotecan with a high risk of FN.

View all citing articles on Scopus

¹: Current address: Roswell Park Cancer Institute, Buffalo, NY, USA.

²: Current address: University of Tennessee, Memphis, TN, USA.

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Prognostic significance of the relative dose intensity of chemotherapy in primary treatment of epithelial ovarian cancer

Abstract

Objective

Methods

Results

Conclusions

Research highlights

Introduction

Section snippets

Methods

Results

Discussion

Conflict of interest

Gynecol Oncol

Lancet

Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer

N Engl J Med

Gynecology Oncology Group. Phase III trial of carboplatin and paclitaxel compared with cisplatin and paclitaxel in patients with optimally resected stage III ovarian cancer: a Gynecologic Oncology Group study

J Clin Oncol

Long-term follow-up and prognostic factor analysis in advanced ovarian carcinoma: the Gynecology Oncology Group experience

J Clin Oncol

The importance of dose intensity in the outcome of chemotherapy

Incidence and predictors of low chemotherapy dose-intensity in aggressive non-Hodgkin's lymphoma: a nationwide study

J Clin Oncol

Optimal delivery of anthracycline-based chemotherapy in the adjuvant setting improves outcome of breast cancer patients

Breast Cancer Res Treat

Dose intensity analysis of chemotherapy regimens in ovarian carcinoma

J Clin Oncol

Importance of multiagent chemotherapy regimens in ovarian carcinoma: dose intensity analysis

J Natl Cancer Inst

Dose and dose intensity as determinants of outcome in the adjuvant treatment of breast cancer

J Natl Cancer Inst