Abstract
Background
One of the primary treatment strategies for advanced epithelial ovarian cancers includes neoadjuvant chemotherapy (NACT) followed by interval debulking surgery (IDS) and adjuvant chemotherapy. Compliance to treatment is important to possibly improve outcomes.
Aim
To audit treatment compliance and its effect on overall survival (OS) and disease free survival (DFS) in women undergoing IDS.
Methods and Results
Women diagnosed with advanced epithelial ovarian cancer undergoing IDS were included. Details of compliance to chemotherapy and surgery as per standard guidelines were assessed, and correlation with survival was studied. Reasons for protocol deviation at various levels were documented and analysed.
A total of 182 patients were included. The total number of deviations was 134 with deviation at any level being 89 (48.9%) and at all levels 5%. Both patient‐ and treatment‐related factors contributed towards deviation. Deviation or noncompliance towards treatment resulted in a significantly reduced 5‐year OS (34.4% vs 58.2%; P = .001) compared with compliant patients, which retained its significance on multivariate analysis (P = .024) as well.
Conclusion
Deviation from treatment guidelines resulted in a significantly lower 5‐year OS compared with those who remained treatment compliant. Both patient‐ and treatment‐related factors contributed towards noncompliance and hence towards lower survival.
Keywords: advanced epithelial ovarian cancer, compliance, deviation, interval debulking surgery, survival
1. INTRODUCTION
Advanced epithelial ovarian cancer remains the most common cause of cancer‐related mortality amongst all gynaecological malignancies,1 due to the advanced stage at presentation in majority of patients. The combination of debulking surgery and platinum‐ and taxane‐based doublet chemotherapy remains the standard of care. The results of two important phase III trials, the EORTC/GCG‐NCIC,2 and CHORUS3 trials have paved the way for an alternative line of management, with both studies demonstrating the noninferiority of neoadjuvant chemotherapy (NACT) over primary debulking surgery. A recent meta‐analysis4 has also confirmed the same.
The two most important predictors of overall survival (OS) in advanced epithelial ovarian cancer patients are sensitivity and response to platinum‐based chemotherapy and optimal debulking surgery at initial diagnosis. NACT, by reducing the tumour burden, improves optimal cytoreduction rates and allows early initiation of adjuvant chemotherapy, thereby providing an optimal time frame for completing the treatment as a whole. This “treatment timeline” becomes important as the benefit of response at each phase of treatment can be potentially lost when delays occur. Timelines are delayed as a result of both logistic and nonlogistic barriers.5 Once a patient has decided to take treatment, logistic barriers such as treatment‐related adverse effects and economic implications of treatment generally affect compliance. Other social barriers such as disruption in daily routine, lack of social support, and belief systems also affect treatment completion but are difficult to measure. Compliance to treatment is often reflected by this temporal relationship of treatment completion. A variety of cancers, including gynaecological cancers, has been studied to understand this relationship of outcomes and compliance to therapy, which has been summarised in Table 1.
Table 1.
Studies that have looked at treatment adherence and outcomes in cancer patients
| Author/Year | Cancer Type | n | Period | Parameter | Study Type | Outcomes |
|---|---|---|---|---|---|---|
| Li et al6/2000 | Breast | 55 | 1990‐1995 | BCT in EBC | Retrospective | 36% compliance with higher local recurrence in those not compliant |
| Thibault et al7/2014 | GCT ovary | 82 | 2000‐2010 | Salvage chemotherapy | Retrospective | 50% compliance with no diff. in outcomes |
| Ray‐Coquard et al8/2004 | Soft tissue sarcoma | 100 | 1999‐2001 | Various treatments and follow‐up | Retrospective | 52%, 81%, and 94% compliance, respectively, for surgery, RT, and chemo |
| Jaap et al9/2018 | Pancreas: stages I and II | 52 540 | NA | Surgery and adjuvant therapy | Retrospective | 37% compliance and improved OS in compliant patients |
| Pathy et al10/2016 | NSCLC | 96 | 2008‐2013 | Survival and morbidity | Retrospective | 65% compliance with lower survival for poor compliance |
| Schwentner et al11/2013 | TNBC | 9156 | 1992‐2008 | Age and survival | Retrospective | Lower compliance in >65 y with improvement in DFS and OS with compliance |
| Xu et al12/2017 | Rectum | 14 742 | 2006‐2011 | Adjuvant chemotherapy | Retrospective | 68% did not receive adjuvant chemotherapy; improved OS in those who received chemotherapy |
| Ohri et al13/2016 | Many cancers | 1227 | 2007‐2012 | Curative EBRT | Retrospective | 21.7% noncompliant; poorer outcomes and increased recurrence rate |
| Puts et al14/2014 | All cancers | 22 studies | 2013 | Variable | Systematic review | 52% to 100% adherence rate |
| Eggink et al15/2017 | Endometrium | 14 564 | 2005‐2014 | Adjuvant therapy | Retrospective | 85% compliance with higher risk patients having lower compliance |
| Hseih et al16/2015 | Cervix | 119 | 2008‐2014 | CTRT | Retrospective | 36.4% compliance for full chemotherapy with improved DFS and OS |
| Bristow et al17/2016 | EOC | 10 296 | 1992‐2009 | Socio‐economic status, race, and ethnicity | Retrospective | 30.2% compliance with a higher mortality for those deviating |
| Erickson et al18/2014 | EOC | 367 | 2004‐2009 | Treatment guideline adherence | Retrospective | 21.5% noncompliant with better PFS and OS in complaint patients |
| Phippen et al19/2013 | EOC and PPC | 48 | 2002‐2010 | Treatment guideline (NCCN) adherence | Retrospective | 85.4% compliance; treatment deviation in 8.6% |
Abbreviations: BCT, breast conservation surgery; CTRT, concurrent chemoradiation; DFS, disease free survival; EBC, early breast cancer; EBRT, external beam radiotherapy; EOC, epithelial ovarian cancer; GCT, germ cell tumour; NSCLC, nonsmall cell lung cancer; OS, overall survival; PPC, primary peritoneal cancers; TNBC, triple negative breast cancer.
The aim of the study is to correlate treatment deviations with survival outcomes in patients undergoing interval debulking surgery (IDS) for advanced epithelial ovarian cancer.
2. MATERIALS AND METHODS
All patients undergoing IDS for advanced epithelial ovarian cancer (stages IIIC‐IV) from 1 October 2012 to 30 September 2013 were included. This study was approved by the Institutional Review Board (IRB) with the Project No. 1178. Informed consent was obtained from all those included in this study. Patients who were initially registered in our hospital with a diagnosis of advanced epithelial ovarian cancer and did not show optimal response to NACT or those who underwent IDS at another institution were excluded. The standard chemotherapy regimen included three to four cycles of taxanes and platinum as combination chemotherapy. The dose of chemotherapeutic agents administered was paclitaxel 175 mg/m2 and carboplatin at a dose of AUC 5‐6 every 3 to 4 weeks. At the end of the third cycle, patients were assessed for chemoresponse by combination of clinical examination, CA 125 levels and computerised tomography (CT) scans. Patients with optimal response to chemotherapy (radiological evidence of no or minimal ascites, absence of pleural effusion, reduction in gross abdominal disease by at least 50% of the initial disease at presentation, and reduction in CA 125 levels were used as parameters of optimal response) underwent IDS. Optimal cytoreduction was defined as no residual disease (R0) or residual disease of less than 1 cm (R1) at the completion of surgery. Two to three cycles of adjuvant chemotherapy (platinum and taxane) was then administered within 3 to 4 weeks from the date of surgery.
All patients were followed up with clinical examination and CA 125 every 3 to 4 months for the first 2 years and 6 months for the next 3 years. Radiological investigations were performed only when there was suspicion of disease recurrence.
The deviations at each phase of treatment (ie, during NACT, surgery, and adjuvant chemotherapy) were documented. Treatment deviation was defined as deviation from the above‐mentioned protocol at any phase whether it was treatment related or patient related. The effect of deviation on OS and disease free survival (DFS) was analysed in all patients.
During the chemotherapy phases, reasons for protocol deviation was categorised as follows:
administration of single agent chemotherapy instead of two agents,
administration of more than four or less than three cycles of chemotherapy,
long interval between chemotherapy cycles (more than 6 weeks), and
administration of nonplatinum‐ and/or taxane‐based chemotherapy.
During the IDS phase, any delay in performing surgery (more than 6 weeks after decision to perform IDS) was considered deviation.
Reasons for protocol deviation was categorised as follows:
Patient‐related factors:
Toxicity of NACT
Fitness issues for IDS
Resource‐related factors:
Nonavailability of beds
Delay in obtaining clinical decision at tumour board
Default for other reasons
The data were analysed using the SPSS ver. 25 software (IBM Corporation, NY; formerly SPSS Inc. Chicago, IL). For continuous variables, descriptive statistics were used to calculate mean, median, and range. Frequency and percentages were used for categorical variables. Kaplan‐Meier method was used to estimate the survival and log‐rank for comparisons between two survival estimates. Cox regression was utilised for multivariate analysis in the estimation of hazard ratios. Statistical significance was defined as P value < .05. OS was defined as the time period from the date of diagnosis till date of last follow‐up or date of death while DFS was defined as the time period from the date of diagnosis till the first recurrence or death.
3. RESULTS
A total of 182 patients were included in the study. The demographic and treatment details are tabulated below (Table 2). The median overall treatment duration was 177 days (range: 91‐376 days).
Table 2.
Demographic and treatment details of the entire cohort (n = 182)
| Variables | Result | |
|---|---|---|
| Age, y | Median (range) | 49 (25‐72) |
| Patient category | General | 81 (44.5%) |
| Private | 101 (55.5%) | |
| ECOG status | 0 | 99 (54.4%) |
| 1 | 78 (42.9%) | |
| 2 | 05 (2.7%) | |
| CA‐125 levels, IU/mL | Median (range) | 1068.5 (3‐37 980) |
| Stage at presentation | III | 143 (78.57%) |
| IV | 39 (21.43%) | |
| No. of NACT cycles | Median (range) | 3 (1‐8) |
| Type of NACT | Paclitaxel + carboplatin (P + C) | 157 (86.3%) |
| Only carboplatin (C) | 5 (2.7%) | |
| Others (non P + C chemotherapy) | 2 (1.1%) | |
| Mixed (both P + C and non‐P + C chemotherapy) | 18 (9.9%) | |
| Histology | Serous | 151 (82.9%) |
| Nonserous | ||
| Endometrioid | 10 (5.5%) | |
| Mucinous | 03 (1.6%) | |
| Clear cell | 03 (1.6%) | |
| Adenocarcinoma, NOS | 07 (3.8%) | |
| Mixed histologies | 08 (4.4%) | |
| Resection status | Optimal cytoreduction | 168 (92.3%) |
| Suboptimal cytoreduction | 14 (7.7%) | |
| No. of adjuvant cycles | Median (range) | 3 (1‐5) |
| Type of adjuvant chemotherapy (n = 167/182) | P + C | 150 (82.4%) |
| Only P | 1 (0.5%) | |
| Only C | 9 (4.9%) | |
| Others | 6 (3.3%) | |
| Mixed | 1 (0.5%) | |
| Disease recurrence | Yes | 139 (76.4%) |
| No | 43 (23.6%) | |
| Follow‐up period, mo | Median | 66.22 |
| Total number of protocol deviations | 134 | |
| NACT | 36 | |
| Surgery | 54 | |
| Adjuvant chemotherapy | 44 | |
| Deviation at any level/phase | Yes | 89 (48.9%) |
| One level/phase | 53 (29.9%) | |
| Two levels/phases | 27 (14.8%) | |
| At all three levels/phases | 09 (4.9%) | |
| No | 93 (51.1%) | |
Abbreviations: ECOG, Eastern Cooperative Oncology Group; NACT, neoadjuvant chemotherapy; NOS, not otherwise specified.
The phases at which deviation in the primary treatment occurred were divided into
NACT phase: The median interval from the date of diagnosis to completion of NACT was 73 days. The number of patients with deviations during this phase was 19.8% (n = 36).
IDS phase: The median interval between completion of NACT and date of surgery was 34 days. Optimal cytoreduction was performed in 168 patients (92.3%). Although deemed resectable after NACT, 7.7% patients had suboptimal cytoreduction. Overall, 54 patients (29.7%) had protocol deviation in this phase.
Adjuvant phase: Following IDS, 167 patients received adjuvant chemotherapy. The median duration from date of surgery till completion of adjuvant therapy was 64 days. Protocol deviation was identified in 44 patients (24.2%).
The total number of deviations in our study was 134 with 89 (48.9%) patients deviating from primary treatment at any one level/phase of care. Table 3 depicts various reasons for deviation in all the phases of treatment.
Table 3.
Reasons for treatment deviation during all phases of treatment
| Reasons | n |
|---|---|
| Single agent chemotherapy | 29 |
| Logistic issues (eg, want of bed for admission/delays) | 20 |
| Administering more cycles (>4 NACT/>3 adjuvant) | 18 |
| Non‐paclitaxel and carboplatin chemotherapy | 8 |
| Treatment‐related toxicity | 10 |
| Administrating fewer cycles (<3 NACT/<2 adjuvant) | 6 |
| Defaulted treatment in between | 3 |
| Post‐operative complications | 2 |
| Anaesthesia fitness issues | 2 |
| Unknown reasons | 37 |
Abbreviation: NACT, neoadjuvant chemotherapy.
3.1. Oncological outcomes
The median follow‐up period was 62.22 months. At the end of follow‐up, 22.5% (n = 41) were alive without disease, 18.7% (n = 34) were alive with disease, and 49.5% (n = 90) were dead (including two patients who died due to unrelated causes). Seventeen patients (9.3%) were lost to follow‐up. The OS of the entire cohort was 41.9%. The 5‐year OS and DFS was 46.6% and 20.1%, respectively. Surgical resection status had a significant effect on 5‐year OS: 52.7%, 35.8%, and 7.7%, respectively, for R0, R1, and R2 resections (Figure 1). The corresponding 5‐year DFS was 25%, 4.2%, and 0% (at 22.4 months), respectively.
Figure 1.
Kaplan‐Meier graph showing relationship of resection status (R status) and overall survival (OS). The P values for OS and disease free survival between R2 and R0 resected patients was 0.002 and <0.001, respectively
The relationship of survival with deviation at each phase of primary treatment (mentioned above) was analysed (Table 4). It was seen that deviation at any phase of primary treatment reduced the 5‐year OS significantly (58.2% vs 34.4%: P = 0.001) (Figure 2). Similarly, as the number of deviations increased (from one to two/three deviations), there was reduction in the OS (58.2% for no deviation vs 11.1% for three deviations: P = 0.004) (Figure 3). However, there was no effect of treatment deviation (type or number) on the DFS (23.9% vs 16.1%: P = 0.082 for any deviation) except during the adjuvant chemotherapy phase (P = 0.01).
Table 4.
Comparison of OS and DFS in patients at 5 y in the compliant and noncompliant groups
| Variables | 5‐y OS | 5‐y DFS | ||
|---|---|---|---|---|
| % | P value | % | P value | |
| Deviation during NACT | ||||
| No (n = 146) | 51.0 | 0.003 * | 21.4 | 0.152 |
| Yes (n = 36) | 28.6 | 14.9 | ||
| Deviation during surgery | ||||
| No (n = 128) | 53.5 | 0.05 * | 21.4 | 0.761 |
| Yes (n = 54) | 32.2 | 17.3 | ||
| Deviation during adjuvant therapy | ||||
| No (n = 138) | 52.0 | 0.004 * | 22.7 | 0.01 * |
| Yes (n = 44) | 28.9 | 11.1 | ||
| Any deviation from treatment | ||||
| No (n = 89) | 58.2 | 0.001 * | 23.9 | 0.082 |
| Yes (n = 93) | 34.4 | 16.1 | ||
| Number of deviations | ||||
| 0 (n = 93) | 58.2 | 0.004 * | 23.9 | 0.267 |
| 1 (n = 53) | 41.0 | 17.7 | ||
| 2 (n = 27) | 31.8 | 18.1 | ||
| 3 (n = 9) | 11.1 | 0a | ||
Abbreviations: DFS, disease free survival; NACT, neoadjuvant chemotherapy; OS, overall survival.
At 36.69 mo.
Significant value.
Figure 2.
Kaplan‐Meier graph showing relationship of treatment deviation and overall survival (OS). The P value was 0.003 on multivariate analysis
Figure 3.
Kaplan‐Meier graph showing relationship of number of treatment deviations and overall survival (OS). As the number of deviations increased, there was a corresponding reduction in OS (P value = 0.004).
We undertook univariate and multivariate analysis (using the Enter method) of variables including patient age, Eastern Cooperative Oncology Group (ECOG) status, category (general/private), surgical resection status (optimal/suboptimal), tumour histology (serous/nonserous), and treatment deviation for OS and DFS. Resection (R) status and treatment deviation were significant both in the univariate and multivariate analysis for OS (Table 5). Histology and R status were significant variables in the univariate and multivariate analysis for DFS (Table 6). Although patient category/class showed significance in the univariate analysis for OS, using the chi‐squared test, treatment deviation and class/category were highly correlated. Hence, this variable was not included in the multivariate analysis when determining OS.
Table 5.
Univariate and multivariate analysis of variables for OS
| Variables | Univariate | Multivariate | ||
|---|---|---|---|---|
| HR (95% CI) | P value | HR (95% CI) | P value | |
| Age | 1.004 (0.982‐1.028) | 0.708 | 1.000 (0.976‐1.025) | 0.988 |
| Resection status | ||||
| R0 (n = 144) | Referent | Referent | ||
| R1(n = 24) | 1.622 (0.909‐2.897) | 0.102 | 1.500 (0.833‐2.701) | 0.177 |
| R2 (n = 14) | 2.977 (1.599‐5.541) | 0.001 * | 2.754 (1.462‐5.190) | 0.002 * |
| ECOG | ||||
| ECOG 0 (n = 99) | Referent | Referent | ||
| ECOG 1 (n = 78) | 1.029 (0.674‐1.573) | 0.893 | 1.109 (0.719‐1.711) | 0.639 |
| ECOG 2 (n = 5) | 1.424 (0.443‐4.578) | 0.553 | 1.434 (0.436‐4.721) | 0.553 |
| Histology | ||||
| Nonserous (n = 24) | Referent | Referent | ||
| Serous (n = 158)a | 1.513 (0.759‐3.104) | 0.239 | 1.416 (0.697‐2.871) | 0.336 |
| Deviation from treatment | ||||
| No (n = 93) | Referent | Referent | ||
| Yes (n = 89) | 1.978 (1.295‐3.020) | 0.002 * | 1.925 (1.251‐2.964) | 0.003 * |
| Class/Category | ||||
| Private (n = 101) | Referent | ‐ | ‐ | |
| General (n = 81) | 1.583 (1.044‐2.400) | 0.03 * | ||
Abbreviations: CI, confidence interval; ECOG, Eastern Cooperative Oncology Group; HR, hazard ratio; OS, overall survival.
Serous papillary, poorly differentiated histologies, and mixed variants with serous component.
Significant value.
Table 6.
Univariate and multivariate analysis of variables for DFS
| Variables | Univariate | Multivariate | ||
|---|---|---|---|---|
| HR (95% CI) | P value | HR (95% CI) | P value | |
| Age | 1.015 (0.996‐1.033) | 0.121 | 1.013 90.994‐1.034) | 0.181 |
| Resection status | ||||
| R0 (n = 144) | Referent | Referent | ||
| R1(n = 24) | 2.419 (1.521‐3.848) | <0.001 * | 2.379 (1.475‐3.809) | <0.001 * |
| R2 (n = 14) | 4.417 (2.462‐7.924) | <0.001 * | 3.960 (2.188‐7.165) | <0.001 * |
| ECOG | ||||
| ECOG 0 (n = 99) | Referent | Referent | ||
| ECOG 1 (n = 78) | 1.043 (0.742‐1.466) | 0.809 | 1.084 (0.765‐1.538) | 0.649 |
| ECOG 2 (n = 5) | 0.986 (0.360‐2.699) | 0.979 | 1.046 (0.377‐2.901) | 0.931 |
| Histology | ||||
| Nonserous (n = 24) | Referent | Referent | ||
| Serous (n = 158)a | 3.379 (1.710‐6.676) | <0.001 * | 3.244 (1.620‐6.495) | 0.001 * |
| Deviation from treatment | ||||
| No (n = 93) | Referent | Referent | ||
| Yes (n = 89) | 1.344 (0.961‐1.879) | 0.084 | 1.339 (0.950‐1.887) | 0.096 |
| Class/Category | ||||
| Private (n = 101) | Referent | ‐ | ‐ | |
| General (n = 81) | 1.102 (0.789‐1.538) | 0.568 | ||
Abbreviations: CI, confidence interval; DFS, disease free survival; ECOG, Eastern Cooperative Oncology Group; HR, hazard ratio.
Serous papillary, poorly differentiated histologies, and mixed variants with serous component.
Significant value.
4. DISCUSSION
Disease‐ and treatment‐related factors contribute to oncological outcomes in most cancers along with demographic variables. The two most important predictors of survival in patients with advanced epithelial ovarian cancer are platinum sensitivity and optimal debulking of tumour. Some studies have shown that centralisation of ovarian cancer services improve optimal debulking rates.20, 21 We included patients who underwent IDS at our hospital (a tertiary referral cancer centre); 82.4% patients in our study received paclitaxel and carboplatin combination chemotherapy. The optimal debulking rate was 92.3%, which is similar to the per protocol analysis of various studies.2, 3 Furthermore, survival in these patients was higher than those suboptimally debulked (7.7%). The optimal debulking rates for those receiving NACT and IDS in the intention to treat (ITT) cohorts of both the EORTC/NCIC2 and CHORUS3 trials were 88% and 85.77%, respectively. A retrospective study from our institution22 reported optimal cytoreduction rates of 81.5% in patients treated by NACT and IDS.
Compliance to standard prescribed treatment is yet another complex variable and has shown to impact recurrence and OS in many cancers. For ovarian cancers per se, studies have shown that treatment compliance improves outcomes. Phippen et al19 studied 48 patients of advanced high grade ovarian cancers in relation to treatment compliance to the NCCN guidelines. They observed 85.4% compliance rate towards treatment. Studies by Bristow et al17 and Erickson et al18 demonstrated higher mortality rates for noncompliant patients (Table 1). However, in the above‐mentioned studies,17, 18, 19 patients had undergone primary debulking surgery and the number of evaluable patients following NACT was few.
In the EORTC,2 CHORUS,3 and Mayo Clinic23 trials, certain patients in the NACT arm deviated from the assigned protocol (Table 7). Such deviations could have been a result of disease progression or chemotherapy‐related complications, with the type and dosage of chemotherapy administered, both playing an important role. In our study, we found that 5% patients deviating all phases of primary treatment with 48.9% of patients deviating as part of treatment guidelines at any phase. Furthermore, patients deviating from treatment at any level (ie, any deviation) had lower OS rates as compared with compliant patients (34.4% vs 58.2%; P = .001). An increase in the number of deviations (one or two or all three) also affected OS significantly (41.0% vs 11.1% for one and three deviations, respectively), even though the number of patients who deviated at all phases of primary treatment was low (5%).
Table 7.
Treatment deviation from standard protocol in the NACT arm in various published clinical trials
| Parameters | EORTC/NCIC Trial2 | CHORUS Trial3 | Mayo Clinic (Rochester)23 | Present Study |
|---|---|---|---|---|
| Patients undergoing IDS after NACT | 295 + 57:352a | 217 + 4 = 221a | 87 | 182 |
| Age (median) | 63 | 65 | 66.6 (mean) | 49 |
| 3 cycles of NACT received | NA | 197 | 44 | 98 |
| <3 or >3 cycles NACT received | 136b | 24 | 43 | 84 |
| Optimal debulking rate | 80.6% (238/322) | 73% (144/219) | 100% | 92.3% (168/182) |
| Patients receiving adjuvant chemotherapy | NA | 204 | 81 | 167 |
| 3 cycles of adjuvant chemotherapy received | NA | 173 | 36 | 108 |
| <3 or >3 cycles of adjuvant received | 136b | 31 | 45 | 59 |
| Single agent chemotherapy | 6.20% (20/322) | 30.0% (75/254) | 19.75% (16/81) | 15.93% (29/182) |
| Non‐paclitaxel + carboplatin chemotherapy | 5.9% | 0% | 4.4% | |
| Mixed chemotherapy (few paclitaxel and carboplatin cycles; few non paclitaxel and carboplatin cycles) | <1% (1/254) | 10.44% (19/182) | ||
| Median overall treatment duration, d | NA | 156 | NA | 177 |
| Median interval from diagnosis/randomisation till IDS, d | NA | 87 | 103c | 117 |
Abbreviations: IDS, interval debulking surgery; NA, not available; NACT, neoadjuvant chemotherapy.
Patients receiving NACT irrespective of the allotted treatment arm at randomisation.
Numbers include both NACT and adjuvant chemotherapy cycles.
From start of NACT till surgery.
Other factors contributing to adverse oncological outcomes in any cancer, including ovarian cancer are advanced age, low socio‐economic status, poor performance status, serous/aggressive histology, and suboptimal resection of disease at surgery. These factors were analysed in the univariate and multivariate analyses with treatment deviation. It was seen that suboptimal resection and treatment deviation had significant adverse effect on survival. Resection (R) status during surgery is largely dependent on chemosensitivity, surgical expertise, and disease biology. Complete chemosensitivity versus optimal chemosensitivity depends on the biology of the disease and also on compliance to chemotherapy during the neoadjuvant phase of treatment. The tumour biology makes a difference not only at achieving complete resection but also to chemotherapy response, though it is difficult variable to measure accurately in real‐life scenario and can only be hypothesised in a clinical setting. Despite tumour biology being a strong predictor and confounder for OS, the deviation from guidelines clearly led to inferior survival in all women in our study, which would have given an added survival advantage to women with good biology disease if they had adhered to the protocol.
Deviation in the treatment is related not only to tumour‐related/clinical factors but can be a result of administrative or economic reasons especially in low‐middle income countries where there is a significant disparity in health economics. Such deviations, in one way, are correlated with socio‐economic status of patients. In our study, general category/class of patients showed a high protocol deviation. This brings out a valid point for assessing such disparity.
A number of barriers often predict compliance to therapy. Overcoming such barriers improves compliance and thus reduces deviation from treatment protocols. More often than not, more than one barrier needs to be overcome in order to maintain compliance. In our study, we identified both resource‐ and patient‐related factors contributing to deviation. In the chemotherapy phases, administration of single agent chemotherapy was one of the main reasons for deviation that could be related to fitness issues or toxicity and/or hypersensitivity to chemotherapeutic agents. In the surgery phase, again, persistence of chemotherapy‐induced haematological toxicity and fitness concerns were the main causes of deviation. Nonavailability of theatre slots for surgery and patients refusing to undergo surgery elsewhere also contributed towards delay in a few patients. Economic considerations that involve cost of chemotherapy, surgery, and additional cost for treatment‐related complications influence compliance. For example, at our centre, the total cost for six cycles of standard chemotherapy (generic drugs) is approximately 500 US dollars ($500), which increases three fold ($1500) when nongeneric (innovative) agents are administered. Costs, however, exclude hospitalisation and treatment of complications arising from them. These factors affect compliance in countries, where health is only partly state sponsored and private health insurance policy not well developed. All of the above‐mentioned factors could have contributed to the high rate of treatment deviation in our study, despite subsidised health costs provided by the hospital.
This is the first study to assess protocol deviations at various levels/phases of care in advanced ovarian cancer patients undergoing IDS with 5‐year follow‐up outcomes. The limitations include retrospective nature of the study and other factors (eg, economic factors), which could have contributed towards deviation from treatment but were not measured directly in this study.
5. CONCLUSIONS
Majority of patients following initial diagnosis of advanced ovarian epithelial cancer received doublet chemotherapy with paclitaxel and carboplatin and had optimal debulking surgery in this study making them a good prognostic group to start with. However, patients who deviated from the standard guidelines (at one or more phases of primary treatment) had a significant reduction in OS compared with those who did not deviate. These deviations were attributable to both treatment‐related factors and resource limitations. Our study is the first of its kind, addressing the real‐life issues in compliance to various phases of primary treatment in advanced ovarian cancer affecting survival adversely. There is an array of on‐going sophisticated research and funds spent for a small increment in survival for advances in ovarian cancers across the globe. Hence, emphasis must also be on studies looking into various reasons for deviation in standard treatment such as reducing chemotherapy‐related sensitivity and toxicity along with policy decisions on resource allocations that could directly translate to improved survival outcomes globally. This study paves way to improve compliance in low‐ and medium‐resource countries, which can possibly predict good outcomes before considering expensive drugs or advanced technologies for treatment.
CONFLICT OF INTEREST
The authors have no conflict of interest.
AUTHORS' CONTRIBUTION
All authors had full access to the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Conceptualization, T.S.S.; Methodology, T.S.S., A.K.K., M.G., and R.H.; Investigation, all authors (except R.H.); Formal Analysis, T.S.S., A.K.K., M.G., J.G., and R.H.; Resources, all authors; Writing ‐ Original Draft, all authors; Writing ‐ Review & Editing, T.S.S., A.K.K., J.G., A.M., R.H., J.B., S.G., S.G., R.A.K.; Visualization, T.S.S., A.K.K.; Supervision, T.S.S; Funding Acquisition, None.
FUNDING INFORMATION
None.
Shylasree TS, Kattepur AK, Gupta M, et al. Compliance to treatment guidelines and survival in women undergoing interval debulking surgery for advanced epithelial ovarian cancer. Cancer Reports. 2020;3:e1217. 10.1002/cnr2.1217
This manuscript has been accepted for poster presentation at the 57th Annual Meeting of the Japan Society of Clinical Oncology (JSCO) 2019 at Fukouka, Japan, in October 2019.
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.