黑料网

Health-related quality of life; Patient-reported outcomes; Ovarian cancer; Advanced cancer; Palliative care

Introduction

The frequent absence of a survival benefit linked to a new medication, despite data suggesting there may be some utility to treatment, has made it difficult to interpret cancer clinical trials. New therapies may enhance surrogate endpoints like time to disease progression and progression-free survival, but they might not correspond with overall survival [1]. This may happen due to a variety of post-study therapies that are accessible to patients after they stop taking study medication, unequal crossover following study therapy, or the fact that these surrogate endpoints are poor substitutes for overall survival. Cancer symptom evaluation can offer an early signal of benefit that is directly relevant to patients' life, whether they are symptoms of the disease or side effects of therapy. Assessment of cancer symptoms can potentially foretell future events, such as tumour response, disease progression [2-5], and survival [6-9]. It may be really critical to properly appreciate the worth of new treatments if you comprehend the most significant symptoms and associated worries linked with advanced solid tumors. With ovarian cancer serving as a model illness to highlight the significance of this evaluation as a key component to determining treatment value, we present a method in this study for effectively evaluating the most significant symptoms and concerns of patients receiving advanced cancer treatment. Health-related quality of life (HRQOL) has increasingly become accepted as a clinical trial outcome; however, clinicians and regulatory organisations have been hesitant to incorporate HRQOL assessment into clinical research and practise [10-13] due to concerns about the use and interpretability of multi-item, multi-dimensional HRQOL measures. The Food and Drug Administration Oncology Drug Advisory Committee's Quality of life Subcommittee responded to concerns about HRQOL measurement in clinical trials by stating that pharmaceutical company claims of improved HRQOL must be specific to the QOL domain measured, with the recommendation that assessment of particular symptoms serve as a starting point for improved measurement of HRQOL domains [14].

Recent research sought to enhance currently validated cancerrelated HRQOL and symptom measures in order to develop clinicallyrelevant symptom-specific measures that are sensitive to interventionrelated changes and that reflect the symptoms thought to be most important to measure by both oncology clinicians and patients. This was done in recognition of the importance of assessing HRQOL and symptom improvement, particularly in the case of advanced cancer. Patients were asked to rank the most significant symptoms for 11 distinct forms of advanced cancer, and medical professionals determined whether the symptoms were mostly caused by the disease or the therapy.

These findings were in agreement with previously released indices that assessed the most crucial symptoms, as judged by oncology experts. By a multi-step approach, advanced cancer symptom indices reflecting the symptoms given the greatest importance by patients and doctors were developed and initially validated [15]. The creation of these symptom indices shows increased adherence to FDA recommendations on patient-reported outcomes in addition to offering clinically useful tools for the assessment of the most significant symptoms to evaluate across 11 distinct forms of advanced cancer. It does this by guaranteeing the final questionnaire's content validity. The published results of closely related predecessor instruments with substantial content overlap can be used to infer validity in other areas. To give an example, that, using the FDA-recommended methodology, the number of new questions added to previous FACT-specific questionnaires ranged from 0 to 4, with new material never reaching 20% of the final index.

Palliative oncology

The relevance of using patient-reported HRQOL as an endpoint for assessing the efficacy of treatment is highlighted by the frequently constrained availability of curative treatment choices in late stage cancer. Many physical and mental symptoms may negatively impact HRQOL in people with advanced cancer. Hence, the major objectives of therapeutic trials in advanced cancer are symptom management, functioning preservation, and maintenance or enhancement of HRQOL. The focus on these endpoints in palliative interventions highlights the importance of psychometrically sound HRQOL assessment that provides clinically useful information, as well as HRQOL measurement that follows regulatory guidance by concentrating specifically on the symptoms important for that condition. The NCCNFACT symptom indices were developed using a strict, multi-step technique that uniquely qualifies them for use in clinical research and practise addressing palliative therapy for advanced cancer.

Clinical professionals and academics now have a new method for evaluating patients' symptom-specific responses to therapy thanks to the NCCN-FACT symptom indexes. The NCCN-FACT symptom indices provide a special blend of clinical relevance and succinctness. They may thus be particularly well-suited to circumstances and settings that call for a quick, clinically relevant, and change-sensitive evaluation of HRQOL. Because each index has between 16 and 24 questions, it may be easier to address long-standing issues with HRQOL adoption in clinical practise and research settings, such as patient burden, disruption of clinic workflow, and interpretability [16]. While patients may be more affected by fatigue and other symptoms in the palliative setting, which might prevent them from completing longer HRQOL evaluations, minimising patient burden may be especially crucial. The NCCN-FACT indexes are shorter than the original FACT cancerspecific measurements, which are lengthier and more labor-intensive to complete. This represents an improvement. The NCCN-FACT symptom indexes were created primarily to assess the most significant signs and symptoms for chemotherapy-treated patients with advanced (stages III and IV) cancer. They are thus particularly well adapted for clinical practise or clinical trials that aim to evaluate the concentrated symptom experience of patients with advanced disease as well as the impact of the illness and therapy on the symptom experience. The original FACT cancer-specific measures may be a preferable option in cases when healthcare practitioners and researchers want to look at the multidimensional HRQOL experience of people with advanced cancer or HRQOL in people with early stage cancer. The FDA's guideline on patient-reported outcomes was specifically taken into account while developing the NCCN-FACT symptom indexes, which may be a benefit in terms of their acceptance in a regulatory framework [17]. When analysing the impact of novel medicines on the symptoms deemed most essential across cancer types in clinical research including regulatory filing, they offer a suitable option for quantifying HRQOL. There is no other instrument or index that is more sensitive to the FDA Patient-Reported Outcome (PRO) Guidelines, for example, in the case of ovarian cancer. The Functional Assessment of Cancer Therapy- Ovarian Cancer (FACT-0) and the Quality of Life Instrument-Ovarian Cancer Patient Version (QOL-OVCA) are two currently accessible ovarian cancer-specific HRQOL assessments.

The FDA's guideline on patient-reported outcomes was specifically taken into account while developing the NCCN-FACT symptom indexes, which may be a benefit in terms of their acceptance in a regulatory framework. When analysing the impact of novel medicines on the symptoms deemed most essential across cancer types in clinical research including regulatory filing, they offer a suitable option for quantifying HRQOL. There is no other instrument or index that is more sensitive to the FDA Patient-Reported Outcome (PRO) Guidelines, for example, in the case of ovarian cancer. The Functional Assessment of Cancer Therapy- Ovarian Cancer (FACT-0) and the Quality of Life Instrument-Ovarian Cancer Patient Version (QOL-OVCA) are two currently accessible ovarian cancer-specific HRQOL assessments. Although patients' opinion was included when these measures were being developed, they had no direct say in the decisions made for the scale's individual components. As a result, the FACT-O and QOLOVCA may not accurately reflect the symptoms that patients have prioritized, failing to fulfill FDA regulatory standards. At the period of measure development, the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Ovarian Cancer Module (EORTC-QLQ-OV-28) [18,19] did take into account ovarian cancer patients' assessments of the significance of each symptom or worry. Women with both early and late stage ovarian cancer contributed relevant rankings of the symptoms/concerns throughout the measure creation phase, although the measure was not created especially to reflect the concerns among women with advanced ovarian cancer. Because of this, not all of the items included may be particularly pertinent to women with advanced ovarian cancer or those receiving palliative care, even if the EORTC-QLQ-OV-28 may meet regulatory guidelines for the inclusion of direct patient input in item selection.

Interpreting the NCCN-FACT symptom indexes

An essential measurement attribute is interpretability, which has an impact on both how the measure is used and how relevant the results are. Similar with all FACT/Functional Assessment of Chronic Illness Treatment [20] surveys, a total score may be calculated for the NCCNFACT symptom indexes, and higher scores suggest better outcomes than lower ones. At the level of the overall index, this can be clinically instructive, but a closer look at the individual subscales (such as disease-related, treatment side effects, and function and wellbeing) can provide more detail about how the target symptoms change over time or in response to an intervention. Given that the NCCNFACT indexes are new, measures to ascertain their interpretability or significance have not yet been created, but they represent a significant field for future research. It is fair to expect that a significant change for the NCCNFACT indices would be in the region of 4-5 points based on the work of Yost and Eton [21]. This is in line with the previously mentioned, greater-than-four-to-five-point variances in NCCNFACT ratings amongst Eastern Cooperative Oncology Group (ECOG) performance status groups [22]. The topic of how to interpret the NCCN-FACT symptom index scores in relation to the original FACT measure scores may emerge given that many healthcare practitioners and researchers may have employed the original FACT cancerspecific HRQOL measurements. This may be particularly significant for clinicians and researchers who seek to switch to utilising the more recent NCCN-FACT symptom indices after previously using the earlier FACT measures longitudinally. The NCCN-FACT symptom index scores cannot be derived directly from the original FACT measures due to the fact that the more recent NCCN-FACT scales contain items that were not initially included in their original FACT equivalent. However, if more than 50% of the NCCN-FACT items are completed, the scores obtained using the original FACT measures can be prorated to be comparable to the NCCNFACT measures using the following established formula: (number of items in NCCN-FACT measure) x (sum of NCCN-FACT item responses)/(number of NCCN-FACT items completed) [23]. We have given the following example involving the NCCN-FACT Ovarian Symptom Index-18 (NFOSI-18) [24] for use as a potential outcome measure in evaluating the effectiveness of chemotherapy for advanced ovarian cancer in order to demonstrate how the NCCN-FACT symptom indexes can be applied when assessing the efficacy of palliative treatment for advanced cancer.

Analyze the results of advanced ovarian cancer treatment

With approximately three-fourths of women presenting with advanced stage (stage III-IV) illness, ovarian cancer is the second most frequent and deadliest gynecologic malignancy in the United States [25]. Increasing progression-free and overall survival rates as well as reducing the number of symptoms brought on by the illness and therapy have historically been the main objectives of ovarian cancer treatment. Nevertheless, recent studies looking at clinically significant patient-centered outcomes have become more and more interested in optimising HRQOL as a crucial end-point. Research has increasingly noticed the effect of disease and therapy on HRQOL as it has placed a larger emphasis on HRQOL. The balance between efficacy and safety, or benefit and damage, is frequently taken into account while choosing a course of therapy for ovarian cancer since certain clinical advantages may degrade HRQOL. In contrast, a therapeutic benefit may also enhance HRQOL, so elevating the therapeutic benefit above and above the clinical outcomes of response, disease-free survival, progressionfree survival, and overall survival. As a result, ovarian cancer offers a pertinent backdrop for discussing how the NFOSI-18 is applied to assess treatment results in advanced ovarian cancer. The NFOSI-18 was created as a component of a broader cross-sectional research that created symptom indices for 11 various forms of advanced cancer (before reported). While treating advanced ovarian cancer, 51 women with the disease evaluated which symptoms were most crucial, and 10 gynecologic oncologists determined whether these symptoms were mostly caused by the disease or the therapy. An 18-item symptom index for advanced ovarian cancer was created by combining the patient-rated priority symptoms with previously reported clinicianrated priority symptoms. The NFOSI-18 showed strong initial reliability, with subscale reliability ranging from =0.55 (Treatment side effects) to =0.64 (Function and Well-Being) and whole scale internal consistency reliability (16 items with data) of =0.80. The NFOSI-18's preliminary validity was also strong; there were notable variations in scores between performance status groups as determined by the ECOG measure of performance status, and lower NFOSI-18 scores were linked to lower performance status. The differences in NFOSI-18 scores between ECOG performance status groups exceeded the range of 4 to 5 points discussed in previous research to establish standards for clinically meaningful differences in measures from the FACIT measurement system, even though more research is required to define what constitutes a clinically meaningful difference and change on the NFOSI-18. The Functional Assessment of Cancer Therapy-Ovarian (FACT-O) HRQOL assessment and the NFOSI-18 are extremely redundant. The 26-item FACT-O Trial Outcome Index was the most popular clinical trial endpoint in advanced ovarian cancer clinical trials prior to the development of the NFOSI-18 (TOI). It contrasts the item content of the FACT-O TOI with the NFOSI-18, which was created in response to the U.S. FDA PRO Guideline on content validity (built to be more inclusive of HRQOL considerations beyond the most important symptoms and concerns). The majority of the NFOSI-18 questions (n=14) are also in the TOI, indicating that the published data on the TOI would offer reliable and pertinent evidence for the NFOSI-18's expected performance in upcoming trials. The NFOSI-18 therefore differs from the FACT-O in a number of ways, including its brevity, focus on symptom measurement for advanced ovarian cancer, and improved satisfaction with regulatory guidance. However, given the NFOSI-18's recent development, we must extrapolate much of its validity from its strikingly similar predecessor, the TOI.

Clinical trial outcomes

In a recent prospective phase II randomised clinical study, women with platinum-sensitive recurrent ovarian cancer were randomly assigned to receive either docetaxel plus carboplatin or docetaxel alone, followed by carboplatin, with HRQOL being assessed as a secondary outcome. Overall survival did not vary, but the combination arm had substantially longer progression-free survival, greater neurotoxicity, and more neutropenia. The sequential therapy, however, had a much less effect on the results for HRQOL. Particularly, compared to the combination arm, the sequential arm had less of an effect on the FACT-O TOI during the duration of the experiment. From baseline to trial completion, the TOI in the combination arm reduced by 4.9 points, but it increased by 1.4 points in the sequential arm. The median time to TOI worsening did not differ across groups, albeit. The NFOSI-18 therefore differs from the FACT-O in a number of ways, including its brevity, focus on symptom measurement for advanced ovarian cancer, and improved satisfaction with regulatory guidance. However, given the NFOSI-18's recent development, we must extrapolate much of its validity from its strikingly similar predecessor, the TOI. Women with advanced ovarian cancer had a higher chance of survival while receiving intraperitoneal (IP) treatment. The FACT-O TOI was significantly lower in the IP group compared to the IV group before cycle four (10 point difference) and three to six weeks after treatment (7 point difference), despite a phase III randomised trial finding that intravenous (IV) paclitaxel plus IP cisplatin and paclitaxel significantly increased progression-free and overall survival when compared to IV-only paclitaxel and cisplatin. As compared to patients receiving IV therapy, patients receiving IP therapy reported considerably and clinically meaningfully more physical, functional, and ovarian cancerspecific issues both during and immediately after treatment. Notably, both groups reported improving TOI over time, with no differences between the IP arm and the IV arm at one year, with the exception of the IP group prior to cycle four. In particular, the TOI increased in the IV arm from 70.0 (baseline) to 83.2 (12 months) and in the IP arm from 64.5 (baseline) to 82.2 (12 months). These results emphasise the need to balance possible survival benefits of IP chemotherapy with its short-term HRQOL impairments in talks regarding treatment decision-making. Also, the size of variations in TOI scores across treatment groups and longitudinally over time may offer suggestions for future clinical trials that may use the NFOSI-18 to evaluate HRQOL outcomes.

A quest for new therapeutic agents, such as innovative biologic medicines, has been spurred by the limited number of curative therapy choices for women with advanced ovarian cancer, despite advancements in surgical and chemotherapeutic treatment regimens. The selective oral epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 was tested in two Phase I studies among patients with advanced ovarian cancer and other advanced solid tumours, and is one of the innovative biologic treatments being developed and investigated. ZD1839 works by obstructing signalling pathways that are crucial for the development of tumours. LoRusso et al. note that while this was not the case for other solid tumour types in the study, the median TOI for patients with advanced ovarian cancer decreased with time from baseline in both Phase I trials of ZD1839. The total TOI median decline from baseline in the European/Australian experiment was -4.50. Interpretability of TOI change over time is constrained by the small number of ovarian subjects in the U.S. experiment. These results emphasise the need of considering HRQOL together with safety and tolerability when evaluating innovative medicines. Future trials using the NFOSI-18 as an HRQOL outcome measure in trials looking at innovative biologic therapy may be able to put the NFOSI- 18's significant change in the TOI among ovarian cancer patients into context.

Discussion

Researchers and clinical professionals now have a new tool for assessing how well advanced ovarian cancer patients respond to treatment thanks to the NFOSI-18. The shortness of the NFOSI-18, focused evaluation of the key symptoms unique to advanced ovarian cancer, and improved adherence to FDA regulatory advice are all advantages. As a result, it could be especially tempting for usage in clinical settings where reducing patient and provider burden is important as well as clinical research where following regulatory instructions is crucial. The NFOSI-18 is patient-centered, which sets it apart from previous HRQOL measures for ovarian cancer. Patients, in addition to doctors, participated in item development and selection by ranking the most significant symptoms.

Conclusion

The preliminary nature of research reporting on the usage of the NFOSI-18 is its main drawback. We do, however, believe that published results using item subsets common to both the FACT-O and the NFOSI-18 can be used to aid in the development of future research using the NFOSI-18 as an advanced ovarian cancer specific HRQOL measure due to its redundancy with the FACT-O, which has been used in a number of published studies. The validity and interpretability of the NFOSI-18 will be further improved by more study employing it. The NFOSI-18 and other NCCN symptom indexes are also thought to be short in nature, but further study is required to see if it's necessary to modify them in order to lessen patient burden in both clinical research and therapeutic therapy contexts. There is currently little data available about how widely the NCCN symptom indices are used in clinical practise settings, both domestically and abroad. It is predicted that when these measurements become more well known, they will be used more often in clinical and research settings. Therefore, ongoing assessment of these measures' adaptability to change, generalizability to patient samples from a wider range of backgrounds, and generalizability across administration contexts (e.g., clinical trials versus clinical practise) represent crucial steps in the future development and establishment of these measures' psychometric properties. Moreover, it will be crucial to regularly update the scales to make sure that they continue to reflect the current priority symptoms given changes in symptom profiles as new treatment and supportive care strategies emerge.

Acknowledgement

Not applicable.

Conflict of Interest

Author declares no conflict of interest.

1. Booth CM, Eisenhauer EA (2012) J Clin Oncol 30: 1030-1033.

, ,

2. Eton DT, Fairclough DL, Cella D, Yount SE, Bonomi P, et al. (2003) J ClinOncol 21:536-543.

, ,

3. Cella D, Cappelleri JC, Bushmakin A, Charbonneau C, Li JZ, et al. (2009) J Oncol Pract 5: 66-70.

, ,

4. Carey MS, Bacon M, Tu D, Butler L, Bezjak A, et al. (2008) Gynecol Oncol 108:100-105.

, ,

5. Reck M, Thatcher N, Smit EF, Lorigan P, Szutowicz-Zielinska E, et al. (2012) Lung Cancer 78:276-281.

, ,

6. Chase DM, Huang HQ, Wenzel L, Cella D, McQuellon R, et al. (2012) Gynecol Oncol 125:315-319.

, ,

7. Wenzel L, Huang HQ, Monk BJ, Rose PG, Cella D (2005) J Clin Olncol 23:5605-5612.

, ,

8. Maisey NR, Norman A, Watson M, Allen MJ, Hill ME, et al. (2002) Eur J Cancer 38:1351-1357.

, ,

9. Chau I, Norman AR, Cunningham D, Waters JS, Oates J, et al. (2004) Multivariate prognostic factor analysis in locally advanced and metastatic esophago-gastric cancer-pooled analysis from three multicenter, randomized, controlled trials using individual patient data. J Clin Oncol 22:2395-2403.

, ,

10. Armstrong DK, Bundy B, Wenzel L, Huang HQ, Baergen R, et al. (2006) NEJM 354:34-43.

, ,

11. Taylor KM, Macdonald KG, Bezjak A, Ng P, DePetrillo AD (1996) Qual Life Res 5:5-14.

, ,

12. Bezjak A, Taylor KM, Ng P, MacDonald K, DePetrillo AD (1998) Cancer Prev Control 2:230-235.

,                 

13. Gill TM, Feinstein AR (1994) JAMA 272:619-626.

,                 

14. Alvarez Secord A, Berchuck A, Higgins RV, Nycum LR, Kohler MF, et al. (2012) Cancer 118: 3283-3293.

, ,

15. Cella D, Rosenbloom SK, Beaumont JL, Yount SE, Paul D, et al. (2011) J Natl Compr Canc Netw 9:268-278.

, ,

16. Basen-Engquist K, Bodurka-Bevers D, Fitzgerald MA, Webster K, Cella D, et al. (2001) J Clin Oncol 19:1809-1817.

, ,

17. Ferrell B, Cullinane CA, Ervine K, Melancon C, Umman GC, et al. (2005) Oncol Nursing Forum 32:1143-1149.

, ,

18. Cull A, Howat S, Greimel E, Waldenstrom AC, Arraras J, et al. (2001) Eur J Cancer 37:47-53.

, ,

19. Greimel E, Bottomley A, Cull A, Waldenstrom AC, Arraras J, et al. (2003) Eur J Cancer 39:1402-1408.

, ,

20. Cella D, Nowinski CJ (2002) Arch Phys Med Rehab 83:10-17.

, ,

21. Yost KJ, Eton DT (2005) Eval Health Prof 28:172-191.

, ,

22. Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, et al. (1982) Am J Clin Oncol 5:649-655.

,                 

23. Jensen SE, Rosenbloom SK, Beaumont JL, Abernethy A, Jacobsen PB, et al. (2011) Gynecol Oncol 120:214-219.

, ,

24. Fairclough DL, Cella DF (1996) Qual Life Res 5:321-329.

, ,

25. Benedet JL, Bender H, Jones H, Ngan HY, Pecorelli S (2000) Int J Gynaecol Oncol 70:209-262.

,