Ovarian cancer continues to be a challenge to treatment teams with approximately 20 new diagnoses in the UK each day. Survival at 10 years post-diagnosis is now improving and currently sits at 35% (Cancer Research UK, 2021). Ovarian cancer is a complex disease where traditional treatment pathways include surgery where possible, and platinum-based chemotherapy. However, most recently with an understanding of genetics and the molecular basis of cancer, some targeted therapies have emerged, including anti-angiogenesis agents such as bevacizumab and now poly (ADP-ribose) polymerase inhibitor (PARP) inhibitors such as niraparib (Mittica et al, 2018).
The utility of chemotherapy treatment approaches for ovarian cancer were primarily based on the number of disease-free months between regimens and judgements based on sensitivity to platinum compounds, whereas now, it is recommended platinum-based chemotherapy should be offered to all patients with a reasonable chance of responding to this therapy (Baert et al, 2021). Therefore, the disease-free interval is only one of the factors now considered as bevacizumab increases the response to chemotherapy irrespective of the cytotoxic regimen and can be valuable in patients with an urgent need for symptom relief (such as pleural effusion, ascites). PARP inhibitors are the newest area of focus and are a welcome addition to the treatment pathway following platinum therapy.
PARP inhibitors and links to BRCA genes
PARP inhibitors have recently entered the treatment pathway for gynaecological cancers; primarily ovarian, fallopian tube and peritoneal cancers (The National Institute of Health and Care Excellence [NICE], 2018).
PARPs are proteins that help damaged cells repair themselves and this is a normal physiological process to maintain good health. PARPs are vital for our cells' ability to repair single-stranded DNA breaks. If PARPs are blocked in healthy cells, this creates DNA damage that they repair, using other proteins. However, cancer cells often have defects affecting DNA repair processes. Therefore, blocking PARPs in cancer cells can cause excessive DNA damage that leads to their death (Vickers, 2018).
A recent further change is the importance of breast cancer gene (BRCA) status as a new prognostic factor now widely used in the management of ovarian cancer. BRCA genes are present in all individuals and are essential for normal cell growth and control. They are known as tumour suppressor genes as their role is to repair double-stranded DNA, ensuring healthy function. Any mutations of the BRCA genes will prevent healthy repair known as homologous recombination and a fault that may lead to cancer could occur (Vickers, 2018).
PARP proteins focus on single-stranded DNA breaks, which if left will become a double-stranded break and require BRCA proteins to repair the cells. If BRCA genes are faulty and they are unable to repair effectively, so the cancer continues to develop and grow.
BRCA status is an important prognostic factor in ovarian cancer. About 1.2% of women in the general population will develop ovarian cancer at some time during their lives. However, this greatly increases to 39%–44% for women who inherit a harmful BRCA1 genetic variant and 11%–17% of women who inherit a harmful BRCA2 variant (National Cancer Institute [NCI], 2021).
These innovations were the focus of a pivotal trial known as NOVA. This was a phase II randomised trial examining the value of niraparib, a new PARP inhibitor (Mirza et al, 2016). Niraparib was found to significantly improve progression-free survival in germline BRCA mutated and non-germline BRCA mutated patients.
In the NOVA trial patients in the niraparib group had a significantly longer median duration of progression-free survival than did those in the placebo group, including 21.0 vs. 5.5 months in the gBRCA cohort (hazard ratio: 0.27, 95% confidence interval [CI], 0.17 to 0.41), as compared with 12.9 months vs 3.8 months in the non-gBRCA cohort. The most common grade 3/4 toxicity reported in the niraparib group were thrombocytopenia (in 33.8%), anaemia (in 25.3%), and neutropenia (in 19.6%), which were managed with appropriate dose modifications (Mirza et al, 2016). Further studies of additional PARP inhibitors have shown similar results.
Treatment pathway
Niraparib is now available to women who have had a response to their initial chemotherapy and is given as maintenance therapy (NICE, 2018).
The initial starting dose is 300 mg by mouth daily though there is a concern to consider a starting dose of 200 mg in those women of 70 kg and under (Royal Pharmaceutical Society, 2020). A blood test is required each week for a month thereafter. As well as checking the blood profile, an assessment of toxicities is required, specifically thrombocytopenia. There is no dose reduction for hepatic impairment and the drug can be maintained in the presence of mild to moderate renal failure. There are some drug interactions to be aware of, including clozapine, theophylline, opinirole and cyclosporin, which might potentiate the effect of niraparib, as such prescribers should check and coach patients accordingly. Treatment should continue until disease progression or toxicity impacts activities of daily living or performance status.
As this is a new maintenance therapy, further understanding of the toxicity profile of the pathway is needed to potentially determine if a nurse-led pathway was appropriate as outlined in the United Kingdom Oncology Nursing Society (UKONS) position statement for best practice in nurse-led clinics (Lennan et al, 2012).
Audit
As this was a new therapy, an audit of routine practice was carried out as required following a technical appraisal by NICE (2021). The audit aimed to collect information describing the routine practice, tolerance to treatment and management of niraparib maintenance therapy within the regional network to see if results presented similar findings to the pivotal NOVA study.
Method
A data collection tool was created and the authors each collected retrospective data from four hospitals within the region, using case notes of patients who received treatment with niraparib between January 2018 and September 2019. A spreadsheet was created for analysis purposes.
- Data collected included:
- Weight
- BRCA mutation status
- Adverse events (haematological and non-haematological)
- Duration of treatment
- Dose.
Results
Table 1 represents the characteristics of patients included in the audit
Table 1. Details of patients
| No of patients | 25 |
| Age range | 48-79 |
| BRAC negative | 22 |
| BRAC positive | 1 |
| Not tested | 2 |
| Mean baselines platelet count | 279 (200-516) |
| Mean weight | 77.05 kg (47.5-125 kg) |
| Dose | < 77 kg 200 kg> 77 kg 300 mg30% reduction dose reduction at initiation of treatment at oncologists discretion |
Adverse events
The treatment was very well tolerated with fatigue and myelosuppression being the main concern. These are outlined in Table 2
Table 2. Reported toxicities
| Adverse event | Any gradeNumber of patients | Grade 3 or 4Number of patients |
|---|---|---|
| Sore mouth | 3 (all grade 1) | 0 |
| Oral candidiasis | 1 (all grade 1) | 0 |
| Thrombocytopenia | 6 | 0 |
| Anaemia | 5 | 2 |
| Neutropenia | 2 | 1 |
| Fatigue | 2 | 1 |
| Constipation | 8 | 4 |
| Insomnia | 3 | 0 |
| Nausea | 3 | 0 |
| Rash | 3 | 1 (severe eczema, no improvement despite dose interruption, restarted at same dose) |
| Misc | 1 | 0 |
Dose
Given the ability to alter the dose but remain within a therapeutic index it was important to examine actual doses tolerated. Figure 1 outlines these results.
Figure 1 represents the patients by dose against month on treatment. Results in the main did show longevity of treatment corresponding to a 200 mg dose.
A reduction in platelet count was noted over time in all patients but not to levels of concern ie less than 50 per microlitre. Figure 2 maps the effects on the platelet count over time on therapy.
Discontinuation
Several reasons were detailed as to why niraparib was discontinued, these included:
- Progressive disease 48% (12) of cohort
- 20% (5) required withdrawal of treatment due to significant toxicity namely fatigue with a reduction in quality of life
- 32% (8) were continuing on treatment with niraparib at the end of the data collection period (including a patient who is BRCA positive).
Discussion
The findings from the audit were consistent with the results of the NOVA study offering reassurance to the treating teams. The main toxicities were myelosuppression and fatigue, which were manageable with routine monitoring and clear advice to patients. Anaemia was also noted but this did not necessarily correspond to those reporting fatigue which is again consistent with routine practice. The oncologists were comfortable using 300 mg as a starting dose but equally this audit confirmed to us a 200 mg dose does not appear to reduce the duration of response in suitable patients in line with later analysis from the NOVA trial (Mansoor et al, 2020).
Niraparib and other PARP inhibitor drugs are now standard therapy for appropriate gynaecological patients who have responded to platinum therapy. This audit has demonstrated safe practice and informed the team of common toxicities in a real clinical setting. For patients with ovarian cancer, this treatment has offered a positive proactive therapy rather than simply waiting to relapse like previously.
However, the success of these drugs has created some workforce challenges. The introduction of these drugs is an addition to the treatment pathway with a corresponding impact on activity, workload and capacity. The duration of our data collection involved just under 150 extra outpatients slots for review, ~150 phlebotomy appointments and laboratory activities and ~150 dispensing events.
A creative solution was needed, and a nurse-led review clinic at the cancer centre was developed to specifically monitor the patients on PARP inhibitors and where possible to do this remotely, that is without the patient having to attend the hospital. This is in line with the best practice statement from UKONS (Lennan et al, 2012).
Nurse-led clinics are nothing new and were first postulated in mainstream policy in The NHS Cancer Plan (2000) and reinforced in the Cancer Reform Strategy (2007). Later in 2010, the Prime Minister's independent commission on nursing and midwifery stated, more direct access to nurse-led services would improve cost-effectiveness and health outcomes, and remove system blockages that delay appropriate care (Commission on the Future of Nursing and Midwifery in England, 2010). Furthermore, looking specifically at the management of patients with cancer, a systematic review found nurse-led care to be more beneficial than doctor-led care in terms of physical outcomes, patient satisfaction, and care organisation, and that specialised cancer nursing improves patients' ability to cope with their cancer. Crucially, the report notes that long-term survival is not impaired by nurse-led care, compared with the traditional medical model (Caird et al, 2010).
A decade on from when the independent commission nurse-led clinics were established, no singular model of nurse-led chemotherapy reviews fits all but will need adaption in local areas (Commission on the Future of Nursing and Midwifery in England, 2010). However, it is important nurses do not seek to duplicate the medical model or attempt to work in isolation from multidisciplinary teams (MDT). Nurse-led chemotherapy review provides an opportunity to add nursing values to the wider chemotherapy service, with holistic care and family support, addressing living with uncertainty complemented by the aspects of advanced nursing practice (Lennan, 2012).
The cancer centre included in this audit created a new pathway involving:
- The oncologist decided a PARP drug was indicated and commenced therapy
- The advanced nurse practitioner organising a home blood test, a telephone assessment and if appropriate arranging a supply of drugs each month
- A review by the oncologist is arranged every 3-6 months following monitoring scans.
This PARP clinic is suitable for the nurse-led service as the nurse can talk through fatigue management, implications of blood results and activities of daily living. To be clear it does not replace the vital specialist service provided by the gynaecology clinical nurse specialist (CNS) who remain the key worker and nursing specialist in the field. The CNS continues to support the patient and family as with every other patient and there are open communication channels from the clinic for specialist advice. Any signs of relapse including rising tumour markers (CA125) or development of ascites would necessitate a referral or discussion back with the oncologist.
This arrangement has worked very well thus far and has been expanded to include the new PARP inhibitors but as discussed earlier it is important for nurses to not work in isolation and only as part of the MDT. Additionally, this clinic does not address the workload for the pharmacy teams as community dispensing at this stage is not appropriate. A three month supply has been established in some patients who have been having ongoing therapy for 3 months, monthly blood tests and assessments are continued. Patients have reported great satisfaction with the service citing time-saving and a reassurance that referral back to the oncologist was available.
The success of these drugs and longevity of response means this workload will continue to increase and others could consider a nurse-led approach. Guidance is provided in a position statement by the United Kingdom Oncology Nursing Society (Lennan et al, 2012), which is currently under review. This audit has confirmed and given confidence to the MDT the suitability of managing the patients on PARP inhibitors in this way.
Conclusion
This is a small retrospective audit of local practice to confirm real-world practice reflecting the findings of the NOVA trial. It does also represent findings from only one PARP inhibitor – niraparib, others have since been licensed.
The findings were consistent with the results of the NOVA study offering reassurance to the treating teams. The main toxicities were myelosuppression and fatigue, which were manageable with routine monitoring and clear advice to patients. Anaemia was also noted but this did not necessarily correspond to those reporting fatigue, which is consistent with routine practice. Given the tolerable side effect profile and the relative wellness of the patient cohort, this treatment lends itself very well to nurse-led care where in addition to the task of supplying medicines the focus can be on well being and living with and beyond cancer.
In conclusion, managing this group of patients in this way is:
- Efficient and safe
- Suitable for a nurse-led model
- Highly satisfactory to patients.
This paper has confirmed the suitability of this class of drugs to be managed in a nurse-led pathway and others might like to consider this approach ensuring nurses always work within an MDT approach. Local adaptation will be needed in determining the level of nurses required to take responsibility for the clinic.
Key Points
- Niraparib is a safe addition to the treatment pathway for women with ovarian cancer
- The maintenance pathway is suitable for nurse led care
- Patients can be cared for safely in a remote setting
- The treatment regimen is very well tolerated by women.
CPD reflective questions
- Think about how you might support the ongoing needs of patients being supported remotely
- How might your practice avoid being isolated from the main MDT
- How would the nurse supporting this clinic complement the CNS service.