Thanks Dr Harrell.
To understand this clearly I will go through the example study protocol. Please do correct any amateurish mistakes I make along the way.
Design
Two group parallel randomized trial with equal allocation in each group.
Participants
Patient with node negative cervical cancer planned for definitive radiotherapy.
Interventions
Control Arm : Pelvic external beam radiotherapy to a dose of 45 Gy in 25 fractions over 5 weeks along with 5 cycles of concurrent chemotherapy and brachytherapy.
Experimental Arm : Pelvic external beam radiotherapy to a dose of 41.4 Gy in 23 fractions over 5 weeks along with 5 cycles of concurrent chemotherapy and brachytherapy.
Outcome
Difference between Control Arm and Experimental arm at 2 years for survival and patient reported outcomes.
Endpoint
A composite patient reported endpoint created using the EORTC QLQ C30 and CX24 scales.
The EORTC QLQ C30 questionnaire has 30 items related to the following domains:
- Global health QoL
- 5 functional domains
- 8 symptom domains
- 1 on financial difficulty
Recently Geisinger et al have also proposed a summary score for EORTC QLQ C30 incorporating information from 27 of 30 items and ranges between 0 - 100 with higher scores indicative of a better outcome (better function and lower symptoms).
The EORTC CX24 questionnaire has 24 items that was designed to obtain the symptom burden of patients with cervical cancer which gathers additional information on:
- Symptom experience (13 items)
- Body image
- Sexual / vaginal function
- Lymphedema
- Peripheral neuropathy
- Menopausal symptoms
- Sexual activity and sexual enjoyment
Note that the proposed PROM questionnaire set captures information on most of the common symptoms patients of cervical cancer face due to the disease and its treatment. Each of the domains are again scaled on a score of 0 - 100 where 100 represents the best outcome.
Additionally there are the following clinical outcomes of interest:
- Death due to any cause (anticipated in about 10% - 15% patients at 2 years)
- Distant metastases (anticipated in about 10 - 20% of patients at 2 years)
- Para-aortic nodal recurrence (anticipated in about 5 - 8% patients at 2 years). A portion of these recurrences can be salvaged (approximately 20%)
- Pelvic nodal recurrence: anticipated to be about 3 - 5% at 2 years. This is more difficult to salvage than para-aortic nodal recurrence but local treatment approaches like SBRT.
- Local recurrence: anticipated to be about 2- 3% at 2 years. If isolated patients can be salvaged with exentrative surgery
Note that the local recurrence rates are unlikely to be different as the dose received by the cervix will be kept as the same with the use of brachytherapy.
Also noteworthy is that patients may have various combinations of recurrences
The ideal state would be one where the patient has the highest PROM with none of the recurrences.
Question
We generally have PROMs completed weekly during the course of treatment (so 5 weeks). After that patients can complete PROMs on each followup visit which would be done three monthly for the first 2 years. At each visit we have:
- If patient is dead or alive
- Patient has recurrence at any of the specified site or not (multiple sites possible).
- PROM scores of the:
a. 15 item summary score from EORTC QLQ C30 (0 - 100)
b. 13 item symptom experience score from EORTC QLQ CX24 (0 - 100)
c. Additional items from EORTC QLQ CX24 - each with score 0 - 100
d. Global QoL from EORTC QLQ C30 (0 - 100) - this is a very poor and coarse differentiator and it takes a lot to make it change.
How can we combine these to make the composite endpoint ? Also a weekly assessment of the QoL during followup will not be practical. However a three monthly or even a monthly assessment is feasible.