When oncologists cannot agree, where does that leave the patient?
A little while back, I wrote about the next step in my sister's long battle with her brain tumour, and the striking fact that the chemotherapy regimen she was due to receive after her radiotherapy (which is currently ongoing) consists of three drugs that were approved many decades ago.
It is generally accepted (and indeed listed in the guidelines, to which I will refer back shortly) that there are two main adjuvant chemo treatment options for grade 2 oligodendrogliomas (those harbouring IDH mutations and 1p/19q codeletions), which is the type of cancer my sister was diagnosed with. Other than PCV, there is also temozolomide (TMZ). While TMZ is technically "newer" (it was first approved in 1999) than PCV, and comes with the advantages of being a single oral drug regimen (as opposed to PCV, which consists of 2 oral drugs and an IV drug) that is generally relatively well-tolerated, its efficacy data in the context of this specific type of brain tumours isn't as convincing as that of PCV. For example, see the below Kaplan-Meier curves, taken from a 2018 review by K. Hafazalla et al [1]:
Kaplan-Meier curve showing superimposed studies that assessed overall survival of their patients with low-grade glioma based on 1p/19q status. “Intact” and “codel” refer to intact and co-deleted chromosome 1p and 19q status.
It is important to note that these curves are taken from a systematic review and do not include any head-to-head comparisons. Also, the differences observed in the Kaplan-Meier curves, while trending towards better OS for PCV for codel patients, are not very pronounced. Nevertheless, there appears to be a larger volume of higher-quality data to support the use of PCV in this setting (see further down this article for more details on this point).
Two hospitals, two opinions
The doctors at the hospital where my sister's second craniotomy was conducted (let's call it hospital A) were the ones who took the iniative to recommend adjuvant radiotherapy (RT) followed by chemotherapy, after several rounds of consultation with the multi-disciplinary team (MDT). It was this MDT that settled on 28 days of RT followed by 6 cycles of PCV.
As hospital A is relatively far from where my sister lives, and the RT would involve daily administrations, they agreed with my sister that she could be treated at hospital B, much closer to her home. Even though hospital A is larger and sees more brain cancer patients, hospital B also has access to the necessary equipment and drugs to oversee the full treatment course. So far, all clear.
Last week (during the second week of RT), my sister received a call from hospital B, saying that the treating oncologists had recently attended a conference and as a result decided that there was no reason to subject her to the potential side-effects of PCV, that TMZ was most likely equivalent in its efficacy, and that they would therefore be proceeding with TMZ after the radiation. When my sister questioned this, she was told "not to worry too much about this" and basically just accept that the doctors knew what was best for her.
My advice to my sister was to inform hospital A of this decision, and to get their opinion on the proposed course of action. They wrote back quickly, saying that while TMZ wasn't necessarily wrong, they were sticking with their view that PCV was the best option, and included a paper that summarised the reasons why. I suggested to my sister to forward this response to hospital B, and to also include in her response some additional papers and charts, such as the one above.
Shortly thereafter, my sister received a call from hospital A. They had had another consultation with the MDT, in which they reiterated that PCV was the best option, and asked my sister to inform the oncologist at hospital B of this decision.
The following day, my sister had a (scheduled) meeting with the oncologist at hospital B. In response to her sharing the recommendation from hospital A, the oncologist at hospital B explained that while there was indeed some data showing potential superiority for PCV, none of those trials were conclusive or directly comparable with the TMZ trials, and hence there was no reason to proceed with PCV over TMZ. Their position was that if other large hospitals abroad were using TMZ, then that was reason enough for them to do the same. The decision would ultimately be with my sister, leaving her to choose between two options based on two opposing opinions from the two different hospitals involved in her cancer management.
Data and guidelines
When I was informed of this, I looked up the NCCN (National Comprehensive Cancer Network) guidelines again. These guidelines, last updated in March 2023 [2], clearly state that PCV is a category 1 recommendation for high-risk, IDH-mutant, 1p19q co-deleted oligodendrogliomas, whereas TMZ is a category 2A recommendation (the one exception being for patients with a Karnofsky Performance Score below 60, which is not the case for my sister). These recommendation categories are defined as follows:
Where does that leave us? On the one hand, the recommendation for PCV is based on a higher level of evidence than the recommendation for TMZ. On the other hand, there is uniform consensus that both options are seen as "appropriate". My view (and the NCCN's view) is that options with higher degrees of evidence should be prioritised (unless there is a good reason not to do so).
This is what the NCCN guidelines state (my emphasis):
Following surgery, RT followed by PCV is a category 1 recommendation for patients with WHO grade 2 glioma who are considered to be at high risk for tumor progression, based on the practice-changing results from the RTOG 9802 study [...] There is currently a lack of prospective randomized phase 3 data for the use of radiation and TMZ in patients with low-grade glioma, but interim data from the phase III CATNON trial illustrate that there is a benefit from adjuvant TMZ in patients with newly diagnosed 1p19q non-codeleted WHO grade 3 gliomas. Therefore, RT followed by adjuvant TMZ is a category 2A option. [...] Because PCV is generally a more difficult chemotherapy regimen to tolerate than TMZ, it may be reasonable to treat an elderly patient or a patient with multiple comorbidities with RT and TMZ instead of RT and PCV, but there are currently no data to show that doing so would result in similar improvement in OS.
Key lessons from this experience
(Disclaimer: please note that my sister gave her consent for the above information to be shared. Hospital names have been withheld in the interest of confidentiality; furthermore, the objective of the above was certainly not to evaluate the quality of care of individual institutions, as it is impossible to argue which approach is the "correct" one, based on currently available data.)
References
[1] Hafazalla K, Sahgal A, Jaja B, Perry JR, Das S. Procarbazine, CCNU and vincristine (PCV) versus temozolomide chemotherapy for patients with low-grade glioma: a systematic review. Oncotarget. 2018 Sep 14;9(72):33623-33633. doi: 10.18632/oncotarget.25890. PMID: 30263090; PMCID: PMC6154749.
[2] NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) Central Nervous System Cancers Version 1.2023 — March 24, 2023 (retrieved 31 October 2023)
Thank you for sharing Pieter. I am thinking of your family . I have experienced very similar scenarios over the last years as a caregiver. The weight of the decision, the uncertainty and the deep fear of making the right decision when there are conflicting opinions plays a heavy toll on the patient and their loved ones - on top of the already difficult journey. Although differing opinions often exist and there is more often than not not one right way - measures must be take in the communication with patients to avoid as best we can to not make a difficult journey even more difficult.
Senior Director - Global Oncology Monitors at Ipsos
1yThank you for sharing this personal experience, Pieter. Unfortunately, I think many of us experienced a situation where different opinions given by experts in their field left us more confused than ever. When important choices relate to cancer treatments, though, there should definitely be more effort towards a clear communication between a patient and a physician.