Reporting harms more transparently in trials of cancer drugs

We agree with many of the sentiments expressed by Gyawali et al in their article “Reporting harms more transparently in trials of cancer drugs”. In particular, we agree that the incidence and severity of adverse events should be reported accurately and objectively, using recognised scales such as the NCI CTCAE (a five-point scale in which Grade 5 indicates a fatal outcome). We also agree that many drugs used in oncology have toxicity profiles that would not be acceptable in other medical conditions, that it is important to assess quality of life/patient-reported outcomes in randomised studies, and that only individual patients can decide what is acceptable or tolerable for them.

However, we do not agree that descriptive terms (such as acceptable, manageable, feasible or tolerable) should be eliminated from oncology trial publications. As long as the meaning is clear and substantiated by data, it seems reasonable to use such terms in discussions or when succinctly summarising the overall safety data. Nor do we agree that such descriptive terms automatically imply a down-playing of harms. Furthermore, we feel that analysing individual words or phrases out of context is over-simplistic and potentially misleading.

Using the examples provided by Gyawali et al:

• The full sentence used in the discussion section of the ribociclib study publication is, “Most patients had an acceptable adverse-event profile with long term administration of ribociclib plus letrozole, with 7.5% requiring permanent discontinuation of both ribociclib and letrozole because of similar adverse events and similar percentages because of decisions made by either patients or physicians in the two groups” (1).

The full sentence makes it clear that the adverse event profile was considered acceptable based on rates of physician and/or patient-instigated treatment discontinuation, which were similar in the experimental and control arms. When viewed in context, the phrase, "Most patients had an acceptable adverse-event profile" does not appear to downplay the harms of ribociclib.

• The full sentence used in the discussion section of the tasquinimod study publication is, “The tolerability of tasquinimod was good overall, and the vast majority of patients were able to escalate to the maximum 1-mg/day dose according to the pre-defined schedule” (2).

In this trial, individual patients underwent dose escalation over a 6-week period and, earlier in the paper, the authors indicate that 82% of patients escalated to the target dose (1 mg/day) in the tasquinimod arm versus 92% of patients in the placebo arm. The statement when viewed in its entirety and in context seems to be a reasonable summary of the data and in no way underplaying the harms of tasquinimod.

• The concluding paragraph in the publication of liposomal irinotecan in pancreatic cancer starts with the sentence “In conclusion, the results of this phase 3 study show that nanoliposomal irinotecan in combination with fluorouracil and folinic acid extends survival and improves other efficacy variables in patients with metastatic pancreatic ductal adenocarcinoma previously treated with gemcitabine-based regimens, and has a manageable and mostly reversible safety profile.”

Gyawali et al indicate that this is incompatible with the fact that five treatment-related deaths occurred in the “intervention arm”. However, the study included two intervention arms – nanoliposomal irinotecan monotherapy and nanoliposomal irinotecan plus fluorouracil and folinic acid. Four of the five treatment-related deaths occurred in the nanoliposomal irinotecan monotherapy arm and indeed, toxicity in this treatment arm was considerably greater than in the combination arm and the control arm, consistent with the higher doses of nanoliposomal irinotecan used. The difference in toxicity (based on a range of parameters) and quality of life between the combination arm and the control arm was much smaller and this is described in detail in the publication. Viewed in its entirety and in context, this sentence does not seem to underplay the harms of nanoliposomal irinotecan when given in combination with fluorouracil and folinic acid (the regimen supported by the authors of the NAPOLI trial publication).

Although we give our interpretation of the three examples above, it is pertinent to note that all three papers would have undergone peer review before publication (as would all the papers in the prestigious journals selected for review by Gyawali et al). It is highly unlikely that peer reviewers (undoubtedly including practising oncologists) would have allowed misleading or unsubstantiated claims to be published in these journals.

Finally, the harms of therapeutic agents cannot be viewed in isolation. The condition being treated and the efficacy of the product have a bearing. A patient with cancer might well accept greater side effects from a new therapy if there is the prospect of benefit in terms of progression-free or overall survival.