Fever in advanced cancer can prove to be a challenge. The main issue concerns the question of decision making pertaining to escalation especially in the absence of localizing signs. There is also the nagging question of a lack of standard protocol while deciding the need for antibiotics. Should one perform baseline procalcitonin for every patient in whom empirical antibiotics are being considered?

This brings us to the question of cancer-related fever, which is considered a diagnosis of exclusion.

The Naproxen challenge test, which involves prescribing naproxen sodium 550 mg two times daily to a patient with fever, and takes defervescence as a marker of response acquires a completely different dimension in those with chronic kidney disease stage 5 on regular dialysis, given the paucity of safe treatment options.

Given that Naproxen may be contraindicated in this setting, and has particularly grave implications for residual renal function in stage 5 CKD, made me go through the existing guidance on the topic for safe available options. A cursory reading of the existing literature throws up important insights. A review by Baker et al states that NSAIDs should be considered absolutely contraindicated in stage v chronic kidney disease except under the circumstances of palliative care. Note that this guidance does not state those approaching dying or those in the last few days of their life or the imminently dying – it says palliative care. And the breadth of patients being referred for palliation might encompass all the aforementioned categories. This statement sheds important light on the implications of a patient being referred to palliative care and raises serious questions on whether renal and hepatic dose modifications are given due consideration in advanced cancer especially in those receiving palliative care.

The fact that dialysis might not prove to have a beneficial effect on survival in those with advanced cancer and multiple comorbidities has been discussed earlier, but that palliative dialysis is a category unto itself cannot be ignored. There is also the existence of various documents that guide anticipatory prescribing in end stage chronic kidney disease and end stage hepatic disease which put due emphasis on recognition of declining organ function to optimize prescribing. That the Palliative Care Formulary offers specific guidance on these scenarios is difficult to ignore.

But this is a different discussion, and concerns the implications of prescribing for the palliative patient. The unresolved question remains whether the use of medications in the palliative setting nullifies the need for hepatic and renal dose modifications. It is important to understand that the end of life period might encompass a length of time equal to six to twelve months before the patient’s demise and that assuming that dosing need not take organ function into consideration, strikes at the very heart of foundational teaching in Internal medicine and throws up multiple questions pertaining to whether the discipline has devolved into a hagiographic construct which tends to ignore basic tenets of rational, organ function concordant prescribing.

Is it safe to assume then that his may be justified merely on the basis of lack of resources? Would I deny fentanyl or buprenorphine in the setting of renal dysfunction just because of the financial and panresource constrained setting, that one is expected to be associated with? Two grim realities come to the fore, the insistence on positioning fentanyl and buprenorphine as reserve drugs only and the tendency to ignore patient safety by refusing to consider basics of dose modification in prescribing at the end of life.

There is also the need to distinguish the imminently dying from those at the end of life. While, dose modification may not be presumed to be essential to responsible prescribing once a patient enters a terminal stage when death seems foreseeable, and doctrine of double effect holds centrestage, it is still important to titrate any kind of symptomatic treatment to response. Personally, what remains essential to this Palliatrist, is the patient’s sensorium and his ability to respond to his family members (something that might be considered an irrevocable part of the shared dying experience).

Editor’s take

In my training, at a time when there was an ongoing struggle to understand the lack of prevailing safeguards and comprehend the reasons for gatekeeping by healthcare professionals who were expected to provide due guidance for prescribing at the end of life, my insistence on calculating creatinine clearance for all my patients proved to be a boon in disguise. It led me to engage with questions of responsible prescribing and renal titration of important medications. The realization that the conversation around choice of appropriate drug was to occur in the background of a paucity of available resources was never lost on this clinician. So if the formative question involved understanding dose modification of zoledronic acid as per creatinine clearance in the prevention of skeletal related events in those with metastatic bone disease, the very next involved the choice of bisphosphonate in renal dysfunction. Could I use Ibandronic acid, in the absence of denosumab, and would increasing the duration over which it was infused, expected to have a protective effect on renal function?

The fact that this engagement could be met with resistance was also evident and somehow formed the basis of a movement away from a mainstream that believed in propagation of less-well nuanced and possibly unsafe decision making in the name of an oversimplification (for which no accountability was sought). These questions concerning dose titration touch upon various issues which form the basis of safe practice in palliative medicine and not addressing them risks relegating the discipline to a category of broad specialty rather than the subspecialty designation, which is what it rightfully deserves.

For the patient in question, paracetamol was continued and advised to be used regularly in analgesic doses (which were expected to provide antipyretic cover too). The family who were understandably distressed with the radiological diagnosis of advanced malignancy, and were yet to make a decision on whether to undergo a repeat biopsy (previous two aspirates had yielded granulomatous inflammation only), given the deteriorating general condition were explained the risks associated with naproxen use and advised to continue regular dialysis.

References

Baker, M., & Perazella, M. A. (2020). NSAIDs in CKD: Are They Safe?. American journal of kidney diseases : the official journal of the National Kidney Foundation, 76(4), 546–557. https://doi.org/10.1053/j.ajkd.2020.03.023

Roy, P. J., Weltman, M., Dember, L. M., Liebschutz, J., Jhamb, M., & HOPE Consortium (2020). Pain management in patients with chronic kidney disease and end-stage kidney disease. Current opinion in nephrology and hypertension, 29(6), 671–680. https://doi.org/10.1097/MNH.0000000000000646

Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group (2024). KDIGO 2024 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. Kidney international, 105(4S), S117–S314. https://doi.org/10.1016/j.kint.2023.10.018

Somerset NHS Foundation Trust. (2024, January). Somerset guidance on anticipatory prescribing in renal failure at end of life (Version 1.0). Somerset NHS Foundation Trust.

Wilcock, A., Howard, P., Toller, C. S., Droney, J., & Charlesworth, S. (Eds.). (2025). Palliative care formulary (9th ed.). Pharmaceutical Press.

Disclaimer

Artificial intelligence tools, primarily Claude (Anthropic), have been employed for language refinement. They do not replace critical scholarship, clinical experience, or editorial judgment. Final responsibility for all interpretations, factual accuracy, originality of synthesis, and the quality of the published material rests entirely with the Founder and Editor.