Cachexia, toxicity and the limits of the patient
Patients often die of wasting or cannot tolerate the doses that would work. Treating the patient, not just the tumour, lags far behind.
Cancer cachexia, a syndrome of muscle and fat loss driven by tumour-derived and host inflammatory signals (IL-6, GDF15, activin), affects most patients with advanced pancreatic, gastric and lung cancer and is implicated in a large share of cancer deaths, yet anamorelin in Japan is the only approved drug anywhere and there is none in the US or Europe. Beyond cachexia, treatment-limiting toxicities determine what dose a patient can receive: neuropathy, cardiotoxicity, cytopenias, interstitial lung disease from ADCs, cytokine release and neurotoxicity from cell therapies, and fatigue. Supportive-care research receives a small share of funding relative to its effect on survival and quality of life, and effective interventions such as structured exercise and geriatric assessment are rarely prescribed. Treating the host is a therapeutic target in its own right.
- Cachexia is driven by systemic inflammation and neuroendocrine signalling that tumour-directed therapy does not address.
- Supportive-care trials have no patent-protected asset to fund them and attract little industry investment.
- Toxicity is graded by clinicians on the CTCAE scale, which under-captures patient-experienced symptoms.
- Dose-finding uses maximum tolerated dose, so many regimens start above what most patients can sustain.
- Nutrition, exercise and psycho-oncology are delivered inconsistently and rarely reimbursed as oncology care.
- Pfizer's ponsegromab (anti-GDF-15) produced weight gain and improved activity in a phase 2 trial and is in phase 3.
- Anamorelin (Ono) is approved in Japan for cachexia in lung, gastric, pancreatic and colorectal cancer.
- The Cancer Grand Challenges CANCAN team is dissecting the neural and metabolic circuits of cachexia.
- ASCO published its first cachexia management guideline in 2020, and PRO-CTCAE (NCI) provides a validated patient-reported toxicity instrument.
- Cardio-oncology and exercise-oncology services (including the CHALLENGE trial of structured exercise in colon cancer) are formalising host-directed care.
- Scalp cooling, biosimilar growth factors and ILD-monitoring algorithms for ADCs are reducing treatment-limiting toxicity.
A low dose of an old, inexpensive tablet improved appetite and weight in a randomised trial of people with advanced cancer. It could be used almost everywhere tomorrow.
Wasting and side-effects kill or stop treatment for a large share of patients but attract almost no dedicated funding. This would create a standing programme for them.
Malnutrition is the commonest untreated complication in cancers of the gut, throat and pancreas. Putting a dietitian in the meeting where treatment is decided means it is seen and treated before chemotherapy starts, not after weight has been lost.
For treatments of symptoms like nausea, fatigue or neuropathy, each patient can try the drug and a placebo in alternating periods and see what works for them; pooling many such personal trials gives a population answer too.
A supportive-care ARPA would be a well-funded, milestone-driven agency that develops drugs for nausea, nerve damage, mouth sores, fatigue and brain fog from cancer treatment, which the market has largely ignored.
Slow weight loss and falling daily activity are the first signs of cancer wasting, and both can be measured at home. An alert could bring help months earlier.
A new antibody blocks the hormone that makes people with cancer lose appetite and weight. Weight regained as muscle, not fat, needs exercise and protein alongside it.
An Indian trial found a cheap antipsychotic pill in very low dose improved appetite and weight gain in patients with advanced stomach, lung and pancreatic cancer. It needs confirming and adopting worldwide.
Chemotherapy doses are calculated from height and weight, a formula from the 1950s. Doses based on actual muscle mass may cause fewer severe side-effects.
Getting fitter and better nourished before an operation reduces complications and speeds recovery. It is cheap, but only a few hospitals do it.
A drug that improves appetite and lean weight in cancer wasting is approved in Japan but almost nowhere else. Reviewing the existing evidence could widen access quickly.
A large trial showed a structured exercise programme improved survival after bowel cancer. Almost no health system pays for it, so almost no patient gets it.
Regulators are unsure what to accept as proof that an anti-wasting drug helps. Agreeing on a simple measure such as stair climbing would unblock the whole field.
Every staging scan contains a precise measure of muscle mass that nobody looks at. Software could report it automatically and flag patients heading for wasting.
Wasting has several causes. Measuring the specific hormone in each patient's blood would put the right patients into the right trial instead of mixing everyone together.
Muscle is an immune organ as well as a movement organ. Building it during immunotherapy might improve how well the treatment works, not just how patients feel.
The wasting that kills many cancer patients has had no effective drug. New antibodies against GDF-15 restored weight in early trials. Combine them with exercise and nutrition and test properly.
Hospitals have fast, standard responses to sepsis and heart attacks. Cancer wasting has no such pathway, so it is noticed late and treated inconsistently.
Pages like this
not linked directly; found by shared links- TechnologyNutrition support and cachexia management
Shares Enteral and parenteral nutrition support, Malnutrition screening tools (MUST, NRS-2002, MST, PG-SGA), Resistance training and protein for cachexia and sarcopenia, A dietitian in every gastrointestinal and head and neck tumour board.
- TechnologyCachexia-directed therapy (GDF-15 blockade)
Shares ROMANA 1 and ROMANA 2, Ponsegromab phase 2 in cancer cachexia, Resistance training and protein for cachexia and sarcopenia, Cancer cachexia.
- TermBody composition (lean mass, fat mass, visceral fat)
Shares Read muscle loss automatically from scans patients already have, ROMANA 1 and ROMANA 2, Ponsegromab phase 2 in cancer cachexia, Sarcopenia.
- PathwayCancer cachexia
Shares ROMANA 1 and ROMANA 2, Ponsegromab phase 2 in cancer cachexia, Resistance training and protein for cachexia and sarcopenia, Cancer cachexia.
- BottleneckToxicity and quality of life are undervalued
Shares An ARPA-style programme to develop supportive-care drugs nobody else will, Catch wasting early with a smart scale and a step counter, Scalp cooling, A dedicated programme for cachexia and treatment toxicity research.
- Key paperASCO 2021 guideline: how to recognise and manage the immune-related side effects of checkpoint inhibitors
Shares ICANS (neurotoxicity), Cardio-oncology, Immune-related adverse events (irAEs), Cytokine release syndrome (CRS).
- Key paperCHALLENGE: a structured exercise programme after chemotherapy improves survival in colon cancer
Shares Combine the new anti-wasting antibody with exercise and protein, Pay for supervised exercise the way we pay for drugs, Structured exercise prescribed like a drug in all curative-intent cancer care, Exercise & lifestyle oncology.
- BottleneckSurvivorship and late effects are neglected
Shares Scalp cooling, Trastuzumab cardiotoxicity, Four weeks of training and nutrition before major cancer surgery, as standard, Pay for supervised exercise the way we pay for drugs.