Stage 4 to No Evidence of Disease

No evidence of disease means that scans, examination and blood tests currently detect no cancer. It is a statement about the limits of measurement. Imaging cannot see microscopic disease, so NED is not automatically the same as cure — though for some cancers, a long enough NED interval becomes strong evidence of one. What NED means in a particular case depends on the cancer type, the treatment given and how long the interval has lasted, which is a question worth asking directly.

Complete response is the related term used during treatment: all measurable disease has disappeared. It can be temporary or lasting.

NCI ran an Exceptional Responders Initiative specifically to study people who did far better than the trial they were in predicted. The working definition was concrete: a complete or partial response lasting at least six months to a treatment in a setting where fewer than one in ten patients respond, or a response to a drug not generally effective for that disease. A feasibility search of phase 2 trials from 2002 to 2012 found roughly a hundred qualifying cases — rare, but numerous enough to sequence and learn from.

The case that prompted the work is instructive. A person with bladder cancer had a complete response lasting more than two years on everolimus, a drug that rarely works in that disease. Sequencing found mutations in TSC1 and NF2. When other bladder cancer patients were checked, three of four with TSC1 mutations responded, while none of nine without them did. The unusual outcome had a molecular reason, and finding it produced information useful to other people.

Where explanations exist, they are biological.

Driver mutations can make a tumour unusually dependent on a pathway that a specific drug blocks. Defects in DNA repair — mismatch repair deficiency, high microsatellite instability, BRCA and related mutations — change both how a tumour behaves and which treatments it is vulnerable to, and mismatch repair deficiency predicts response to immune checkpoint inhibitors across tumour types. High tumour mutational burden makes a cancer more visible to the immune system. Occasionally, characteristics of the immune response itself appear to matter more than the tumour genome.

Oligometastatic disease is a separate route to the same headline. When metastatic disease is limited to a small number of sites, local treatments such as surgery or stereotactic ablative radiotherapy can be added to systemic therapy with the intention of long-term control. International consensus recommendations now classify these states formally, and long disease-free intervals after a stage 4 diagnosis are a recognised outcome in this group.

Immunotherapy contributes the most visible plateaus. In ten-year follow-up of a large randomised trial in advanced melanoma, a substantial minority of people treated with checkpoint inhibitors were alive a decade after starting, many of them long off treatment. That is a genuine change from what advanced melanoma meant twenty years ago. It is also a minority: most people in that trial did not have that outcome.

None of the mechanisms above involve the patient's attitude, determination, diet, stress levels or refusal to give up. There is no evidence that positivity influences who responds exceptionally, and the belief that it does has two costs. It burdens people who are already ill with responsibility for their own scan results. And it tells the bereaved that their person did not want it enough, which is both false and unkind.

Exceptional responses happen to people who were frightened, exhausted and pessimistic as often as to anyone else.

Access, not attitude. Comprehensive molecular or genomic profiling of the tumour, where it is available and might change options. Testing for mismatch repair status and tumour mutational burden where relevant. A second opinion at a centre running trials in your disease. Asking whether disease is oligometastatic and whether local therapy is being considered. Clinical trial eligibility, checked more than once as disease and trial menus change.

These are the questions with something behind them.

• NCI: Exceptional Responders Initiative Moving Forward
• The Exceptional Responders Initiative: feasibility of an NCI pilot study (PMC)
• NIH: Study of exceptional responders yields clues to cancer and potential treatments
• Final 10-year outcomes with nivolumab plus ipilimumab in advanced melanoma (PubMed)
• Stereotactic radiotherapy for oligometastasis (PMC)