Stage 4 to No Evidence of Disease

No evidence of disease, or NED, means that scans, examination and blood tests currently find 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. For some cancers, though, a long enough NED interval does become strong evidence of one. What NED means in your case depends on three things. The cancer type. The treatment given. How long the interval has lasted. That is a question worth asking directly.

Complete response is the related term used during treatment. It means all measurable disease has gone. It can be short-lived or lasting.

NCI ran an Exceptional Responders Initiative to study people who did far better than the trial they were in predicted. The working definition was concrete. It meant a complete or partial response that lasted at least six months. The treatment had to be one where fewer than one in ten patients respond. It also covered a response to a drug that is not generally effective for that disease. A feasibility search of phase 2 trials from 2002 to 2012 found roughly a hundred cases that qualified. They are rare, but there are enough of them to sequence and learn from.

The case that prompted the work makes the point. A person with bladder cancer had a complete response lasting more than two years on everolimus. That drug rarely works in bladder cancer. Sequencing found mutations in TSC1 and NF2. Other bladder cancer patients treated with everolimus were then checked. Three of four with a TSC1 mutation had some tumor shrinkage. Of the nine whose tumors progressed, eight had no such mutation. The unusual outcome had a molecular reason. Finding it produced information useful to other people.

Where explanations exist, they are biological.

Driver mutations can make a tumor unusually dependent on one pathway. A drug that blocks that pathway then leaves the tumor nowhere to go. Faults in DNA repair also matter. These include mismatch repair deficiency, high microsatellite instability, and BRCA and related mutations. They change how a tumor behaves. They also change which treatments it is vulnerable to. Mismatch repair deficiency predicts response to immune checkpoint inhibitors across tumor types. High tumor mutational burden, meaning a large number of mutations, makes a cancer easier for the immune system to see. Sometimes the immune response itself seems to matter more than the tumor genome.

Oligometastatic disease is a separate route to the same headline. Here the cancer has spread, but only to a small number of sites. Doctors can then add local treatment to systemic therapy. That local treatment may be surgery, or stereotactic ablative radiotherapy. The aim is long-term control. International consensus recommendations now classify these states formally. Long disease-free intervals after a stage 4 diagnosis are a recognized outcome in this group.

Immunotherapy gives the most visible plateaus. A large randomised trial in advanced melanoma has ten-year follow-up. A substantial minority of people treated with checkpoint inhibitors were alive a decade after starting, many of them long off treatment. That is a real 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 affects who responds exceptionally. 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. That 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. Ask about comprehensive molecular or genomic profiling of the tumor. Ask where it is on offer and where it might change your options. Ask about testing for mismatch repair status and tumor mutational burden where relevant. Ask about a second opinion at a center running trials in your disease. Ask whether your disease is oligometastatic, and whether local therapy is being considered. Ask about clinical trial eligibility. Then ask again later. Disease changes, and so does the list of open trials.

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)