How a Negative Result Paved the Way for Better Prostate Cancer Treatments
For men with advanced prostate cancer, the journey often follows a predictable path. The initial treatment, designed to block the male hormones that fuel the cancer's growth, often works well—for a time. But when the cancer stops responding and progresses despite this hormone therapy, patients and doctors in the early 1990s faced a bleak landscape with few options 2 .
It was in this challenging context that a major European research group launched a clinical trial to answer a critical question: could either of two chemotherapy drugs—mitomycin C or estramustine—provide a lifeline for these patients? The results, however, were not what researchers had hoped for. This is the story of that important study, a trial whose "failure" ultimately helped steer prostate cancer research in more promising directions 1 .
Before delving into the trial itself, it's helpful to understand the two drugs that were put to the test. Both were repurposed agents with different mechanisms of attack.
An intravenous chemotherapy drug that works by crosslinking DNA strands inside cells. This prevents cancer cells from replicating their genetic material and multiplying, ultimately triggering cell death.
This unique oral drug is a hybrid molecule. It links a form of estrogen (a female hormone) to a nitrogen mustard (a chemotherapy agent). Initially, it was thought to deliver chemotherapy directly to prostate cells using hormonal pathways, though its precise mechanism was complex and not fully understood 1 .
The European Organization for Research and Treatment of Cancer (EORTC) designed a straightforward "head-to-head" trial to determine which of these two drugs offered a better chance for men with hormone-resistant metastatic prostate cancer 1 .
The study, known by the code EORTC 30865, was a phase III prospective randomized trial—the gold standard for comparing treatments in clinical research 1 .
Between 1987 and 1990, it enrolled 171 men whose prostate cancer had spread (metastasized) and was progressing despite hormonal treatment. These were heavily pre-treated patients; 70% had undergone more than one previous therapy, with some having received as many as five different treatments 1 .
The participants were randomly assigned to one of two groups:
The goal was to see which drug could more effectively stall the disease and extend lives.
When the final analysis was published in 1993, the conclusions were starkly negative. The table below summarizes the key outcomes, which were nearly identical for both drugs.
| Outcome Measure | Estramustine Group | Mitomycin C Group |
|---|---|---|
| Median Time to Progression | ~5 months | ~5 months |
| Median Length of Survival | ~10 months | ~10 months |
The researchers reported that "the overall results were disappointing" and noted that "there was no difference in efficacy between the 2 treatment arms" 1 . The battle against the cancer was being lost quickly, regardless of the chosen weapon.
Making the negative results even harder to bear was the significant toll the treatments took on patients. The toxicity was, in the researchers' words, "severe in both arms" 1 .
| Aspect | Estramustine | Mitomycin C |
|---|---|---|
| Administration | Oral, daily | Intravenous, every 6 weeks |
| Common Toxicities | Gastrointestinal issues | Hematological (blood-related) issues |
| Onset of Problems | Toxicity appeared earlier | |
| Impact on Patient | Earlier deterioration in performance status |
The study found that side effects from estramustine tended to appear sooner, leading to an earlier decline in patients' overall well-being and ability to perform daily activities 1 . The interim analysis had already flagged that "toxicity was very considerable in both arms" 3 .
The trial's final analysis left no room for ambiguity: "In this group of heavily pretreated patients there appears to be no justification for the use of either of these agents at the present time" 1 .
This clear, negative conclusion was a disappointment, but it served a vital purpose for the medical community. It stopped the use of ineffective and toxic therapies, preventing unnecessary patient suffering and freeing up resources to explore more promising avenues.
While this particular combination of drugs was abandoned for single-agent use, the knowledge gained was not entirely lost. Years later, researchers continued to test estramustine in combination with other drugs, such as vinblastine and mitomycin C, in different protocols, seeking a more effective and tolerable regimen 8 .
The EORTC 30865 trial highlights a crucial but often overlooked truth in science: a "negative" result is still a result. It provides critical data that helps scientists abandon dead ends and redirect their efforts. The struggle against hormone-resistant prostate cancer did not end with this trial; it evolved.
Today, the treatment landscape for advanced prostate cancer has been transformed, largely by moving away from non-specific chemotherapies toward more targeted approaches 2 . The most exciting advances have come from leveraging Prostate-Specific Membrane Antigen (PSMA), a protein highly expressed on prostate cancer cells 2 .
PSMA-based PET imaging has revolutionized how doctors stage the disease and locate metastases with unprecedented clarity 2 .
Research is now exploring even more advanced strategies, including alpha-emitting isotopes and bispecific antibodies that recruit the patient's own immune cells to attack the cancer 2 .
The journey from the disappointing results of the EORTC trial to the targeted therapies of today underscores the iterative nature of medical progress. Each study, whether a success or a "failure," builds upon the last, gradually illuminating the path forward toward more effective and kinder treatments for patients.