Adjuvant sequential chemotherapy plus radiotherapy for LABC after radical cystectomy: Urothelial carcinoma subgroup analysis

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Published: 18 Feb 2019
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Prof Brian Baumann - Washington University in St. Louis, St. Louis, USA

Prof Brian Baumann speaks to ecancer at the 2019 ASCO Genitourinary Cancers Symposium about a randomised phase III clinical trial comparing adjuvant sequential chemotherapy plus radiotherapy versus adjuvant radiotherapy alone for locally advanced bladder cancer (LABC) after radical cystectomy.

He explains that a sub group analysis was presented looking at the 53% of patients with urothelial carcinoma, the most common histology in Europe and North America, to see if adjuvant chemotherapy had a benefit in that population.

Prof Baumann reports that the addition of adjuvant chemotherapy significantly improved disease free survival with a difference of 62% at 2 years to 48% at 2 years for radiotherapy alone.

The aim of this clinical trial was to assess whether the addition of adjuvant chemotherapy to adjuvant radiotherapy would improve disease free survival outcomes in patients with locally advanced bladder cancer. The hypothesis was that there would be a disease free survival benefit to the addition of adjuvant chemotherapy.

Dr Zaghloul, who was the PI of the study, he designed the trial as a randomised phase III trial in patients who had undergone radical cystectomy with negative margins, they had pelvic lymph node dissections, they had good performance status and no evidence of secondary malignancies or metastatic disease on cross-sectional imaging. They were randomised to receive what in Egypt, where the study was conducted, is considered standard of care which is post-operative radiation, that was the control arm, or sandwich chemotherapy and radiotherapy, so two cycles of gemcitabine cisplatin followed by radiotherapy to the pelvis followed by two additional cycles of gemcitabine cisplatin. The primary endpoint was disease free survival; secondary endpoints were overall survival and toxicity as well as local, regional and distant metastasis free survival.

The original trial enrolled patients regardless of whether they had urothelial or non-urothelial histology and it was reported at ASCO GU previously and was a negative study. At this ASCO GU we’re presenting the results of the urothelial subgroup analysis, so 53% of the 153 patients on the study actually had urothelial carcinoma which is by far the most common histology in Europe and North America. We wanted to see if adjuvant chemotherapy had a benefit in that population because other trials of adjuvant chemotherapy, most did not complete their accrual, were underpowered and many showed little to no benefit with the use of adjuvant chemotherapy. There is some meta-analysis data suggesting a benefit, pooling multiple trials, and there are retrospective studies that have demonstrated survival benefit but adjuvant chemotherapy remains more investigational whereas neoadjuvant chemotherapy is clearly established as a standard of care option.

In the subgroup analysis there were 81 patients with urothelial carcinoma, 41 in the chemotherapy plus radiotherapy arm, 40 in the radiotherapy alone arm. Even though this analysis was not done a priori, the arms were actually quite well balanced in the urothelial cohort so it was really only number of lymph nodes removed where there was a difference in the baseline characteristics. We looked at disease free survival and found that the addition of adjuvant chemotherapy actually significantly improved disease free survival in this cohort. The difference was 62% disease free survival at two years for combined modality versus 48% at two years for radiotherapy alone and the p-value was significant. Similarly with overall survival there was a significant improvement in overall survival with the addition of chemotherapy, that was 71% versus 51% so a 20% absolute benefit in overall survival which is really quite large.

In terms of toxicity one of the concerns with radiotherapy is late GI toxicity, particularly bowel obstruction. The rates of bowel obstruction were 7% and 8% so were actually quite low using more modern 3D conformal radiotherapy.

The results of this study are actually somewhat surprising. Again, the original trial was completely negative; in this study when we look at the urothelial cohort we’re seeing a positive result whereas other larger studies of adjuvant chemotherapy have not shown such a strong effect. So the question is why are we seeing this benefit in these patients and I think a lot of this has to do with the problem of local regional failures. So the prior chemotherapy trials which showed either a small progression free survival benefit or no benefit to adjuvant chemotherapy, none of those trials had an adjuvant therapy to effectively deal with the problem of local regional failure. So in patients with locally advanced bladder cancer local failure rates are around 30% and this is based on the SWOG and MRC trial data, so this is prospective, high quality data. In addition we know from those studies that chemotherapy does not reduce the risk of local failures at all so its benefit is chiefly and exclusively in reducing distant mets. So this is the first study that actually had an adjuvant therapy directed against local recurrences so our hypothesis is that radiation therapy was acting synergistically with chemotherapy to reduce the overall failure.

We know that adjuvant radiation has a big impact on reducing local failures because there was a third arm of this Egyptian study that was added on as a randomised phase II and that was chemotherapy alone. We compared the chemotherapy and radiotherapy arms to the chemotherapy alone arm in a previously published paper and saw that local control was 96% with the addition of radiation therapy versus 69% at two years and that was very significant on our statistical testing. So clearly radiation can reduce local failures significantly; local failures are common in this patient population and when we combined the two treatments we saw a big impact.

So, as far as how this may impact care going forward, these results do strongly suggest a role for adjuvant local therapy in addition to adjuvant systemic therapy for patients with locally advanced bladder cancer because, again, we just haven’t seen these types of results with adjuvant chemotherapy alone. In addition, for patients with negative margins we have good data to say that they don’t have to receive radiation to the cystectomy bed. Now, on Dr Zaghloul’s trial all patients received radiation to the cystectomy bed but more modern data suggests that that isn’t necessary and that could significantly reduce some of the long-term side effects, particularly GI side effects, as well as toxicity to a neo-bladder for patients who have a diversion that’s in the central pelvis.