Friday, July 20, 2012

Radical Prostatectomy versus Observation for Localized Prostate Cancer

This weeks NEJM:

The PIVOT trial is published in the NEJM, a randomized comparison of observation vs radical prostatectomy for localized prostate cancer.  The headline findings: no difference in overall survival.  However, this one is worth looking a little more closely at. 

The first item that strikes me is the low numbers of this trial.  This is in theory a non-inferiority trial of observation, however, one can rarely design these with any relevant power with less than a couple of thousand.  And in fact when reviewing the statistical design, the investigators downgraded their definition of non-inferiority due to poor accrual - to at 25% reduction in mortality.  This is a pretty low bar for non-inferiority.  The trial was initially designed to accrue 2000.

Moreover, in the observation arm 20% of the enrollee's entered into a curative treatment, 10% prostatectomy, and 10% radiation (mix of EBRT and brachy).  This further dilutes the potential power of this study.  15% of the prostatectomy arm also underwent observation.

And in fact, when one looks at the forest plots in figure 3, the hazard ratios for benefit are pretty consistently in the favoring prostatectomy side, with only the confidence intervals overlapping one.  Only in the low risk subgroup did the HR cross to favoring observation.

I feel the investigators should have qualified their conclusions a little more in this trial.  When a study is underpowered one expected not to see a significant result: however, in non-inferiority trials, when a positive result hinges on there being no difference in results between two arms - these issues of power, accrual and crossover become much more troublesome.  All these factors work to deteriorate the quality of a trial, and make a non-statisically significant result more likely.


Radical Prostatectomy versus Observation for Localized Prostate Cancer: New England Journal of Medicine, Volume 367, Issue 3, Page 203-213, July 2012.

Monday, July 2, 2012

Temozolomide vs RT in the Elderly with GBM

In the Lancet Oncology this week:

A trial from German is published reported the results of a phase III trial of RT alone vs Temozolomide alone in the elderly.  They find that temozolomide is "non-inferior" to RT alone - however, they define "non-inferior"as not >25% worse that RT.  This would be a hard sell for a new standard therapy in almost any other setting, and if one looks at the survival curves, RT does appear to do better for the first 6 months or so for RFS, and most paitents crossed over so that most patients on this trial eventually recieved both.  I find the MGMT findings quite interesting (though only 'hypothesis generating'), in that MGMT methylation predicted for a benefit of temozolomide alone, but had little predictive power in the RT alone group.   The larger question I guess is that if most of these patients received both treatments anyway, why not have a go at concurrent treatment for the most benefit?


[Articles] Temozolomide chemotherapy alone versus radiotherapy alone for malignant astrocytoma in the elderly: the NOA-08 randomised, phase 3 trial: Temozolomide alone is non-inferior to radiotherapy alone in the treatment of elderly patients with malignant astrocytoma. MGMT promoter methylation seems to be a useful biomarker for outcomes by treatment and could aid decision-making.

5FU Oxaliplatin in Rectal Cancer

In the Lancet Oncology this week,

An interesting phase III study from Germany is reported, finding a modest increase in pathologic complete response in patients treated with oxaliplatin + 5FU + RT, vs 5FU + RT alone.  This is interesting in that a prior report in the JCO, demonstrated no such increase.  How to square these two accounts?  I think firstly the benefit is modest with a pCR rate of 17% with oxaliplating and 14% without.  This could have been missed in the STAR-01 trial as it was a smaller study.  I think fundamentally, however, we need to follow both of these trials for long term outcome.  Oxaliplatin surely has not been a slam dunk for increasing the pCR rates to 30%+ as some may have hoped; it may however still have some benefit in long term followup.


[Articles] Preoperative chemoradiotherapy and postoperative chemotherapy with fluorouracil and oxaliplatin versus fluorouracil alone in locally advanced rectal cancer: initial results of the German CAO/ARO/AIO-04 randomised phase 3 trial: Inclusion of oxaliplatin into modified fluorouracil-based combined modality treatment was feasible and led to more patients achieving a pathological complete response than did standard treatment. Longer follow-up is needed to assess DFS.

Carbo + RT in the elderly with NSCLC

In the Lancet Oncology this week:

A Phase III trial from Japan is reported, showing a survival benefit with the addition of a modest dose of carboplatin with Thoracic RT.  What I think is perhaps most interesting in this trial lies in the introduction: A prior JCOG study was halted prematurely due to excess deaths in the carbo arm - turns out that much of the toxicity related to poor radiotherapy design.  With more stringent QA, this trial was conceived and executed - now demonstrating a significant effect.  I would find this as cautionary tale for trial design moving forward - treatment escalation is well and good, but needs to be very carefully.


[Articles] Thoracic radiotherapy with or without daily low-dose carboplatin in elderly patients with non-small-cell lung cancer: a randomised, controlled, phase 3 trial by the Japan Clinical Oncology Group (JCOG0301): For a select group of elderly patients with locally advanced NSCLC, combination chemoradiotherapy provides a clinically significant benefit over radiotherapy alone, and should be considered for this population.

INT 0116 updated: Adjuvant CTRT for Gastric Cancer

In The JCO this week:

INT-0116 (or the "Macdonald" trial) is updated with longer followup.  The OS and DFS benefit remains at long follow up, confirming this as a standard of care.   I would hesitate to make too much of the subgroup analysis, which should be interpreted as a hypothesis generating exercise. 


Updated Analysis of SWOG-Directed Intergroup Study 0116: A Phase III Trial of Adjuvant Radiochemotherapy Versus Observation After Curative Gastric Cancer Resection [Gastrointestinal Cancer]: Purpose
Surgical resection of gastric cancer has produced suboptimal survival despite multiple randomized trials that used postoperative chemotherapy or more aggressive surgical procedures. We performed a randomized phase III trial of postoperative radiochemotherapy in those at moderate risk of locoregional failure (LRF) following surgery. We originally reported results with 4-year median follow-up. This update, with a more than 10-year median follow-up, presents data on failure patterns and second malignancies and explores selected subset analyses.

Patients and Methods
In all, 559 patients with primaries ≥ T3 and/or node-positive gastric cancer were randomly assigned to observation versus radiochemotherapy after R0 resection. Fluorouracil and leucovorin were administered before, during, and after radiotherapy. Radiotherapy was given to all LRF sites to a dose of 45 Gy.

Overall survival (OS) and relapse-free survival (RFS) data demonstrate continued strong benefit from postoperative radiochemotherapy. The hazard ratio (HR) for OS is 1.32 (95% CI, 1.10 to 1.60; P = .0046). The HR for RFS is 1.51 (95% CI, 1.25 to 1.83; P < .001). Adjuvant radiochemotherapy produced substantial reduction in both overall relapse and locoregional relapse. Second malignancies were observed in 21 patients with radiotherapy versus eight with observation (P = .21). Subset analyses show robust treatment benefit in most subsets, with the exception of patients with diffuse histology who exhibited minimal nonsignificant treatment effect.

Intergroup 0116 (INT-0116) demonstrates strong persistent benefit from adjuvant radiochemotherapy. Toxicities, including second malignancies, appear acceptable, given the magnitude of RFS and OS improvement. LRF reduction may account for the majority of overall relapse reduction. Adjuvant radiochemotherapy remains a rational standard therapy for curatively resected gastric cancer with primaries T3 or greater and/or positive nodes.