Intermittent oxaliplatin (oxali) administration and time-to-treatment failure (TTF) in metastatic colorectal cancer (mCRC): Final results of the phase III CONCEPT trial

Reviewer: Arpi Thukral, MD
Abramson Cancer Center of the University of Pennsylvania
Last Modified: June 1, 2008

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Presenter: A. Grothey
Presenter's Affiliation: Mayo Clinic
Type of Session: Scientific

Background

  • Oxaliplatin is widely used as a 1st line treatment for metastatic colorectal cancer (mCRC). The addition of Bevacizumab has also been shown to improve efficacy, and these 2 agents are often used in combination.
  • Although oxaliplatin is relatively safe and tolerated, its dose-limiting toxicity is a sensory neurotoxicity (sNT) which can be severe in many cases.
  • It has been shown in multiple phase III trials that the reason for early discontinuation of oxaliplatin-based chemotherapy is due to reasons other than progressive disease. In fact, the primary reason for discontinuation was secondary to the peripheral sensory neuropathy associated with this drug.
  • It was hypothesized by the authors of this study that the neuropathy may be reduced by intermittent administration of Oxaliplatin.
  • The CONCEPT trial (Combined Oxaliplatin Neuropathy Prevention Trial) was designed to study patients with mCRC receiving Oxaliplatin/Bevacizumab as 1st line treatment and to evaluate whether an intermittent Oxali (IO) schedule of FOLFOX/Bevicizumab reduces cumulative neurotoxicity, and therefore allows patients to stay on treatment longer than those receiving conventional Oxali (CO).
  • The authors also explored the impact of calcium and magnesium (CaMg) administration on neurotoxicity.
  • It was hypothesized that patients receiving the IO regimen will not discontinue Oxaliplatin prematurely, but rather stay on it longer compared to the CO group. It was also postulated that CaMg infusion will help to reduce neurotoxicity.

Materials and Methods

  • Patients were randomly assigned to either:
    • folinic acid, leucovorin, fluorouracil, and oxaliplatin (FOLFOX) plus bevacizumab every 2 weeks until progression or toxicity (CO group) vs.
    • alternating blocks of eight cycles FOLFOX with bevacizumab and biweekly fluorouracil and leucovorin infusion with bevacizumab (without oxaliplatin) (IO group)
  • The study was done as a 2x2 factorial design (CO vs. IO) x (CaMg vs. placebo).
  • Eligibility criteria: measurable disease; PS 0-1; no previous neuropathy.
  • Primary endpoint: Time to treatment failure/discontinuation (TTF). This was calculated as time from randomization to discontinuation of treatment.
  • Secondary endpoint: impact of CaMg infusion on incidence and severity.
  • An interim analysis which was unplanned, suggested that of the data from the 174 patients analyzed, those patients who received calcium and magnesium salts reported a significantly lower response rate than the placebo group. However, in this analysis, response was not confirmed and was based on investigator bias.
  • Due to this finding, this study was closed early by the Independent Data Monitoring Committee, and further tests are now being done to verify all the data related to this study.

Results

  • Prior to the early termination of the study, there were 139 patients in the 2x2 phase of the trial.
  • A protocol amendment eliminating the CaMg vs. Placebo arm was written after 140 patients, so the last 40 patients on the study all received CaMg and were not randomized. This took place prior to the data reported suggesting that CaMg may lower efficacy.
  • The patient characteristics were similar between the 2 groups, except that the patients in the IO group were slightly older in age.
  • TTF was prolonged in the IO group compared to CO group, 5.6 vs. 4.2 months respectively (HR=0.58, p=0.0025). The difference in TTF was not significant between the CaMg group and placebo group.
  • Progression-free survival (PFS) was significantly longer in the IO group compared to the CO group, 12 months vs. 7.3 months respectively.
  • There was also a 50% significant reduction in incidence of severe neurotoxicity between the 2 groups, 24% vs. 10%.
  • Neurotoxicity events leading to dose reduction is decreased as well for IO group compared to CO group (10% vs. 22% respectively, p<0.05). No differences were seen in acute toxicity.

Author's Conclusions

  • The authors conclude that even though this study was terminated early, the primary endpoint was achieved. IO is associated with a significant improvement of TTF compared with CO without compromising PFS.
  • CO leads to higher numbers of discontinuations from Oxaliplatin.
  • However, they acknowledge that the study was not properly designed to evaluate effects of CaMg on response rate. The sample size was too small and the trial was discontinued early.

Clinical/Scientific Implications

  • It has been shown in multiple trials that the addition of Oxaliplatin to 5-FU based chemotherapy is an effective treatment in mCRC. Since these patients have metastatic disease and need systemic treatment to prevent further disease, it is important that patients remain on the Oxaliplatin for as long as possible until disease progression. However, this is often limited secondary to the neurotoxicity caused by Oxaliplatin.
  • Therefore, it is very important to find ways to limit the neurotoxicity and potentially keep patients on Oxaliplatin for longer time periods. This study has made a significant attempt to accomplish this goal.
  • As the author’s noted, TTP for the IO group is statistically longer than that for the CO group. In addition, neurotoxicity is effectively decreased with CaMg as shown in this study. This method, if administered properly, may ultimately lead to a better outcome in metastatic colorectal cancer patients.
  • But this study has many flaws, and the authors have acknowledged these appropriately. The sample size was small, and the study was discontinued early due to a suggestion that CaMg reduced efficacy of chemotherapy without any sound basis. In addition, the results on response rates are inconclusive.
  • Even though CaMg seems promising for reducing neurotoxicity, we need to bear in mind that the data from this trial regarding response rates and safety are preliminary and unconfirmed. We should recognize that there is a possibility that CaMg reduces the efficacy of FOLFOX, as suggested by the authors of this study in a previous analysis. However, this has not been confirmed with objective radiological evidence. Until further studies are done to verify this hypothesis, we must have appropriate clinical judgment when administering these agents to our patients.


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