ABOUT NEWS MEETINGS TOPICS VIDEOS CME SUBSCRIBE Search...

ADVERTISEMENT
Duration of Adjuvant Oxaliplatin-Based
Therapy for Stage III Colon Cancer
Does the Benefit Justify the Long-Term Toxicity?
N OV
By Steven E. Vogl, MD 03 TODAY IN ONCOLOGY
March 25, 2018

FDA Grants Breakthrough Therapy Designation to

LOXO-292 for RET Fusion–Positive Thyroid Cancer
“At Microphone 1” is an occasional column written by Steven E. Vogl, MD, of the Bronx, New York. When he
ESMO 2018: CTONG 1103 Finds Benefit With
is not in his clinic, he can generally be found at major oncology meetings and often at the microphone,
Neoadjuvant Erlotinib in Some EGFR-Mutated
where he stands ready with critical questions for presenters of new data. The opinions expressed in this NSCLCs
report are those of the author. If you would like to share your opinion on this or another topic, please write
to editor@ASCOPost.com.  ESMO 2018: CheckMate-142 Reports New Data on
First-Line Nivolumab Plus Low-Dose Ipilimumab in
At the 2017 ASCO Annual Meeting, Qian Shi, PhD, of the Mayo Clinic in Rochester, MSI-H/dMMR Metastatic Colorectal Cancer
Minnesota, presented a combined individual patient analysis of six studies conducted
Suicide Risk Among Head and Neck Cancer
around the world, looking at 6 vs 3 months of adjuvant chemotherapy for node-
Survivors
positive colon cancer.1 Despite enrolling almost 13,000 subjects, the results remain
equivocal.  2018 ASTRO: Phase I Trial of SBRT for
Oligometastatic Disease With Multiple Metastases
Overall, the analysis failed to exclude a 5% chance that longer therapy improves 3-year
Steven E. Vogl, MD disease-free survival by a relative increase of 12%. If the 6-month course had a 3-year VIEW MORE 
disease-free survival of 75.5% (the actual observation in the 6-trial meta-analysis
called “IDEA”), the goal was to exclude with 95% con dence that reducing therapy to a 3-month course
;
decreased the 3-year disease-free survival to 72.6%. In the landmark MOSAIC trial that established FOLFOX
for 6 months as the standard adjuvant therapy for resected node-positive colon cancer, 3-year disease-free MOST READ STORIES
survival improved by 6.9% if 6 months of oxaliplatin was added to 6 months of an every-2-week program
of leucovorin plus 44-hour infusion of uorouracil (5-FU). The six studies asked how much of this gain is
Has the Promise of Precision Medicine Been
lost if only 3 months of oxaliplatin are given and the uoropyrimidine (5-FU or its oral prodrug
Oversold?
capecitabine) course also is reduced to 3 months. 

Final Overall Survival Results for First-Line VR-CAP
In his presentation of the French contribution to the IDEA meta-analysis (called “IDEA-France”), Thierry vs R-CHOP in Transplantation-Ineligible Mantle Cell
Andre, MD, of the University Pierre et Marie Curie in Paris, estimated that surgery cures 50% to 60% of Lymphoma
node-positive colon cancer cases, LV5FU2 (leucovorin plus the 44-hour 5-FU infusion) cures another 12%
to 15%, and the addition of oxaliplatin (making FOLFOX) cures another 6%.3 In IDEA-France, 90% of Weighing the Cost and Value of CAR T-Cell Therapy
patients received FOLFOX. This trial showed that a second 3 months of therapy improved 3-year disease-
New ASTRO/ASCO/AUA Guideline for Early-Stage
free survival by 4% (2% for patients with T1–3N1 disease and 8% for higher-risk patients with T4 or N2
Prostate Cancer Supports Use of Hypofractionated
disease).  Radiotherapy

Bene t vs Toxicity: The Real Question  ESMO 2018: CheckMate 067: 4-Year Follow-up of
Nivolumab Plus Ipilimumab in Advanced Melanoma
ALTHOUGH THE duration of adjuvant therapy was the focus of these studies, it became clear from Dr. Shi’s
presentation that the real question was whether the added long-term toxicity of the second 3 months of VIEW MORE 
therapy is justi ed by the bene t. The long-term toxicity is entirely neurotoxicity from oxaliplatin. At 48
months after completion of 6 months of FOLFOX treatment, 15.4% of patients still had neuropathy; 3.5%
had grade 2 or 3 neuropathy interfering with daily function.4 
We recommend
The question asked in each of these six studies should have been whether oxaliplatin therapy could be
safely stopped after 3 months. Had the only variable been the duration of oxaliplatin, we would not now be FOLFOX or CAPOX in Stage II to III Colon Cancer:
Efficacy Results of the Italian Three or Six Colon
having a discussion analyzing the results by which uoropyrimidine was used. In previous adjuvant trials
Adjuvant Trial
for which the choice of uoropyrimidine was the main issue, capecitabine proved equal to or slightly better Alberto Sobrero et al., J Clin Oncol
than 5-FU/leucovorin. 
ASCO 2017: The IDEA Collaboration: Global Study Sets
Focus on Tolerability  New Risk-Based Standard to Personalize

“
“Fairness and ethics would Chemotherapy for Colon Cancer After Surgery
have been better served by STRATIFICATION TO ensure comparable populations in the By The ASCO Post, The ASCO Post

obtaining patient consent at study arms was done before randomization in all six trials; Adjuvant FOLFOX or CAPOX for 3 or 6 Months in Stage
the 3-month point, when he or therefore, treatment assignment was not balanced according to II or III Colon Cancer
she has experienced the patient characteristics during and at the conclusion of the rst 12 By Matthew Stenger, The ASCO Post
toxicities.” weeks of therapy, when the treatment arms diverged. We do not Adjuvant Chemotherapy Duration in Stage III Colon
know how the 6-month patients did according to their dose, Cancer
— Steven E. Vogl, MD
toxicities, treatment delays and modi cations, performance By Matthew Stenger, The ASCO Post
status, and blood cell counts during and at the conclusion of the
Tweet this quote IDEA Trial: ‘Going Beyond Statistics’ in Stage III Colon
rst 3 months of receiving FOLFOX or CAPOX (capecitabine and Cancer
oxaliplatin). By chance, the group assigned to 6 months could By Caroline Helwick, The ASCO Post
have had more mucosal, hematologic, or neurologic toxicity in the rst 3 months than the group assigned
Adjuvant chemotherapy duration in stage III colon
to 3 months of chemotherapy. Some of this toxicity in the rst 3 months (especially neurotoxicity) may
cancer: One size does not fit all
have led to premature cessation of all chemotherapy short of the 6-month point. 
Medicine Matters oncology

To ensure comparability of the assigned groups and that all patients completed the rst 3 months of Researchers Begin Promising New Trial To Fight
therapy, randomization should have occurred after the completion of 3 months of therapy. Treatment Colorectal Cancer
assignment should have been strati ed by patient condition, prior toxicity, and current characteristics New York University Medical Center And School Of
Medicine, ScienceDaily
(performance) as well as restricted according to organ function, blood cell counts, neurologic function, and
willingness of the patient to proceed with treatment at the time treatment arms diverge.  Chemotherapy Options Improve For Patients With
Advanced Colorectal Cancer
Fairness and ethics would have been better served by obtaining patient consent at the 3-month point, when European Society for Medical Oncology, ScienceDaily
he or she has experienced the toxicities—skin and mucosal for 5-FU or capecitabine and cold intolerance,
Deficient MMR phenotype linked to favorable FOLFOX
infusional pain, and sensory neuropathy for oxaliplatin. The consent at this point would have been better colon cancer DFS
informed, and the study would have been more likely to answer the question by excluding those who Medicine Matters oncology
already had stopped chemotherapy or, if toxicity was already severe, would have been likely soon to refuse
First-line molecular therapies in the treatment of
to proceed with more chemotherapy.  metastatic colorectal cancer – a literature-based review
of phases II and III trials
It makes sense to stratify by events during the rst 3 months of

“
“Probably few patients would
risk significant rates of severe
neuropathy for an absolute 5-
year survival benefit under
1%, and many would risk
moderate neuropathy for a
benefit over 3%.”
— Steven E. Vogl, MD
Tweet this quote
Table 1
2017 Plenary Session, Dr. Shi herself suggested the duration of therapy for higher-risk patients should be
determined in part by tolerability of the chemotherapy during the rst 3 months.
Arndt Vogel et al., Innovative Surgical Sciences
therapy and to exclude some patients based on these events.
Those who have much more toxicity during the rst 3 months
likely will have more toxicity in the second 3 months—as well as Powered by
more dose reductions—and more often will fail to complete
therapy. They may prove to gain no bene t at all from trying to
complete 6 months. After just 3 months of therapy, 3% of both
I consent to the use of Google Analytics and related
FOLFOX and CAPOX patients already had grade 3 or 4 neuropathy
(Table 1).  cookies across the TrendMD network (widget, website,
blog). Learn more
Many would argue these patients should stop neurotoxic agents
Yes No
permanently and not be randomized—14% of FOLFOX patients
and 12% of CAPOX
patients already had
grade 2 neuropathy after MOST VIEWED VIDEOS
3 months. Cautious
investigators also would
Caroline Robert, MD, PhD, on Advanced
exclude these patients
Melanoma: Research Highlights
with grade 2 neuropathy
from further neurotoxic Cora N. Sternberg, MD, on Renal and Bladder
oxaliplatin as well. In her Cancers: Focus on Immunotherapy
nal slide at the ASCO
Daniel E. Spratt, MD, on Prostate Cancer in
African American Men: Results of a Meta-analysis
 

Too Late to Compare Toxicities?  Thomas Galloway, MD, on Oropharyngeal

Cancer: Improving Outcomes and Reducing Toxicity
IT MAY NOT be too late to compare toxicities in the rst 3 months for both groups to assure both groups
Suresh S. Ramalingam, MD, on Lung Cancer:
were comparable at the point the treatments diverged. Unfortunately, the SCOT trial stopped collecting
Research Highlights
toxicity data after the rst 617 patients were enrolled.5 The other ve trials, only two of which have been
presented separately at medical meetings, may have these data. Disease-free and overall survival also VIEW MORE 
should be evaluated according to toxicity during the rst 3 months of therapy. It may be that those patients
with grade 2 or worse neuropathy in the rst 3 months obtained no bene t from an attempt to prolong
therapy. This information would be very helpful in counseling already numb patients considering whether
to endure 3 more months of progessively more toxic therapy. 

The analyses of progression-free and overall survival should be redone to exclude patients in both groups
who stopped therapy before the 3-month point. This step would eliminate the early noncompliers and early
deaths, which would dilute any apparent bene t from proceeding beyond 3 months of FOLFOX or CAPOX. 

If the six studies included in the IDEA collaboration had randomized after 3 months (thus excluding early
stoppers from both groups) and excluded patients who clearly would fail to complete 6 months’ therapy
because of already existing severe peripheral neuropathy, the bene ts of continuing treatment beyond 3
months might be more obvious. They might even appear in the lower-risk group. 

What Would Your Patient Want? 

IT SEEMS LIKELY that a patient with good analytic skills would prefer to defer a decision on how long
adjuvant chemotherapy should continue until the last possible moment, hoping the decision would be
rendered easy. This could happen if poorly reversible toxicity (such as peripheral neuropathy) during initial
therapy was severe or moderately severe, if there were early distant relapse, or if some intercurrent
catastrophic event occurred. Similarly, if a patient adamantly wants to avoid a venous access device, and
infusional pain in the accessed vein during the rst few oxaliplatin administrations was nearly intolerable,
the decision becomes easy. These events are fairly uncommon, however. 

Even if the decision is not that easy, a patient would want to know in what ways his or her body’s reaction to
the initial chemotherapy predicts his or her reaction to further therapy. Presumably, uoropyrimidine
doses have been adjusted to make reversible toxicities tolerable for patients, so continuing the
uoropyrimidine is not the issue, unless there is severe sensitivity to the uoropyrimidine from
dihydropyrimidine dehydrogenase de ciency. A patient would want information on how many patients
with early ( rst 3 months) grade 1 or 2 peripheral neuropathy go on to develop grade 3 neuropathy with an
additional 3 months of oxaliplatin, and how many actually stop treatment with oxaliplatin before reaching
the 6-month point. The patient would ask whether the early onset of neuropathy from oxaliplatin predicts
neuropathy that will last longer and remain more severe. And the patient would ask whether the absence of
neuropathy after 3 months predicts a lower rate of severe and long-lasting neuropathy after 6 months of
therapy are complete. 

Most important, the patient would ask for the best estimate of the absolute bene t in terms of disease-free
and overall survival from an additional 3 months of oxaliplatin. The bene t rate should now be based on the
patient’s T and N stage, the number of resected nodes, as well as whether the primary tumor is right- or
left-sided. In the near future, once the tests are standardized, the rate of bene t should also include risk
estimates based on tumor genetics and gene expression. 

Probably few patients would risk signi cant rates of severe neuropathy for an absolute bene t in 5-year
overall survival under 1%, and many would risk moderate neuropathy for a bene t over 3%. Concert
pianists and violinists, guitar virtuosi, and microvascular surgeons would likely require much greater
bene ts to risk career-ending toxicities to increase 5-year overall survival by percentages in the low single
digits. 

The IDEA collaborators owe it to our patients to analyze 6-month toxicity by the toxicity observed after 3
months. They should add tumor location (right vs left side of the colon) to the risk pro les of the tumors.
They have already shown that 3 months of CAPOX is a pretty good adjuvant treatment for colon cancer that
has not penetrated the colon serosa or invaded adjacent organs and is metastatic to no more than three
nodes, although defects in study design and analysis have not nailed this down completely. 

DISCLOSURE: Dr. Vogl reported no con icts of interest. 

Disclaimer: This commentary represents the views of the author and may not necessarily re ect the views

of ASCO or The ASCO Post. 

REFERENCES 

1. Shi Q, Sobrero AF, Shields AF, et al: Prospective pooled analysis of six phase III trials investigating

duration of adjuvant oxaliplatin-based therapy (3 vs 6 months) for patients with stage III colon cancer: The
IDEA (International Duration Evaluation of Adjuvant chemotherapy) collaboration. 2017 ASCO Annual
Meeting. Abstract LBA1. Presented June 4, 2017. 

2. André T, de Gramont A, Vernerey D, et al: Adjuvant uorouracil, leucovorin, and oxaliplatin in stage II to
III colon cancer: Updated 10-year survival and outcomes according to BRAF mutation and mismatch repair
status of the MOSAIC Study. J Clin Oncol 33:4176-4187, 2015. 

3. Andre T, Bonnetain F, Mineur L, et al: Oxaliplatin-based chemotherapy for patients with stage III colon
cancer: Disease-free survival results of the three versus six months adjuvant IDEA France trial. 2017 ASCO
Annual Meeting. Abstract 3500. Presented June 5, 2017. 

4. André T, Boni C, Navarro M, et al: Improved overall survival with oxaliplatin, uorouracil, and leucovorin
as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial. J Clin Oncol 27:3109-3116, 2009.

5. Iveson T, Kerr R, Saunders MP, et al: Final DFS results of the SCOT study: An international phase III
randomised (1:1) non-inferiority trial comparing 3 versus 6 months of oxaliplatin based adjuvant
chemotherapy for colorectal cancer. 2017 ASCO Annual Meeting. Abstract 3502. Presented June 5, 2017.

© 2018 HSP News Service, L.L.C.

Editorial Board Advertising Disclosures Contact Privacy Policy Disclaimer ASCO.org