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NIHR Signal Fewer side-effects and similar benefits from shorter chemotherapy after bowel cancer surgery

Published on 12 June 2018

doi: 10.3310/signal-000603

A three-month course of chemotherapy after surgery for bowel cancer seems no less effective than the standard six-month course, and half as many people suffered from nerve damage as a side-effect. Three-quarters of people survived to three years without disease progression on either treatment.

This international trial, part funded by the NIHR, included over 6,000 people with high-risk stage II or III bowel cancer that had spread through the bowel wall or to nearby lymph nodes. Standard treatment after surgery is usually six months of an oxaliplatin-containing regimen. This study evaluated a shorter course.

Oxaliplatin is known to damage nerves, causing numbness, tingling and pain in feet and hands, which tends to get worse with prolonged use. Shorter chemotherapy reduced the frequency and severity of such side effects.

Shorter course chemotherapy could become an option to discuss with patients when balancing the benefits and risks of treatment.

  •   Cancers, Gastrointestinal disorders, Medicines
Fewer side-effects and similar benefits from shorter chemotherapy after bowel cancer surgery

Why was this study needed?

There were 41,804 new cases of bowel cancer in the UK in 2015. Around a quarter of people are diagnosed at stage III when the cancer has already spread to the lymph nodes. An estimated 25-60% of people with this stage will survive to five years. Following surgery to remove the cancer, over half will develop later recurrence. Chemotherapy is therefore given after surgery.

People with stage III are recommended to receive chemotherapy regimens including the drug oxaliplatin for six months. But oxaliplatin causes disabling long-term problems with balance and sensation in the hands and feet (peripheral neuropathy) which becomes worse with increasing dose and duration.

Several other studies have assessed whether giving three-month chemotherapy could reduce side effects without being less effective than the standard duration. The SCOT study is the largest to-date to address this question.

What did this study do?

The SCOT randomised controlled trial was conducted across 244 centres in six countries including the UK. It included 6,088 adults who were within 11 weeks of curative surgery to treat high-risk stage II or stage III bowel or rectal cancer.

Patients were treated with one of two oxaliplatin-containing chemotherapy regimens: either FOLFOX which includes fluorouracil or CAPOX including capecitabine. They were randomised to receive the treatment for three or six months. Patients were followed up for at least three years to look at survival without relapse of their cancer. They also completed questionnaires assessing quality of life and neuropathy.

The study was a non-inferiority trial that aimed to show that there was a less than 2.5% difference in survival on the shorter course, a difference worth accepting to get a marked reduction in side effects and therefore an improvement in quality of life.

What did it find?

  • Three months of chemotherapy was no worse than six months of the same treatment. The proportion of patients who survived to three years without disease progression was 76.7% after three-month treatment and 77.1% after six-month treatment (hazard ratio [HR] 1.006, 95% confidence interval [CI] 0.909 to 1.114).
  • Peripheral neuropathy was more common in patients treated for six months, affecting 58% compared with only 25% in the three-month group.
  • Overall more people in the six-month group experienced the most severe side effects, affecting 59% compared with 36% of the three-month group. Alongside neuropathy these included diarrhoea, nausea and low white cell count.
  • Quality of life assessments revealed that the difference between groups was mainly restricted to months four, five and six when the six-month group were still receiving treatment. After this, there was little difference between groups up to six years.
  • Site or stage of cancer made no difference to disease-free survival. However, there was some difference between the two chemotherapy regimens. Three months of CAPOX treatment was not inferior to six months. However, fewer people received FOLFOX, so we can’t be sure that the shorter course of this regimen is as good as the longer.
  • These results were combined with the other trials giving similar results.

What does current guidance say on this issue?

NICE guidance (2006) recommends the options below following surgery for stage III colon cancer:

  • Capecitabine as single therapy.
  • Oxaliplatin in combination with 5-fluorouracil and folinic acid.

It’s advised that the choice of chemotherapy should be made jointly by individuals and their clinicians after an informed discussion. This should take into account contraindications to treatment, side effects of the drug(s) and the method of administration, as well as the clinical condition and preferences of the individual.

What are the implications?

This study provides good evidence that a shorter duration of oxaliplatin-containing chemotherapy could halve the serious side effects compared with the standard six months, with little effect on survival.

Chemotherapy was not randomised but decided on an individual basis and patient characteristics – including disease risk, other illnesses and concerns about side effects, which remain important when choosing the appropriate treatment course.

Citation and Funding

Iveson TJ, Kerr RS, Saunders MP, et al. 3 versus 6 months of adjuvant oxaliplatin-fluoropyrimidine combination therapy for colorectal cancer (SCOT): an international, randomised, phase 3, non-inferiority trial. Lancet Oncol. 2018;19(4):562-78.

This trial was funded by the National Institute for Health Research Efficacy and Mechanism Evaluation (project number 09/800/34) and supported by the Medical Research Council, Swedish Cancer Society and Cancer Research UK Core Clinical Trials Unit Funding (Funding Ref: C6716/A9894).

Bibliography

Cancer Research UK. Bowel cancer statistics. London: Cancer Research UK; accessed 2018.

Cancer Research UK. Bowel cancer incidence statistics. London: Cancer Research UK; accessed 2018.

NICE. Capecitabine and oxaliplatin in the adjuvant treatment of stage III (Dukes' C) colon cancer. TA100. London: National Institute for Health and Care Excellence; 2006.

NICE. Colorectal cancer: diagnosis and management. CG131. London: National Institute for Health and Care Excellence; 2014.

Expert commentary

Many guidelines worldwide recommend a six-month combination of a fluoropyrimidine chemotherapy drug with oxaliplatin for high-risk stage II and III colorectal cancer as adjuvant treatment post-surgery. Side effects of oxaliplatin, including disabling neuropathy, increase with dose.

The SCOT trial enrolled 6,088 patients and demonstrated similar effectiveness with a three-month chemotherapy course with the same drugs. Less than half as many patients reported severe neuropathy. Quality of life scores were better with this regimen.

The SCOT regimen gives the potential to greatly improve the quality of life of these patients and improve acceptability and uptake of the treatment.

Kenneth Keogh, Post CCT Pelvic Oncology Fellow, Morriston Hospital; Trainees Forum Editor "Bulletin"; Associate Editor, Annals of Royal College of Surgeons