Nix Oxaliplatin, Up Radiation in Locally Advanced Rectal Cancer

MIAMI BEACH  – For patients with locally advanced rectal cancer, hold the oxaliplatin, but up the preoperative radiation dose from 45 to 50 Gy, French investigators advised oncologists at a meeting here.

Chemoradiation with a less-toxic capecitabine (Xeloda)–containing regimen and 50 Gy radiation should become the standard of therapy for preoperative chemoradiation in patients with locally advanced rectal cancer, according to Dr. Jean-Pierre Gerard and his colleagues.

The assertion is based on evidence from a large phase III trial presented by Dr. Gerard and from earlier American and Italian studies suggesting better local control with higher radiation doses, but added toxicity from oxaliplatin (Eloxatin) without additional therapeutic benefit.

The evidence also suggests that capecitabine, which is given orally, can replace intravenous 5-fluourouracil (5-FU) infusions in this clinical setting, said Dr. Gerard, a radiation oncologist at the Centre Antoine-Lacassagne in Nice, France.

"When we take all the trials together, we propose the regimen we call ‘CAP50,’ where we give 5 weeks of treatment with 50 Gy, not 45 Gy. You sterilize more tumor, have only 4% local recurrence, replace 5-FU infusion with capecitabine by mouth – it’s very easy – and you delete oxaliplatin," Dr. Gerard said in a briefing at annual meeting of the American Society for Radiation Oncology, where he gave 3-year results from the ACCORD 12 trial.

Not everyone was convinced. Dr. Karyn A. Goodman, the invited discussant of Dr. Gerard’s featured talk in the meeting’s plenary session, said it’s difficult to tease out this conclusion from the data presented because the ACCORD 12 investigators, in an attempt to conduct a "pragmatic trial," moved the goalposts by changing the treatment parameters three times.

"The investigators took several leaps in the design of the study which make interpretation of their results more difficult," said Dr. Goodman from Memorial Sloan-Kettering Cancer Center in New York.

"First, they simultaneously increased the radiation dose to 50 Gy in 2-Gy fractions and added oxaliplatin in the experimental arm," she explained.

"Second, they changed the baseline chemotherapy from 5-FU to capecitabine, which is at a slightly lower dose than has been given in other preoperative chemoradiotherapy trials.

"Third, the primary end point was pathologic complete response, a marker for response that has not been validated as a surrogate for overall survival, and has even been shown ... to have not yet fulfilled the criteria to be a surrogate for overall survival or local control."

In addition, the study was powered to detect a large difference in pathological complete response rate, thus allowing for a smaller sample than would ordinarily be required to evaluate the effect of adjuvant therapy on colorectal cancer, Dr. Goodman added.

The rationale for ACCORD 12 came from large studies showing that even with total mesorectal excision, preoperative radiotherapy decreased local recurrence rates and that chemoradiotherapy – particularly preoperatively – was better than radiotherapy alone.

The trial designers emulated the design of the Italian STAR 01 trial (which was ongoing at the time the ACCORD 12 was started) by including oxaliplatin and with 50 Gy radiation prior to surgery in 747 patients. That trial, results of which were reported at the 2009 ASCO annual meeting, showed that oxaliplatin added nothing but toxicity to the therapeutic regimen

Dr. Gerard presented 3-year results from the study on 598 patients in an intention-to-treat population. The patients were randomized to receive either preoperative capecitabine 1600 mg/m² for 5 days plus 45 Gy radiation in 1.8-Gy fractions or capecitabine at the same dose plus oxaliplatin 50 mg/m² weekly plus 50 Gy divided into 2-Gy fractions. All patients then underwent total mesorectal excision, with adjuvant therapy at the treating center\'s discretion.

Early results, published in 2010 (J. Clin. Oncol. 2010;28:1638-44) showed no significant differences between capecitabine and 45 Gy (Cap45) and capecitabine plus oxaliplatin and 50 Gy (Capox50) for the primary end point of pathological complete response rates according to the Dworak criteria: 13.9% for 287 patients treated with Cap45 vs. 19.2% for 287 patients treated with Capox50 (P = .09). Grade 3 or 4 toxicities, however, were twice as high in the Capox50 patients, at 25%, compared with 11% of patients treated with Cap45 (P less than .001). This analysis was for the as-treated population.

At 3 years (intention-to-treat population, 299 patients in each arm), Dr. Gerard reported no significant differences between Cap45 and Capox50 in local recurrence (6.1% vs. 4.4%), distant metastases (25% vs. 21%), disease-free survival (71% vs. 73%), overall survival (85% vs. 88%), or grade 3 or great toxicities (2.7%, 4 patients, vs. 1.3%, 2 patients).

In exploratory analyses, significant predictors for 3-year disease-free survival were pathological stage (T0-1 vs. T2 or T3; P less than .00001), nodal status (N0 vs. N1-2; P less than .0001), and close margins (1 mm or less vs. greater than 1 mm; P less than .0001).

The investigations concluded that oxaliplatin increases toxicity (primarily diarrhea) without affecting pathological response, that 50 Gy over 5 weeks is compatible with surgery and may help to sterilize the surgical sample, and that capecitabine has activity equivalent to that of 5-FU, without the need for intravenous infusion.

The ACCORD 12 trial was supported in part by Roche and Sanofi-Aventis together with a grant of the French National Program of Research Programmes Hospitaliers de Recherche Clinique. It was conducted under the auspices of Institut National du Cancer. Dr. Gerard and Dr. Goodman reported that they had no relevant financial disclosures.

MIAMI BEACH  – For patients with locally advanced rectal cancer, hold the oxaliplatin, but up the preoperative radiation dose from 45 to 50 Gy, French investigators advised oncologists at a meeting here.

Chemoradiation with a less-toxic capecitabine (Xeloda)–containing regimen and 50 Gy radiation should become the standard of therapy for preoperative chemoradiation in patients with locally advanced rectal cancer, according to Dr. Jean-Pierre Gerard and his colleagues.

The assertion is based on evidence from a large phase III trial presented by Dr. Gerard and from earlier American and Italian studies suggesting better local control with higher radiation doses, but added toxicity from oxaliplatin (Eloxatin) without additional therapeutic benefit.

The evidence also suggests that capecitabine, which is given orally, can replace intravenous 5-fluourouracil (5-FU) infusions in this clinical setting, said Dr. Gerard, a radiation oncologist at the Centre Antoine-Lacassagne in Nice, France.

"When we take all the trials together, we propose the regimen we call ‘CAP50,’ where we give 5 weeks of treatment with 50 Gy, not 45 Gy. You sterilize more tumor, have only 4% local recurrence, replace 5-FU infusion with capecitabine by mouth – it’s very easy – and you delete oxaliplatin," Dr. Gerard said in a briefing at annual meeting of the American Society for Radiation Oncology, where he gave 3-year results from the ACCORD 12 trial.

Not everyone was convinced. Dr. Karyn A. Goodman, the invited discussant of Dr. Gerard’s featured talk in the meeting’s plenary session, said it’s difficult to tease out this conclusion from the data presented because the ACCORD 12 investigators, in an attempt to conduct a "pragmatic trial," moved the goalposts by changing the treatment parameters three times.

"The investigators took several leaps in the design of the study which make interpretation of their results more difficult," said Dr. Goodman from Memorial Sloan-Kettering Cancer Center in New York.

"First, they simultaneously increased the radiation dose to 50 Gy in 2-Gy fractions and added oxaliplatin in the experimental arm," she explained.

"Second, they changed the baseline chemotherapy from 5-FU to capecitabine, which is at a slightly lower dose than has been given in other preoperative chemoradiotherapy trials.

"Third, the primary end point was pathologic complete response, a marker for response that has not been validated as a surrogate for overall survival, and has even been shown ... to have not yet fulfilled the criteria to be a surrogate for overall survival or local control."

In addition, the study was powered to detect a large difference in pathological complete response rate, thus allowing for a smaller sample than would ordinarily be required to evaluate the effect of adjuvant therapy on colorectal cancer, Dr. Goodman added.

The rationale for ACCORD 12 came from large studies showing that even with total mesorectal excision, preoperative radiotherapy decreased local recurrence rates and that chemoradiotherapy – particularly preoperatively – was better than radiotherapy alone.

The trial designers emulated the design of the Italian STAR 01 trial (which was ongoing at the time the ACCORD 12 was started) by including oxaliplatin and with 50 Gy radiation prior to surgery in 747 patients. That trial, results of which were reported at the 2009 ASCO annual meeting, showed that oxaliplatin added nothing but toxicity to the therapeutic regimen

Dr. Gerard presented 3-year results from the study on 598 patients in an intention-to-treat population. The patients were randomized to receive either preoperative capecitabine 1600 mg/m² for 5 days plus 45 Gy radiation in 1.8-Gy fractions or capecitabine at the same dose plus oxaliplatin 50 mg/m² weekly plus 50 Gy divided into 2-Gy fractions. All patients then underwent total mesorectal excision, with adjuvant therapy at the treating center\'s discretion.

Early results, published in 2010 (J. Clin. Oncol. 2010;28:1638-44) showed no significant differences between capecitabine and 45 Gy (Cap45) and capecitabine plus oxaliplatin and 50 Gy (Capox50) for the primary end point of pathological complete response rates according to the Dworak criteria: 13.9% for 287 patients treated with Cap45 vs. 19.2% for 287 patients treated with Capox50 (P = .09). Grade 3 or 4 toxicities, however, were twice as high in the Capox50 patients, at 25%, compared with 11% of patients treated with Cap45 (P less than .001). This analysis was for the as-treated population.

At 3 years (intention-to-treat population, 299 patients in each arm), Dr. Gerard reported no significant differences between Cap45 and Capox50 in local recurrence (6.1% vs. 4.4%), distant metastases (25% vs. 21%), disease-free survival (71% vs. 73%), overall survival (85% vs. 88%), or grade 3 or great toxicities (2.7%, 4 patients, vs. 1.3%, 2 patients).

In exploratory analyses, significant predictors for 3-year disease-free survival were pathological stage (T0-1 vs. T2 or T3; P less than .00001), nodal status (N0 vs. N1-2; P less than .0001), and close margins (1 mm or less vs. greater than 1 mm; P less than .0001).

The investigations concluded that oxaliplatin increases toxicity (primarily diarrhea) without affecting pathological response, that 50 Gy over 5 weeks is compatible with surgery and may help to sterilize the surgical sample, and that capecitabine has activity equivalent to that of 5-FU, without the need for intravenous infusion.

The ACCORD 12 trial was supported in part by Roche and Sanofi-Aventis together with a grant of the French National Program of Research Programmes Hospitaliers de Recherche Clinique. It was conducted under the auspices of Institut National du Cancer. Dr. Gerard and Dr. Goodman reported that they had no relevant financial disclosures.

MIAMI BEACH  – For patients with locally advanced rectal cancer, hold the oxaliplatin, but up the preoperative radiation dose from 45 to 50 Gy, French investigators advised oncologists at a meeting here.

Chemoradiation with a less-toxic capecitabine (Xeloda)–containing regimen and 50 Gy radiation should become the standard of therapy for preoperative chemoradiation in patients with locally advanced rectal cancer, according to Dr. Jean-Pierre Gerard and his colleagues.

The assertion is based on evidence from a large phase III trial presented by Dr. Gerard and from earlier American and Italian studies suggesting better local control with higher radiation doses, but added toxicity from oxaliplatin (Eloxatin) without additional therapeutic benefit.

The evidence also suggests that capecitabine, which is given orally, can replace intravenous 5-fluourouracil (5-FU) infusions in this clinical setting, said Dr. Gerard, a radiation oncologist at the Centre Antoine-Lacassagne in Nice, France.

"When we take all the trials together, we propose the regimen we call ‘CAP50,’ where we give 5 weeks of treatment with 50 Gy, not 45 Gy. You sterilize more tumor, have only 4% local recurrence, replace 5-FU infusion with capecitabine by mouth – it’s very easy – and you delete oxaliplatin," Dr. Gerard said in a briefing at annual meeting of the American Society for Radiation Oncology, where he gave 3-year results from the ACCORD 12 trial.

Not everyone was convinced. Dr. Karyn A. Goodman, the invited discussant of Dr. Gerard’s featured talk in the meeting’s plenary session, said it’s difficult to tease out this conclusion from the data presented because the ACCORD 12 investigators, in an attempt to conduct a "pragmatic trial," moved the goalposts by changing the treatment parameters three times.

"The investigators took several leaps in the design of the study which make interpretation of their results more difficult," said Dr. Goodman from Memorial Sloan-Kettering Cancer Center in New York.

"First, they simultaneously increased the radiation dose to 50 Gy in 2-Gy fractions and added oxaliplatin in the experimental arm," she explained.

"Second, they changed the baseline chemotherapy from 5-FU to capecitabine, which is at a slightly lower dose than has been given in other preoperative chemoradiotherapy trials.

"Third, the primary end point was pathologic complete response, a marker for response that has not been validated as a surrogate for overall survival, and has even been shown ... to have not yet fulfilled the criteria to be a surrogate for overall survival or local control."

In addition, the study was powered to detect a large difference in pathological complete response rate, thus allowing for a smaller sample than would ordinarily be required to evaluate the effect of adjuvant therapy on colorectal cancer, Dr. Goodman added.

The rationale for ACCORD 12 came from large studies showing that even with total mesorectal excision, preoperative radiotherapy decreased local recurrence rates and that chemoradiotherapy – particularly preoperatively – was better than radiotherapy alone.

The trial designers emulated the design of the Italian STAR 01 trial (which was ongoing at the time the ACCORD 12 was started) by including oxaliplatin and with 50 Gy radiation prior to surgery in 747 patients. That trial, results of which were reported at the 2009 ASCO annual meeting, showed that oxaliplatin added nothing but toxicity to the therapeutic regimen

Dr. Gerard presented 3-year results from the study on 598 patients in an intention-to-treat population. The patients were randomized to receive either preoperative capecitabine 1600 mg/m² for 5 days plus 45 Gy radiation in 1.8-Gy fractions or capecitabine at the same dose plus oxaliplatin 50 mg/m² weekly plus 50 Gy divided into 2-Gy fractions. All patients then underwent total mesorectal excision, with adjuvant therapy at the treating center\'s discretion.

Early results, published in 2010 (J. Clin. Oncol. 2010;28:1638-44) showed no significant differences between capecitabine and 45 Gy (Cap45) and capecitabine plus oxaliplatin and 50 Gy (Capox50) for the primary end point of pathological complete response rates according to the Dworak criteria: 13.9% for 287 patients treated with Cap45 vs. 19.2% for 287 patients treated with Capox50 (P = .09). Grade 3 or 4 toxicities, however, were twice as high in the Capox50 patients, at 25%, compared with 11% of patients treated with Cap45 (P less than .001). This analysis was for the as-treated population.

At 3 years (intention-to-treat population, 299 patients in each arm), Dr. Gerard reported no significant differences between Cap45 and Capox50 in local recurrence (6.1% vs. 4.4%), distant metastases (25% vs. 21%), disease-free survival (71% vs. 73%), overall survival (85% vs. 88%), or grade 3 or great toxicities (2.7%, 4 patients, vs. 1.3%, 2 patients).

In exploratory analyses, significant predictors for 3-year disease-free survival were pathological stage (T0-1 vs. T2 or T3; P less than .00001), nodal status (N0 vs. N1-2; P less than .0001), and close margins (1 mm or less vs. greater than 1 mm; P less than .0001).

The investigations concluded that oxaliplatin increases toxicity (primarily diarrhea) without affecting pathological response, that 50 Gy over 5 weeks is compatible with surgery and may help to sterilize the surgical sample, and that capecitabine has activity equivalent to that of 5-FU, without the need for intravenous infusion.

The ACCORD 12 trial was supported in part by Roche and Sanofi-Aventis together with a grant of the French National Program of Research Programmes Hospitaliers de Recherche Clinique. It was conducted under the auspices of Institut National du Cancer. Dr. Gerard and Dr. Goodman reported that they had no relevant financial disclosures.