Intravenous calcium plus magnesium (IV CaMg) given before or after adjuvant FOLFOX chemotherapy has absolutely no effect on the development of sensory neurotoxicity induced by oxaliplatin, new research shows. Findings were presented July 6, 2013 during the European Society for Medical Oncology 15th World Congress on Gastrointestinal Cancer in Barcelona.

Axel Grothey, MD, professor of Oncology at the Mayo Clinic in Rochester, Minnesota, and multicenter colleagues found that IV CaMg has no effect on any aspect of sensory neuropathy commonly seen in patients who receive oxaliplatin-based chemotherapy relative to placebo controls.

“We actually surveyed oncologists around the world and more or less 50% of them said they use IV CaMg based on non-definitive data because there was such an unmet need,” Grothey told 

. “For oncologists like myself who believed it could work, this study changes our standard of care, because now we know IV CaMg doesn’t work. It’s unfortunate, but it shows that even negative trials can be very informative for clinical practice.”

The N08CB prospective, randomized, phase III study enrolled 362 patients with colon cancer who were undergoing adjuvant FOLFOX chemotherapy. Patients were randomized to one of three treatment arms. The first arm received IV CaMg (1 g calcium gluconate and 1 g magnesium sulfate) before and after chemotherapy. The second group received IV placebo before and after chemotherapy, and the third received IV CaMg prior to chemotherapy but placebo after chemotherapy.

The primary endpoint was cumulative sensory neurotoxicity as repeatedly measured by the sensory subscale of the European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire—Chemotherapy-Induced Peripheral Neuropathy (EORTC QLQ-CIPN20) scale. Secondary endpoints using the Common Terminology for Adverse Events (CTCAE 4.0) and an oxaliplatin-specific neurotoxicity scale were also assessed. Acute neuropathy data were also collected for 5 days following each oxaliplatin dose.

The curves mirroring the overall incidence of sensory neuropathy in each of the three treatment arms were virtually superimposable across 12 treatment cycles, Grothey said.

Time to the development of grade 2 sensory neuropathy was also not significantly different between the three treatment arms. Changes in measurements reflecting sensitivity to touching cold items as well as discomfort swallowing cold liquids were also similar across all treatment groups, Grothey reported, as were scores measuring throat discomfort and muscle cramps.

Importantly, there were no significant differences between arms regarding the doses of oxaliplatin administered or discontinuation rates from chemotherapy, and no substantial differences in acute neuropathy scores or side effects were seen between the three study arms.

 “Neurotoxicity is actually the dose-limiting toxicity of oxaliplatin—the longer we treat patients with it, the more likely they will develop neurotoxicity, and it can be disabling,” Grothey said.

Unlike other chemotherapy-induced side effects, such as diarrhea and hair loss, “neurotoxicity can also stick around for months and sometimes years, and some patients never recover from it, particularly when we are treating in a palliative setting,” he added.

Whereas other chemotherapy agents are associated with neurotoxicity, certain types of neuropathy associated with oxaliplatin are unique to the drug. For example, some patients develop sensitivity to cold which can be quite burdensome. Patients can also develop jaw spasms and throat discomfort that are again unique to oxaliplatin, Grothey continued.

The use of IV CaMg emerged a number of years ago based on the premise that the neurotoxicity of oxaliplatin was related to the chelating effect it had on calcium ion channels. Magnesium was added in an attempt to prevent the jaw spasms that some patients also develop, Grothey explained. There also were several nonrandomized trials—one of which was carried out by Grothey himself&mdash;which at least initially gave a perception of benefit from using IV CaMg to prevent oxaliplatin-induced neurotoxicity.

“There were a lot of trials showing an inconsistent effect, so there was a need to have a definitive study,” said Grothey. “We now have that definitive study, and it shows IV CaMg does not work to prevent oxaliplatin-induced neurotoxicity. This should be the nail in the coffin for using IV CaMg as a neuroprotectant against oxaliplatin-induced acute and chronic neurotoxicity.” 

	Grothey A, et al. Phase III randomized, placebo-controlled, double-blind study of intravenous calcium/magnesium (CaMg) to prevent oxaliplatin-induced sensory neurotoxicity, N08CB: an alliance for clinical trials in oncology study. Presented at: ESMO 15th World Congress on Gastrointestinal Cancer; July 3-6, 2013; Barcelona, Spain. Abstract 0-0032.

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Intravenous calcium plus magnesium given before or after adjuvant FOLFOX chemotherapy has absolutely no effect on the development of sensory neurotoxicity induced by oxaliplatin.

IV Calcium/Magnesium Has No Effect on Oxaliplatin-Induced Neuropathy

A simple and inexpensive blood test is being developed that can be used to screen patients for premalignant colorectal cancer (CRC) lesions which, once perfected, will be a real “game changer,” predict researchers at ESMO 15th World Congress on Gastrointestinal Cancer.

“My laboratory just published this work a week ago,” C. Richard Boland, MD, chief of gastroenterology, Baylor University Medical Center, Dallas, Texas, told 

. “And if it works, people who won’t have a colonoscopy, sigmoidoscopy, or won’t get their stool tested year after year might well have a blood test. What we want is to find a test that will be good enough that a person can be reassured that they do not need a colonoscopy for maybe a year, and that will change everything.”

 (2013;105(12):849-859), investigators from the Gastrointestinal Cancer Research Laboratory at Baylor University Medical Center set out to determine whether several oncogenic microRNAs that negatively regulate tumor-suppressor genes could be used as potential serum biomarkers in human CRC.

Investigators first screened expression in medium from two CRC cell lines to determine whether microRNA-21 and microRNA-31 are secretory microRNAs. They then analyzed serum from 12 patients with CRC and 12 controls to see if microRNA-21 was released into the blood stream. The same team then went on to validate expression of candidate microRNAs in serum samples from a cohort of 186 CRC patients; 60 postoperative patients; 43 patients with advanced adenomas, and 53 control subjects.

In this validation cohort, Boland and his colleagues found that microRNA-21 levels were statistically significantly elevated in preoperative serum from both patients with adenomas as well as those with CRC (

<.001 for both groups). Importantly, they also found that the expression of the same microRNA dropped in postoperative serum in patients who had undergone curative surgery (

<.001) and that serum microRNA levels “robustly distinguished” patients with adenomas and CRC from controls.

Furthermore, high levels of microRNA-21 expression in both serum and tissue were significantly associated with tumor size, distant metastases, and poor survival. “The sensitivity of the test for colon cancer is still only 82%—and for advanced adenomas it’s 72%&mdash;so it’s not ready to be marketed yet,” Boland said. “But we can look at other microRNAs. In fact, we already have data that suggests other microRNAs may be involved in CRC and could be good predictors of what’s going on. So, we can build on what we have and we’re already starting a prospective trial.”

In the meantime, Boland reminded delegates at the World GI Congress that colonoscopy is still the “gold standard” for CRC screening and is recommended in the United State for all patients aged 50 years and over. However, the test does have significant shortcomings—it’s invasive, it can cause bleeding and perforation (though uncommon), and there is considerable variability in terms of quality of the test done and subsequent impact from the test on patient outcomes.

“Colonoscopy may still be the best test, but it’s far from perfect. Besides, people won’t do it—they have to do the prepping; they understand the dangers of colonoscopy; and the test is expensive,” Boland noted. “So, it’s my belief that when we have our first good blood test to screen for colon cancer, it will be a microRNA-based test. And while people will still need to have a good colonoscopy to locate the lesion, a microRNA test has the potential to be a simple, inexpensive test and one of the easier ones to do in any molecular laboratory.”

A simple and inexpensive blood test is being developed that can be used to screen patients for premalignant colorectal cancer lesions which, once perfected, will be a real game changer.

Simple, Inexpensive Blood Test Poised to Be a Real "Game Changer" in CRC Screening

Better responders within a cohort of patients from the VELOUR study derive enhanced benefit from aflibercept when combined with FOLFIRI, a post-hoc analysis of the study shows. Findings were presented during a poster session at the ESMO 15th World Congress on Gastrointestinal Cancer in Barcelona, Spain.

Ian Chau, MD, Royal Marsden Hospital, Sutton, United Kingdom, and colleagues reported that median overall survival (OS) in the intent-to-treat (ITT) population was 13. 50 months for aflibercept plus FOLFORI-treated patients compared with12.06 months for placebo plus FOLFORI patients (

 = .0032). In the subgroup categorized as “better responders,” median OS was 16.2 months for those who received additional aflibercept compared with a median OS of 13.1 months for placebo plus FOLFIR patients. The subgroup of “better responders” constituted two-thirds of all patients in both arms of the study, the investigators noted.

“The difference in survival between treatment arms also increased over time,” the authors stated. They also noted that there was a significant improvement in progression-free survival (PFS) with aflibercept compared with placebo in both the ITT population and in the better responders subgroup. In the ITT population, mean PFS was 6.9 months in the aflibercept plus FOLFIRI arm compared with a median PFS of 4.6 months for the placebo plus FOLFIRI arm—a 25% improvement in PFS time in favor of aflibercept (hazard ratio = 0.75; 

In the better responders subgroup, the median PFS was 7.2 months for the aflibercept plus FOLFIRI arm versus 4.8 months for placebo plus FOLFIRI for a median difference of 2.4 months between the two treatment arms.

		Median Overall Survival in Patients With and Without Prior Bevacizumab Therapy

There was also no difference in median OS among VELOUR patients who had received prior bevacizumab treatment compared with those who had not (

Investigators also noted that in the ITT population, the overall response rate (ORR) consisting of both complete and partial responses was 19.8% for the aflibercept plus FOLFIRI cohort compared with 11.1% for their placebo counterparts. For the better responders subgroup, the ORR was 23.7% among those who received additional aflibercept versus 11% for placebo controls.

The most commonly reported adverse events (AEs) in the aflibercept plus FOLFIRI arm were gastrointestinal-related issues. This was true for both the overall VELOUR population and for the better responders subgroup. Grade 3 and higher AEs in the aflibercept plus FOLFIRI arm included diarrhea, stomatitis, fatigue, hypertension, and neutropenia. However, the authors noted that the AEs in the better responders subgroups closely approximated those in the ITT population and were consistent with expected anti-VEGF class effects.

“The addition of aflibercept to FOLFIRI chemotherapy in patients with metastatic CRC that is resistant to or has progressed after an oxaliplatin-containing regimen resulted in clinically meaningful survival gains in the better responders subgroup,” the investigators concludes. “And these statistically significant and clinically meaningful efficacy benefits in the better responders subgroup were obtained without any compromise in safety.”

	Chau I, et al. A VELOUR post hoc subset analysis: prognostic groups and treatment outcomes in patients with metastatic colorectal cancer treated with aflibercept and FOLFIRI. Presented at: ESMO 15th World Congress on Gastrointestinal Cancer; July 3-6, 2013; Abstract P-0196.

Better responders within a cohort of patients from the VELOUR study derive enhanced benefit from aflibercept when combined with FOLFIRI, a post-hoc analysis of the study shows.

Better Responders in VELOUR Derive Enhanced Benefit From Aflibercept

Ramucirumab, a novel monoclonal antibody that targets vascular epithelial growth factor receptor-2 (VEGFR-2), significantly prolongs survival in patients with advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma following progression on first-line therapy—the first single biologic agent to do so, according to a randomized phase III study presented July 4, 2013 at the European Society for Medical Oncology 15th World Congress on Gastrointestinal Cancer in Barcelona, Spain.

Joseph Tabernero, MD, PhD, of Vall d’Hebron University Hospital, Barcelona, and multicenter colleagues in the REGARD trial found that ramucirumab significantly prolonged overall survival (OS) by 22% (

 = .0473) as well as progression-free survival (PFS) by 52% (

<.0001) compared with placebo in patients with metastatic gastric or GEJ adenocarcinoma following progression on first-line platinum or fluoropyrimidine-containing regimens or both.

“These results confirm VEGFR-2 as a viable therapeutic target in gastric cancer,” Tabernero said, “and ramucirumab represents a potential new second-line standard of care in this patient population.”  

For the study, 355 patients were randomized to either ramucirumab (8 mg/kg IV) or placebo, given every 2 weeks until disease progression or intolerable toxicity. Approximately two-thirds of patients were >65 years of age at randomization. The primary tumor was gastric in approximately75% of patients, the remainder being at the GE junction. A significant proportion of patients in both arms also had three or more metastatic sites prior to randomization.

Few to no patients achieved a complete response (CR) but 2.9% of ramucirumab patients achieved a partial response (PR) as did 2.6% of placebo patients. Disease stabilized in more than twice as many patients in the active therapy arm (~45%) compared with approximately 20% among placebo controls. Disease control (CR plus PR plus stable disease) was also achieved in almost half of patients on active therapy versus 23% for controls (

Tabernero reported that median OS was 5.2 months for patients receiving ramucirumab compared with 3.8 months for placebo. At 6 months, 42% of patients on ramucirumab were still alive compared with 32% of placebo controls. At 12 months, 18% and 12% of patients were alive on active versus control therapy, respectively. The median interlude before patients progressed was 2.1 months for the ramucirumab arm compared with 1.3 months for placebo, Tabernero added.

At 12 weeks, 40% of patients on active treatment still had not progressed compared with only 10% of placebo patients. Both the OS and the PFS benefit seen with the VEGFR-2 inhibitor appeared consistent across all subgroups analyzed and after adjustment for other prognostic factors. Following discontinuation of treatment in REGARD, 29% of patients formerly treated with ramucirumab went on to chemotherapy compared with approximately 37% of those formerly on placebo.

Overall, investigators felt that ramucirumab had an acceptable safety profile. Rates of grades 3 and 4 fatigue and anemia were 6.4% for each event in patients on active therapy, but these events were more common among placebo patients (9.6% and 7.8%, respectively). Rates of hypertension and bleeding or hemorrhage were higher for those receiving active therapy, but no specific treatment effects were seen in >10% of patients on active therapy.

	Tabernero J, et al. REGARD phase III, randomized trial of ramucirumab in patients with metastatic gastric or GEJ adenocarcinoma following progression on first-line chemotherapy. Presented at: ESMO 15th World Congress on Gastrointestinal Cancer; July 3-6, 2013; Abstract 0-0008.

Ramucirumab significantly prolongs survival in patients with advanced gastric or gastroesophageal junction adenocarcinoma following progression on first-line therapy.

Novel VEGFR-2 Inhibitor Prolongs Survival in Advanced Gastric/GEJ Adenocarcinoma

Treatment with weekly nab-paclitaxel plus gemcitabine remains a strong independent predictor of both overall survival (OS) and progression-free survival (PFS) in patients with metastatic pancreatic cancer compared with gemcitabine alone, even after correcting for all confounding prognostic variables, a new analysis of the MPACT study shows.

Josep Tabernero, MD, PhD, of Vall d’Hebron University Hospital, Barcelona, Spain, and multicenter colleagues found that after correcting for known prognostic factors in metastatic pancreatic cancer, treatment with weekly nab-paclitaxel plus gemcitabine improved OS by 28% and PFS by 34% relative to gemcitabine alone in predominantly stage IV metastatic pancreatic cancer patients who had received no prior treatment for metastatic disease (

Tabernero reported these findings July 3, 2013 at the European Society of Medical Oncology 15th World Congress on Gastrointestinal Cancer in Barcelona

“In order to understand what the real impact of the addition of nab-paclitaxel is, we needed to consider other well-known prognostic factors that are usually evaluated in pancreatic cancer,” Tabernero explained in an interview with 

“The data show that by introducing all these variables in our multistep model, the addition of nab-paclitaxel to gemcitabine continues to be the most important factor. So this is another statistical model to show that there is no bias related to other confounding factors and that the treatment effect is the most significant one.”

For the MPACT trial, 842 patients with metastatic pancreatic cancer were randomized to receive nab-paclitaxel, 125 mg/m

 on days 1, 8, and 15 every 4 weeks (that is, every week for 3 weeks, with the 4th week off) or the same dose of gemcitabine alone weekly for 7 weeks followed by 1 week of rest, and then on days 1, 8, and 15 every 4 weeks from cycle 2 onwards. Patients were also stratified by region, presence of liver metastases, and Karnofsky performance status (KPS ≥70).

At 36 months, median OS in the intent-to-treat (ITT) population was 8.5 months in the combination arm compared with 6.7 months for the gemcitabine alone arm (

“KPS, presence of liver metastases, age, region, and number of metastatic sites were the most important predictors of survival,” Tabernero said.

On univariate analysis, the baseline for cancer antigen 19-9 (CA19-9), a tumor marker for pancreatic cancer, also significantly predicted OS in the overall cohort. However, after correction for an array of other prognostic factors on multivariate analysis, CA19-9 no longer emerged as significant predictor of OS.

For the PFS analysis, MPACT investigators found that the region of Australia; being 65 years of age and older; a KPS of 70-80, and the presence of liver metastases were all significant predictors of worse PFS.

“The safety profile of this regimen is also acceptable and manageable compared to other regimens, so this study suggests that nab-paclitaxel plus gemcitabine should definitely be considered as one of the most important treatment options for this disease,” Dr. Tabernero concluded.

	Taberner J, Von Hoff DD, Moore MJ, et al. Phase III trial (MPACT) of weekly nab-paclitaxel plus gemcitabine in metastatic pancreatic cancer: influence of prognostic factors of survival. Presented at: ESMO 15th World Congress on Gastrointestinal Cancer; July 3-6, 2013; Abstract 0-001.

Treatment with weekly nab-paclitaxel plus gemcitabine remains a strong independent predictor of both OS and PFS in patients with metastatic pancreatic cancer compared with gemcitabine alone.

Nab-paclitaxel Plus Gemcitabine a Strong Predictor of Survival in Metastatic Pancreatic Cancer

Patients who express low levels of a critical gene involved in transporting gemcitabine into pancreatic tumor cells have virtually no overall survival (OS) advantage from treatment with the drug in the adjuvant setting, according to research presented at the ESMO 15th World Congress on Gastrointestinal Cancer in Barcelona, Spain.

Christophe Louvet, MD, PhD, Hopital Saint Antoine, Paris, France, reviewed a series of studies in which patients with pancreatic cancer who received gemcitabine following surgical resection of the tumor had dramatically different outcomes based on whether they were high- or low- to moderate-expressers of the human equilibrative nucleoside transporter (hENT1) protein responsible for activating gemcitabine. In the French-Belgium experience, for example, (

Marechal R et al. Gastroenterology, 2012 ;143(3) :664-74)

, a total of 434 evaluable patients were assigned to either adjuvant treatment following surgical resection of their tumor or no adjuvant treatment.

Those who were assigned to adjuvant treatment received either gemcitabine or a non-gemcitabine regimen consisting of radiotherapy alone or radiotherapy plus 5-fluorouracil (5-FU). At 60 months follow-up, OS in patients who had high levels of hENT1 expression and who had received gemcitabine had a 66% longer survival time versus those with low- to moderate-hENT1 expression (

The same clinically meaningful difference in OS was also seen in moderate to high-expressers of deoxycytidine kinase (dCK) where high dCK expression was associated with a 43% longer survival time compared with low-dCK expressers. dCK is involved in the activation of gemcitabine once inside the tumor cell.

In contrast, no difference in OS was seen among the French-Belgium cohort who received non-gemcitabine adjuvant therapy regardless of their level of hENT1 or dCK expression. In the randomized ESPAC1/3 trial presented by 

 at ASCO this year, “investigators found exactly the same thing,” Louvet observed. Again stratified into high- versus low-hENT1 expressers, median survival was 26.2 months in high-hENT1 expressers following treatment with gemcitabine versus 17.1 months among those who expressed low levels of the same protein (

Again in contrast, median OS between high hENT1 expressers at 25.6 months and low hENT1 expressers at 21.9 months was not statistically significant following adjuvant treatment with 5-FU (

 = .0362). “Unfortunately, we still have problems diagnosing hENT1 and we cannot be sure which antibody test is best to test patients for hENT1 expression,” Louvet said.

However, looking at results from several different trials of pancreatic cancer patients—the RTOG in primary tumor patients and two meta-analyses&mdash;Louvet estimated that approximately two-thirds of patients with pancreatic cancer are low- to null-expressers of hENT1. Given this, “we can say that gemcitabine might be considered as placebo for two-thirds of pancreatic cancer patients in the adjuvant setting because gemcitabine is unable to enter the tumor cell,” Louvet said.

It also suggests that the majority of pancreatic cancer patients who receive any sort of couplet regimen containing gemcitabine following surgical resection are really only receiving single-agent therapy, he added.

In the future, Louvet argued that pancreatic cancer patients should be stratified into high- versus low- to moderate-hENT1 expressers; based on their levels of expression, gemcitabine would be a good choice for those with high levels of hENT1 expression whereas FOLFIRINOX would be a better choice for those with low to moderate levels of hENT1 expression.

“Adjuvant treatment with 6 months of gemcitabine remains the 2013 gold standard after pancreatic cancer resection,” Louvet concluded. “But in the very near future, treatment will be based on molecular approaches in order to customize treatment and improve overall outcomes of patients with pancreatic cancer.”

Patients who express low levels of a critical gene involved in transporting gemcitabine into pancreatic tumor cells have virtually no overall survival advantage from treatment with the drug in the adjuvant setting.

Pam Harrison