Online First/Online Only
Articles/items published ahead of print or only online.
Thursday, August 28, 2014
BY KURT SAMSON
When administered for up to two years, the monoclonal antibody trastuzumab did not increase heart-related problems in otherwise healthy women with early-stage human epidermal growth factor receptor 2 (HER2)-positive breast cancer after chemotherapy or radiotherapy, according to results from the multinational Herceptin Adjuvant (HERA) trial, published in the Journal of Clinical Oncology (2014;32:2159-2165).
During an eight-year median follow-up period, few adverse cardiac events occurred with trastuzumab, which kills HER-2 cells. Moreover, when cardiac problems did arise, discontinuing treatment reversed them.
The drug was approved in 1998, but the Food and Drug Administration issued a black box label warning of potential cardiac risks, especially left ventricular ejection fraction (LVEF). Since then, however, several large trials have found that the risk may be lower unless women received anthracycline-based chemotherapy.
The researchers—first author is Evandro de Azambuja, MD, PhD, Medical Director of the the Breast Adjuvant Study Team (BrEAST) Data Center at Jules Bordet Institute in Brussels--note that they believe this to be the first clinical trial to evaluate cardiac events in patients taking trastuzumab for two years.
Included were 5,102 patients with normal LVEF after receiving neoadjuvant chemotherapy with or without radiotherapy randomized into either one or two years of trastuzumab. LVEF measures how much blood is being pumped from the left ventricle with each contraction. Subjects in the trial had LEVF levels of 55 percent or greater at the start of the study--LVEF of 55 percent or higher is considered normal.
A total of 1,673 patients were treated for two years, while 1,682 received trastuzumab for one year. An additional 1,744 women were in an observational cohort.
Adverse cardiac events that led to having to discontinue trastuzumab occurred in 9.4 percent of patients in the two-year arm, and in 5.2 percent of those taking the drug for one year. Cardiac deaths, incidence of severe congestive heart failure (CHF), and significant decreases in LVEF were low in all three groups of patients.
“This is reassuring for both short- and long-term patients,” de Azambuja said in an interview. “The main message from our study is that when adjuvant trastuzumab was given after the completion of all chemotherapy and radiotherapy, the incidence of trastuzumab-associated adverse events is low and reversible in the vast majority of patients if there are problems.”
Severe CHF occurred in just 0.8 percent in both the one- and two-year treatment groups, while decreased LVEF was observed in 7.2 percent of the two-year patients and 4.1 percent among one-year subjects. Among patients receiving two years of trastuzumab and had a decrease in LVEF, 87.5 percent completely recovered after treatment was halted, as did 81.2 percent of those in the one-year study arm.
He emphasized, however, that despite the low incidence of cardiac toxicity, patients treated with adjuvant trastuzumab do need to have a cardiac assessment before and during administration to ensure early detection and treatment of any cardiological problems that do occur.
“Direct communication between cardiologists and oncologists should take place prior to treatment in these patients,” de Azambuja said. “I believe that it is important for medical oncologists to carefully evaluate the cardiac risk of any of these patients before making a decision on which type of chemotherapy should be used and when adjuvant trastuzumab should be prescribed. A careful cardiac assessment, including LVEF measurement, should take place prior to chemotherapy.”
Problems with Earlier Trials
According to the authors, a problem with prior trials has been that they used LVEF values to define cardiotoxicity: “It lacks sensitivity,” de Azambuja explained. “A decrease in LVEF does not necessarily mean myocardial damage, whereas an unchanged LVEF value does not necessarily exclude myocardial damage.
“The European Society for Medical Oncology released guidelines on the surveillance of cardiac toxicity induced by anti-HER2 drugs, and according to the guides, patients should be followed with cardiac assessment before treatment; at three, six, and nine months during treatment; and then at 12 and 18 months after therapy--and if clinically indicated, patients should have their LVEF assessed at any time.”
Risk Stratification Needed
Asked for his opinion, Jersey Chen, MD, MPH, a research scientist at Kaiser Permanente’s Mid-Atlantic Permanente Research Institute, said he thinks the findings are accurate for the patients included in the study, but for older women--especially those with diabetes and hypertension—the cardiac risks do appear to be significantly greater.
“Trastuzumab trials can underestimate these risks because they tend to involve younger subjects with fewer cardiac risk factors, and in this study many subject fell into this category,” he said.
In a paper published in the Journal of the American Heart Association earlier this year, he and his colleagues (first author was Ghideon Ezaz, MD, MPP) found an almost twofold increase in cardiomyopathy and heart failure among women over an average of 73 years of age who had received trastuzumab (doi: 10.1161/JAHA.113.000472). When factors such as adjuvant chemotherapy, coronary artery disease atrial fibrillation or flutter, diabetes, hypertension, and renal failure were stratified, the three-year risk scores ranged from a low of 16.2 percent to a high of 39.5 percent.
In a 2012 study of Surveillance, Epidemiology, and End Results (SEER) data, published in the Journal of the American College of Cardiology (2012;60:2504-2512), Chen and colleagues at Yale examined the rates of heart failure and cardiomyopathy after trastuzumab therapy and chemotherapy in some 45,000 older women with early-stage breast cancer. The adjusted three-year rates for both heart failure and cardiomyopathy were higher (32.1 per 100 patients) in women receiving trastuzumab and 41.9 for those given anthracycline and trastuzumab, when compared with patients who received no adjuvant therapy (18.1 per 100 patients).
“I think the question remains open,” he said, adding that some kind of risk-benefit system should be created based on all of these factors and each individual person’s risk of cancer mortality. “It could be a trade-off in terms of risk, and where indicated, a shorter course of trastuzumab might be in order.”
He said he and his colleagues are now looking into developing a risk-scoring algorithm similar to the Framingham Risk Score, which is widely used to estimate cardiovascular risk, including comorbidities.
Risks and Benefits
Also asked her opinion, Edith A. Perez, MD, the Serene M. and Frances C. Durling Professor of Medicine and Deputy Director of the Mayo Clinic Cancer Center in Jacksonville, Florida, said she was not surprised by the new findings and that the long-term data are similar to those at Mayo.
“I think what is most important here is that any problems that arise in trastuzumab patients are reversible with discontinuation,” she said. “FDA’s black box was mandated in the 1980s, and treatment has moved beyond that. The real risk is using it with anthracyclines or cytotoxic chemotherapy agents. Since then there is wide awareness of these risks, and today trastuzumab would never be used concurrently with anthracyclines.”
Still, she noted that greater awareness of newer studies is needed by oncologists. There is also a need for longer-term outcomes data with follow-up periods of 10 to 15 years.
“My take is that there is some risk of cardiotoxicity with trastuzumab, but it is reversible in most cases, and the benefit of survival in general outweighs the risk.”
Monday, August 25, 2014
BY KURT SAMSON
Presurgical application of a gel containing an active metabolite of tamoxifen was just as effective in inhibiting cell proliferation as oral tamoxifen in women with estrogen receptor-positive ductal carcinoma in situ (DCIS), but with lower levels in the blood and hence potentially fewer serious side effects, according to a small Phase II trial.
In the study, published in Clinical Cancer Research (2014;20:3672-3682), researchers tested the gel, which contains the breakdown product 4-hydroxytamoxifen (4-OHT), in 26 patients enrolled in the randomized, double-blind, placebo-controlled study, 12 of whom used the gel. After six to 10 weeks, the gel was found to reduce Ki-67, a key marker of cell proliferation in the breast, at rates comparable to those achieved with oral tamoxifen over a similar period of time.
The team, led by senior author Seema A. Khan, MD, Professor of Surgery at Northwestern University Feinberg School of Medicine, found equal amounts of 4-OHT in the breast tissue of patients in both the gel and oral arms (5.8 versus 5.4 ng/g, respectively) collected during surgery, but the level of 4-OHT in the blood of patients from the gel arm was 5.5-fold lower than in those in the oral tamoxifen arm (0.2 versus 1.1 ng/ml, respectively).
Oral tamoxifen decreases the risk of cancer recurrence in the same breast and secondary primary cancer in the other breast. Studies have shown, however, that as many as half of eligible women decline or fail to adhere to treatment out of concern for side effects, which can include an increased risk of thromboembolism, endometrial and uterine cancers, hot flashes, vaginal, and other symptoms.
Oral tamoxifen must be broken down by the liver into its active components, which include 4-OHT, but it then enters the bloodstream. Because of this, harmful side effects can arise, such as the activation of certain proteins that cause blood clots and increased risk of endometrial and uterine cancers.
“We found that applying the gel to the skin resulted in high drug levels in the breast but not in the blood, which mean that it maintains the effectiveness of the drug but should minimize serious side effects,” she said in an interview. “When the 4-OHT gel is applied directly to breast skin it is not directly metabolized by the liver, which should eliminate the risk of blood clots.”
Unfortunately, though, the trial had to end before the researchers could accrue their full target of subjects because the shelf-life of 4-OHT gel expired and the manufacturer had made a decision to stop making it. “Until then we had worked up a good head of steam, so it was back to the drawing board,” Khan said.
She noted, though, that other tamoxifen breakdown metabolites are either available or in development and the team is planning a study using a similar gel, endoxifen, another tamoxifen breakdown metabolite. At the most recent San Antonio Breast Cancer Symposium, Matthew P. Goetz, MD, Deputy Director of the Mayo Clinic Breast Cancer Specialized Program of Research Excellence, reported encouraging anti-tumor results using the oral form of endoxifen in a Phase I trial involving 22 women with estrogen receptor (ER)-positive breast cancer (Abstract PD3-4)
In the Northwestern trial (first author is Oukseub Lee, PhD), all the patients had ER-positive ductal carcinoma in situ and were between the ages of 45 and 86. Starting six to 10 weeks before surgery, half of the women applied 1 ml of the gel to the skin of each breast every morning. Patients in the oral tamoxifen group took a 20 mg tamoxifen capsule every day. One ml of the gel contains 2 mg of 4-OHT.
Each patient provided blood samples at the beginning and end of the trial and completed the Breast Cancer Prevention Trial Eight Symptom Scale (BESS) questionnaire at 15 days, at the end of the study, and at a post-surgery visit.
Responses to the questionnaire showed that the women who applied tamoxifen gel had no significant improvement over those in the oral medication arm in vaginal or gastrointestinal symptoms, hot flashes, or night sweats. Khan noted that such side effects, although not serious, may be responsible for the less than optimal adherence rates to oral tamoxifen.
‘Intrigued, but Still Early’
Asked for her opinion for this article, Anees Chagpar MD, Director of the Breast Center at Smilow Cancer Hospital of Yale University School of Medicine, said, “I am not sure we are quite ready to switch to the gel yet. This was a small study, with just 12 women in the tamoxifen-gel arm. While I am encouraged that Ki-67 was reduced to the same degree in both oral and topical gel arms, and that both resulted in similar side effects like vaginal drying and hot flashes, it may be premature to draw any conclusions from differences in clotting profile because the study was not powered for this endpoint, and actual thromboembolic events were not quantitated.
“Even so, I am intrigued,” she continued. “The study was well thought out, and I like the presurgical window design. While the authors wondered whether the study accrued slowly as patients did not want to delay surgery, it allowed for pre- and post-Ki67 measurements that were critical for discovering that perhaps transdermal tamoxifen therapies deserve more research.”
Chagpar noted that transdermal approaches for hormonal therapy have so far not generated much interest. “This study, however, suggests that such an approach might be beneficial. I wonder if a patch might be more conducive for patients rather than the gel, and perhaps a larger randomized trial with longer follow-up would provide greater insight into whether the changes noted in coagulation parameters will translate into a meaningful difference in thromboembolic events.”
Khan said that there is interest in a transdermal patch of tamoxifen breakdown, including one study of an NSAID patch used for pain relief by athletes that might also provide some anti-inflammatory benefits in breast cancer. The researchers, though, found that distribution of the active agent was uneven with the patch. Moreover, it was deemed more intrusive by trial subjects.
“We have a study of a gel containing an anti-progesterone agent and endoxifen gel that we expect to be ready to start this fall. It should take about two year to complete and another year for the data to be analyzed. In terms of timing, realistically the likelihood of widespread availability of some type of tamoxifen gel is probably seven to eight years away.”
Sunday, August 24, 2014
BY KURT SAMSON
Older men diagnosed with depression who develop localized prostate cancer are more likely to have more aggressive cancers, receive less effective treatments, and survive for shorter times than those who are not depressed, a multi-institutional study has found.
“To the best of our knowledge, this is the first study demonstrating that a preexisting diagnosis of depressive disorder is independently associated with treatment choice and outcomes of localized prostate cancer,” said the lead author, Jim C. Hu, MD, MPH, the Henry E. Singleton Professor of Urology and Director of Robotic and Minimally Invasive Surgery at the David Geffen School of Medicine at UCLA.
The team also included Sandip M. Prasad, MD, MPhil, of Medical University of South Carolina, the first author; as well as Scott E. Eggener, Stuart R. Lipsitz, Michael R. Irwin, and Patricia A. Ganz.
The observational study, available online ahead of print in the Journal of Clinical Oncology (examined data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results Medicare database. The researchers focused on 41,275 men diagnosed with localized prostate cancer between 2004 and 2007 and observed through 2009, including 1,894 who had a diagnosis-related group code of depressive disorder filed within two years prior to their cancer diagnosis.
Across all risk factors, men with depressive disorder had worse overall mortality, with a relative risk of 1.86, but there was no variation in clinicopathologic characteristics among the men. Those with depressive disorder were also less likely to seek out definitive therapy such as surgery or radiation and to instead elect androgen-deprivation therapy or expectant management/“watchful waiting.”
Hu explained that treatment disparity and negative outcomes may be the result of several factors, including bias against people with mental illness, depression's impact on cancer's biological processes, a patient's lack of investment in his general health and/or disinterest in more effective care, and physicians missing opportunities to more fully explain treatment options.
"The effect of depressive disorders on prostate cancer treatment and survival clearly warrants further study because both conditions are relatively common in men in the United States," he said. “Although demographic and socioeconomic differences are known to affect treatment and outcomes in prostate cancer, the effect of mental health disorders remains unclear.”
Studies in patients with other cancers, including breast and liver cancers, have also shown that depressed patients do not get the best treatment and tend to have worse overall survival, he added.
The new study also found that men with prostate cancer were more likely to be depressed if they were older, Caucasian or Hispanic, unmarried, lived in non-metropolitan areas, and had lower incomes as well as other medical problems. Overall, they were also more likely to have high-risk disease compared with men without depression, and saw a physician, on average, 43 times in the two years before cancer diagnosis, compared with an average of 27 visits by men without depression.
"This was surprising,” Hu said. “The results suggest a newly identified disparity in the management of men with incident prostate cancer, and additional efforts are needed to better understand and address this issue.”
The challenge is threefold, he continued. The first is to ensure that such patients are getting and taking their medication as indicated and showing up for radiation treatment: “I believe some providers may not be emphasizing the need, although it is probably more likely due to patients not adhering to instructions. Second, we need greater focus on this issue. The third challenge is to better understand why survival rates are lower in these patients. There may be biological factors.”
He said a smaller study is needed in order to more closely investigate the issues involved.
“We need to get away from a panoramic exploration--there appears to be a microcosm of patients who fall into this category. And we need focus groups on why they are less likely to undergo radiotherapy.”
He noted that this is similar to investigations when it was learned that suicides increased among some heart attack patients who balked at undergoing percutaneous coronary angioplasty, and the same has been found in women diagnosed with a certain type of aggressive breast cancer.
“One could infer that these patients are more vulnerable,” he said. “The best way to address this might be to provide greater access to care and better ways to identify depression, especially in aging men.”
Asked for his opinion for this article, Alexander S. Parker, PhD, the Cecilia and Dan Carmichael Family Associate Director for the Center for Individualized Medicine and Vice Chair of the Department of Health Sciences Research at Mayo Clinic in Jacksonville, Florida, said that while this is a large, very well-designed observational study addressing a long-standing issue in prostate cancer, it is important to recognize some of its limitations.
“We need to be careful not to over-interpret the results,” he said. “Chief among these limitations is that patients were followed for only five years and, equally important, the primary outcome was death from any cause rather than cancer-specific death.”
Parker, a professor of epidemiology and urology, said that while the authors reported that depression was associated with a mild increase in mortality after prostate cancer diagnosis and treatment, it is not clear that all the deaths were due to prostate cancer.
“A better endpoint would have been death due to prostate cancer. Unfortunately, accurate cause-of-death information is difficult to get when using large databases like SEER-Medicare. Other limitations center on the fact that the authors excluded several groups of men, including those younger than 67, those with a diagnosis of more than one cancer, and more than 25,000 men with Medicare claims that may not have been reliably filed. This means that we cannot generalize the finding from this study.”
The most compelling data, he said, is the evidence that depressed men were 25 to 30 percent less likely to choose definitive therapy for prostate cancer, regardless of whether they have low-, intermediate-, or high-risk disease. “The data from this study suggest that specific interventions can and should be developed and evaluated for their ability to help depressed men choose appropriate treatment for their cancer, especially those with intermediate- and high-risk cancers who could benefit from more definitive therapy.”
Given that there was very little evidence that depression delayed the diagnosis or dramatically affected survival, and no evidence of an effect on cancer-specific survival, this study by itself does not support the need for specific interventions to improve diagnosis and outcomes for depressed men,” Parker noted. “To be clear, these may indeed be needed; however, these data do not support them specifically.
“From the study it is only possible to conclude that there is evidence that depressed men are less likely to choose definitive therapy--potentially a big problem. It is not a stretch to imagine that if men are depressed they might be less likely to choose a more aggressive therapy that could save their lives but at the same time is associated with notable side effects such as incontinence and erectile dysfunction.”
Large-scale studies in younger men are difficult because there are fewer opportunities to use existing databases like Medicare, he continued. “It is very possible that the effect of depression on prostate cancer diagnosis and survival in younger men could be different, which is another important area for further study.”
Sunday, August 24, 2014
The International Myeloma Foundation has changed its logo, designed to reflect, a news release notes, “movement and hopefulness.”
“We are excited to share our new logo with the world,” said IMF President and co-founder Susie Novis. “Our original logo served us well for 24 years. Our new logo retains our signature burgundy color, a nod to the importance of the IMF’s long history of work on behalf of myeloma patients. The image of the man has evolved and so has the IMF. But the constant is that he is moving forward with his arms out, welcoming everyone: patients, families, doctors, nurses, and the entire myeloma community. He represents One Myeloma Nation, where all are welcome.”
Sunday, August 24, 2014
BY ROBERT H. CARLSON
BARCELONA -- Thirty experts in gastrointestinal cancer pooled their opinions on the best current treatments for metastatic colorectal cancer, the results of which were presented here at the European Society for Medical Oncology’s 16th World Congress on Gastrointestinal Cancer.
“Because medical practice is undergoing very rapid changes in data and environment, and rapidly increasing knowledge, recommendations need frequent updates and refinements,” Congress Co-Chair Eric Van Cutsem, MD, PhD, Professor of Internal Medicine at the University of Leuven and Head of the Digestive Oncology Unit at University Hospital Gasthuisberg in Belgium, said in his introduction of the expert discussion report.
In his recap of the panel’s findings, he said that the discussion was initiated with questions sent in advance to the panel members selected, based on their scientific credentials and recognition as opinion leaders from different disciplines. The answers were analyzed beforehand and discussed again by 20 of those experts during the session at the meeting. The decisions were based on evidence from clinical trials, but in many cases were also influenced by clinical experience, he said.
Still, he cautioned, “while the opinions from this discussion can help guide clinicians for treatment choices, they are not official guidelines or true consensus statements.”
Clinically Relevant Categories in Non-Resectable Patients
For the purposes of their review, the panelists divided metastatic colorectal cancer into four categories:
· potentially resectable (borderline);
· not resectable but with heavy tumor burden and aggressive biology; and
For those needing aggressive treatment, the goal is tumor shrinkage to convert to resectable disease. “There is clear evidence that patients should receive all available agents, but the optimal sequence is not known,” Van Cutsem said. “Strategy and continuum of care are important, since 70 to 80 percent of patients will receive second-line therapy, and 50 to 60 percent will receive third-line.”
Chemotherapy Backbone of First-Line Therapy
The experts agreed that a cytotoxic doublet is the appropriate first-line chemotherapy for most patients with metastatic colorectal cancer, with the three most proposed options FOLFOX (fluorouracil-leucovorin-oxaliplatin); CAPOX (capecitabine-oxaliplatin); and FOLFIRI (fluorouracil-leucovorin-irinotecan). A cytotoxic triplet was considered, specifically FOLFOXIRI, but the experts were uncertain for whom it would be appropriate.
He said that for patients with BRAF-mutant disease, a triplet with bevacizumab may be an option, although trials to date have been small. In some cases of downsizing of borderline resectable metastases, the triplet could be an option--again possibly with bevacizumab for RAS-mutant tumors.
In patients not needing aggressive treatment, such as those who are asymptomatic, fluoropyrimidine monotherapy with capecitabine in combination with bevacizumab can be considered.
Combine Biologicals in First-Line Therapy
Biologicals are indicated in first-line treatment in most patients, unless there are contraindications such as organ function involvement, poor performance status, or cardiovascular contraindications. Bevacizumab can be combined with FOLFOX, CAPOX, or FOLFIRI, Van Cutsem said, and anti-EGFR antibodies can be combined with FOLFOX or FOLFIRI.
But the experts recommended against combining a capecitabine-containing regimen with anti-EGFR antibodies: “Extended RAS analysis should be performed in order to determine resistance to anti-EGFR antibodies,” Van Cutsem said.
The panel said there is no unequivocal evidence of superiority of one biological compared with another in first-line treatment--that is, bevacizumab versus anti-EGFR antibodies. “The choice [of a biological] is determined by continuum of care and management strategy and may be influenced by safety and quality-of-life considerations, as well as by reimbursement criteria after discussion with the patient,” van Cutsem said.
In the future there may be further refinement of biological selection based on tumor localization and molecular criteria, he added.
There was uncertainty among the experts about the best cytotoxic-biological combination for potentially resectable patients if conversion is the goal, Van Cutsem said.
For RAS-mutant tumors, a doublet with bevacizumab or FOLFOXIRI with or without bevacizumab could be appropriate. For RAS wild-type tumors, a doublet with an anti-EGFR antibody, or FOLFOXIRI with/without bevacizumab, or even a doublet with bevacizumab, are all options.
“We suggest these patients be reevaluated regularly in order not to overtreat those who are resectable,” van Cutsem said. “Several of the experts, but not all, suggested a change in the cytotoxic doublet if no response is seen on first evaluation in order to maximize the chance of resection.”
The panel voiced concern about the detrimental effects of a doublet plus anti-EGFR antibody in patients categorized as being in non-tumor related performance status 2.
The final point regarding first-line therapy was that the concept of early tumor shrinkage and depth of response are related to survival, but it is unclear how specific this is for a specific drug combination, Van Cutsem said.
Extended RAS Analysis Mandatory
As has become clear with recent research, “KRAS exon-2 analysis is not enough, and extended RAS analysis is mandatory before anti-EGFR antibodies are prescribed,” he said, also referring to an earlier presentation at the meeting in which he said that extended RAS testing finds another 10 to 15 percent of patients with mutated colorectal tumors above what KRAS testing finds.
Molecular analysis of BRAF, KRAS exon-3 and -4, and NRAS exon-2, -3, and -4 should also be performed, the panel said, and there are even experimental studies on taking a new biopsy and retesting after different lines of treatment.
But full genome screening is not recommended. “Molecular analysis is hampered at the moment by lack of quality control on validated testing and sensitive testing methods, and also the cut-off of sensitivity for these molecular markers is not well defined,” Van Cutsem said.
Patients with metastatic colorectal cancer harboring any activating RAS mutation, not only KRAS, are unlikely to benefit from the addition of cetuximab to FOLFOX or to FOLFIRI. But in cases in which cetuximab is appropriate, panitumumab is equally acceptable, as the experts held that these are equally active as single agents in chemorefractory patients, although there are some differences in toxicity patterns.
The panelist said that the combination of cetuximab with irinotecan is more active than cetuximab alone in irinotecan-refractory patients, but that there are concerns about the activity in BRAF-mutant tumors.
“Many of us recommend not to treat BRAF-mutant tumors with anti-EGFR antibodies,” Van Cutsem said. On the other hand, if a patient is refractory to one of the anti-EGFR antibodies, there is no evidence to administer the alternate anti-EGFR antibody.
Optimal Maintenance Treatment is Combination
Maintenance treatment after induction benefits patients with metastatic colorectal cancer, the experts said, and the optimal maintenance treatment is a combination of a fluoropyrimidine (specifically mentioning capecitabine) plus bevacizumab.
“The challenge is to determine in which patients treatment can be stopped for a 'drug holiday,'” Van Cutsem said.
Bevacizumab monotherapy as maintenance is not recommended, since in two clinical trials non-inferiority was not proven. Also, there is limited data on maintenance with anti-EGFR antibodies.
The duration of induction treatment was recommended as six to eight cycles of FOLFOX, or six cycles of CAPOX. But the data on FOLFIRI are not clear, he explained.
Second-Line Treatment Depends on First-Line
In second-line treatment, 70 to 80 percent of the general population of patients with metastatic colorectal cancer are candidates, he said. The cytotoxic agent used in second-line therapy depends on the first-line treatment, but oxaliplatin can follow irinotecan and vice versa.
The experts listed three options in second-line treatment with biologicals:
· Post-progression continuation of bevacizumab with bevacizumab as second-line for patients not previously treated with bevacizumab;
· The VEGF inhibitor aflibercept in combination with FOLFIRI; and
· For RAS wild-type or BRAF wild-type tumors, anti-EGFR antibodies can be used in combination with FOLFIRI or irinotecan.
Unfortunately, no randomized Phase III studies comparing different biologicals are yet available, he noted.
Aflibercept is the preference for fast-progression disease in first-line therapy, although in RAS wild-type tumors the anti-EGFR antibodies are preferred.
Single Agents in Third-Line Treatment
In third-line and later lines, cetuximab or panitumumab are recommended in RAS wild-type and BRAF wild-type tumors. These are equally active as single agents, Van Cutsem said, but there is no unequivocal evidence to administer the alternate anti-EGFR antibody if a patient is refractory to one of the anti-EGFR antibodies.
Regorafenib is recommended for third-line therapy in patients pretreated with fluoropyrimidines, oxaliplatin, irinotecan, bevacizumab, or anti-EGFR antibodies.
The recommended starting dose for regorafenib is 160 mg/day on days 1 to 21 of a four-week cycle, Van Cutsem said, adding, though, that some of the experts have doubts about whether this is the optimal starting dose. “The reality is that in some regions, many physicians may start with a lower dose and then increase if there is no toxicity.” That is a matter for further exploration, he said, but frequent and close monitoring for toxicity are clearly recommended.
The 30 members on the expert panel were: Eric van Cutsem, Mario Dicato, Josep Tabernero, Nadir Arber, Dirk Arnold, Johanna Bendell, Jordan Berlin, Andrés Cervantes, Fortunato Ciardiello, David Cunningham, Stefano Cascinu, Aimery de Gramont, Eduardo Diaz-Rubio, Michel Ducreux, Richard Goldberg, Thomas Gruenberger, Karin Haustermans, Volker Heinemann, Herbert Hurwitz, Roberto Labianca, Heinz-Josef Lenz, Fotios Loupakis, Bernard Nordlinger, Philippe Rougier, Hans-Joachim Schmoll, Daniel Sargent, Alberto Sobrero, Thomas Seufferlein, Julian Taib, and John Zalcberg.
Alternate Opinion from Aimery de Gramont
In an interview at the end of the meeting, panel member Aimery de Gramont, MD, Head of the Internal Medicine-Oncology Department at Saint-Antoine Hospital in Paris, said he agreed with the majority of the report but felt that some of the statements could be improved upon.
Regarding the four patient groups that the expert report focused, de Gramont offered a suggestion about the third group, borderline resectable patients: “If borderline resectable patients could not be resected, then we don't know what happens to them.” Trials and statistics are looking at the unresectable population as well as the resected population in the borderline resectable population, but not at the unresected population in the borderline group.
This leads, he said, to what he called an “inverse Will Rogers effect” – “If you take the best unresectable borderline patients out of the unresectable group, you will decrease the results in the group of the surgical patients because those are not the best surgical patients. And you will also decrease the results in the unresectable group, because they are the best of that group.”
De Gramont said he would prefer a new idea, that resection might be a primary objective in trials in unresectable patients.
He said he also thought that “very low” front-line treatment may not be the best strategy for patients in the fourth group, those who are asymptomatic with non-aggressive unresectable tumors.
“For the patient who cannot receive aggressive therapy, if they have an indolent tumor, the deepness of response would be a way to improve survival. But if you do not choose an active treatment, you will not have a deepness of response, so it might not be the optimal way to treat even the patient with good prognosis.”
On the subject of chemotherapy, de Gramont differed from the expert recommendation on the number of cycles of oxaliplatin-based chemotherapy, saying he would not give more than six cycles of oxaliplatin (in FOLFOX).
“We have demonstrated that six is enough,” he said. “In all cancers outside of GI, I don't believe they give more than six cycles of platinum compounds. The patient cannot be reintroduced to treatment because of the neuropathy if he receives more than six cycles, so we miss the effect of reintroduction.”
On the issue of maintenance issue, de Gramont said he believes bevacizumab can be used as maintenance monotherapy: “Bevacizumab alone has been shown to be non-inferior in survival to bevacizumab-capecitabine. If the patient has any toxicity with capecitabine, I believe they can go on with bevacizumab alone.”
All these issues, he said, will need discussions in the panel's future meetings.