Many patients have to stop oxaliplatin chemotherapy with before getting its maximum effectiveness because of peripheral neuropathy — tingling, numbness, or pain in their hands and feet.  Xeloda® (capecitabine) can cause painful skin redness and cracking on the hands and feet or hand-foot syndrome, which can also affect time on chemotherapy.

Giving only six treatments of Avastin® (bevacizumab) plus XELOX chemotherapy and then stopping XELOX and using only Avastin until cancer progressed was as effective for the initial or first-line treatment of colorectal cancer as continuing XELOX.  XELOX combines Xeloda® (capecitabine) with oxaliplatin.

In addition, the strategy reduced both severe peripheral neuropathy and hand-foot syndrome.

In the MACRO study, 480 patients who had not received previous chemotherapy for metastatic colorectal cancer were randomly assigned to get either get

• XELOX and Avastin until their cancer progressed or side effects made it impossible for them to continue treatment or
• Six treatments (18 weeks) of XELOX and Avastin followed by Avastin alone until progression.

After a median follow-up of 16 months, there were no significant differences in response rate, progression-free survival, or overall survival time.

• Median progression-free survival was 11.0 months when XELOX continued and 10.3 months when XELOX was dropped and Avastin continued as a single agent.
• Median overall survival was 25.3 months with continuous XELOX and 20.7 months continuing Avastin alone.
• Overall response rate was 60 percent for the continuing strategy and 57 percent for Avastin as a single agent after XELOX was stopped.

Severe grade three or worse side effects were

• Diarrhea:  11 percent in continuing strategy and 13 percent when Avastin was used alone.
• Hand-foot syndrome:  12 percent versus 6 percent.
• Neuropathy: 24 percent versus 7 percent

The researchers also pointed out that about 1 in 10 patients in both arms of the trial were able to have successful surgery to remove metastatic tumors.

Josef Tabernero, MD, and his colleagues concluded,

Bevacizumab (BEV) as a maintenance therapy following induction XELOX-BEV was not inferior to continuation XELOX-BEV. This study suggests that maintenance therapy with single agent bevacizumab is an appropriate option following induction XELOX-BEV in patients with metastatic colorectal cancer. Further studies evaluating single agent bevacizumab after standard chemotherapy in metastatic colorectal cancer are warranted.

SOURCE: Tabernero et al., 2010 ASCO Annual Meeting Abstracts, Abstract #3501

C3 has accepted donations from Roche and Genentech in  the form of unrestricted educational grants. C3 has ultimate authority over web site content.

Combining results of four randomized clinical trials of Avastin and chemotherapy in patients with advanced colorectal cancer, researchers found that adding Avastin increased both the time older patients lived and the time before their cancer got worse.

Patients who were 70 and older had similar improvements.

There were more serious problems caused by blood clots (thromboembolic events) in patients who got Avastin, mostly related to arterial events.  However, other serious side effects were no more common in older patients than in those who were younger than 65.

Although two-thirds of patients with advanced colorectal cancer are 65 or older and four out of ten are older than 74, older patients are not well represented in clinical trials.  Even when there are no age limits on trials, they may not be enrolled because of other medical problems or a conservative approach to treatment of the elderly.

Therefore, to get a clearer idea of how adding Avastin to chemotherapy affects patients 65 and older, the research team combined information from three first-line and one second-line trial of Avastin and chemotherapy together including 1,100 patients who were 65 or older.

They found that both progression-free survival and overall survival improved when Avastin was added to chemo, and that age made little difference in benefits.

Progression-free survival time with and without Avastin was:

• For those under 65:  6.7 months vs 9.5 months
• Those 65 and older:  6.9 months vs 9.3 months
• Those 70 and older:  6.4 months vs 9.2 months

Overall survival time with and without Avastin was:

• For under 65: 16.5 months vs 19.9 months
• 65 and older:  15.0 months vs 17.9 months
• 70 and older:  14.1 months vs 17.4 months

As patients got older arterial thromoembolytic events (ATE) such as heart attack, stroke, TIA’s, and angina increased with the addition of Avastin.

• Under 65:  no difference in ATEs was found — 2 percent in both Avastin and non-Avastin groups
• 65 and older: 5.7 percent ATE for Avastin compared to 2.5 in non-Avastin group
• 70 and older: 6.7 percent ATE for Avastin, 3.2 with no Avastin

Age made no difference in other serious side effects including bleeding, hypertension, and gastrointestinal perforations.

The study authors point out that patients in clinical trials are carefully chosen and may not reflect the health of a patients in the general population.  They warn that overall health should be carefully assessed before beginning treatment.

James Cassidy and his colleagues wrote,

In conclusion, this pooled analysis of data from phase II and III metastatic colorectal cancer studies demonstrates that bevacizumab in combination with chemotherapy had a similar impact on PFS and OS in protocol-eligible older versus younger patients. Careful patient selection, however, remains important and should include an objective assessment of the patient’s physical and mental status.

SOURCE: Cassidy et al., Journal of Cancer Research and Clinical Oncology, Online First November 10, 2009.
Disclosure: C3 has accepted funding for projects and educational programs from Genentech in the form of unrestricted educational grants. C3 has ultimate authority over website content.

Compared to patients with consistently rising carcinoembryonic antigen (CEA), patients who had a CEA flare had more tumor shrinkage, longer time before their cancer got worse, and longer survival time.

Researchers measured CEA before chemotherapy started and at least twice during chemo in patients with advanced colorectal cancer who were receiving their first course of chemotherapy.

They grouped patients according to how the CEA measurements changed over time:

• flare
  
• decreasing CEA
• normal baseline CEA
• stable CEA
• increasing CEA

Comparing patients with increasing CEA measurements to patients whose CEA rose and then fell (flared):

• Overall response rate was 11 percent in increasing CEAs compared to 73 percent in flares.
• Progression-free survival time was 3.1 months compared to 8.3 months with flares.
• Overall survival was 10.9 months compared to 17.7 months when CEA flared.

A. S. Strimpakos and colleagues at the Royal Marsden Hospital in London concluded,

Compared with patients with rising CEA, flare was an independent favourable predictive and prognostic factor for tumour response and survival.

More information on the CEA flare during first-line chemotherapy  is available from Dr. Strimpakos’ poster presented at the 2009 GI Symposium.

SOURCE: Strimpakos et al., Annals of Oncology, Advance Access, October 27, 2009.

Finding the best imaging methods to diagnosis and monitor cancer and comparing new colorectal cancer screening technologies to current standards are among recommended priorities for comparative effectiveness research (CER).  The FDA reports new egg safety rules and the recall of a powdered dietary supplement.

Videos of cancer patients are now online discussing the emotional impact of their diagnosis in The Day I Found Out.

Research Reports

• Reduced uptake on FDG/PET after the first chemotherapy treatment may be able to predict how well patients will respond to chemo. In early information from a study of  advanced colorectal cancer patients reported at ASCO 2009, PET scans before initial chemo and  again two weeks later accurately predicted tumor response on later CT scans.   Dr.  Alain Hendlisz said, “Our results show that if tumor metabolism does not respond after 14 days, the patient is not likely to experience tumor shrinkage two or three months later on. Finding this out early on in treatment can help us avoid unnecessary side effects and also allows us to try another type of therapy sooner, if possible, to optimize results for our patients.”
• Chemotherapy before surgery to remove colorectal cancer that has spread to the liver makes CT scan evaluation less accurate. Doctors in France compared whether liver metastases were correctly identified in 92 patients, 30 of whom did not have chemotherapy before surgery.  CT either failed to find lesions or identified tumors that weren’t there in half of the chemotherapy patients but only about a third of those who went directly to surgery.  Other factors making CT scans less accurate were more than three liver tumors and fatty deposits (steatosis) in more than 30 percent of liver tissue.  Benjamin Angliviel and the team from the Hôpital Ambroise Paré in Boulogne report their results in the May, 2009 issue of the Annals of Surgical Oncology.

Other Headlines

• Finding the best imaging strategies for the diagnosis, staging, and monitoring of cancer is among the 25 most important priorities for comparative-effectiveness research (CER) recommended by a new Institute of Medicine report.  Comparing the effectiveness of new colorectal cancer screening methods, including CT colonographyand FIT, to usual care with FOBT and colonoscopy to prevent colorectal cancer is among the second tier of 25.  The IOM report chose 100 priorities from an initial list of 1,300 as important for $1.1 billion in CER funding to help Americans make good health care decisions based on evidence from research.  Said Dr. Harold C. Sox, co-chair of the IOM panel, “Healthcare decisions too often are a matter of guesswork because we lack good evidence to inform them.”
• Cancer survivors share their stories of diagnosis and treatment on video talking about The Day I Found Out. Developed by the Seattle Cancer Care Alliance, the videos include several colon cancer patients including C3 advocate and stage IV survivor Anita Mitchell who talks about her oncologist who gave her hope when he said, “I have a plan for you.”  She says, “All I needed was that hope.”
• The FDA has issued new rules to help reduce Salmonella infections from eggs.   Large egg farmers will have to buy chicks from bacteria safe sources, keep facilities clean and bacteria-free, test their facilities regularly, and refrigerate eggs promptly for storage and shipment.  Salmonella enteritidis causes more than 140,000 illnesses every year, some of which are life-threatening.  FDA tells consumers to buy only refrigerated eggs, check for clean and uncracked shells, refrigerate eggs promptly at home, and cook eggs until yolks are firm.
• FDA: Vital Pharmaceuticals has recalled lots of its powdered dietary supplement Stealth Chocolate and Stealth Vanilla because it may be contaminated with Salmonella. Milk protein concentrate, one of the supplement’s ingredients, was recalled by the supplier.  The dietary supplements were sold nationwide, including at GNC stores.  Consumers with questions may contact Vital Pharmaceutical Inc. at 1-800-954-7904 or 954-641-0570 during the hours of 9 am – 5 pm, Monday through Friday.

Doctors in New York followed 111 patients who had chemotherapy before surgery to remove liver metastases (neoadjuvant chemotherapy). After five years of follow-up, median overall survival was 62 months.  Overall survival was similar in three different groups:  those who had a complete or partial response to neoadjuvant chemotherapy, those whose tumors remained stable, and those whose cancer progressed during chemotherapy.

All patients the study had liver tumors that surgeons believed could be cured surgically.

Median overall survival after liver surgery:

• For all patients:  62 months
• Patients with complete or partial response to chemo: 58 months
• Patients with stable disease after chemo: 65 months
• Patients with progressive disease: 61 months

Factors that predicted better survival after surgery were:

• CEA (carcinoembryonic antigen level) less than 5 ng/dL.
• Metastatic lesions 5 centimeters or less.
• Negative lymph nodes in the primary tumor in colon or rectum.
• No cancer cells in margins of surgically removed tissue.

There was a trend for patients whose cancer progressed during pre-surgical chemotherapy to do better if they had chemotherapy infused directly into their livers after surgery (hepatic arterial infusion). Those who had HAI had 70 percent survival three years after surgery compared to 50 percent of those who didn’t.

David J. Gallagher and the team from Memorial Sloan Kettering Cancer Center and Weill Medical College of Cornell University concluded,

Response to neoadjuvant chemotherapy did not correlate with overall survival even after controlling for margins, stage of primary tumor, and postoperative carcinoembryonic antigen level. Postoperative salvage treatment may have helped the survival of some patients.

SOURCE: Gallagher et al..Annals of Surgical Oncology, Volume 16, Number 7, July 2009.

Patients who got ginger (Zingiber Officinale) in capsules twice a day for three days before chemo and three days after reported significantly less nausea that those who were treated with placebo.  All patients in the study also received standard anti-nausea therapy on the day of chemo.

Almost 650 patients, mostly women, were randomly assigned to ginger supplements or a placebo in a blinded trial that will be reported at the 2009 ASCO annual meeting.

Julie Ryan, PhD, MPH, who headed the study at the University of Rochester, told reporters at an ASCO press briefing,

As many as 70 percent of patients who undergo chemotherapy experience nausea and vomiting. We found that patients who received traditional anti-nausea drugs along with ginger supplements prior to chemotherapy experienced significantly less nausea associated with their chemotherapy. However, as with all supplements, patients should speak with their doctors first before taking ginger.

SOURCE: Ryan et al., Ginger for Chemotherapy-related Nausea in Cancer Patients, ASCO 2009 Abstract #9511.

Patients who undergo chemotherapy know that every time they receive chemotherapy, oncologists take blood to test for blood counts and also for liver and kidney function.

There are many drugs which need their doses reduced or treatment held held if the kidney function changes. One of the common mistakes is that Xeloda, the oral 5-FU drug used for colon cancer, does need to have its dose reduced for kidney dysfunctions. However 5-FU and oxaliplatin don’t have to be dose reduced, which is astonishing since cisplatin has tremendous kidney toxicities which oxaliplatin does not.

Avastin needs to closely monitored for kidney toxicities. Rarely patients can develop proteinuria, which means the kidney loses too much protein. In this situation Avastin needs to be stopped. This is usually reversible within weeks. Proteinuria has been well described, particularly in patients with renal cancer. We have seen proteinuria in patients with colorectal cancer treated with Avastin, which is the reason we check a urinanalysis every 4 weeks to make sure there is no significant protein in the urine.

Patients can monitor proteinuria at home. Whenever there is a lot of protein in the urine, urine foams and makes a lot of bubbles in the toilet. Let your doctor know if this is happening.

Erbitux has also some toxicity to the kidney. It is very rare but needs to be monitored too. It can make the kidney loose magnesium. Your oncologist should test magnesium levels in the blood at every visit. Clinically patients can experience cramping in their legs and hands or can feel lethargic. Make sure magnesium levels are within normal range. This is particular important for patients who have diarrhea who may lose additional magnesium in the stool. If any of these symptoms occur you need to contact your oncologist to work you up.

In my own practice we have a number of patients who are on dialysis and treated effectively with chemotherapy. This is possible depending on the amount of the drugs being eliminated by the dialysis. Usually we treat these patients after their dialysis to allow optimal exposure of drugs to the tumor. Please discuss this with your oncologist if you have a chronic renal failure.

One of the problems for patients who have some increased creatinine levels is using contrast agents when they undergo CT scans. With any decreased kidney function you need to be very careful using IV contrast which can be harmful to your kidney. Discuss this with your oncologist.

Again for patients with kidney dysfunction, we offer very specific clinical trials which should consider if you do not qualify for other clinical trials.

Results of a randomized phase III clinical trial that added the monoclonal antibody Erbitux® (cetuximab) to Xeloda® (capecitabine), oxaliplatin, and Avastin® (bevacizumab) showed shorter time to cancer progression for patients who got Erbitux in addition to the standard treatment. There was no difference in whether the tumor shrank or overall survival time. Patients who got Erbitux were about 20 percent more likely to have tumors get worse or to die than patients who didn’t.

This was the first chemotherapy treatment for metastatic cancer that these patients were given.  All of them had metastatic tumors that had spread beyond their colons.

While patients with wild-type (normal) KRAS genes in their tumors had longer progression-free time on Erbitux than those with KRAS mutations, that time did not reach the median progression-free interval for patients in the standard treatment group.

Doctors in the Netherlands randomly assigned 732 patients to a chemotherapy regimen of Xeloda and oxaliplatin with Avastin or the same regimen with the addition of an infusion of Erbitux every week.

• Arm One (CAPOX plus Avastin):  Standard treatment of IV infusion of oxaliplatin and Avastin on the first day of each treatment cycle followed by 14 days of oral Xeloda and 7 days of rest.
• Arm Two (CAPOX plus Avastin with added Erbitux): Experimental treatment with weekly IV Erbitux added to CAPOX/Avastin.

Comparing the  experimental and standard treatments, researchers found:

• Significantly lower median time to progression of 9.4 months in the experimental group with Erbitux compared to 10.7 months with standard treatment.
• No different in response rates: about half in each group had tumors shrink.
• Median overall survival time was almost the same: 19.4 months in the Erbitux group, 20.3 months in the standard arm.

Looking at KRAS status in tumor tissue, the study learned,

• There was a KRAS mutation in almost 40 percent (39.4%) of tumors.
• Erbitux-treated patients with KRAS mutations had significantly shorter progression-free survival than Erbitux-treated patients with wild-type (normal) KRAS: 8.1 months versus 10.5 months.
• Erbitux-treated patients with KRAS mutations also had shorter progression-free time than patients with KRAS mutations who didn’t receive Erbitux: 8.1 months versus 12.5 months.  They also had worse survival time: 17.2 vs 24.9 months.
• Among Erbitux-treated patients, response rates were lower for those with KRAS mutations than for wild-type KRAS: 45.9 percent versus 61.9 percent.
• For patients who didn’t get Erbitux, KRAS status made no difference in progression free survival or response rate.

Side effects and quality of life

• There were worse side effects in the group treated with Erbitux, but most of the difference was due to severe skin rash.  When skin toxicity was excluded, about 3 out of 4 patients in both arms of the study experienced at least one serious adverse event.
• Most common serious side effects were skin rash in the Erbitux group and hand-foot syndrome, diarrhea, neuropathy, hypertension, and fatigue for both.
• Blood clots in veins were experienced by 6.8 percent of patients in the standard group and 8.2 percent of those receiving Erbitux.  Arterial blood clots occurred in 3.3 percent of standard and 2.2 percent of the experimental groups.
• Measures of quality of life and overall health were similar in both groups at the beginning of the trial.  However, both improved significantly more with the standard treatment.  Global health measures didn’t change at all for the group that got Erbitux.

The results of the trial were similar to the lack of benefit in the PACCE trial which added similar EGFR-inhibitor Vectibix™ (panitumumab) to chemotherapy with 5-FU and either oxaliplatin (FOLFOX) or irinotecan (FOLFIRI).  Again, progression-free survival time was shorter with the addition of Vectibix and there was no difference in response rate.

Writing in the New England Journal of Medicine, Julien Tol, M.D. and colleagues concluded,

The addition of cetuximab to capecitabine, oxaliplatin,and bevacizumab resulted in significantly shorter progression-free survival and inferior quality of life. Mutation status of theKRAS gene was a predictor of outcome in the cetuximab group.

SOURCE: Tol et al., New England Journal of Medicine, Volume 360, Number 6, February 5, 2009.

Well, for the treatment of colon cancer patients we have different cocktails to choose from such as FOLFOX and FOLFIRI. Both are combinations of 5-FU and leucovorin and either irinotecan or oxaliplatin. Both regimens have similar efficacy and similar extent of side effects, with oxaliplatin having more neurotoxicity and irinotecan more diarrhea.

However, depending how you mix and deliver the three drugs you may have significant differences in toxicity. It is amazing what differences exist among oncologists in how they mix up their chemotherapeutic cocktails. Not only the doses but also the timing of administration can differ dramatically, which can result in differences in toxicities for patients.

I have seen many patients with severe diarrhea and nausea and low blood counts using FOLFOX being labeled allergic to 5-FU. Taking the 5-FU bolus infusion away (when they inject 5-FU quickly into your bloodstream), can reduce the side effects dramatically without jeopardizing the efficacy. Similarly adjusting the dose of leucovorin to 20mg/m2 and not 200mg/m2 makes no difference in efficacy but can reduce diarrhea.

When you give 5-FU as a bolus (quick infusion) we know you can develop nausea, vomiting, diarrhea and low white blood cells. When you give 5-FU over time with a slow infusion over 46 hours you don’t see the same amount of these side effects. More likely, you will see dry skin and mouth sores. It is very well established why this is the case based on how 5-FU interferes with the normal cells DNA and RNA.

If you develop significant side effects please discuss modifying the schedule and dose of 5-FU and leucovorin with your oncologist.

Last week, I saw a woman who was receiving bolus 5-FU and leucovorin weekly with a weekly infusion of irinotecan for colon cancer, which is an outdated regimen and should not be given. We have learned a lot over the years to optimize administering drugs.

A lot of patients ask whether you can take a break from chemotherapy, particularly around the holidays or vacation times. Do you take a break from insulin or your high blood pressure medication? In the last two years, clinical trials have been conducted to answer exactly this question.

There is also a difference in treatment philosophies around the world. In Europe many oncologists feel if the tumor does not shrink anymore, it is time to stop chemotherapy completely. In the USA most oncologists treat until the tumor starts growing, assuming that no change in tumor is a good sign of control.

Interestingly, two studies in Europe have looked at patients with treatment holidays or with reduced treatment regimens. These studies were initiated to test whether when we can stop oxaliplatin to avoid neurotoxicity, only give 5-FU for a period of time, and then reintroduce oxaliplatin when the tumor starts growing again to give oxaliplatin the most time to work.

In the first of these studies, it was found that when you stop or hold oxaliplatin, you don’t jeopardize outcome to treatment if you still continue with maintenance therapy with 5-FU. It became also clear that the patients who did the best with this approach were the ones who had good control of disease and had good performance status. Based on this study, another follow up study was conducted to evaluate whether a real chemoholiday would be possible. This study was presented at ASCO last year and showed that a chemoholiday may be not a good idea for patients, particularly patients with stable disease, significant tumor volume, or cancer symptoms. For patients who had a great response and were doing well, stopping chemotherapy was not threatening, but ones with stable disease, large tumor volume, or symptoms did worse when treatment was stopped. We already know that for patients with a lot of disease and symptoms related to the cancer the best palliation is effective chemotherapy.

In my practice we skip a week or two or continue on a modified regimen in patients with great tumor shrinkage and overall good status. However in patients with great response and the chance of a curative resection, I don’t recommend a break because I try to get the patients to a point where we may be able to take the tumors out with the goal of curing the patient. We have learned over the last two years that we can hold oxaliplatin if the tumor seems to be controlled and resume when the tumor begins growing again, but in patients with symptoms associated with cancer such as pain or bleeding, I don’t stop oxaliplatin.

To completely stop chemotherapy has shown not to benefit patients, but in fact jeopardizes their outcome.