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.

Researchers compared progression-free survival between patients who got either FOLFOX or FOLFIRI chemotherapy with Avastin and a group who got the same chemo regimen with GDC-0449. There was no difference

GDC-0449 was being developed by Genentech in collaboration with Curis.

Hopes for the new treatment were raised at ASCO earlier this month where reports showed no increased side effects with the new combination.

Researchers thought that blocking the Hedgehog gene on the surface of cancer cells would stop a series of signalling events in a pathway inside the cell leading to cell death and lengthening the time until cancer began to grow again.

Hedgehog is involved in embryonic development, particularly in growth of limbs. It was first observed in fruit flies where mutations led to many spiky extra legs making the curled up fly look like a hedgehog. You can watch a video of how it works.

Read the news release from Curis.

Disclosure: C3 has received funding from Genentech in the form of unrestricted educational grants. C3 has ultimate control over website content.

The answer is yes, according to a pooled analysis of two large randomized clinical trials comparing chemotherapy alone to chemotherapy plus Erbitux® (cetuximab).  However, benefits depend on whether or not patient tumors have mutations of two genes, KRAS and BRAF.

Previous studies have shown that only patients with normal or wild type KRAS get any benefit from EGFR inhibitors Erbitux or Vectibix™ (panitumumab) so a combined analysis of the CRYSTAL and OPUS studies looked only a outcomes in KRAS wild type tumors.  In addition, the research team studied the effect of mutations to BRAF.

They found that adding Erbitux to initial chemotherapy improved overall survival time, time until cancers got worse (progression-free survival), the percent of tumors that shrank with treatment (overall response rate) for tumors with wild-type KRAS.  The best outcomes were in patients who had both wild-type KRAS and wild-type BRAF.

Overall, benefits were smaller for both chemotherapy and chemotherapy plus Erbitux when BRAF was mutated.  But even in patients with BRAF mutations, adding Erbitux appeared to help.

The pooled analysis of KRAS wild type patients showed:

• Adding Erbitux to chemotherapy added four months to median survival time for the entire group of KRAS wild-type patients. With chemo alone, median overall was 19.5 months while it improved to 23.5 months with chemo and Erbitux.
• Progression-free survival was 7.6 months with chemo alone and 9.6 months with the combination of chemo and Erbitux.
• 38.5 percent of chemo only patients had tumors shrink at some point during their treatment compared to 57.3 percent of patients who also got Erbitux.

When just patients with both wild type KRAS and wild type BRAF were reviewed:

• Overall survival time was 21.1 months with chemo alone and 24.8 months with chemo plus Erbitux.
• Progression–free survival was 7.7 months with chemo and 10.9 months with the combination of chemo and Erbitux.
• Overall response rate was 40.9 percent for chemo and 60.7 percent for chemo and Erbitux.

Prognosis appeared to be poorer when KRAS wild type patients had mutated BRAF, but the researchers noted that there were too few BRAF mutated tumors to make the results statistically significant.  However, adding Erbitux did improve outcomes. In those patients.

• Median overall survival was 9.9 months with chemo and 14.1 months with the addition of Erbitux.
• Progression-free survival was 3.7 months versus 7.1 months.
• Overall response was 13.2 percent for chemo alone and 21.9 percent with Erbitux and chemo.

In presenting the study results at the 2010 ASCO Annual Meeting in Chicago, Carsten Bokemeyer said,

Based on these results, BRAF mutations cannot be used as a relevant predictive marker for the use of cetuximab in first line therapy for metastatic colorectal cancer.

Bokemeyer and his colleagues concluded,

This analysis confirms that the addition of cetuximab to chemotherapy first line in patients with KRAS wild type tumors achieves a statistically significant improvement in overall response rate, progression-free survival, and overall survival compared with chemotherapy alone. The best outcome was observed in patients with KRAS wild type/BRAF wild type tumors (90% of KRAS wild type patients). BRAF mutation status does not appear to be a strong predictive biomarker for the addition of cetuximab to chemotherapy but the sample size may be too small to be reliable.

SOURCE:  Bokemeyer et al., 2010 ASCO Annual Meeting Abstracts, Abstract #3506.

Disclosure:  C3 has received funding from Bristol Myer Squibb and ImClone Systems in the form of unrestricted educational grants.  C3 has ultimate authority over website content.

Colondar Models Erika and Cathy

When colorectal cancer spreads to other parts of the body, young people under 50 who get chemotherapy benefit as much as those who are older.

With drug combinations, there is no difference between those under 50 and those who are 50 and older in responding to chemotherapy, how long it takes before cancer gets worse, or in survival time.

Although colorectal cancer is primarily diagnosed in older people — the median age at diagnosis is 70 — about 10 percent of colon and rectal cancers are diagnosed under the age of 50.

While common wisdom was that younger patients had worse outcomes, a review of information from 9 randomized Phase III clinical trials testing first-line chemotherapy for metastatic colorectal cancer found this wasn’t true.

When a single drug was used, patients younger than 50 had shorter time before their cancer got worse (progression-free survival), but response to chemotherapy and overall survival time remained the same as patients who were fifty and older.

With combination treatments:

• Median progression free survival was 7.2 months for patients under 50 and 8.4 months for those fifty and older.
• Overall survival was 16.3 months for under 50 and 14.8 months for older patients.
• 54 percent of younger patients had tumors shrink with chemotherapy compared to 51 percent of patients fifty and older.

None of these small differences were statistically significant.

Younger patients did have more severe nausea, with 10 percent experiencing grade 3 or worse nausea with chemo compared to 7 percent of older patients, but they had less severe diarrhea ( 11 percent versus 14 percent) and less incidence of low white cell counts (16 percent vs 23 percent).

Nearly 6,300 patients were included in the review with 793 under age 50 (13 percent) with 188 under 40 (3 percent).

Charles D. Blanke and his colleagues presented their study results in an abstract  during the 2010 meeting of the American Society of Clinical Oncology in Chicago.  They concluded,

Based on a comparison with SEER,  young advanced colorectal cancer patients are proportionally represented on phase III studies. Young age is modestly associated with poorer progression-free survival but not overall survival or response rate in treated advanced colorectal cancer patients, and young patients have more nausea but less diarrhea and neutropenis with chemotherapy in general. Young versus older patient derive the same benefits from combination chemotherapy.  Based on these data, in the absence of a clinical trial, standard combination chemotherapy approaches are appropriate for young advanced colorectal cancer patients.

SOURCE:  Blanke et al., 2010 ASCO Annual Meeting Abstracts, #3520.

Erika Kratzer and Cathy Aiken are the cover models for the 2010 Colondar, produced by the Colon Club. Erika is a ten year survivor of stage IV colon cancer, diagnosed when she was 22.  Cathy was 27 when she heard she was diagnosed in 1950 and this year celebrates 60 years of survival. You can get a copy of the Colondar and see all fourteen models, diagnosed under the age of 50, and read their stories.

Over 230 patients were studied with metastatic colon cancer. and the data showed that patients did very well when started with chemotherapy without surgery for the primary tumor. Only 7 percent required surgery for symptoms during chemotherapy.

Usually, in the conventional approach to treating stage IV disease, patients underwent colon surgery immediately following their diagnosis and would typically start chemotherapy treatments three to six weeks later. The rationale for immediate colon resection was to prevent future symptoms and complications from the primary tumor. It was assumed that the majority of colorectal cancers would have little response to chemotherapy.

However we have now more effective and less toxic chemotherapy  which can shrink both colon tumors and the metastases. We need to caution that of course there are individual exceptions and each of these decisions needs to discuss with the surgeons and medical oncologists.

Patients in the BOND study had already gotten worse on standard chemotherapy and were receiving either Erbitux® (cetuximab) alone or in combination with irinotecan.  CT scans  for about a third of them showed at least a 10 percent decrease in the size of their tumors six weeks into treatment.

Of 289 patients in the study, 99 or 34 percent had tumor size decrease at the six-week scan, 190 or 66 percent showed no change.

Comparing those who responded to treatment at six weeks with those who didn’t:

• Median time to progression was 6.1 months compared to 1.5 months.
• Overall survival was 13.7 months compared to 6.9 months.

In predicting long-term outcome, early tumor shrinkage was more important than skin rash, another way of estimating how well Erbitux is working.

H. Piessevaux and the study team in Belgium concluded,

Tumor shrinkage at 6 weeks is a strong predictor of time to progression and overall survival in metastatic colorectal cancer patients treated with cetuximab with or without irinotecan. This suggests early tumor shrinkage is the hallmark of efficacy of cetuximab and reliably identifies the subpopulation that is sensitive to the drug. Early tumor shrinkage can be used as a marker of efficacy in clinical practice, as such or in combination.

SOURCE: Piessevaux et al., Annals of Oncology, Volume 20, Number 8, August 2009.

Surgeons at Memorial Sloan Kettering Cancer Center in New York followed 233 patients who began chemotherapy without surgery to remove their primary colon or rectal tumor. Almost 90 percent never had a problem with their tumor that needed intervention with surgery, radiation, or a stent. Only 7 percent required emergency surgery.

Researchers found among the group of 233:

• 16 patients (7 percent) needed emergency surgery because of an obstruction or bowel perforation.
• 10 patients (4 percent) had radiotherapy or a stent placed to relieve problems.
• 47 had the primary tumor removed at the same time they had surgery to remove metastastes.
• 8 had their colorectal tumor removed with surgery to place a pump in the abdomen to deliver chemo through the hepatic artery.

Use of Avastin, having a rectal tumor, or the number and size of metastatic tumors did not increase the risk of a complication in the primary tumor needing intervention.

Dr. George A. Poultsides and colleagues at Memorial Sloan Kettering concluded,

Most patients with synchronous, stage IV CRC who receive up-front modern combination chemotherapy never require palliative surgery for their intact primary tumor. These data support the use of chemotherapy, without routine prophylactic resection, as the appropriate standard practice for patients with neither obstructed nor hemorrhaging primary colorectal tumors in the setting of metastatic disease.

The study was also presented as a poster at ASCO 2009.

SOURCE: Poultsides et al., Journal of Clinical Oncology, Early Release, June 1, 2009.

The trial has already enrolled 84 of the 90 patients with metastatic colon cancer needed.

All patients in the study will be treated with FOLFOX (oxaliplatin, leucovorin, and continuous infusion 5-FU) and Avastin® (bevacizumab) every two weeks for as long as their cancer doesn’t get worse and they are able to tolerate side effects.  

The major goal of the study is to measure how often leaving a primary tumor in place causes a major problem that requires surgery or results in the patient dying.  In addition, researchers will be looking at serious problems that don’t require surgery, side effects from treatment, and overall survival.

Eligible patients include those with:

• Colon cancer that has spread to a distant site in their body. (Stage IV)
• No previous chemotherapy, radiation, or surgery for the particular tumor.
• Primary tumor in the colon that has no symptoms such as bleeding or obstruction.
• Metastases in other parts of the body cannot be surgically removed. (unresectable)

The trial does not include patients with rectal cancer or cancer that has spread to their brain.

If treatment with chemotherapy makes it possible to remove metastases that were initally unresectable, patients will have both the mets and primary tumor removed surgically.

First opened in March, 2006, the trial is being conducted in a number of centers throughout the United States.  You can contact a center near you for more information or to consider enrolling.

I often ask them if they had diabetes or hypertension how long would they expect to take medication for that disease, and there is no hesitation answering that you take it for a long time, if not forever. So I try to explain that we give chemotherapy as long it works and is tolerated.

Patients always wonder if they can be give a break or change to a less toxic regimen to make it easier. Interestingly, two studies in Europe have looked at patients with treatment holidays or with a kind of reduced treatment regimens. These studies were initiated to test whether we could stop oxaliplatin to avoid neurotoxicity, only give 5-FU, and then reintroduce oxaliplatin when the tumor starts growing in order to give oxaliplatin the best time to work.

In the first of these studies, it was found that when you stop or hold oxaliplatin you don’t jeopardize treatment outcome because you continue with 5-FU maintenance therapy. It became also clear that the patients who did the best with this approach were the ones who had good control of disease and good performance status.

Based on this study, another follow up study was conducted to evaluate whether a real chemoholiday with no chemotherapy at all would be possible. This study was presented at ASCO last year and showed that a chemoholiday may be not a good idea for all patients, particularly patients with stable disease, significant tumor volume, or symptoms.  For patients who had a great response and were doing well stopping chemotherapy was not threatening, but those 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. I think it is absolutely ok to skip a week or two or to 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.

In other words if a patient has multiple liver metastases and they are shrinking, I would not stop in the middle of it and give a chemoholiday. I would continue treatment to see if the tumors shrink or disappear so we are able to perform a tumor resection.

However we always are willing to accommodate special requests like an extra week for special trips, family events, holidays, since one or even two weeks will not threaten with any downsides.

I have told you about a young cancer patient in her thirties, diagnosed with metastatic colon cancer with diffuse liver metastases. Only five years ago we would have not thought of cure looking at her.  She was told by her HMO oncologist there there was little he could do and that her life expectancy was about six months. She could not accept this and started to look online for information.

It was Easter three years ago when she emailed Dr. Robert Beart, our colorectal surgeon. to find out if he could help. Within three minutes he answered her and asked her to contact me, which she did. I replied and set her up to come in to evaluate her options.

When we saw her we promised that we would do everything possible to make sure she got the best and most effective therapy. We tested her tumor for genetic markers to help us guide our treatment selection. Of course we did KRAS, which was which was normal wild type, and we also tested for two genes called TS and ERCC-1 which predict efficacy of FOLFOX versus FOLFIRI. We screen all our patients for these genes prior to start of treatment. She was enrolled in a clinical trial — CALGB 80405 — where we choose FOLFIRI and not FOLFOX because she would have not benefitted from FOLFOX. She received Erbitux and Avastin and had an incredible response allowing us to do a liver surgery with the intent to cure her.

Surgery went well, and we removed all the tumors. Since her tumor was all over in her liver, we were worried about it recurring in the liver so we also gave her chemotherapy after surgery and followed her very closely. About eight months later we found one spot in her liver. We treated her again with chemotherapy and were able to resect her again. She now has no evidence of cancer. The moral of this story is that you should never give up. Even when the tumor comes back, we can still beat this disease.

We have cured a number of patients who underwent multiples surgeries for liver or lung lesions and have no evidence of cancer today. We could have easily followed standard thinking that these surgeries are very rarely successful. However with more effective therapies this has changed. We are curing more and more patients, but not all. We should be aggressive, particularly in patients with metastatic disease in one organ.

Colon cancer is one of the few cancers which we can cure with resection of metastases. Selection of the most effective therapy is the first important step. We work closely with Response Genetics who have who developed a colon and lung cancer panel of gene tests.

Happy Easter.