Moscone Center

We’re getting ready for the 2012 Gastrointestinal Cancers Symposium next week at the Moscone Center in San Francisco.

Kim Ryan, Nancy Roach, and I will be there checking out the latest colon and rectal cancer prevention and treatment research and talking with leaders in the colorectal cancer field.

Colon and rectal cancer is featured on Saturday, January 21, but we’ll also be looking at research results for cancers in the upper digestive tract, liver, and pancreas on Thursday and Friday, visiting exhibits, and meeting with members of the Fight Colorectal Cancer Medical Advisory Board.

• Watch for our reports from the Symposium on the Fight Colorectal Cancer Research and Treatment News.
• Follow our tweets on Twitter @FightCRC.
• In February, join us and Dr. Dan Sargent from the Mayo Clinic for a Report from the 2012 GI Cancers Symposium webinar.

Each year, ASCO gives a few posters special mention as Merit Awards.  We’ll be stopping by to see those related to colorectal cancer.

• Association of NCCN guideline adherence with improved survival in high-risk stage II and stage III colon cancer.  Genevieve Boland, MD, PhD, University of Texas M. D. Anderson Cancer Center.
• A 21-year analysis of lymph node trends in colon cancer: Do quality measures really matter? Danielle Hari, MD, John Wayne Cancer Institute at St. Johns Health Center.
• Association between delays in adjuvant chemotherapy for stage III colon cancer and increased mortality. Alex Haynes, MD, MPH, University of Texas M. D. Anderson Cancer Center.
• Lymph node metastasis in patients with early pathologic T-stage rectal cancers: What does local excision leave behind? Maria Russell, MD, University of Texas M. D. Anderson Cancer Center.

Stay tuned for more breaking research information as we bring it to you.

“Studies show that palliative therapies not only improve patient quality of life, but can even extend life,” said ASCO President George W. Sledge, Jr., MD. In fact, a recent study found that patients with advanced lung cancer who received both chemotherapy and palliative care immediately after diagnosis lived almost three months longer than those receiving chemotherapy alone (N.Engl. J.Med.2010; 363:733-42).

Many people think palliative care means end-of-life care. It’s not the same. Palliative care is a growing specialty focused on symptom control and maintaining quality of life—according to the patient’s goals.  Experts say it should be initiated, along with disease-directed treatments, soon after diagnosis—especially in patients having aggressive disease or severe symptoms or side effects. (Hospice, or end-of-life care, begins when the patient is expected to live less than six months and when disease-directed treatments are discontinued.)

In a special January 24^th article in its Journal of Clinical Oncology, ASCO called on physicians to start candid discussions about prognosis, benefits and risks of treatments, and palliative care options soon after initial diagnosis of advanced cancer. Currently this happens with less than 40% of such patients.

Even the best oncology practices have great room for improvement. In an ongoing ASCO study of 5,500 patient records from 600 oncology practices who joined a quality improvement initiative, medical records showed that only 45% of cancer patients were enrolled in hospice before death: Of those, one-third were enrolled in the last week of life. And even in these practices, records from the last visits with the oncology team showed that two of three patients did not receive appropriate management for shortness of breath and 20 % did not receive appropriate pain management. Both are key components of palliative care.

ASCO also called on medical schools to include palliative care training into oncology programs, and on insurers to expand pilot programs that cover palliative care without requiring patients to abandon cancer-focused treatments.

To help patients, ASCO has released a new booklet that clearly explains options for advanced cancer care, with examples of disease-directed treatment, palliative care to manage symptoms and side effects; and hospice care.

Source: American Society of Clinical Oncology, J. of Clinical Oncology, Jan. 24 2011

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.

The consensus of experts who reviewed recent research was that patients with metastatic colorectal cancer whose tumors have mutations in the KRAS gene do not benefit from treatment that targets the epidermal growth factor receptor (anti-EGFR therapy).  Patients should be tested for KRAS mutations and, if those mutations are found, not receive anti-EGFR antibodies as part of their treatment..

A PCO, based on expert consensus, is designed to help decision-making for oncologists faced with major research results that can potentially change the way they treat patients.

The expert panel wrote in the Journal of Clinical Oncology

Provisional Clinical Opinion: Based on systematic reviews of the relevant literature, all patients with metastatic colorectal carcinoma who are candidates for anti-EGFR antibody therapy should have their tumor tested for KRAS mutations in a CLIA-accredited laboratory. If KRAS mutation in codon 12 or 13 is detected, then patients with metastatic colorectal carcinoma should not receive anti-EGFR antibody therapy as part of their treatment.

The opinion is based on five randomized clinical trials that evaluated patient outcomes in relation to KRAS status — either mutated or normal (wild-type). In addition, another five single-arm studies reviewed tumor changes depending on whether or not the tumor had mutated KRAS.

C3:Colorectal Cancer Coalition patient advocate Dr. Pamela K. McAllister was a member of the expert panel.

In an accompanying editorial Daniel  G. Haller, M.D. and John V. Cox discuss reasons for developing the Provisional Clinical Opinion, the first issued by ASCO.

The purpose of PCOs is to provide ASCO members with direction on issues that have been informed by recent data that should affect clinical practice, such as KRAS testing. The need for timely opinion from ASCO is apparent as science becomes ever more complex and the pace of change increases. Additionally, the demands of clinical practice make it difficult for oncologists to stay abreast of many of these changes. ASCO President Richard L. Schilsky, MD, recently commented that the goal of the PCO is to answer a member’s query after hearing new data, “Does this change my practice?”

SOURCE: Allegra et al., Journal of Clinical Oncology, Volume 27, Number 12, April 20, 2009.

The recommendation is a provisional clinical opinion reflecting consensus on current evidence and is designed to help doctors and patients make decisions about treatment.

The panel said,

Based on systematic reviews of the relevant literature, all patients with metastatic colorectal carcinoma who are candidates for anti-EGFR antibody therapy should have their tumor tested for KRAS mutations in a CLIA-accredited laboratory. If KRAS mutation in codon 12 or 13 is detected, then patients with metastatic colorectal carcinoma should not receive anti-EGFR antibody therapy as part of their treatment.

Members of the panel included C3 patient advocate Dr. Pamela McAllister.

Although men and women with metastatic colon or rectal cancer have similar overall survival after their diagnosis, age has an impact.  Women in premenopausal years, 18 to 44, live longer than younger men.  However, after the age of 75, women have significant worse survival than men.

Across all age groups, Hispanics survive the longest, followed by whites, Asians, African Americans, and, finally, Native Americans according to a study from the University of Southern California Norris Comprehensive Cancer Center and reported at ASCO.

USC researchers reviewed information for 56,600 men and women with metastatic colon and rectal cancer in the Surveillance, Epidemiology and End Results (SEER) database from 1988 through 2003.  Independent of age, there was no difference in survival between men and women, but once age was added to the analysis, there were significant differences between how long men lived compared to women. Ethnic background also affected survival.

In a news release from USC, Heinz-Josef Lenz, M.D., professor of medicine at the Keck School of medicine one of the researchers leading the study, said,

This study provides further evidence that estrogen may play an important role not only in colon cancer development but also progression of the disease, and may impact how we develop therapies for women and men with colon cancer.

SOURCE: Abstract 4015, Andrew Hendifar, M.D. MPH, Sex, age, and ethnicity are associated with survival in metastatic colorectal cancer, ASCO 2008.

Provigil® (modafinil) reduced fatigue in cancer patients receiving chemotherapy according to a study reported by Gary Morrow PhD at the 2008 ASCO meeting.

Patients who were severely fatigued after their first chemotherapy treatment had less fatigue after they received Provigil than those who got a placebo. They were also less sleepy during the day.

Severe fatigue was considered more than 6 on a 10 point scale. Patients with mild or moderate fatigue did not have a similar improvement.

Despite improvement in severe fatigue, there was no effect on depression.

Cancer-related fatigue is a feeling of overall exhaustion that isn’t relieved by rest or sleep.  It can be debilitating, leading to sleepiness during the day, difficulty sleeping at night, and depression.

Dr. Morrow and his team at the University of Rochester Medical Center concluded,

Modafinil appears useful in the control of severe cancer-related fatigue, especially for patients with severe baseline fatigue. This eugeroic agent also has a significant beneficial effect on sleepiness but no effect on depression.

SOURCE: Morrow et al, A phase III randomized, placebo-controlled, double-blind trial of a eugeroic agent in 642 cancer patients reporting fatigue during chemotherapy: A URCC CCOP Study, 2008 ASCO Abstract #9512.

Patricia Ganz, MD received the American Cancer Society Award at ASCO this year.  Professor of Medicine at the University of California at Los Angeles and Director of Cancer Prevention and Research at Jonsson Comprehensive Cancer Center, Dr. Ganz has a long history of concern for cancer patients and their quality of life.

In the lecture that accompanied the ACS Award, Dr. Ganz discussed the importance of research that looks at quality of life and the effects of cancer treatment, both during treatment and after it.  In particular she encouraged the development of survivorship care plans that improve communication among patients, their oncology care providers, and other health professionals who care for them after their cancer treatment ends.

Discussing such plans, Dr. Ganz explained the reasons for a survivorship care plan.

• To summarize and communicate what transpired during cancer treatment.
• To describe known and potential late effects of cancer treatment.
• To communicate what has been done and what needs to be done in the future.
• To promote a healthy lifestyle to prevent recurrence and reduce the risk of other comorbid conditions.

She pointed out the key elements that needs to be included in an effective survivorship care plan,

• Specific tissue diagnosis and stage
• Initial treatment plan and dates of treatment
• Expected short and long-term effects of treatment
• Late toxicity monitoring needed
• Surveillance for recurrence or second cancer
• Who will take responsibility for survivorship care
• Psychosocial and vocational needs
• Recommended preventive behaviors and recommendations

Dr. Ganz has been a good friend to cancer advocates, encouraging their work and involvement in the lives of people living with cancer.   We at C3 applaud this award and the special woman who received it.

Three studies reported during the 2008 American Society of Clinical Oncology found that colorectal cancer patients whose tumors have mutated KRAS genes do not benefit from treatment with the EGFR-inhibitor Erbitux® (cetuximab).

At the same time, patients with tumors that aren’t aren’t mutated (wild-type) have significantly better results when Erbitux is added to either FOLFIRI or FOLFOX chemotherapy.

Two randomized trials of initial treatment of chemotherapy with or without Erbitux found responses and improved progression-free survival only in patients with wild-type KRAS. The CRYSTAL Phase III study compared FOLFIRI to FOLFIRI with the addition of cetuximab. The Phase II OPUS trial used FOLFOX as chemotherapy and compared FOLFOX to FOLFOX plus cetuximab. Neither found benefit for patients whose tumor had mutated KRAS.

However, both trials found that adding cetuximab to chemotherapy improved both tumor shrinkage (response rates) and the time until the cancer got worse (progression free survival) for people with wild-type KRAS.

Tumors can be tested for mutated KRAS before beginning treatment providing information that can help patients and doctors make better decisions about the right therapy for each individual.

During the Plenary session at ASCO on Sunday, Dr. Eric Van Cutsem presented an analysis of tumors of patients enrolled in the CRYSTAL trial according to KRAS mutation status.

Thirty-five percent of patients in CRYSTAL had mutated KRAS in their tumors. When the two groups, FOLFIRI alone and FOLFIRI with cetuximab were compared, there was no difference in either response to treatment or progression-free survival.

However, wild-type KRAS made a significant difference. When cetuximab was added to FOLFIRI, response rate went up from 43 percent to 59 percent. Median progression-free survival improved from 8.7 months to 9.9 months.

At one year, 43 percent of patients with wild-type KRAS on FOLFIRI plus cetuximab still hadn’t had their cancer progress, compared to 25 percent of those on FOLFIRI alone.

Dr. Van Cutsem concluded,

KRAS is the first molecular marker for the selection of a targeted therapy in combination with a standard chemotherapy in first-line treatment of metastatic colorectal cancer. Cetuximab in combination with a standard first-line treatment for metastastic colorectal cancer is an important new option in patients with KRAS wild-type tumors.

The OPUS trial tells a similar story. OPUS compared FOLFOX alone to FOLFOX plus cetuximab for the initial or first-line treatment of colorectal cancer.

Dr. Carsten Bokemeyer reported the results of an analysis of both response rate and progression-free survival for wild-type KRAS and mutated KRAS in the OPUS study.

The OPUS trial had previously shown an increased response rate when cetuximab was added to FOLFOX, but this did not translate into better progression-free survival.

However, when the KRAS mutation groups were considered separately there there was an even better improvement in response rate for the wild-type group with cetuximab — an increase from 37 percent to 61 percent. Progression-free survival was almost 50 percent better, as well.

When there was a mutation in tumor k-ras, response rate appeared to fall somewhat, although this was not statistically significant. Progression-free survival was actually worse in the FOLFOX plus cetuximab group.

Dr. Bokemeyer and his team concluded,

These data suggest that the benefit from addition of cetuximab to standard treatment is higher for the population with wild-type KRAS. For patients with KRAS mutations, no benefit could be shown of adding cetuximab to FOLFOX in this study.

In a third ASCO presentation, Dr. Sabine Tejpar analyzed the impact of KRAS mutation when doses of cetuximab were increased.

The EVEREST trial selected patients who showed little or no skin rash when treated with FOLFIRI and cetuximab and randomly assigned them to continue the standard dose of cetuximab or have their dose increased until skin rash appeared.

Again, patients with wild-type KRAS did better. Response rate improved as dose increased. But, once more, those with mutant KRAS showed no benefit. Even with dose escalation, there were no responses to treatment.

There was no difference in skin rash between wild-type and mutated KRAS groups.

Dr. Tejpar and her team concluded,

These data suggest that patients with KRAS wild-type achieve considerable benefit from irinotecan plus cetuximab treatment. Patients with KRAS mutation did not profit from irinotecan plus cetuximab treatment and cetuximab dose escalation did not increase responses in these patients.

Previously, similar results were reported for clinical trials of Vectibix™ (panitumumab) that compared Vectibix to best supportive care for patients who had already had standard chemotherapy for colorectal cancer. In that trial patients with mutated KRAS had no benefit, either in response or progression-free survival.

Vectibix targets the same EGFR receptor on the surface of the cancer cell that Erbitux does. Signals to the cancer cell nucleus to divide are sent from the EGFR receptors through a pathway controlled by the KRAS gene. In normal, wild-type tumor cells, blocking that receptor reduces cancer growth. But if the gene is mutated, blocking EGFR doesn’t seem to have any positive effect.

What this means for patients

If you are currently taking either Erbitux® or Vectibix™, you should discuss continuing the drug with your doctor and having your tumor tested for KRAS mutations.

If your doctor recommends Erbitux or Vectibix, ask about testing your tumor for KRAS mutation before deciding on treatment.

Some points to remember during that talk:

• Evidence in several clinical trials have shown no benefit when Erbitux was added to chemotherapy or used alone for patients whose tumors were KRAS mutated.
• There can still be a benefit from chemotherapy or other biologic agents such as Avastin™ in patients with KRAS mutations.
• Patients with wild-type KRAS had a significant increase in responses and time to cancer progression when Erbitux was added to either FOLFIRI or FOLFOX chemotherapy as an initial treatment.
• Testing for KRAS is available and may be reimbursed by your insurance.
• The presence or severity of skin rash doesn’t have anything to do with KRAS status and can’t be used to determine if you have a mutation or are wild-type.
• Testing can be done with the sections of your tumor that were preserved in paraffin blocks at the time of your surgery. These blocks are available.
• Since the mutation is in the tumor, a blood test will not tell you if you have a KRAS mutation. Your family members cannot inherit this mutation.

A study presented during the American Society of Clinical Oncology meeting showed that adding IV infusions of calcium and magnesium to oxaliplatin treatment reduced peripheral neuropathy.

Eloxatin® (oxaliplatin) is part of the FOLFOX treatments for colorectal cancer.  As doses accumulate, patients begin to experience tingling and numbness in their hands and feet.  Some patients will find it difficult to use their hands for small tasks like buttoning or will have problems with pain, balance or walking.  Often patients have to stop treatment before the full benefit is reached because of this difficult side effect.

In a study with patients who were receiving adjuvant FOLFOX treatment after surgery to prevent colon cancer recurrence, doctors randomly assigned patients to receive an intravenous infusion of calcium and magnesium before and after their oxaliplatin infusion or a placebo IV.  Neither oncologist nor patient knew which treatment was being administered.

Although the clinical trial was ended early because of concerns from another study that calcium and magnesium might reduce treatment effectiveness, it was able to show that fewer patients developed grade 2 neuropathy.  Two scales were used to measure neurotoxicity.

• The NCI Common Toxicity Criteria measure for neuropathy found that 22 percent of patients on calcium and magnesium developed grade 2 neurotoxicity compared to 38.5 percent who got a placebo.
• With the Oxaliplatin Specific Neurotoxicity (OSN) scale, 28 percent of patients on calcium and magnesium experienced grade 2 sensory neuropathy compared to 52 percent who didn’t receive the active intervention.
• With both scales, the time to when grade 2 sensory neuropathy began was longer when calcium and magnesium were given.

The research team, headed by Daniel A. Nikcevich, M.D. of the Mayo Clinic, pointed out using calcium and magnesium to prevent serious sensory neuropathy was inexpensive and safe.  They wrote,

Despite early termination, our study demonstrates the activity of IV CaMg as neuroprotectant against oxaliplatin-induced sensory neurotoxicity in adjuvant colon cancer. If further studies refute the notion that IV CaMg decreases the efficacy of FOLFOX, IV CaMg could be regarded as a standard component of oxaliplatin-based chemotherapy.

SOURCE: Nikcevich et al., Effect of intravenous calcium and magnesium (IV CaMg) on oxaliplatin-induced sensory neurotoxicity (sNT) in adjuvant colon cancer: Results of the phase III placebo-controlled, double-blind NCCTG trial N04C7, 2008 ASCO Abstract #4009.