Pembrolizumab approved for a slew of cancers all at once

Pembrolizumab approved for a slew of cancers all at once

Pembrolizumab (a drug that inhibits PD-L1) recently received FDA approval for any type of cancer that’s failed to respond to first line therapy, as long as the tumor carries a specific molecular defect.

Let me repeat that – ANY TYPE OF CANCER.

Mind not blown yet? OK, OK – I should give you some background information about how FDA approval works.

It used to be that drug-makers could advertise and sell medicines even if there was no proof the drugs were effective. It wasn’t until 1978 that the FDA required that medicines actually did what they claimed to do. This was great news for cancer treatment, because it led to the removal of a great many ineffective and fraudulent medicines from pharmacy shelves. But it also caused drug approvals to become much more narrowly focused.

Think about it: if you’ve got a drug that shrinks the majority of breast cancers, almost half of lung cancers, and a third of bladder cancers, you’re going to submit the drug for approval for each separate disease  since you don’t want the poor-responding bladder cancer to jeopardizing drug’s approval for breast cancer patients. But the result is cancer drugs usually only get second-tier testing in one specific type of cancer (or cancer situation) at a time. And though the FDA’s approving more drugs in less time than ever before, I still find it hard to be patient sometimes, even though I understand how important a proper approval process is. No one wants to go back to the “buyer beware” days before 1978.

Back to the main topic at hand, though – the FDA approved pembrolizumab for any type of cancer with a specific defect in DNA mismatch-repair.  That means the drugs work so well in so many different types of cancer that the manufacturer was confident enough to test it in multiple different cancers.

Nothing like this has ever happened in my professional career.

(Up Next: How do checkpoint inhibitors work, anyway?)

Aspirin and Gastrointestinal Cancer: It May Keep the Doctor Away

Aspirin and Gastrointestinal Cancer: It May Keep the Doctor Away

I recently came across a great review article from the UK titled “Aspirin in Gastrointestinal Oncology: New Data on an Old Friend” and I wanted to share some insights I learned from this review.

Aspirin has been around for over 100 years and had been used for a long time to treat pain, inflammation and fever. It later was discovered that it is a powerful inhibitor of blood platelets which subsequently made it one of the most important components in the treatment and prevention of heart attacks and strokes. In tissue cells and in blood platelets it blocks an enzyme called cyclooxygenase.

There is good evidence that aspirin reduces the risk of colon and other gastrointestinal cancers. One study from the UK with more than 20 years of follow-up evaluated over 7500 patients who had taken aspirin for the prevention of stroke and heart attacks. Once the follow-up period passed the 10-year mark, it became evident that patients who had taken aspirin once daily for 5 years or more, had a reduced risk of colon cancer. Subsequent large studies also showed that aspirin reduced the risk of getting stomach or esophageal cancer as well as the risk of dying from stomach or esophageal cancer. However these benefits did not manifest themselves until 8 to 10 years after starting aspirin. This observation is similar to what was seen with aspirin and colon cancer prevention and explained by the fact that it takes a long time for gastrointestinal cancer to progress from a precancerous growth to an obvious cancer.

An  exception to this is a condition called Lynch syndrome where patients develop colon cancer and other cancers at a younger age. Here the protective effect of aspirin is already noted after 4 to 5 years.

Once a cancer has formed, a big concern is that it will spread to other places in the body forming sister growths (metastases). In an analysis of all the large British aspirin prevention studies it was noted that patients who developed colon cancer while on aspirin had a substantially lower risk of forming metastases which brings me back to  blood platelets. One intriguing hypothesis is that platelets may protect circulating tumor cells from being detected by the immune system and by aspirin disrupting this process, circulating colon cancer cells could be eliminated by the body’s own immune cells.

We can expect more research data to be presented in the future how our old friend aspirin protects against cancer.

A Few Facts About Stomach (Gastric) Cancer

A Few Facts About Stomach (Gastric) Cancer

In the 1930s, gastric cancer (which then was mainly cancer of the lower stomach) was the most common cause of cancer deaths for American men. However, over the course of the 20th century, classical cancer of the lower stomach became much less common; probably because of the use of refrigeration as the principal means of food preservation rather than salt-based food preservation. Conversely, over the last 30 years cancers of the upper stomach and junction of the esophagus and stomach have increased greatly — mainly related to an increase in obesity, gastroesophageal reflux disease and related changes of the lining of the lower esophagus (Barrett’s esophagus).

Overall, the epidemiology of stomach cancer has multiple facets with great variations based on geographic location, race, age, and lifestyle.

There is a bacterial organism called helicobacter pylori which can cause chronic inflammation of the lining of the stomach and over time precancerous lesions.

The risk of stomach cancers is doubled for smokers.

Certain genetic factors can result in an increased stomach cancer risk.

There are families who have a mutation in a gene called CDH1 (also called E cadherin) which encodes a cell adhesion protein. Over two thirds of affected patients will develop gastric cancer and often a prophylactic gastrectomy is warranted. Affected women are also at risk for lobular breast cancer.
Another genetic syndrome called Lynch syndrome in which affected patients carry genetic mutations in DNA mismatch repair genes is not only associated with a high risk of cancers of the colon and rectum, but also with an increased risk of gastric cancer and other cancers.
Mutations in the breast cancer genes BRCA1 and BRCA2 also confer an increased risk for the development of gastric cancer.

Research To Improve Survival Outcomes

When patients are diagnosed with stomach cancer, up to two thirds of patients will have advanced disease. In order to improve treatment outcomes beyond the benefits of chemotherapy, a lot of research has focused on targeting signaling pathways of the gastric cancer cell. 
The Her2/Neu/c-erb-2 protein belongs to a group of cell receptor proteins called human epidermal growth factor receptors. It is overexpressed in 15 to 37% of patients with advanced gastric cancer and targeting it with a Her2 specific monoclonal antibody in addition to chemotherapy has shown to improve treatment outcomes.
Another cell receptor called Her1/EGFR/c-erbB1 is overexpressed in 30 to 80% of patients with gastric cancer. However monoclonal antibodies targeting Her1/EGFR have not proven to be beneficial.
The formation of new blood vessels (angiogenesis) has been identified as an important factor in the development and progression of stomach cancer. Particularly a blood vessel formation receptor called VEGFR-2 appears to play a central role in the promotion of blood vessel formation and tumor growth.
Two recent studies showed that a new monoclonal antibody targeting VEGFR-2 either by itself or when added to chemotherapy improved gastric cancer treatment outcomes and has been approved by the FDA for the treatment of patients with advanced gastric cancer where the cancer has worsened after initial chemotherapy.
Another pathway under intensive investigation is the MET/hepatocyte growth factor (HGF) signaling pathway. The MET proto-oncogene encodes the receptor tyrosine kinase c-MET. MET activation leads leads to tumor cell detachment, migration and invasion and has been associated with a poor prognosis.
There are presently two ongoing larger nationwide studies looking at the use on monoclonal antibodies targeting the MET/HGF pathway, but it will be some time before results of those studies will be available.
In conclusion, it is exciting to see such a flurry of research activity looking at novel treatment strategies for our patients with stomach cancer, and I am hopeful that survival outcomes will continue to improve.

Preventing Colorectal Cancer – Second in the Colon Cancer Series

Preventing Colorectal Cancer – Second in the Colon Cancer Series

The focus of the second blog in the colon cancer series has a focus on preventive aspects of colorectal cancer. A third blog looking at pharmacalogical prevention of colon cancer will follow later this year.

       Physical activity:  Regular physical activity through either work or leisure appears to reduce the risk of colon cancer by almost a third when comparing the least physically active to the most active individuals. 

       Fruits, vegetables,red meat and animal fat: There are a number of studies which have  shown a mild protective effect of fruit and vegetable consumption. Excessive consumption of fruits and vegetables does not seem to better than what is offered in a balanced diet (an apple a day seems to be adequate). A diet low in red meat and animal fat also appears to have protective benefit independent of fruit and vegetable consumption. However, it has to be pointed out that there was one large study which did not show a clear benefit of fruit and vegetable consumption regarding the risk of colorectal cancer.

       Dietary fiber: There is some controversy regarding the benefits of dietary fiber and colon cancer risk. However in a recent large review of 25 studies it was concluded that high intake of dietary fiber, in particular cereal fiber and whole grains, was associated with a reduced risk of colorectal cancer.

       Folic acid and folate: It is not clear if there is a role for folate (which is food-derived) or synthetic folic acid used in food supplements in the prevention of colon cancer. There was one large study suggesting a reduced colon cancer risk for individuals taking 800 mcg of folate or more per day. However, other studies did not confirm any benefit of folic acid with one study even raising the question of increased colon cancer risk with folic acid supplementation.  

–        Vitamin B6: There is a modest association between higher Vitamin B6 intake and decreased colorectal cancer risk.

–        Calcium: There are several large studies which suggest that high calcium intake either through supplements or dietary intake reduces the risk of colorectal cancer. Calcium supplementation may be effective in reducing the risk of colorectal adenomas which are benign growths which later can turn into cancer. Calcium supplementation is recommended by the American Society of Gastroenterology to prevent colon adenomas.

–       Vitamin  D: A number of studies have shown  an association between low Vitamin D blood levels and increased colorectal cancer risk. However the data regarding the benefits of Vitamin D supplementation in preventing colorectal cancer have been conflicting and there are important studies ongoing trying to answer this question.  

–      Magnesium: Based on a large study from Scandanavia with more than 60,000 participants, there appears to be a signal that higher magnesium intake is associated with a reduced risk of colon and rectal cancer.

 With summer upon us, let’s celebrate with lots of physical activity and don’t forget that apple a day!

First in a series: Contributing Factors – Colorectal Cancer

First in a series: Contributing Factors – Colorectal Cancer

Over the last fifteen years, the number of new cases of colorectal cancer has gone down by 2 to 3 percent per year. There are a number of factors that still result in over 140,000 new cases of colorectal cancer being diagnosed each year.  The following is an overview of these factors.

The incidence of colon cancer appears to increase with age although more recently,  a growing number of new cases have been diagnosed between the ages of 40 to 44.

The risk for colon cancer is higher in men and in patients of African-American descent.

There are genetic conditions associated with a very high risk of colon cancer, often at a young age, such as familial adenomatous polyposis (FAP) and its variants; MUTYH-associated polyposis and Lynch syndrome.

Inflammatory bowel disease (Crohn’s disease and ulcerative colitis) carries an increased risk of colorectal cancer; particularly if there are ongoing inflammatory changes in the bowel wall over an extended period of time.

Evidence exists that adult survivors of childhood cancer who received abdominal radiation are at a higher risk for developing colorectal cancer.

Acromegaly, a condition which is caused by excess growth hormone in  the body, carries an increased risk as well.

Kidney transplant patients appear to have a significantly increased risk of colon cancer.

Patients with prostate cancer who had been on androgen-blocking therapy have increased colorectal cancer risk which appears to increase with longer duration of the therapy.

Diabetes mellitus results in a higher risk of colorectal cancer; even in studies which controlled for smoking, obesity and physical activity.

Obesity itself is associated with a higher risk of colorectal cancer – more in men than in women – and the risk appears to increase the higher the body mass index(BMI).

There appears to be a slightly increased risk of cancer of the right side of the colon in patients who had undergone a cholecystectomy (removal of the gallbladder).

The risk of colorectal cancer increases with alcohol consumption in a number of studies, even when evaluating  light drinkers.

Cigarette smoking, which is a risk factor for a number of cancers – most notably cancer of the lung, is also associated with an increased risk of colorectal  cancer.

Long-term consumption of  red and processed meats appears to increase the risk of colorectal cancer, particularly in the left side of colon and in the rectum.

This concludes my brief review. There are many elements that contribute to a colorectal cancer diagnosis.  There are also a number of preventive measures which I will look at in my next blog entry.

Colorectal Cancer: Being Physically Active is Better

Colorectal Cancer: Being Physically Active is Better

A study published recently in the Journal of Clinical Oncology in March of this year and sponsored by the American Cancer Society has reported that patients with localized colorectal (large bowel ) cancer had improved overall survival with increased physical activity; whereas a more sedentary lifestyle was associated with reduced survival.

In this study, participants completed detailed questionnaires regarding their physical activities and leisure time before and after being diagnosed with cancer of the colon or rectum. There were 3 categories of activity -walking less than 1 hr/wk, walking 1 to less than 2.5 hrs/wk and 2.5 hrs or more walking/week. Leisure time categories were sitting less than 3 hrs/day, 3 to less than 6 hrs/day and 6 or more hours/day. Patients were followed over an extended period of time (up to 16.1 years).

In patients with the highest activity level, there was a 42% reduced risk of death from all causes. In patients who reported sitting for 6 or more hours/day, there was a 62% increased risk of dying from complications related to colorectal cancer.

The authors acknowledged certain limitations of the study, but concluded that physicians should consider counseling colorectal cancer survivors to adopt a physically active life style aiming to achieve 2.5 hrs or more of moderate intensity activity per week, such as walking, and to avoid prolonged sitting.

I have to admit that in my practice, I need to be more proactive in talking to my patients about the benefits of physical activity and better understand the obstacles to a less sedentary lifestyle.

Diffuse B-cell large cell lymphoma: Beware of the double hit

Diffuse B-cell large cell lymphoma: Beware of the double hit

Lymphomas are cancers of lymph cells (lymphocytes). B-lymphocytes play an important role in the immune system and are involved in producing antibodies against viruses and bacteria during an infection.

When B-lymphocytes become malignant, they can form slower growing tumors (low grade lymphomas) or faster growing tumors (high grade lymphomas).

Diffuse large B-cell lymphoma is one of the most common form of high grade lymphomas. Standard treatment consists of a monoclonal antibody called rituximab and  four other agents (Adriamycin, vincristine, cyclophosphamide, prednisone). This combination is known as R-CHOP – and can cure up to two-thirds of patients with B-cell large cell lymphomas.

But what about patients who don’t seem to benefit from R-CHOP? We’re starting to understand important biological differences in some of these more difficult cases. In a large international study of lymphoma patients receiving R-CHOP, some of the patients responding poorly to treatment were found to have abnormal gene activity. Specifically, patients whose cancer cells expressed both MYC and BCL-2 did not do nearly as well as the rest of the study group. only 30% of these patients were still alive at 5 years.

The authors concluded that staining of lymphoma tissue for MYC and BCL2 is a useful tool to help assess prognosis of patients  with B-cell large cell lymphoma and help identify patients who potentially could benefit from novel therapies.

This is a very active area of research and I am hopeful that we will have exciting breakthroughs in the future.

Qigong: Improving Quality of Life in Women Undergoing Radiotherapy for Breast Cancer

Qigong: Improving Quality of Life in Women Undergoing Radiotherapy for Breast Cancer

Qigong (“qi” or “chi”= energy flow, “gong”= skill or achievement) is a practice with its roots in Chinese medicine, martial arts and philosophy. It involves rhythmic breathing coordinated with repetition of fluid movements and a calm mindful state guiding “qi” through the body. There are many million practitioners of Qigong in China and the rest of the world. When I travelled to China a few years ago, it was amazing to see hundreds of Qigong practitioners simultaneously engage in their fluid exercises at a park or other public location.

In a study recently published in the journal Cancer, researchers from China, the United States and Germany examined the benefits of regular Qigong practice in Chinese women undergoing radiation therapy for breast cancer.

In this study, women were scheduled to undergo breast radiation therapy for 5 to 6 weeks. About half of the women receiving radiation also practiced Qigong weekly for forty minutes.

Women with depressive symptoms at the outset showed improvements in depression, fatigue, and overall quality of life after participating in Qigong. I am intrigued by the data as Qigong appeared to help women with cancer who showed high baseline depressive symptoms.

Based on a recent review, there also appear to be positive effects of Qigong on patients undergoing chemotherapy.

Watch for more information about the practice of Qigong as it becomes more common worldwide.

Treatment for Medullary Thyroid Cancer

Treatment for Medullary Thyroid Cancer

Medullary thyroid cancer is a rare form of thyroid cancer. On November 29, 2012 the FDA announced the approval of an oral drug called cabozantinib (brand name Cometriq) for the treatment of patients with medullary thyroid cancer where the cancer has spread to other sites in the body. It is a tyrosine kinase inhibitor blocking multiple pathways important for medullary thyroid cancer cells.

In one study with 330 patients, those who received cabozantinib lived for 11 months without their cancer worsening compared to four months for patients who received a placebo. There are some significant side effects patients need to be monitored for as listed in the actual prescribing information.

If you have any questions about this or any other treatment, please talk with your physician.

Focus on Esophageal Cancer

Focus on Esophageal Cancer

There are 2 types of esophageal carcinoma: squamous cell carcinoma and adenocarcinoma. Adenocarcinoma typically develops in the lower part of the esophagus. Since 1975, it has increased fivefold in the United States. As far as risk factors for this increased incidence are concerned, chronic acid reflux is at the top of the list.

Chronic acid reflux is a condition where stomach acid flows back into the esophagus over a period of years. Over time, the cells which line the esophagus can start to resemble cells of the stomach lining. This condition is called Barrett’s esophagus. In some patients with Barrett’s esophagus, there are further tissue changes, showing increased cell proliferation and in some cases progression to adenocarcinoma of the esophagus.

There is some recent data showing that when patients with Barrett’s esophagus take stomach acid reducers called proton pump inhibitors, there is less risk of progression to adenocarcinoma.

In addition, some evidence shows that low dose aspirin taken by patients with Barrett’s esophagus over many years may reduce the risk of adenocarcinoma by as much as 20 percent.

Obesity and diet appear to be important risk factors in the development of esophageal cancer. In one large study looking at data from 218854 AARP members, it was noted that a body mass index of 35 kg/m2 or greater was linked to an increased risk of adenocarcinoma of the esophagus and upper part of the stomach.

A diet low in vegetables and fruit consumption also appears to result in a higher rate of esophageal cancer.

There has been concern that oral biphosphonates which are commonly taken by women to reduce the risk of thinning of the bone are a risk factor for adenocarcinoma of the esophagus. However in a recent British study looking at 42,000 patients, this did not seem to be the case. For patients on biphosphonates, it is still important that they remain in an upright position for at least 30 minutes after taking their biphosphonate pill in order to avoid chronic irritiation of the esophagus.

So, what would be practical advice for esophageal cancer prevention?

Speaking for myself, I definitely will watch my diet and weight more, have fruits on the kitchen table instead of cookies and hope to have more guidance regarding the use of aspirin once more information from a large prospective British Chemoprevention trial looking at aspirin and esophageal cancer is available.

I already had a screening scope exam of my esophagus and stomach and plan to recommend it to my patients, particularly if there are symptoms of reflux.