Metastatic colorectal cancer (cancer that has spread from the colon or rectum, beyond the lymph nodes) can be cured about 10% of the time, thus is usually incurable with a median survival of less than 2-years with treatment, about 9-months without treatment and 5-year survival of 10%. (Holland Frei Cancer Medicine 6th edition).  At PCR Oncology we do somewhat better than national averages with 33% 5-year survivals for metastatic colon cancer. 

The options for treatment of metastatic colon cancer include:

1. Chemotherapy

a. 5-FU, leucovorin and oxaliplatin (FOLFOX)

b. 5-FU, leucovorin and irinotecan (FOLFIRI)

2. Targeted therapy

a. Cetuximab and panitumumab (antibodies aimed at the epidermal growth factor receptor)

b. Bevacizumab (antibody aimed at VEG-F, a hormone that stimulates growth of new blood vessels, thus preventing growth of new blood vessels)

3. Immunotherapy

Pembrolizumab – PDL1 antibody that exposes tumor cells to immune system and is FDA approved for “microsatellite unstable” colon cancer.  This comprises about 15% of colon cancers.

The 85% of patients with metastatic colon cancers that are not candidates for immunotherapy and who choose to try treatments usually receive FOLFOX or FOLFIRI with a targeted treatment.  I have patients with metastatic colon cancers that were controlled for 4 or more years with FOLFIRI.  Unfortunately FOLFOX can generally not be used for more than 6-months because of nerve damage caused by oxaliplatin. 

Neuroprotective agents may permit the use of FOLFOX without nerve damage, extending the use of this combination and allowing longer control of colon cancer.

PCR Oncology was the first practice in the United States to open a Phase III trial testing PledOx to prevent nerve damage from FOLFOX chemotherapy in combination with a targeted agent for initial treatment of metastatic (stage IV) colon cancer.  We are one of only about 20 sites in the United States with this treatment and the only practice in central California. 

Metastatic colon cancer is a frightening disease.  PCR Oncology is committed to improving outcomes as evidenced by our first-in-country status opening an exciting new clinical trial.  The basic eligibility criteria are: Good underlying health, diagnosis of metastatic colon cancer and no prior treatment for metastatic colon cancer.

Anyone interested in this trial may call (805-474-9143) and ask for additional information.

David Palchak MD


Since there were no practice-changing articles in this week's reading I've opted to review a few older articles on lymphedema.

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Five new studies

There are at least 5 articles published in this week's journals that are worthy of discussion.


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Pembrolizumab for Triple Negative Breast Cancer

One of the most interesting articles in the last few weeks was on immunotherapy for triple negative breast cancer.  The technology tested in this trial (PD1 blockade) was described in the April 2 2016 post titled "Immunotherapy of Cancer: Immune Checkpoint Inhibitors". 

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Aromatase Inhibitors, Aches and Pains

The articles that interested me most this weekend were part of a reading project I've worked on for a few weeks.  They are about the aches and pains caused by hormonal treatments for breast cancer. 

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The biggest advance in cancer medicine this week is the planned re-opening of the MATCH trial.

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CAR-T cell therapy

This week's article is by Brudno J et al, JCO vol 34 NO 10 April 1 2016, describing a type of immunotherapy called "CAR-T cell therapy".  CAR-T therapy, or chimeric antigen receptor T-cell therapy, may be the next major immunotherapy for patients wtih cancer.

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Bispecific T-cell engager ab:

Steady advances are occurring in immunotherapy resulting in two of this week's most interesting articles describing bispecific T-cell engager antibodies (BiTE Ab).  Click the link to read more.

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Met Gene and Lung Cancer

While the molecular traits that can be targeted with FDA-approved targeted agents for lung cancer are found in only a few per-cent of lung cancer patients, alterations of the MET gene (mutations or amplification) have been found in about 30% of lung cancers.  The MET gene encodes a receptor found on the cell surface that binds a growth factor called hepatocyte growth factor. 

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Alk inhibitor and lung cancer:

The most interesting article in this week's reading is on the molecular biology of lung cancers.  These articles describe the effect of a new drug (alectinib) in the treatment of lung cancers harboring mutations in the anaplastic lymphoma kinase (Alk) gene.

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Molecular biology of Her-2/neu

The most interesting article in this week's reading was on the preoperative treatment of breast cancer.  L Cary et al (JCO Vol 34, No 6 Feb 20, 2016 p 542) report on 305 patients with Her-2/neu over-expressing breast cancers who received chemotherapy with trastuzumab, lapatinib or both for 16-weeks and were then taken to the operating room.  The authors observed significant differences in response rates that were (partially) explained by genetic differences between the cancers.  These genetic differences give some insights into who is most likely to benefit from our current standard breast cancer treatments.  To read more about this study, click on this link: Full review

Everolimus and breast cancer

Breast cancer, like nearly all cancers, is caused by acquired genetic changes, i.e. mistakes copying DNA.   People are often skeptical when I tell them their cancer is caused by a mistake copying DNA.  There are about 6 billion nucleotides that make up the DNA in each cell.  Whenever a cell divides all 6 billion nucleotides must be copied to make new DNA for the new cell.  If you have made a mistake dialing a phone number or spelling a word then you can understand that DNA Polymerase could make a mistake copying 6 billion nucleotides.

Once you accept the idea of cancer as an acquired genetic disease you begin to wonder: In which genes do these mistakes occur and how do these genetic changes cause cancers?

In general the genetic mistakes that cause cancers occur in genes that control cell division, “programmed cell death” or DNA repair.  The easiest mistakes for me to understand are those that occur in genes that control cell division leading to uncontrolled cell division and cancer.  This concept was understood in the 1980’s at which time a decades-long search for treatments to act on the abnormal genes and their products began. 

One of the genes involved with the control of cell division is the mTOR gene.  The product of this gene is an enzyme (a serine-threonine kinase) that adds a phosphate group to other proteins when activated.  This enzyme catalyzes one of a series of reactions in a pathway that leads to cell division.  In many cancers one of these enzymes is defective, leading to uncontrolled cell division.  The mTOR gene product is neither the first nor the last step in this pathway, located somewhere in the middle.  Upstream molecules include Her-2/neu, EGFR, PI3K, pTEN and AKT.

Everolimus is an oral mTOR inhibitor that blocks the enzyme encoded by the mTOR gene, blocking this pathway.  One would predict that cancers caused by activation of the pathway prior to mTOR would stop growing under the influence of everolimus, while cancers caused by activation of the pathway after mTOR would be resistant.

G Hortobagyi et al (JCO Feb 10, 2016 vol 34 No 5 p 419) attempted to correlate responses to everolimus with the genetic makeup of the breast cancer being treated in patients with metastatic breast cancer.  They specifically looked for a correlation between activation of molecules upstream from mTOR and response to everolimus.  They report very little correlation, meaning we cannot predict which patients with metastatic breast cancer will respond to everolimus. 

The inability to predict which patients should try everolimus is disappointing, but not surprising in light of the complexity of the genetic pathway everolimus blocks. 

The FDA has approved everolimus for 2nd line treatment of estrogen-receptor-expressing metastatic breast cancers in combination with exemestane.  We have seen dramatic responses to this combination, including a patient seen last week.  The paper cited above tells us we do not yet know enough about the mTOR pathway to predict which patients will respond based on the genetic profile of their tumor.  So this combination may be considered as a second treatment for any patient with metastatic breast cancer expressing the estrogen receptor. 

We are also participating in S1207, a trial of adjuvant everolimus with hormonal therapy in women with “high-risk” breast cancer that expresses the estrogen receptor but does not over-express Her-2/neu.  These patients may choose to participate in a clinical trial that randomly assigns to receive the hormonal treatment of their choice with or without everolimus.  This treatment is administered after a surgeon has removed all visible cancer and following "adjuvant" chemotherapy.

Ovarian Cancer Trial

The commonest variety of ovarian cancers arise from the same cells as most fallopian tube and "primary peritoneal" cancers.  For this reason research on these 3 cancers is combined and these cancers are typically treated the same way.

Ovarian cancer is usually diagnosed in advanced stages (stage III or IV).  In most cases the initial treatment is surgery followed by "adjuvant" chemotherapy (with or without bevacizumab).  Cure rates with this approach are about 20%, which means 80% of patients are destined to suffer relapses of their cancers.

The highest response rate for recurrent ovarian cancer in my library is with Abraxane (Teneriello M et al JCO Vol 27 No 9 March 20 2009) which yielded a 64% response rate in a small phase II trial.  Most of the patients whose cancers responded suffered progression of their cancers in 15-months.  Obviously better treatments are needed, making recurrent ovarian cancer an obvious target for cancer research.

Recurrent ovarian cancer is divided into "platinum refractory" and "platinum sensitive" disease.  Platinum refractory disease is diagnosed when the cancer grows within 6-months of the last dose of cisplatin or carboplatin.  While all recurrent cancer is bad, platinum refractory disease is worse than platinum sensitive disease. 

NRG-GY005 is a clinical trial testing targeted agents in the treatment of platinum refractory recurrent ovarian cancer, fallopian tube cancer or primary peritoneal cancer.

Cediranib is a drug that is taken by mouth and blocks growth of new blood vessels.  It does this by blocking 3 enzymes: Tyrosine kinases linked to the three receptors for vascular endothelial growth factor (VEGF). 

Olaparib inhibits an enzyme called polyadenosine diphosphate-ribose polymerase 1 (PARP1).  This enzyme's job is to repair single strand breaks in DNA.  Normal cells have little trouble when PARP1 is inhibited, but for some cancer cells PARP inhibition is lethal. 

NRG-GY005 is a trial of Cediranib and olaparib compared with either drug alone or standard chemotherapy in women with recurrent platinum-resistant or refractory ovarian, fallopian tube or primary peritoneal cancer. 

It has been reviewed by the National Cancer Institute's (NCI) central Institutional Review Board (cIRB) and as a result is available at select medical oncology practices that are permitted to use the NCI's cIRB.  PCR Oncology was allowed to use the NCI's cIRB following a long vetting process after which we joined the National Community Oncology Research Program.  As a result this clinical trial is available at our office in Pismo Beach.  It is the same treatment that would be offered to patients with platinum resistant ovarian cancer who flew to Bethesda and enrolled as patients at the NCI. 

If you or someone you know is interested in this trial call the office and request an appointment.

Chronic lymphocytic leukemia: New treatments coming

Cancer is (usually) caused by acquired genetic change.  Whenever a cell divides it must copy the roughly 6 billion nucleotides that make up our DNA.  Copying this DNA results in some mistakes and mistakes that occur in parts of the DNA controlling cell division or the death of cells results in uncontrolled cell division or failure of cells to die when they should.

Lymphocytes are always dividing, with new lymphocytes being formed to replace old ones that are no longer needed.  As new ones are formed it is important that the old ones die, or else lymphocytes will accumulate.

Chronic lymphocytic leukemia (CLL) is caused by a variety of acquired genetic changes.  Among the commonest are those that involve the BCL2 gene.  (BCL stands for B cell leukemia.)  The BCL2 gene product is a protein that interferes with cell death and the common change in this gene is over-expression.  Lymphocytes that over-express the BCL2 gene do not die when they should.

Drugs that interfere with the product of the BCL2 offer the potential to control CLL.  The New England Journal of Medicine (Roberts, A et al, January 28 2016, vol 374, No 4, p 311 report on a trial of venetoclax, an inhibitor of the BCL2 gene product.  One hundred and sixteen patients with relapsed CLL were treated and 79% of these patients enjoyed a response.  Side effects were tolerable and the commonest side effects were caused by the rapid death of leukemic cells. 

The same journal reported on another new drug for treatment of CLL, acalabrutinib.  This drug inhibits an enzyme called Bruton tyrosine kinase, an enzyme in the "B cell receptor signalling pathway" that leads to division of lymphocytes.  Inhibition of this enzyme is a proven treatment for CLL.  Acalabrutinib is a second generation bruton tyrosine kinase inhibitor that is expected to have fewer side effects than that first-in-class drug, ibrutinib.  Sixty-one patients with relapsed CLL received acalabrutinib resulting in a 95% response rate.

Neither acalabrutinib nor venetoclax are FDA approved yet.  Both drugs will need to undergo additional testing before submission for FDA approval.  However current treatments for CLL are quite effective and new treatments are on the horizon. 

These 2 drugs attack both of the problems that can cause cancer/leukemia: Failure of cells to die when they should (venetoclax) and excess cell division (acalabrutinib).  Advances in the molecular biology of cancer and development of treatments aimed at the abnormal genes causing cancers are among the most exciting developments in cancer research.  Most current cancer research is aimed at either this kind of drug or others that harness the power of the immune system. 


New treatment for myeloma: Elotuzumab (Empliciti)

Medical Oncologists have been steadily moving away from chemotherapy treatments for the last decade.  With rare exceptions, new cancer treatments are aimed either at specific gene products promoting growth of cancers or at enabling the immune system to fight the cancer.  Elotuzumab is an immunotherapy aimed at the CS1 molecule found on myeloma cells and "null killer" cells, or NK cells.

When elotuzumab binds to NK cells it activates them and when it binds to myeloma cells it identifies them for destruction by the immune system.

The first article on elotuzumab in our library at PCR Oncology is by A Jakubowiak et al in the Journal of Clinical Oncology Vol 30 No 16, June 1 2012.  This is a Phase I study of elotuzumab in 28 patients with relapsed myeloma, who were treated with escalating doses of elotuzumab in combination with bortezomib (Velcade).  About half of patients responded and side effects were tolerable.

The second article on elotuzumab in our library is by S Lonial et al in the New England Journal of Medicine, volume 373, No 7, August 13, 2015.  This paper describes the treatment of 646 patients with relapsed myeloma, who were treated with lenalidomide and dexamethasone with or without elotuzumab.  The response rate in the elotuzumab group was 79% (compared with 66% without elotuzumab).  Side effects were mild enough that elotuzumab did not interfere with quality of life.

The FDA approved elotuzumab for treatment of recurrent myeloma in combination with dexamethasone and lenalidomide on 11/30/15. 

We have now treated our first patient with this combination.  While it is too early to judge his response to treatment, we can say he, like those treated in the studies above, has not experienced significant side effects.