Putting the name of this imperious disease in the title of my homily places a weighty responsibility on me.   Who am I to attempt to put forth relevant information and sensible opinions on this topic, the mere mention of which makes most normal folk distinctly uneasy?   But I probably pay more attention to the news about cancer and its treatment than most of Gumshoe nation, and I will try hard to present a balanced and sober view of what’s going on, sometimes surveying the terrain from thirty thousand feet, and sometimes coming in for a closer look.

Let me start off with a very general observation: most of the news about cancer that appears in the media is about developments that will affect a relatively thin slice of the total population of cancer patients.   The new drugs that we keep reading and hearing about are, initially at least, for a fairly small minority of cancer patients – usually those with rare cancers for which no other therapies are available, or for patients with advanced cancers who have failed previous courses of therapy.   That’s not because the drug makers are preferentially targeting those patient classes, but because those are the patient classes for which it is feasible to gain regulatory approval for their new candidate drugs.   I’ll explain in more detail later.   What I want to do now is look broadly at the picture as a whole – what’s happening with incidence and mortality of the cancers as a class, and to what extent is cancer treatment changing.   And, of course, where it is heading.     

Some of you may be wondering if this piece is going to be good news, in which case you will read it to the last sentence, or dire warnings, in which case you will be inclined to chuck it in the trash along with the rest of the day’s dire warnings.   On the whole, permit me to say that what you will take from this installment of the Doc Gumshoe is mostly bona fide good news, so please do read on.

However, just to get it over with, a bit of bad news: according to the Centers for Disease Control, it is predicted that the number of new cancer cases diagnosed each year in the US will rise in the next 20 years or so, from 1,735,000 this year to 2,387,000 in 2035.   Why is this?   The main reason is that here has been a huge decline in heart disease in our land.   If heart disease rates had remained at their 1996 peak, there would have been about 10 million more deaths attributable to heart disease since then.   But those 10 million individuals who avoided death from heart disease have not had immortality conferred on them.   At some time, their sojourn on our planet comes to an end, and the vehicle that conveys them to the exit is, with increasing frequency, cancer.   

What is unquestionably good news is that the rate of cancer deaths in the US has declined considerably.   If the overall cancer death rate in 1990 had persisted, the result would have been about 2.4 million more cancer deaths between 1991 and 2015.   Cancer deaths are projected to continue to decline, despite the increase in the number of cancer diagnoses due to the factors mentioned above.   Overall, age-adjusted cancer mortality in the US declined by 26% from 1991 to 2015.   And, whereas in the mid-1970s about 49% of cancer patients survived 5 years after diagnosis, by 2014 that 5-year survival rate had increased to 69%.

Globally, the picture is not nearly so rosy.   The International Agency for Research on Cancer just published on September 12^th the GLOBOCAN 2018 estimates of worldwide incidence and mortality for cancer.   Data from local registries (which in some parts of the world capture information from only a small portion of the population) show that 18.1 million people were diagnosed with cancer in the previous year, and 9.6 million died of cancer.   Cancer incidence is on the rise, and the predictions are that by 2030, as many as 30 million people will die of cancer annually, at least three-quarters of whom will be in lower income nations.  As in the US, the rise in cancer incidence is largely propelled by increasing life expectancy, although the spread of unhealthy life-styles no doubt has something to do with it.  

Although breast cancer is the most common type of cancer for women in most countries, in sub-Saharan Africa and parts of Asia, it is surpassed by cancer of the cervix.   Lung cancer is now the commonest cancer globally, accelerated at least in part by the so-called “tobacco epidemic.”   It is predicted to result in 2.1 million cancer diagnoses in 2018, and 1.8 million deaths.     

Returning to data for the US, here’s a table that lists the estimated cancer statistics for 2017, showing the number of estimated new cases in males and females and the percentage of the total number of cases for each type of cancer.   The last column shows the percentage of patients with each type of cancer who are estimated to survive at least five years beyond the diagnosis.

Type of cancer	Estimated New Cases in Males – No. & % of Total	Estimated New Cases in Females – No. & % of Total	Estimated 5-year Survival – M & F
Breast		252,710       30%	88.7%
Prostate	161,360       19%		97.4%
Lung & bronchus	116,990       14%	105,510       12%	18.3%
Colon & rectum	71,420        9%	64,010        8%	63.5%
Urinary bladder	60,490        7%		75%
Uterine		61,360        7%	80.8%
Thyroid		42,470        5%	96.7%
Melanoma	52,170        6%	34,940        4%	89.4%
Kidney & pelvis	40,610        5%	23,380        3%	71.4%
Non-Hodgkin lymphoma	40,080        5%	32,160        4%	68.1%
Leukemia	36,290        4%	25,840        3%	54.9%
Oral & pharynx	35,720        4%		60.6%
Liver & bile duct	29,200        3%		17.2%
Pancreas		25,700        3%	8.3%
All cancer sites	836,150	852,630	65.6%

That table, cobbled together by Doc Gumshoe from several sources, including SEER (Surveillance, Epidemiology, and End Results, part of NIH) and the American Cancer Society is incomplete, listing only the top ten cancer diagnoses by frequency in males and females.   The percentages of diagnoses for each gender do not add up to 100%; the difference between the sum of the percentages and 100% consisting of numerous other cancers whose frequency does not make the top ten.   As you see, uterine cancer is the fourth most common cancer in women while ovarian cancer does not make the list.   

However, it should be of interest on a number of points.   First, the five-year survival rates for the most common cancers in women and men are gratifyingly high, and suggest that those patients will likely benefit from high ten, fifteen, and perhaps twenty-year survival rates as well.   The nasty surprise is the low survival rate for lung and bronchial cancers.   These are also the cause of the highest proportions of cancer deaths, 27% in men and 25% in women.   Non-smokers may take some comfort in the knowledge that they have an excellent shot at avoiding this form of cancer; nonetheless, lung cancer has been known to affect some non-smokers.

The benefit of lung cancer screening was demonstrated in a large randomized European study called NELSON, which was reported at the World Conference on Lung Cancer in Toronto the week of September 23 of this year.   Lung cancer mortality was reduced by 24% to 26% in men and by 40% to 60% in women who had regular chest CT scans.   The subjects in the study were identified as high-risk due to their smoking history.

Even though pancreatic cancer did not make the top ten in estimated new cases in men, this particularly deadly form of cancer is the fourth leading killer in both men and women, accounting for 7% of all cancer deaths in both sexes.    And in spite of the fact that breast cancer and prostate cancer are by far the most common cancers in women and men respectively, they are not the leading cause of cancer deaths in either sex.   Breast cancer is the killer in 14% of women’s cancer deaths, and prostate cancer in only 8% of men’s cancer deaths.

The disproportion between incidence and fatality rates is at least partially explained by the ease of detection – breast cancer via mammograms and biopsies, and prostate cancer by means of the much-discredited PSA test and biopsies.   (It is also of course the case that prostate cancer progresses very slowly, so that many men with indolent cancers die of something else first.)   

In contrast, pancreatic cancer is particularly difficult to detect and in the majority of cases is only diagnosed at a point at which treatment is ineffective.   In general, the cancers with high five-year survival rates are those which are more easily detected, and the ones with lower survival rates are more difficult to detect.   This reinforces the principle that early detection is one of the most important factors in cancer management.

So now let’s take a look at current cancer management and treatment.   

How much has cancer treatment changed in the past few years?

Cancer research today is focusing more closely on such matters as individual cancer variants and on cancers in specific human individuals than on broad treatments for classes of cancer – e.g., not on breast cancer in general, but on the genetic, molecular and cellular characteristics of specific breast cancer variants.   However, cancer treatment – as distinguished from cancer research – continues to rely mostly on surgery, radiation therapy, and cytotoxic chemotherapy.   These have been strongly criticized as falling far short of “cures” for cancer in general or for many or most individual cancers.   A common way of characterize these treatment forms is to damn them with the phrase “cut, burn, and poison.”   

A moment’s reflection may bring us to the realization that if we have an antagonist in our bodies which, if allowed to remain, will grow and eventually kill us, perhaps mounting an attack on this antagonist by cutting, burning, or poisoning it is not such a bad idea.   Thus, surgery, radiotherapy, and chemotherapy continue to be the first line of treatment for the great majority of cancer patients.   Each of these treatment forms has seen considerable refinement and improvement in recent years.   

Advances in surgery

Surgical excision of cancerous tumors has been made far more accurate due to improved imaging of the cancerous lesions.   Whereas formerly the surgeon opened the presumed site of the tumor and delicately poked and pried to find the invader, the surgical procedure today is guided with a high degree of accuracy, minimizing collateral harm to adjacent tissues and maximizing total removal of the target tumor.   

For example, in breast cancer patients undergoing mastectomies, it is frequently advisable to remove those lymph nodes, called sentinel nodes, to which the cancer is most likely to spread.   Examination of these nodes provides crucial information regarding the extent to which the disease may have spread and is an essential part of the patient’s treatment plan.   Patients can be injected with a blue dye or with a radioactive substance to identify these sentinel nodes.   

However, an improved method of locating the sentinel nodes was approved by the FDA in July of this year.   Instead of the dye or the radioactive substance, the surgeon can inject a magnetic tracer and use a magnetic probe to locate the nodes.   This method is equivalent in efficacy with the previous methods, and does not expose the patient to dyes or radioactive materials.

Advances in radiation therapy

Radiotherapy is similarly guided with a degree of precision that increases with the introduction of improved imaging devices.   Stereotactic radiosurgery, in which the surgeon is able to see the tumor in three dimensions, is able to target radiation to tumors far more precisely than traditional radiation therapy.   For example, this technique is being used increasingly in the treatment of cancers that have metastasized to the brain.   It has been shown to cause much less cognitive deficit than irradiating the whole brain. 

Linking radioactive agents to molecules that are able to target specific cancer cells, and deliver radiation to those cells only, is a highly promising field in cancer research.   The FDA recently approved two targeted forms of radiation therapy for treatment of patients with certain types of neuroendocrine tumors.   These are quite rare tumors that grow in hormone-producing cells in most organs of the body, including the pancreas, the stomach, intestines, colon and rectum.   Another group of these tumors arise in the adrenal glands and along nerve pathways, particularly in the head and neck.

Most of these tumors have a surface receptor for a protein called somatostatin.   When somatostatin attaches to this receptor, it suppresses some of the cell functions.   Researchers have linked a radionuclide to a molecule that is similar to somatostatin, which attaches to the tumor cell’s somatostatin receptors, bringing the radiation to the tumor cells, while sparing the rest of the body’s healthy tissue from the effects of more generally-distributed radiation.   A clinical trial in this form of radiotherapy, called Lu-177 dotatate (Lutathera, from Novartis) found that treatment with this somatostatin analog increased the time to disease progression by a factor of six.   Lutathera received FDA approval in January 2018.        

Similarly, some adrenal tumors (pheochromocytomas and paragangliomas) have surface receptors for norepinephrine.   A molecule analogous to norepinephrine has been linked with a radioactive iodine isotope (I-131), forming the radiotherapy agent iobenguane (Azedra, from Progenics Pharmaceuticals), which was approved for the treatment of those adrenal tumors in patients age 12 and older in July 2018.

We can expect to see more targeted radiotherapy agents coming along as research progresses.

Advances in chemotherapy

When cancer chemotherapy was introduced, the rationale was that although the chemotherapy agent being given to the patient might be generally toxic to all cells, not just the cancer cells, it was the excessive greediness of the cancer cells that would cause them to gobble up the poison first.   Thus, the cancer cells would perish due to their own evil nature.   The patient’s healthy cells might suffer, but the cancer cells would go first and the healthy cells would then recover.       

The term “chemotherapy” is usually reserved for those non-specific drugs whose efficacy was based on the high degree of likelihood that the cancerous lesions will be affected to a greater degree than the rest of the body.   However, most current cancer drugs are chemicals and could be classified as chemotherapy, were that term not freighted with negative connotations of the very harsh side effects that accompanied the early chemotherapy agents.   Newer cancer drugs take much more precise aim at cancer, rather than relying on the general assumption that cancer cells will take up the “poison” more rapidly than healthy cells.   Several cancer drugs target certain characteristics of cancer cells that enable them to reproduce and spread at a rate that makes treatment difficult.   And many of the current cancer drugs are targeted to specific characteristics of certain types of cancer. 

Inhibiting cancer cell replication

All cells, whether cancer cells or healthy normal cells, reproduce by splitting, or mitosis.   A crucial difference is that normal cells have a built-in program that eventually kills them off.   This is called apoptosis, and it serves a valuable function, which is to make way for new cells, so that most of the cell population in our bodies consists of young and healthy cells.   Cancer cells are not subject to apoptosis and will go on reproducing endlessly, growing and spreading – that is, unless something prevents them from doing so.   

A number of drugs can inhibit cancer cell replication, and these have demonstrated great clinical benefit in some cancers.   Many of these drugs were initially derived from a substance found in the bark of the Pacific yew tree, called taxol.   These include paclitaxel (Taxol, Bristol-Myers Squibb), docetaxel (Taxotere, Sanofi-Aventis), another formulation of paclitaxel (Abraxane, Celgene).   Capecitabine (Xeloda, Genentech/Roche) also prevents cell replication, but by inhibiting DNA synthesis. 

Another mechanism through which cell replication may be inhibited is targeting telomerase in cancer cells.   Telomerase is an enzyme that protects telomeres, which are the ends of genes, so targeting telomerase is a way of attacking cancer cell replication.   An agent that has shown promise in that approach is imetelstat, from the biotech company Geron, which did much of the basic research into the role telomerase in cancer.   Geron did have a deal with Janssen, but it has just been terminated by Janssen exactly as I am writing this; however, Geron is committed to taking imetelstat, now trade-named IMerge, into Phase 3 trials in coming months.   

Some drugs in the class called tyrosine kinase inhibitors also inhibit cancer cell replication.   Tyrosine kinase is an enzyme which can play a number of roles, including stimulating the growth of new blood vessels, but are also active in cell replication.   In healthy cells, tyrosine kinase activates a kind of “on-off” switch that makes it possible for cells to reproduce, but in cancer cells, tyrosine kinase turns the switch on and keeps it on, so that cells just keep reproducing without cease.   Imatinib (Gleevec, Novartis) is a cancer-cell specific tyrosine kinase inhibitor which is used to treat one form of chronic myelogenous leukemia (CML) and also gastrointestinal stromal tumors (GIST).   CML median 5-year survival has nearly doubled since the approval of imatinib, from about 31% to about 59% currently, and median survival in patients with GIST is also currently about 5 years.

Inhibiting cancer cells from promoting vascularization

Cancer cells need nutrients to survive, and they get them by inducing the growth of blood vessels (angiogenesis).   They release vascular endothelial growth factor, or VEGF, in amounts far greater than normal cells.   A drug that targets angiogenesis through the release of VEGF is bevacizumab (Avastin, from Genentech/Roche).   It binds to the VEGF molecule in such a way that VEGF cannot interact with its receptor on endothelial cells.   Avastin is FDA-approved for a number of cancers, including colon, kidney, brain, and lung cancer; however, the FDA recently recommended that it no longer be used to treat breast cancer, since there are better options, particularly for some forms of breast cancer.   

In one form of breast cancer that is especially difficult to treat, tumor growth is fostered by another type of growth factor, termed HER2, which stands for human epidermal growth factor type 2.   In turn, release of HER2 is triggered by tyrosine kinase in another of its cancer-related roles.   Some drugs have been developed specifically to target tyrosine kinase in HER2 breast cancer, including lapatinib (Tykerb, GlaxoSmith Kline) and trastuzumab (Herceptin, Genentech/Roche).    

 Killing cancer cells with oncolytic viruses

The curious fact that some viruses attack cancer cells preferentially over normal healthy cells has been observed since early in the 20^th century, and research into the possibility of putting this into therapeutic use began about 50 years ago, but only now are we beginning to see approved oncolytic virus-based treatments.   

The first of these originated with BioVex, a small biotech outfit, which developed a drug called OncoVex, based on the herpes simplex virus, for the treatment of melanomas.   In 2011, Amgen made a deal with BioVex worth in total about $1.1 billion for development of the drug, talimogene laherparepvec, which Amgen named T-Vec and is now marketing as Imlygic.   Clinical trials with Imlygic have been highly promising.   The virus-based drug is injected directly into melanomas which are deemed to be not appropriate for treatment by surgery.   One of the most impressive findings in the clinical trials with Imlygic is the relatively high durable response rate, meaning that melanomas treated with this agent tend not to recur, unlike melanomas treated by other means, which do tend to recur.   Imlygic, along with some other oncolytic viruses, launches a two-pronged attack on cancer cells – not only does the virus lyse (destroy) cancer cells directly, but it prompts the patient’s immune system to attack cancer cells as well.

Other oncolytic viruses currently under investigation include a recombinant adenovirus (CG0700) to target bladder, breast, ovarian, colon, and prostate cancers, from Cold Genesys, Inc, a privately held biotech in California.   Another privately-held California outfit, Genelux, has a candidate drug, GL-ONC1, based on  attenuated vaccinia viruses, which has shown effectiveness in head and neck tumors and advanced solid tumors.   (The vaccinia virus is used to vaccinate people against smallpox.)   A Canadian firm, Oncolytics Biotech, has an agent, Reolysin, based on one of the reoviruses, which is now in Phase 3 trials against head and neck cancers and is being studied in lung, colorectal, and pancreatic cancers.   And an Australian biotech, Viralytics Ltd, which was acquired by Merck in June of this year, has an agent named Cavatak in clinical trials against ovarian, lung, gastric, and pancreatic cancers.   Cavatak is based on the coxsackie virus.    Advantages of some of these agents are that they attack several cancers and don’t have to be injected into the tumor cell, but can be given intravenously.           

All of these viruses have been modified in some form so that they target cancer cells only and limit their potential for causing disease in the patient.   A challenge for the developers of virus-based therapies will be to convince patients that it is safe to be treated by a pathogen which could otherwise make them sick.     

Enabling the immune system to attack cancer cells: checkpoint inhibitors

A major part of the function of our immune system is to seek out, identify, and destroy harmful invaders.   Our T-cells mostly carry out that function on the cellular level, except that T-cells are equipped with surface receptors that act as brakes.   These brakes, called immune checkpoints, prevent T-cells from attacking our own healthy cells.   The checkpoints recognize these healthy cells and instruct the T-cells to leave them alone.   Mostly, this system works well, keeping the T-cells focused on attacking the invaders, such as viruses.   The problem is that cancer cells have high levels of the protein that attach to those checkpoints and deflect the attacks from the T-cells.

Researchers spent about 25 years looking into this mechanism as a potential way to liberate T-cells to attack cancer cells before the approval of the first drug that addressed the checkpoints on T-cells.   That was ipilimumab (Yervoy, from Bristol-Myers Squibb), which got FDA approval in March 2011 for the treatment of malignant melanoma.    Yervoy targets the immune checkpoint protein CTLA-4, and it was demonstrated to significantly extend the survival of patients with this deadly form of cancer.   The success of Yervoy was followed by the approval of five more checkpoint inhibitors in the next six years.   These targeted one of two other checkpoint proteins, labeled PD-1 and PD-L1.   Nivolumab (Opdivo, also from Bristol-Myers Squibb) and prembolizumab (Keytruda, from Merck) both target PD-1, while atezolizumab (Tecentriq, from Genentech), avelumab (Bavencio, from Pfizer), and durvalumab (Imfinzi, from AstraZeneca) target PD-L1.

Opdivo has garnered ten FDA indications, most recently in August 2018 for the treatment of patients with small cell lung cancer who have previously been non-responsive to other forms of chemotherapy.   The response rates will not seem highly impressive, with 11% of patients experiencing partial responses and 0.9% complete responses; however, any degree of response is considered by experts to be a notable success in patients with this form of cancer.   In patients who demonstrated any degree of response, the median duration of response was almost 18 months, with 62% of patients continuing to respond at 12 months and 39% still responding at 18 months.

Opdivo has previously received indications for the treatment of non-small-cell lung cancer in individuals who have not responded to previous treatment; also in melanoma; in advanced renal cell carcinoma; in recurrent or metastatic squamous cell carcinoma; and in liver, urothelial, and colorectal cancers as well as Hodgkin lymphoma. 

Another PD-1 inhibitor, Keytruda, also received FDA approval in August 2018 as a combination treatment for metastatic nonsquamous non-small-cell lung cancer.   It is to be used in combination with Eli Lilly’s Alimta (pemetrexed) and platinum chemotherapy for the first-line treatment in these patients, along with platinum chemotherapy.

Keytruda also has several indications in addition to the indication mentioned above.   It is indicated for advanced melanoma, squamous cell cancers of the head and neck, Hodgkin lymphoma, urothelial carcinomas, certain solid tumors that have metastasized or cannot be surgically removed, and cervical cancer.

Imfinzi, a PD-L1 inhibitor, just recently registered a major success.   In patients with non-small-cell lung cancer, patients treated with this checkpoint inhibitor had a 32% lower risk of death than patients treated with what had been standard-of-care treatment.   Previously, Imfinzi had been demonstrated to ward off disease progression for almost a year longer than placebo.   It is projected that Imfinzi will become the standard treatment for patients with this form of lung cancer.   It is the only checkpoint inhibitor to date to prove a benefit in lung cancer maintenance.

Imfinzi is also approved for locally-advanced urothelial carcinoma in patients whose disease has progressed after chemotherapy with an agent containing platinum.

These checkpoint inhibitors, as well as the agents that slow cancer growth by interfering with the mechanism through which cancer cells attract new blood vessels so that they can get nourishment, and those that inhibit replication, occupy a space somewhere between old-time chemotherapy and the projected cancer treatment forms of the future, which aim for much greater precision, targeting the precise cancer subtype as well as the precise genetic characteristics of the patient.   We’ll take a look at precision cancer treatment in a future Doc Gumshoe sermon, but for now let’s get an overview of how current cancer drugs are developed, tested, and put to use in patients.

Cancer drug development

There’s no shortage of ideas about what might make an excellent cancer drug, ranging from the ones that are somewhere between nuts and fraudulent to the ones that actually have a solid scientific basis.   The gigantic obstacle is demonstrating that these agents work – that they eradicate or at least stop the growth of the cancer without undue harm to the patient.   In order to achieve this, as we all know, the entity that wants to get the drug approved by the regulatory authorities has to provide solid and convincing evidence that their drug provides real, substantial benefit to a patient population of some kind.   And to get that evidence, clinical trials are needed.   The candidate drug has to be demonstrably better than what’s out there already.   So, somehow, it has to be tested in patients.

Here’s what is not going to happen:     

• Newly-diagnosed cancer patients volunteer to take part in a lengthy trial in which they may be assigned either to this new candidate drug or to placebo.
• Patients with cancers for which there is an established form of treatment that has a reasonable success rate volunteer to take part in a trial in which they may be assigned either to the newcomer drug or to the established drug.

When faced with those prospects, most patients will refuse to enter the trial.   So it only becomes feasible to do clinical trials in which the patient populations are those who have basically run out of options – tumors that cannot be addressed surgically, cancers that have failed to respond to one or more previous forms of treatment.   Thus a drug may initially be approved for a relatively rare form of cancer, or for cancers that are refractory to treatment.   But they frequently move on from there; witness the numerous indications that Opdivo and Keytruda had won.   And you can be confident that they won’t stop there.   The success of those checkpoint inhibitors points to ways of treating cancer that will benefit a growing segment of cancer patients.   Doc Gumshoe is frankly optimistic.

* * * * * * *

As you see, I didn’t get to the latest of the latest in cancer treatment – CAR-T modalities, gene therapy, and other aspects of precision medicine.   Nor did I take up Travis’s suggestion that I look into Delta 8 as a sure-fire cure for cancer.   Let me know what interests you.   Thanks to all, Michael Jorrin (aka Doc Gumshoe).

[ed note: Michael Jorrin, who we like to call ”Doc Gumshoe,” is a longtime medical writer (not a doctor) who shares his mostly non-investing-related thoughts with the Gumshoe community a couple times a month. You can see all of his columns here.]