Chemotherapy, Then and Now

Epistemic status: fairly confident

Since I am claiming that cancer research is doing something suboptimal, I’m going to have to examine what progress has actually been made in cancer research, and what results it had.  Here, I’ll focus on the history of chemotherapy.

Early history

“A history of Cancer Chemotherapy” is an excellent article that summarizes the early history.

Chemotherapy is actually a fairly recent development. Until the 60’s, cancer was treated with surgery and radiotherapy. Cure rates plateaued at around 33% due to micrometastases that even aggressive therapy couldn’t reach.

The beginnings of modern chemotherapy were in the Chemical Warfare Service during World War II, which studied chemical weapons and discovered the tumor-regressing effects of nitrogen mustards. The use of nitrogen mustards for treating lymphomas spread rapidly, but remissions were brief.

Sidney Farber, as part of a government drug screening program, and in collaboration with Harriet Kilte, discovered methotrexate and found it effective on children with leukemia.   Also in 1948, George Hitchings and Gertrude Elion discovered 6-thioquanine and 6-mercaptopurine, which would prove useful in the treatment of leukemia.

Post-war, Sloane-Kettering hired almost the entire Chemical Warfare Service for a drug development program. Funding for chemotherapy drug development increased. But the general attitude was still skeptical, since chemotherapy had so far not produced durable remissions.  The first true cure was of the cancer of the placenta, choriocarcinoma, using methotrexate. (The clinical investigator was Min Chiu Li, who was fired for continuing these treatments!)

In the 1950’s, the CCNSC drug development program was also founded; it was the precursor to the modern pharmaceutical industry.  All drugs originated through the CCNSC.  (I was surprised to learn just how centralized the mid-20th-century biomedical research world was.)

Through the 1960’s, chemotherapy was still considered (rightly) to be ineffective. The best results were in leukemia, and about 25% of children with leukemia had remissions, but these were usually measured in months.  The discovery of alkaloids from Vinca rosea and the adoption of combination therapy (multiple drugs taken together) made chemotherapy into a viable strategy.  The “VAMP” program (vincristine, amethopterin, 6-mercaptopurine, and prednisone) got remission rates up to 60% by the end of the decade, and at least half the time these remissions were measured in years.  They were also just starting to mitigate the effects of chemotherapy with platelet transfusions. The late 1960’s also saw the development of the MOMP and MOPP protocols for Hodgkin’s disease (methotrexate/procarbazine, nitrogen mustard, vincristine, prednisone). Complete remission rate went from near 0 to 80% and about 60% of the original patients never relapsed.  Hodgkin’s lymphoma is now regarded as a curable disease.

In the 1970s and beyond there was an expanding role for adjuvant chemotherapy, or chemotherapy in addition to surgery.  Yale Medical School professor and former director of the National Cancer Institute Vincent DeVita  said in an  interview that “At least 50% of the decline in mortality [in colorectal cancer and breast cancer] is due to the application of chemotherapy as an adjunct adjuvant therapy to surgery.”

The first effective chemotherapy regimen for breast cancer was CMF (cyclophosphamide, methotrexate, and 5-fluorouracil), developed in the 1970s.  It was succeeded by AC (doxorubicin + cyclophosphamide).

Adjuvant chemotherapy has meaningful effects on breast cancer.  This 1990 paper says it reduces risk of recurrence by 30% a year, from 4% to 2.8% a year.  This 1989 study says it increases 3-year disease-free survival from 64% to 89%.  The original 1981 Bonnadonna study found it increased 5-year disease-free survival from 45% to 77%.

In the 1970s, the taxanes were developed, the first cytotoxic drugs with efficacy against metastatic breast cancer.  AC + paclitaxel was found more effective than AC alone, but pretty marginally: 70% vs. 65% five-year disease-free survival rate.

And that is more or less where the story of “old-school”, cytotoxic chemotherapy ends. All of these drugs are still in use.  The standard drugs for adjuvant therapy for breast cancer are anthracyclines, taxanes, 5-FU, cyclophosphamide, and carboplatin, all of which were discovered before 1970.

Cytotoxic Chemotherapy

Cytotoxic chemotherapy, the drugs developed in the 1940’s-1970’s, kills cells or inhibits their ability to reproduce; it poisons both cancer and you, but it does more damage to cancer cells than healthy cells because they divide more.

Cytotoxic chemotherapy is currently curative for (some kinds of) lymphoma and leukemia, small cell lung cancer, ovarian cancer, and choriocarcinoma.  It extends survival in many other cancers through adjuvant chemotherapy.  It’s not a cure, but it is genuinely effective.

The following are some examples of cytotoxic chemotherapy drugs:

The nitrogen mustards (discovered 1940’s) alkylate DNA, which makes the cell undergo apoptosis via p53, a protein which scans the genome for defects.  Cisplatin (approved 1978) and cyclophosphamide (approved 1959) work the same way.

Methotrexate (discovered 1947) inhibits dihydrofolate reductase, which is required for catalyzing DNA synthesis (via a few extra steps). Thus, it interferes with cell division.

5-fluorouracil (discovered 1957) blocks the synthesis of thymidine, a nucleoside necessary for DNA replication and hence cell division.

Vincristine (approved 1963) is a mitosis inhibitor.

Doxorubicin (discovered 1960’s) inhibits topoisomerase II, which uncoils DNA in replication.

Paclitaxel (discovered 1967) is a cytoskeletal drug that targets tubulin. Once again, this messes with cell division.

Targeted therapy

Targeted chemotherapy consists of drugs that are meant to specifically kill cancer cells and not healthy cells. Most cancer drugs developed recently are targeted chemotherapies.

The first targeted therapy was approved in 1998; this was imatinib (Gleevec), a tyrosine kinase inhibitor developed by Genentech, for use in myeloid leukemia. It was a huge success, nearly doubling the five-year survival rate from 31% to 59% after it hit the market.  It was also a triumph of “big science”, developed by high-throughput screening.

We are now firmly in the era of targeted therapies, often acting through inhibition of growth factors.  I looked at FDA approvals in oncology from 2000-2015, and found that there were

103 new cancer drugs in the past 15 years

69, or 66%, were targeted

37, or 36%, were growth factor inhibitors.

So, it is indeed true that targeted therapies are the majority of cancer drugs (many of the non-targeted therapies were reformulations or new applications of old cytotoxic chemo drugs) and that growth factor inhibitors take up a large share of the new drugs.

How well do targeted cancer drugs work?

Let’s look at the drugs from 2015, for an example.

Panobinostat is a multiple myeloma drug and a histone deacetylase inhibitor. It is for patients who have received at least two previous treatments.  It is used in combination with other chemotherapy.  It has a partial response rate of 38.5% in one study, 73% in another study (but mostly partial responses.). No apparently available data on survival rates.

Palbociclib is a CDK4 and CDK6 inhibitor for ER-positive and HER2-negative advanced breast cancer.  It increases progression-free survival from 10 months to 20 months but does not increase overall survival times (37.5 months with palbociclib + letrozole vs. 33.3 months with letrozole alone.)

Lenvatinib is a multi-kinase inhibitor approved for iodine-refractory thyroid cancer.  It increases progression-free survival (18.3 months vs. 3.6 months on placebo.)  Only 1.5% had complete responses, however; 63% had partial responses.  It causes no significant difference in overall survival either, whether at study endpoint, or at 6 months, 12 months, or 18 months.

Lonsurf is a combination therapy of trifluridine and tipiracil for metastatic colon cancer.  Trifluridine is an antiviral drug which is also a nucleoside analogue, and tipiracil is a thymidine phosphorylase inhibitor.  Overall survival was 9 months in the treatment group and 6.6 months in the placebo group.

Sonidegib is a Hedgehog signaling pathway inhibitor approved for advanced basal cell carcinoma. It has a 34-36% objective response rate.  I can’t find other information about its efficacy.

Nivolumab is a metastatic non-small-cell lung cancer drug, a PD-1 checkpoint inhibitor. A study found overall survival was 9.2 months with nivolumab vs. 6.0 months with doxetaxel.

Dinutuximab is used for pediatric neuroblastoma.  It looks like so far we only have safety data, not efficacy data.

So, as far as I can tell, not one of these drugs extended life for more than a few months. Part of this is due to the fact that many of these are drugs for refractory or late-stage cancer; this in turn may be due to regulatory or medical-ethics issues that make it hard to directly compare a new drug to the standard-of-care old drugs.

But cytotoxic chemotherapy also had a lot of failures before it found its stride. Perhaps it would be fairer to look at the most common targeted therapies instead of just the most recent ones.

Imatinib

Five-year overall survival rates of 89% in chronic myeloid leukemia patients. Five-year survival rate has doubled over a fifteen-year timespan.  This one definitely works. But it’s special because chronic myeloid leukemia is due to a single chromosomal aberration, the Philadelphia chromosome, which can be targeted precisely with a drug.

Trastuzumab

This is an HER2 inhibitor for advanced breast cancer.  In combination with docetaxel, vs. docetaxel alone, it had a median overall survival of 31.2 vs 22.7 months, and a 61% overall response rate vs. 34%.  Another study comparing trastuzumab adjuvant chemotherapy vs. chemo alone found 3-year overall survival was not significantly different between the three groups, but progression-free survival was (71% vs. 56%).  The HERA trial, the largest of these so far with 3401 patients in total, found no significant difference in overall 4-year survival, and a statistically significant but small difference in disease-free 4-year survival (78.6% vs. 72.2%.)  A five-year study  found that overall survival with trastuzumab was comparable to HER2-negative patients (5-year survival of about 30%, 1-year survival of 75% and 86%) and higher than HER2-positive patients without trastuzumab (5-year survival rates of about 20%, 1-year survival of 70%).  A study of 4045 women with HER2 positive, non-metastatic breast cancer found a 4-year survival rate with trastuzumab of 93.0% vs. 85.6% without.

Basically, the good studies give modest but real results, and the bad studies say it literally doesn’t extend life.  This looks like ambiguous evidence.

Gefitinib

This is a lung cancer drug. In a study of 1215 Asians with advanced pulmonary adenocarcinoma, there was no difference between gefitinib and carboplatin/paclitaxel in overall survival, for either EGFR-positive or EGFR-negative.  228-person study of EGFR-positive lung cancer found no significant difference between gefitinib and carboplatin/paclitaxel.  Study of 1093 patients with advanced non-small-cell lung cancer: no difference in survival times or response rates.

Cetuximab

Increases median survival in metastatic colon cancer from 20.0 months to 23.5 months.  And that’s the best-case scenario; median survival differences look worse with different mutation profiles.  Increases median survival in advanced non-small-cell lung cancer from 10 months to 11 months.

Bevaxizumab

In metastatic renal cell carcinoma, extends median overall survival from 21.3 months to 23.3 months.  In non-squamous non-small-cell lung cancer, overall survival was not significantly increased.  In metastatic breast cancer, overall survival was not significantly increased. In metastatic colorectal cancer, improves survival from 14.6 months to 17.9 months.

Rituximab

A meta-analysis shows a statistically significant hazard ratio of 0.63 for chemo + rituximab vs. chemo alone in overall survival for indolent B-cell lymphoma.  Overall survival rate at 3-years from a sample in the post-rituximab era was 75%, vs. 50% from a sample from the pre-rituximab era.  10-year overall survival in elderly patients with diffuse large B-cell lymphoma was 43.5% with R-CHOP vs. 27.6% with CHOP.

Sorafenib

For advanced hepatocellular carcinoma, a study of 276 Asian patients found median survival 6.5 months in the treated group vs. 4.2 months in the placebo group.   903 previously treated patients with renal cell carcinoma had comparable overall survival times with sorafenib vs. placebo.

Sunitinib

For overall survival in patients with metastatic renal cell carcinoma, 26.4 months with sunitinib vs. 21.8 months with interferon-alpha, in a study of 750 treatment-naive patients.  Another study of metastatic renal cell carcinoma found median survival time 8.7 months for IFN and 17.3 months for sunitinib.

Erlotinib

No difference in overall survival between erlotinib + chemo vs. chemo in advanced non-small-cell lung cancer, n = 768.  No difference in overall survival between erlotinib + chemo vs. chemo in EGFR-positive advanced non-small-cell lung cancer.  Study of 1059 patients with advanced non-small-cell lung cancer found no difference in overall survival between erlotinib + chemo vs. chemo.

Ipilimumab

In metastatic melanoma, study of 676 patients found 10.0 months median overall survival with ipilimumab + gp100, vs 6.4 months with gp100 alone.

Basically, most of these drugs do not extend life more than a few months.  Imatinib is a solitary miracle; rituximab and sunitinib have unspectacular but real effects; trastuzumab is ambiguous; and the other leading targeted chemo drugs appear to be ineffective.

A note on progression-free survival

Increasingly since 1975, progression-free survival has been used as a metric in randomized controlled trials.  The proportion of trials in the Journal of Clinical Oncology using progression-free survival increased from 0% in 1975-1984 to 26% in 2005-2009.  Many drugs show progress in progression-free survival without showing effects in overall survival.   The linked study gives three possible rationales why progression-free survival might improve when overall survival does not:

  • if tumors are small to start with, an increase in tumor size might not have much impact on time to death
  • measurement error: estimates of tumor size are easier to make mistakes on than deaths.  (measurement error, timing error, attrition bias, evaluation bias, etc.)
  • biological explanations: delaying progression may make the tumor more virulent later on, balancing out the overall death rate

So, whenever possible, we want to see improvements in overall survival, not just progression-free survival.

What conclusions can we draw?

My read of the evidence looks fairly similar to James Watson’s — targeted chemotherapy doesn’t look good, with a few exceptions. In other words, this is the leading focus of the pharmaceutical industry with regards to cancer, and its results are distinctly unimpressive.

So far as I can tell, where there has been improvement in cancer mortality since the 1970’s, it is mostly due to people smoking less, early detection of some kinds of cancer, and adjuvant (cytotoxic) chemotherapy, not to targeted chemotherapies.

Why recent developments in chemotherapy aren’t effective is a more speculative matter. There are mechanistic reasons, like Watson’s (growth factors may not be the right strategy). And then there are structural reasons, like DeVita’s.

He notes that it now takes 800 days to get a new cancer protocol approved — at which point your research is out of date. Back in the days before the War on Cancer, when all research was centralized through the NCI, turnaround time was much faster. (Normally we associate decentralization with freedom; but consolidating authority in a small number of people rather than a bureaucratic process can make it easier to get things done quickly and iterate.)  He continues, “But basically, I think what we are trying to say is that ultimately you have to test new things in patients.”

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11 thoughts on “Chemotherapy, Then and Now

  1. Hi Sarah,

    First off, I came across your site and wanted to say thanks for providing a great cancer resource to the community.

    I thought you might find this useful infographic interesting, as it shows the detailed effects of chemotherapy in an interactive format: http://www.healthline.com/health/cancer/effects-on-body

    Naturally, I’d be delighted if you share this embeddable graphic on https://srconstantin.wordpress.com/2015/10/11/chemotherapy-then-and-now/ , and/or share it on social. Either way, keep up the great work Sarah!

    All the best,

    Nicole Lascurain | Assistant Marketing Manager
    p: 415-281-3100 | e: nicole.lascurain@healthline.com

    Healthline
    660 Third Street, San Francisco, CA 94107
    http://www.healthline.com | @Healthline

  2. When Jim Allison shows off the success of ipilumamab, he does not stress its increase in median survival. Instead, he claims that it produces permanent cures.
    Consistent with this claim, a [recent study](http://jco.ascopubs.org/content/early/2015/02/18/JCO.2014.56.6018.short) found a five-year survival rate of 18% (95% CI 14-23%) for ipilumamab plus dacarbazine, compared to 9% (95% CI 6-13%) for placebo plus dacarbazine. This large chunk of cured-so-far patients is inconsistent with your overall conclusions about the ineffectiveness of targeted chemotherapies.
    This makes me wonder about another immunotherapy in your (fascinating and thorough) list, nivolumab. It seems the drug is too new to say anything about long-term survival. But I think that median survival might be misleading for immunotherapies. Jim Allison would say we have to wait and see if we have more long-term cures.

    • Ok, looking at that and related studies, ipilimumab does seem to produce consistently better 5-year survival rates than dacarbazine alone, and you’re right, that seems to be a counterargument to my overall claim. I suppose the theory as to why median survival might not improve while five-year survival rates do, is because some minority of the patient population is strongly responsive to ipilimumab?

      • Yes. More specifically, Allison’s claim is that, while targeted chemotherapies lead to resistance and eventually death, immunotherapies like ipilimumab lead to adaptive immunity to the cancer and permanent recovery in a minority of patients.

        I guess it would have to be a very binary response, to affect median survival so little. But my store of remembered content from Jim Allison talks has run dry.

      • Really, though, immunotherapies like ipilimumab and nivolumab aren’t in the same category as targeted therapies at all. They’re not poisons or growth inhibitors that selectively affect cancer cells. They target immune cells.

      • Yes, they have a different mechanism. I’m still on the fence about whether immunotherapies have so far produced really clear-cut results (CAR-T seems to really work on leukemia, as a counterexample). But I’ll be looking into this more.

  3. I just discovered your web site. And, I have to say, bravo. In fact, bravissimo. This is the best, most informative writing on cancer treatment I’ve ever seen.

    I have a question about this post. You point out how the mean survival times are only going up a few months for the newer drugs. But, what kind of a range is there in the response? (ie, the variance). Do the drugs provide basically very unexciting results for everyone? or are a minority of patients helped a LOT (for instance, 10 year increase in survival time, complete remission, etc) and the majority helped little or not at all? If it is the first scenario, then, I agree, the drugs are basically worthless, in fact, worse than useless, since $$$. But, if it’s the second, then we potentially have a solid home run. Lot’s of drugs have ridiculous numbers on the ‘number needed to treat’ to get one life saved. Because we don’t know enough (yet) to be able to predict ahead of time which patients are going to be helped and which ones aren’t. If we’ve got a 10% chance of complete remission, and 90% chance of not being helped at all, the overall numbers on increased survival time are going to look sick, but still, for that 10%, it’s a life saver.

    If what we have is the second scenario, then it seems like the next step is to start doing gene sequencing of everyone that takes the drug, and see if there are common mutation(s) in the people that are helped, or, not helped. If they can find a biomarker with predictive powers, and only give the drug to the people who do (or don’t) have mutation x, and the mean survival time will jump.

  4. I was reading more about trastuzumab, so I’ll write that here.
    So, as you know, trastuzumab is used in two very different settings. One, as adjuvant therapy for local disease (cancer only observed in the breast, so we cut that out but also give you trastuzumab and chemo to kill any invisible metastases). The other is treatment of metastatic disease. The trials you quoted for adjuvant trastuzumab are so weird to me; why do we see overall survival benefits in one big trial but not another?
    Anyway, I wanted to look at long-term survival in metastatic disease. The study you quoted (doi: 10.1200/JCO.2005.04.173, wrong link in text) showed an increase in median survival (31 vs 23 months), but if I’m reading the survival curve right, no increase in 4-year survival.
    Another study of metastatic breast cancer (doi:10.1056/NEJM200103153441101) showed an increase in median survival (7.4 vs 4.6 months) and one-year survival (67% vs 78%). Again, though, the survival curves seem to meet at the end–am I reading these wrong? It seems like both groups have the same overall survival at the end of 3.5 years. I’m not sure if they tracked everybody that long though.
    It wouldn’t surprise me if the survival curves really did meet, with these still reported as positive results. Quoting Ruth Oratz’s chapter in Roses ed. “Breast Cancer” 2nd edition, “At this time, metastatic breast cancer is rarely cured. Median survival after development of metastatic disease is 2 to 3 years. Treatment may be effective for palliating symptoms, with responders enjoying not only an enhanced quality but also, in some cases, prolongation of life. Nonetheless, cure is not an expectation…” That’s from 2009. From 1996: “Unlike early-stage breast cancer, metastatic breast cancer is commonly believed to be incurable, and even though systemic treatments like chemotherapy and hormonal manipulations can induce impressive responses, their use in treating metastatic disease is usually limited to palliative rather than curative purposes. Thus, although long-term survivors exist, their extended survival is attributed to the indolent nature of their disease rather than the therapy.” (PMID: 8708708). So, it seems that while there are long-term survivors, new treatments do not increase the number of long-term survivors, and are not really expected to.
    I wonder if the situation is the same for other cancers. For several other drugs on the list, the only studies quoted are about late-stage disease. I looked into cetuximab, and wasn’t able to find any phase III trials of early stage disease. If late-stage disease is considered as hopeless in other cancers as breast cancer, then my conclusion from this list would not be “most targeted therapies have tended to lead to small improvements in survival,” but “most targeted therapies have not been effective in early-stage disease, and were applied to late-stage disease where they predictably failed to work miracles.”
    I may be inappropriately conflating “locally advanced” and “metastatic” into “late-stage”. I’m not sure how locally advanced breast cancer goes.

    • I would agree with that, and will be clearer in the book. I think for regulatory reasons you can’t give other drugs *instead* of chemo, so they tend to be tested on later-stage patients who have already failed chemo?

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