Chemotherapy, Then and Now
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.
“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 Eliondiscovered 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, 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 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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.”