Introduction: Why Chemotherapy?

Every cancer therapy has two purposes: to improve duration of life, and to improve quality of life. Every other measure of chemotherapy success, such as response rate or progression-free-survival, is a surrogate to these two true goals. I am using the broken record as my pseudo-apology for repeating this mantra repeatedly on GRACE, to my colleagues, and in my mind every time I make a treatment decision.

Chemotherapy is the most important treatment for achieving these two goals in stage IV disease. Stage IV means that the cancer has spread and is no longer curable. Incurable is not the same as untreatable. Cure means eliminating every last cancer cell. Treatment means providing real benefit, in the form of achieving these two goals.

Cancer cells are microscopic. The tip of a pen is the size of more than ten billion cells. So, if a single cell has spread to a site, say, the liver, you won't be able to see that cell on a CT or even the most sophisticated PET/CT. So, once you see the cancer having spread to distant sites, it becomes systemic-in more sites than you can see; we call this "metastatic" or stage IV disease. To achieve our two key goals, you need to knock down the cancer everywhere-the places that you can see and those you can't. Chemo gets almost everywhere in the body and is therefore the best and most important way to do this for most patients with metastatic disease.

Chemotherapy's effect on the quality of life question really is a balance. Chemotherapy can cause side effects, including nausea and fatigue. However, on the flip side, in addition to prolonging duration of life, chemotherapy also provides a quality of life benefit when successful. That's because cancer causes symptoms that chemotherapy can delay or prevent. For example, when cancer spreads to bone, it can cause pain and fractures. When it presses on airways, it can cause shortness of breath and pneumonia. Cancer causes fatigue, organ failure, blood clots, and numerous other problems. When chemotherapy prevents more symptoms than it causes there is a net gain of quality of life.

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What is cytotoxic Chemotherapy? A brief history of swords to plowshares

In 1919, Edward Krumbhaar described the effects on the bodies of soldiers exposed to mustard gas. Their lymph nodes shrank and their bone marrows made fewer blood cells. In 1929, Berenblum found that mustard gas could act against cancer in animals. In 1931, Adair and Brag applied mustard to the skin of patients and injected it into a tumor. However, the first successful use of chemotherapy occurred in 1942 at my alma-mater, Yale Medical School. There, Goodman, Gilman, and Lindskog used nitrogen mustard to effectively induce a short remission in a patient with non-Hodgkin's Lymphoma. Harvard developed methotrexate in the 1940s and chemotherapy for solid tumors scored its first cure in 1956, when Roy Hertz and Min Chui Li used it to cure a patient with metastatic choriocarcinoma.

The history of chemotherapy continued through the 1950s and 1960s with a series of acronymed regimens to treat lymphomas and leukemias. In the 1960s, Barnett Rosenberg discovered cisplatin.

Many chemotherapy drugs in use today were originally derived from natural sources. In 1954, Robert Nobel noted that in Jamaica, diabetics sometimes drank periwinkle tea when insulin was not available. It didn't help the diabetes but it did reduce white blood cell counts. This observation led to the development of the vinca alkaloids-vinorelbine remains a standard lung cancer drug. Taxanes, including paclitaxel and docetaxel were originally derived from the Pacific Yew Tree. In 1966, Chinese ornamental tree extract was found to inhibit topoisomerase, leading to the camptothecans; irinotecan was approved in 1996. Etoposide is derived from the May Apple.

Most cells in the human body do not divide. In contrast, cancer cells frequently divide in order to grow. While dividing, they must copy their DNA, the genetic material of the cell. In some form, all of these drugs work by poisining the process of DNA replication, thus killing dividing cells. Drugs that work by this mechanism are called "cytotoxic" chemotherapy. Since most of the cells dividing in the cancer patient's body will be the cancer cells, the chemotherapy is preferentially poisonous to these bad cells, leaving most of the non-dividing normal body cells alone. However, certain cells in the body do divide, causing side-effects in these areas (for example, the cells lining the gut causing nausea, and the cells in the bone-marrow causing low blood counts).

In contrast cytotoxic chemotherapy, biologic (targeted) agents do not work by damaging the DNA of dividing cells. They work by targeting signaling within the cancer cell. The first targeted agent was imatinib, or gleevec, an extremely effective drug for CML; it was approved in 2001. Herceptin was the first targeted antibody (for some breast cancer), with bevacizumab following in 2004 (now a therapy for multiple cancer types).

Chemotherapy Can Extend Survival in Lung Cancer (At least once you starting using good chemo)

In the mid 1990s, there was still a debate about the efficacy of chemotherapy in lung cancer. In commenting on a major meta-analysis of chemotherapy efficacy in 1995, David Carbone wrote,

For some cancers, treatments are so effective that the question of whether to treat does not arise. For many others, however, while gratifying responses sometimes occur, there are also substantial toxicities related to treatment, and benefits of any kind may be small. The toxicities, inconvenience, and expense of chemotherapy are endured by both patients whose tumors do and do not respond. When faced with such imperfect treatments, clinical trialists must determine, within the limits of biological variability, whether these treatments results in statistically significant benefits and at what cost. Doctors then have to decide whether these benefits are clinically important and whether they outweigh potential risks for a particular patient.

At this time, the meta-analysis (Carbone, BMJ 1995) showed only a marginal survival advantage. However, it depended upon which chemo was given. Trials with alkylating agents hurt patients, trials with single agent vinca alkaloids or etoposide helped, and trials with cisplatin plus another drug helped the most.

In these forest plots, each individual trial is listed. If the box is on the left of 1, chemo helped. If it's on the right, chemo hurt. The diamonds summarize each group of trials. As you can see, when the authors looked just at trials based on cisplatin, the survival difference was bigger, even back when the partner drugs were older ones that have largely been replaced by better lung cancer drugs (vindesine, doxorubicin, etoposide, vinblastine, cylophosphamide, methotrexate, lomustine, mitomycin C). Many of us find survival curves more intuitive-the curves for cisplatin based chemotherapy vs. supportive care alone are shown below.

So, cisplatin doublets help, but many of you will recognize that the solid curve does not reflect the kind of survival numbers that we talk about on GRACE (it's a 1.5 month survival advantage in favor of chemotherapy). That's because we've made multiple advances since that analysis.

How many drugs? 1? 2? 3?

So chemo helped. How much chemotherapy is optimal? Historically, it took many trials and a lot of time to answer this question. I hope that the history buffs (and oncologists involved in this more than a decade effort) will forgive me for jumping right to the answer: 2 drugs are better than 1, but three drugs are not better than 2. More specifically, adding a second drug to platinum or adding platinum to another drug improves both response rate and survival. When you try to push this to three drugs, you improve response rate. However, despite increased toxicity, survival does not improve.

The bulk of the data from these doublet trials were with a platinum drug (cisplatin or carboplatin) plus another drug, leading to this standard of care. However, it is worth noting that several other two drug combinations have smaller amounts of data behind them including gemcitabine/docetaxel, gemcitabine/paclitaxel, paclitaxel/vinorelbine, and gemcitabine/vinorelbine. A meta-analysis suggested that these regimens may be slightly less effective than platinum doublets and they can be difficult to tolerate, leading to less frequent use.

Cisplatin vs. Carboplatin

If you want to start a brawl at a meeting of thoracic oncologists, a good way to start is to have a cisplatin vs. carboplatin debate. Cisplatin lovers feel that cisplatin is slightly more effective than carboplatin. Carboplatin lovers argue that carboplatin is equivalent and that even if cisplatin has a slight edge in efficacy, this small difference is inadequate to compensate for its dramatically higher toxicity.

Multiple meta-analyses have tried to address this question and none were definitive. Survival curves from one representative meta-analysis (Ardizzoni et al., JNCI 2007) are shown below:

Although the difference was not statistically significant, there was a trend towards three weeks of additional survival with cisplatin. When only trials using third-generation partner drugs for the platinum were looked at, cisplatin was statistically superior for survival.

In the US, carboplatin is used much more frequently than cisplatin for metastatic disease. Most oncologists feel that even if real, this very small difference in survival is not worth the dramatic increase in nausea, kidney damage, hearing loss, tinnitus, and nerve damage that cisplatin causes. For detailed information on this debate, I refer the curious to Dr. Sanborn's review article.

The Practical Question: What should I take?

So, where does all of this leave the patient looking to decide on first line therapy? As a trialist, I would be remiss if I did not endorse clinical trials, when available, in all lines of therapy. Good trials exist that try to add to the standard of care. In my opinion, optimal cancer care includes education about available clinical trial options. When I see a patient, this is the first decision point: Is there a good trial that may be better than standard of care?

The next question is whether a cancer pill should be used in the first line. Two similar drugs inhibit the EGFR, tarceva and irressa. Another chapter will cover them (link to follow once it's up) but for now I refer the curious here. For this summary, it suffices to say that patients with a known EGFR mutation should get iressa or tarceva in the 1^st line. Crizotinib (PF-02341066) is a new compound that inhibits the eml4/alk fusion product. While it is still available only in trials, the preliminary data is so good that I believe that any patient with a known translocation should be enrolled on one of these trials, if at all possible, for first line treatment.

If neither of these options is chosen, chemotherapy is the first line, the focus of this chapter. There is a basic formula for first line chemotherapy:

Any of the listed partner agents may be combined with cisplatin or carboplatin. The most common drug used in community practice in the US is probably paclitaxel (Taxol). Traditional wisdom, based on the ECOG 1594, study holds that all partner agents are equivalent, but this idea is being challenged (See Dr. Pennell's post for both information on ECOG 1594 as well as a challenge to this idea that all partner drugs are equivalent). An Italian researcher, Giorgio Scaggliotti did a trial that compared cisplatin plus Alimta (pemetrexed) to cisplatin plus Gemzar (gemcitabine). Overall survival was identical in the two arms. However, patients with adenocarcinoma lived longer with Alimta and patients with squamous cell carcinoma lived longer with Gemzar. Alimta is very tolerable as chemotherapy goes, leading to increased usage in the first line for patients with adenocarcinoma. In squamous cell carcinoma, combinations of platinum plus Taxol, Taxotere (docetaxel) or Gemzar all remain common and reasonable.

For patients with adenocarcinoma who are eligible, Avastin (bevacizumab) may be added to the doublet regimen. The role of Erbitux (cetuximab) is evolving and remains unclear; in the US, the FDA has not yet approved it for first line therapy.

Duration of chemotherapy: Less is more. Or is more, more sometimes?

For a long time, there was a debate among oncologists about how long to continue first line therapy. Some oncologists continued it forever, while others stopped after four or six cycles. Dr. Mark Socinski conducted one of the most important trials in lung cancer chemotherapy to address this question. He randomized first line patients to either four cycles of carboplatin and paclitaxel followed by active surveillance or to this same regimen until progression. Survival was identical. As you might guess, toxicity was worse in the group that got indefinite chemo. Therefore, the standard of care for 1^st line therapy is 4-6 cycles of carboplatin-based chemotherapy. For more information on duration of platinum doublets, see Dr. West's article.

But what about non-platinum therapy? Could we improve survival by giving something else after first line therapy? The JMEN study treated patients with four cycles of carboplatin and Taxol. Patients were then randomized to either placebo or to Alimta, given until the time of progression. Patient with adenocarcinoma lived longer if they were randomized to the Alimta arm. The results of this new trial have resulted in controversy: some oncologists believe that the results are due to receiving ongoing chemotherapy. Others argue that Alimta is a better drug for patients with adenocarcinoma, and patients could have gotten this result if they received the drug up front. Still others feel strongly about using Alimta in the first line and have no data to know if continued Alimta will help patients who already got it. Still others wonder if the results still apply in patients getting Avastin. Jyoti Patel gave some insight to those who believe in 1^st line Alimta by conducting a positive phase II study in which patients received four cycles of carboplatin, Alimta, and Avastin, followed by Alimta/Avastin maintenance. The ongoing POINT BREAK trial randomizes patients to carboplatin, Taxol, and Avastin followed by Avastin maintenance (the regimen that first proved the worth of Avastin) or to carboplatin, Alimta, and Avastin followed by maintenance with Alimta and Avastin. It won't really answer the question of whether you need to switch drugs to get the benefit of maintenance, but if survival is good on the carboplatin, Alimta, and Avastin arm, it will reassure those of us who use this regimen. More controversial is the use of Tarceva (erlotinib) maintenance after 1^st line chemotherapy. The SATURN trial randomized patients after four cycles of chemotherapy to receive erlotinib or placebo. The survival advantage was one month (see Dr. West's post for additional information). For now, all three options are reasonable: active surveillance, switch maintenance, or maintenance with the same partner drug.

A Chemotherapy Timeline

For those who like schematics, this thought process can be visualized as below:

When First Line Therapy Fails

Successful therapy controls cancer for months or longer, but the cancer eventually learns to grow around even the best regimens. As long as you have good tools ready to treat the cancer after progression, it does not have to be a tragedy. We've already talked about the importance of molecular testing. Often the results of this testing don't come back in time for first line therapy. If results will help to choose second line therapy, the time to get them is while first line therapy is working, not after it fails. That way, when the cancer does eventually grow past 1^st line therapy, you can be armed to know your best options for second line therapy. There are many good second line therapies, both targeted and chemotherapeutic-for more information click here.

We thank Pfizer Oncology for the educational grant that made the Lung Cancer Reference Library possible.