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Chemotherapy for Incurable SCCHN

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Is this patient really incurable?

The first question to ask when addressing incurable SCCHN is to be sure that the cancer really is incurable. When SCCHN recurs, it often recurs locally, at or near the site of the original cancer. For this reason, local salvage therapies such as surgery, radiation, chemoradiation or even repeat chemoradiation can sometimes elicit a cure for the patient with a local or local-regional recurrence. These topics are important and will likely be the subject of future posts on GRACE. The rest of this post will assume that the patient truly is incurable, either because local maneuvers are no longer possible, the cancer has spread to distant sites, or the patient has made a choice to not receive further surgeries or radiation.

Why Chemotherapy for Incurable Disease?

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.

For the patient with metastatic disease, chemotherapy is the most important treatment for achieving these two goals. “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 lung, 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.” 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, many patients with SCCHN have pain and problems swallowing. When chemotherapy shrinks their cancer, such patients get pain relief and many start swallowing effectively again. 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 relieves or prevents more symptoms than it causes there is a net gain of quality of life.

For a description of the history of chemotherapy, I refer the curious to Chemotherapy Selection for 1st line Non-Small-Cell Lung Cancer (NSCLC) — The Importance of Getting it Right the First Time. This introduction to lung cancer contains a section called “What is cytotoxic Chemotherapy? A brief history of swords to plowshares” that is also applicable to SCCHN. You’ll also note that I self-plagiarized, with adaptation, much of the intro to this chapter—no need to reinvent the wheel!

Believe it or not, there were no positive phase III trials for incurable SCCHN until 2008!

Author Drugs Patients Median Survival (months)
Jacobs et al. Cisplatin

5-FU

Cisplatin + 5-FU

83

83

79

5.0

6.1

5.5

Forastiere et.al. Methotrexate

Carboplatin + 5-FU

Cisplatin + 5-FU

88

86

87

5.6

6.0

6.6

Burtness et. al. Cisplatin

Cisplatin + C225

57

60

8

9.2

Vermorken et al.

(EXTREME)

Cisplatin (or carboplatin) + 5-FU

Cisplatin (or carboplatin) + 5-FU + C225

220

222

7.4

10.1

Older studies demonstrated activity of both cisplatin and 5-FU, so in 1992 cisplatin was compared to 5-FU and to the two drugs combined; survival was similar. Historically, methotrexate was a standard 1st line regimen for many years, so Arelene Forastiere and colleagues compared cisplatin plus 5-FU and carboplatin plus 5-FU to this older standard. Toxicity was worse with the new regimens, but there was no statistically significant difference in survival. Our first hint at genuine improvement came in 2005 when Barbara Burtness and colleagues added cetuximab to cisplatin. The addition of this targeted agent (cetuximab is a monoclonal antibody against the epidermal growth factor receptor, not a traditional “chemotherapy” drug) showed a strong trend towards improved survival, although it did not reach statistical significance.

The first ever positive phase III trial came in 2008, in the EXTREME trial. This trial randomized patients to receive platinum + 5FU or this same combination plus cetuximab. The resulting 2.7 month improvement in survival was both clinically meaningful and statistically significant. Survival and progression-free survival curves are shown below.

extreme-trial-results (click on image to enlarge)

To me, the real key point of EXTREME ended up being the principal that cetuximab adds to chemotherapy, not that EXTREME is the be-all, end-all regimen. To me, there are three key problems with the regimen:

  1. Survival is inadequate- While I’d much rather have my patients survive an average of 10.1 months than 7.4 months, 10.1 months is not nearly good enough.
  2. The regimen is inconvenient for patients. The total infusion time in the office for this regimen is almost five hours, and then patients must wear a pump to infuse the 5-FU for four days.
  3. The toxicity is way too high. In fact, I’d call it “extreme”… (groan)

Let’s look at the last problem in a bit more detail.

extreme-trial-toxicity-table

The EXTREME regimen had an 82% rate of grade 3 or 4 toxicity. Grade 3 toxicity means “severe adverse event” and grade 4 toxicity means “life threatening or disabling adverse event.” This ultra-high rate of toxicity is unacceptable for a regimen that does not result in cure. While it may increase duration of life, other regimens may better promote quality of life.

No Accepted Standard

The EXTREME regimen represents the “textbook” regimen for the functional patient with incurable SCCHN. However, for the three reasons described above, I have rejected it as a treatment option for my patients. That does not leave me without effective options to increase duration and quality of life. It does leave me without level I evidence to support what I do. As a scientist, I am unhappy and uncomfortable with this situation. That’s why I have dedicated my life to clinical trials to improve care and provide this data. I highly recommend that you strongly consider enrolling on a well designed, promising study. Only with studies will we improve care, and if the experimental treatment really is better, the patients enrolled on the study are the first to benefit.

I cannot say definitively that what I do in practice is the “right” answer; only time and trial results will tell. In practice, I personalize therapy to the patient’s individual situation based on the data that we do have. While the goals of chemotherapy are the same for everyone (to improve duration of life and to improve quality of life) patients come with different personal priorities, different levels of functional status, and different levels of other medical problems. Here is one way to think about regimen choice that I consider reasonable. I have described it not to provide a “cookbook” or substitute for a trained oncologist’s judgment, but rather to give you some insight into one way to think about these regimens.

Highly symptomatic patient

Some incurable head and neck patients present with dramatic symptoms such as pain and complete inability to swallow. For these patients, quickly shrinking the cancer becomes the primary goal of therapy in order to relieve symptoms. In this case, I will often use induction regimens not originally designed for the incurable patient. My personal favorite of these is the Kies / Wanebo regimen of weekly carboplatin, paclitaxel, and cetuximab. We will discuss induction chemotherapy in general and this regimen in particular in the future on GRACE (link to follow, once available).

Less symptomatic patient

The average patient has some symptoms, but cares more about longer-term duration and quality of life than speed of tumor regression. If I had cancer, I’d rather take a regimen that only shrunk my cancer 10%, but stopped it from growing for a year than take a regimen that shrunk it 30% but stopped its growth for only six months. I’d also want a balance in aggressiveness between working well and not causing too many side effects. There are two trials and one off-study regimen that I frequently talk to my patients about in this situation (although there are many good trials out there and local availability varies):

ECOG1305- This trial is available through much of the US. All patients receive their choice of cisplatin plus docetaxel or cisplatin plus 5-FU. I consider cisplatin plus docetaxel as a reasonable 1st line regimen for SCCHN and there are multiple phase II trials to support it, although I prefer to use carboplatin for incurable patients due to its superior side effect profile. I have never chosen cisplatin plus 5-FU when putting a patient on this trial. The toxicity numbers from the cisplatin/5FU arm of EXTREME, shown above, (76% rate of grade III/IV toxicity) are typical and unacceptably high. Half of the patients are randomized to also receive Avastin (bevacizumab), a targeted agent that cuts off the blood supply to tumors. It has proven efficacy in lung cancer, breast cancer, and colon cancer and the trial is asking whether it can also help in head and neck cancer.

UPCC15309- I designed this trial, based on some basic science that I’m not going to get into and two more common sense concerns. This is a phase II trial in which all patients receive the combination of capecitabine (xeloda) and lapatinib (tykerb) for twelve weeks, followed by maintenance lapatinib. I wanted a less toxic regimen for my patients, both because side-effects suck (sorry for the crude language, but I think it’s merited!) and out of the belief that with less toxicity, patients could actually get more of the chemo in without delays (hopefully resulting also in better survival-chemo can only work when you take it!) Right now the trial is only open at UPenn (and our affiliated hospitals Presby and Pennsy), but by the fall of 2010, we hope to also open it at UNC.

Carbo/taxol/cetuximab- For patients without access to trials, I often recommend “Belani regimen” carbo/taxol with weekly cetuximab grafted on. There is essentially no trial data to back up this specific combination, but extrapolation from other trials with good data makes this regimen make common sense, and results in practice have been good.

Patient with poor performance status

Single agent cetuximab- Patients with poor performance status, bad kidney function, or poor blood counts may be treated with cetuximab alone. Side effects are minimal compared to IV chemotherapy-rare allergic infusion reactions, and acne-like rash.

UPCC15309- My study, described above, allows patients with PS2.

Xeloda (capecitabine)- A single phase II study describes efficacy in a heavily pre-treated population, including patients with PS2.

Heavily pretreated patient

This is a growing problem. Presentation with metastatic disease from SCCHN is fairly rare, as the table below shows.

Site Total in SEER Number

Metastatic at

Presentation

Percentage 95% CI
Lip 5,975 20 0.33% 0.20-0.52%
Oral Cavity 16,385 320 1.95% 1.75-2.18%
Oropharynx 17,783 729 4.10% 3.81-4.40%
Hypopharynx 1,866 128 6.86% 5.75-8.10%
Supraglottis 8,114 270 3.33% 2.95-3.74%
Glottis 13,085 87 0.66% 0.53-0.82%
Subglottis 356 12 3.37% 1.75-5.81%
Sinus 1,068 69 6.46% 5.06-8.11%
Nasopharynx 2,610 177 6.78% 5.85-7.81%

from Kuperman, ASCO 2008

This means that most patients arrived at the designation “incurable” after multiple failed attempts at cure, often including induction chemotherapy, chemoradiotherapy, and repeat chemoradiotherapy with different agents. The cancer of such patients may therefore be resistant to some or all of the therapies that we might otherwise choose. For this reason, when chemotherapy is chosen, we prefer to give agents that have not been used before.

This was another reason behind the cap/lap trial-I don’t use capecitabine or the closely related 5-FU in either induction chemotherapy or with radiation; therefore, my patients will still be sensitive. Lapatinib targets both EGFR and its preferred dimerization partner, HER2, so it may be very active against SCCHN. Finally, the regimen is all-oral, and, at least in the breast cancer population where it has been previously tested, not too toxic.

When trials are not available, the basic principle of looking for active, tolerable agents that the tumor may not be resistant to still applies. For example, capecitabine alone or methotrexate alone may be options. Finally, phase I trials are available which allow SCCHN.


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