'Cancer as a Disease, Not a Death Sentence'

My hope at this point is to follow the route described in this article -- hopping from therapy to therapy and living with the disease for as long as possible. There's no direct sarcoma connection in the piece, but some of the drugs directly mentioned (Gleevec) or inferred (new kidney cancer agents) are applicable to or being tested for some sub-types of soft-tissue sarcoma.

Jane Brody's article on new ways to control cancer is here:

Through a better understanding of factors that distinguish cancer cells from normal ones and the development of more specific treatments that capitalize on those differences, cancers that just a decade ago would have been rapidly fatal are now being controlled for years while the patients conduct near-normal lives.

Although these cancers may never be curable, they can often be controlled for long periods by a succession of treatments. When one therapeutic approach no longer works, another one that has come along in the meantime might stop the disease from progressing, at least for a while.

Even patients whose cancers were already metastatic — spread beyond the site of origin — at the time of diagnosis are benefiting from this sequential approach....

ES at Royal Marsden

This ancient article (Sarcoma, 2003) recently popped up on PubMed, probably because free full-text was recently added. It describes an excellent English hospital's experience with the disease concisely and understandably. Keep in mind that the series starts all the way back in 1978. 

Some findings: small tumors (3 cm or less here) offer better prognosis; distal limb locations offer better prognosis; age (younger being better) may be a prognostic factor (other studies contradict this); radiation helps prevent local recurrence after surgery.

The Marsden article may shed some light on when to combine radiation with wide excision, and may provide an interesting contrast with the recent University of Washington article I blogged in May. 

"Treatment of Epithelioid Sarcoma at Royal Marsden Hospital" is here.

A reasonable man

L. and I left the cold state for a couple of days to check in with Dr. Bow Tie (who, on this occasion, lived up to his nickname, wearing a tie that apparently required an MD-Ph.d. to divine how it related to his slacks and shoes). 

The goal was to get a plan in advance of the CT I will have next week, and we got one -- several, actually, depending on how things turn out with the scan. The hope is to continue on with Temodar, but I'm not sure if that's going to be possible. Although being relatively non-symptomatic makes it difficult for me to tell if my chemo is working or not, I tend to believe that the tumors have advanced a bit over the last couple months and we'll need to start something new. I hope I'm wrong.

Fun details of the NY Trip are TK, but here's a few paraphrased comments from the discussion that might interest people who know me or other epithelioid sarcoma patients:

• I "look good" -- I have "low tumor volume." I'm a "great candidate" for a clinical trial because I'm doing relatively well at the moment.
• Why did he try gem/tax again when my cancer began spreading this winter? Because you "go where the money is"; the tumor had shown some sensitivity to that drug combination before and enough time had elapsed to make it reasonable to think it might work again.
• What about temodar? How likely is a good or stable disease response from that? Temodar is a "reasonable choice." So why did he strongly prefer gem/tax after the tumors got into the nodes behind my belly, while my local oncologist advocated for temodar? Because we didn't know what would work best. There's no formula.
• How are you feeling about deforolimus? The mTor inhibitors have a huge amount of promise (some background here), but they aren't quite ready for prime time (though they may be soon). It may turn out that deforolimus needs a little help -- that it will work better in combination with some other drug.
• What about using rapamycin, the transplant drug, off-label as a substitute for deforolimus which is now pretty much only available in Ariad's SUCCEED trial (which is placebo-controlled)? He's done it, and he's even seen an epithelioid sarcoma have a mixed response to it, but it's a down-the-road option for me. Rapamycin doesn't have terrible side effects, so you don't have to worry as much about being too late with it. Incidentally, Dr. BT has also heard about ES responding to deforolimus.
• The caveat he pointed out is while it is reasonable to pore over study tables to look for epithelioid sarcoma responses, it's not a dependable enterprise because you usually don't know if ES has any particular sensitivity to the drug, or if the drug just happens to have positive effects for X% of soft-tissue sarcoma patients and the ES response was just the luck of the draw.
• I may be a good candidate for a trial of a new tyrosine kinase inhibitor -- a member of the "nib" family of drugs being actively developed by several pharma companies. Imatinib, dasatinib, sorafenib... etc.
• How about sorafenib, anyway? Could be a "reasonable choice."
• Other options? Maybe high-dose single-agent ifosfamide since I haven't had any ifos before.

None of this is, of course, is medical advice for anyone -- not even me. The doctors will consult after my scans and then we'll lock down a plan. 

It's great to have so many "reasonable" options; of course, the catch is that there is no compelling third-line drug for metastatic ES that would make more options "unreasonable." 

The clear options come earlier: some sort of doxrubicin-based chemo as the first line, gemzar and taxotere as the second line. Finding the best third- or fourth line defense is much murkier: I will keep you all posted about what we end up trying...

ASCO, but will you receive?

Online abstracts are now available for the sarcoma presentations scheduled for the American Society of Clinical Oncologists meetings later this month. I spent a few minutes going through them and didn't notice any obviously relevant epithelioid sarcoma stuff buried in the abstracts, but I'm not qualified to make that judgement and it's better to wait until after the meetings to see what gets covered in the medical trade press anyway.

Ariad posted some phase I results for deforolimus that look encouraging for soft-tissue sarcoma generally:

Abstract No:
3509
Citation:
J Clin Oncol 26: 2008 (May 20 suppl; abstr 3509)
Author(s):
M. M. Mita, C. D. Britten, E. Poplin, W. D. Tap, A. Carmona, L. Yonemoto, D. S. Wages, C. L. Bedrosian, E. H. Rubin, A. W. Tolcher
Abstract:
Background: Deforolimus is a non-pro-drug rapamycin analog which specifically and potently inhibits mTOR. In Trial 202 intravenous deforolimus demonstrated notable anti-tumor activity in bone and soft tissue sarcomas. (JCO 2006; 24, 18S: 9505). Oral deforolimus allows greater treatment flexibility and offers potential to treat patients in a maintenance setting. We report preliminary results on oral deforolimus in a comprehensive dose finding study in patients (pts) with refractory malignancies. Methods: The trial was an open label single arm study with dose escalation and a standard 3+3 design. Patients had advanced/metastatic solid tumors refractory to therapy. 7 regimens, all over a 28 day cycle were investigated. Definitions of dose limiting toxicity (DLT; Gr 4 or Gr 3>3 days) were based on CTC criteria. Anti-tumor activity was evaluated by modified RECIST criteria. Patients achieving stable disease (SD) or better lasting for at least 4 cycles of 28 days were classified as achieving clinical benefit response (CBR). Results: 147 pts (85 sarcoma) received deforolimus. Median age was 56 (range 23-84 years); 65 (44%) pts were male. Pts had a median of 2 cytotoxic therapies at entry (range 0-7); 113 (77%) of this population had documented progressing disease at enrollment. The median ECOG score was 1 (range 0-2). The DLT for all regimens was aphthous-ulcer like mouth sores which were reversible by dose reduction or symptomatic therapy. 36 pts achieved CBRs (23 sarcomas). MTD was increased with the addition of a weekly dose holiday interval. CBRs were seen in all regimens and several types of sarcomas and a variety of carcinomas. 24 pts received 40 mg QDx5/wk and in this group 3 of 13 (23%) sarcomas had CBR; 2 (liposarcoma, dendritic cell sarcoma) (15.4%) achieved PR. Pharmacodynamic analysis showed potent inhibition of mTOR. 7 patients remain on therapy after 6-24 cycles. Conclusions: Oral deforolimus has a safety and anti-tumor activity profile consistent with the intravenous form. 40 mg QDx5 each week is an active, well tolerated regimen and has been selected for further evaluation in SUCCEED, a global phase 3 trial of patients with metastatic soft-tissue and bone sarcoma in the maintenance setting.

Epithelioid sarcoma: the University of Washington experience.

A forthcoming issue of the American Journal of Surgery has an article on ES:

Epithelioid sarcoma: the University of Washington experience.

Wolf PS, Flum DR, Tanas MR, Rubin BP, Mann GN.
University of Washington Medical Center, Seattle, WA 98195, USA.
BACKGROUND: Epithelioid sarcoma is a rare sarcoma with a high local recurrence rate that frequently metastasizes to lymph nodes. We reviewed our experience with adjuvant therapy in patients with this disease. METHODS: Between 1990 and 2003, we treated 11 patients with epithelioid sarcoma. Patient, tumor, and treatment characteristics were analyzed, and effect of treatment on survival was evaluated by the Kaplan-Meier method. RESULTS: Nine men and 2 women were treated. Tumors presented on the trunk, the upper extremities, and the lower extremities. Five patients developed nodal disease. All patients underwent surgery for the primary tumor, and 7 patients had nodal evaluation. Ten patients underwent adjuvant chemotherapy, and 9 underwent radiotherapy. Recurrence developed in 9 patients. Five-year disease-free and overall survival rates were 46% and 65%, respectively. Chemotherapy and radiation therapy did not impact disease-free survival. CONCLUSIONS: Although surgery remains the primary treatment modality, multi-institutional trials are needed to develop more effective adjuvant therapy for patients with epithelioid sarcoma.

No blockbusters here, though I found it interesting just how heavily men were represented in the series (9 out of 11) and how common presentations in the trunk (5 out of 11) were. Forty-five percent of the group had nodal mets -- the UW authors throw out a range from other studies of 22 to 48 percent. Like pretty much everyone else, the authors here are convinced that a big tumor and node problems are bad news. The authors don't find any benefit to chemo, but the series ended in 2003 so most of the patients received adriamycin/ifosfamide-based therapy.

Lemme know by e-mail if you want a copy.

ES Prognosis (The Median Is Not the Message)

Above is a chart reviewing the "prognostic literature" on epithelioid sarcoma. The chart and the papers its data came from may come in handy for those trying to figure out how they are going to survive this disease, and what factors may influence that survival.

But before you enlarge the chart, read "The Median is not the Message," a short essay by the late Harvard evolutionary biologist Stephen Jay Gould. It is, he writes, "a personal story of statistics, properly interpreted, as profoundly nurturant and life-giving..." Gould was diagnosed with abdominal mesothelioma. He read up on the disease and found a median survival time of 8 months -- he was crushed at first, and then he started thinking.

The problem may be briefly stated: What does "median mortality of eight months" signify in our vernacular? I suspect that most people, without training in statistics, would read such a statement as "I will probably be dead in eight months" -- the very conclusion that must be avoided, since it isn't so, and since attitude matters so much.

Gould lived for 20 years after his treatment, and died of something else entirely. So much for that eight-month median.

The chart here offers no context, and it's important to realize that the results are skewed in all sorts of ways: some of the data is too old, some of the groups of patients were much sicker than others, some of the groups are too small... Even within a given series (group of patients), results can vary hugely by the type of treatment (wide surgery before mets). 

I have to laugh a little here, as I encourage people to not misread the data and become too discouraged, because shortly after my own diagnosis, I skimmed a bunch of prognostic studies myself and completely misread the data -- in my favor. My erroneous optimism was quickly checked by reality, but my strong initial sense that I could and would survive five years, ten years, and possibly many more was a huge help in the early days of adapting to the illness. I should say that this kind of optimism is appropriate to many people diagnosed with epithelioid sarcoma; what I didn't realize then was that my prognosis was worse than the average ES patient's because of the central ("proximal," in the lingo) location of my tumor, the likelihood that it had already spread locally, and the involvement of my lymph nodes. I'll elaborate more on positive and negative prognostic factors in a future post. 

But I still believe strongly in my initial impulse: The key is to get the right treatment and survive right now. Even if the disease boomerangs viciously back in five years -- one year -- who knows what options will exist then? The science is changing all the time; too slowly, yes, but it is changing. Even since August 2006, when I was diagnosed, several promising trials have launched, and one strong effort (yondelis, or ET-743) has apparently bombed, at least for ES. 

The chart comes from an article in Cancer titled Epithelioid sarcoma: Still an only surgically curable disease.

G.D.I

And the news wasn't good. 

Although the tumors hadn't spread, and there was no sign of anything on my lungs or other organs, they continued growing through the two cycles of Gem/Tax. So it's on to a new drug, temodar (temozolomide). 

This is an oral agent, commonly used for brain tumors and as a radiosensitizer. Temodar's record with soft-tissue sarcoma is mixed, to say the least. The idea is that this drug's relatively long cycle (six weeks of daily doses; two weeks off) will align well with my still relatively slow-growing epithelioid sarcoma. If Temodar stabilizes the disease, I will then hopefully enroll in Ariad's trial of deforolimus, which is seen as a promising alternative to "watching and waiting."

L. and I both left marveling at Dr. S's slickness. She delivered some pretty lousy news, and she did so smoothly. The strategy was something like this: 1) get the bad out there quickly; 2) emphasize the normal or positive findings; 3) immediately lay out the revised plan, emphasizing the deforolimus carrot; 4) slip in some bad news about temodar's side effects; 5) listen to my lungs and leave.

I'll start temodar later this week, if the preapprovals go well. (They should: I was previously pre-approved for the drug, so we're not starting from scratch.) The common side-effects are nausea, constipation and fatigue, so Dr. S launches new temodar patients with Zofran, one of the heavier-duty anti-nausea drugs. Hey! I've been telling everyone that this would be easy and you write a script for serious anti-emetics! Damn you, Dr. S! Foiled again by that wily physician....

*

The title of this post is honor of my younger brother, C, who used to draw out "God... Damn... It..." into a kind of mantra, angry but also rueful, dispositive but also somehow searching. I took the soul out of it by reducing it to a compact G.D.I so I could allude to the idea but not pollute the mouths of my kids any more than I already have. 

Anyway, that was pretty much my reaction to the results: God. Damn. It. 

Sarcoma and Smart Drugs

This article from Harvard Magazine tells the story of a man with a particularly ugly form of sarcoma called GIST and his treatment with so-called "smart drugs," agents that destroy tumors by targeting the specific proteins in malignant cells, rather than just mowing down everything growing a la conventional chemotherapy. The patient happens upon the right man, Dana-Farber's Dr. George Demetri, at the right time, just as trials of the smart drug Gleevec are primed to begin.

A caveat on the piece is that it is written by a former president of Dana-Farber, so it's not objective. It doesn't end well, either. But it melds a moving human story with insight into the science behind smart drugs and some of the medical and ethical issues presented by drug trials. It also briefly discusses dasatinib, a Gleevec-like agent that is currently being assessed for action against epithelioid sarcoma in a new study. I'll have more on that soon.

Temodar

My doctor thinks temodar, or temozolomide, a relatively well-tolerated oral chemotherapy agent, is the next way to go. I'm not sure it's effective enough. I'm all for minimizing side-effects, but if that means minimizing the effect also, I'm just not down. First paper I picked up on PubMed is reasonably encouraging:

A phase II trial of temozolomide as a 6-week, continuous, oral schedule in patients with advanced soft tissue sarcoma: a study by the Spanish Group for Research on Sarcomas. The upshot from the abstract is "RESULTS: Among 45 eligible patients in the STS arm, there were 7 partial responses, for an overall response rate of 15.5% (95% confidence interval [95% CI], 5-26%). Responses were seen in 5 of 11 patients who had gynecologic leiomyosarcoma. The median response duration was 12.5 months (range, 3.9-58.0 mos). In 4 patients, response lasted > 1 year, and 2 of those patients remained progression free for > 3 years. The median time to progression was 2.2 months (95% CI, 1.8-2.5 mos), and the median overall survival was 8.1 months (95% CI, 5.6-10.6 mos). Progression-free survival rates at 3 months and 6 months were 39.5% and 26%, respectively. In the GIST arm, no responses were noted."

This is the highest response-rate I've seen for temodar in a study, but the series here, while reasonably sized, was heavily tilted toward uterine leiomyosarcoma, which temodar is an established decent drug for.

This study, from MD Anderson, found a 5 percent response rate in people with non-GIST soft-tissue sarcoma.

Another Phase 2 had about an 8 percent response rate; the responders all had some sort of leiomyosarcoma.

This 1999 European phase 2 is quite discouraging. Just one response (3.3 percent).

What's left to check? Temozolomide is often used with irinotecan. I'll try to find some studies on that soon. It also has potential as a radiosensitizer. The full text of this paper Outpatient chemotherapy plus radiotherapy in sarcomas: improving cancer control with radiosensitizing agents could be very interesting.

More soon.