Docetaxel, cisplatin, and trastuzumab show great result

[kk1]

This article came across my desk this morning. Very encouraging.
kk1

Unique Chemo Regimen is Extremely Effective in Certain Breast Cancers, UM Oncologist Shows in Journal of Clinical Oncology Early-Release Study

4/21/2006

A study led by Judith Hurley, M.D., associate professor of clinical medicine at the University of Miami Sylvester Comprehensive Cancer Center, showed that platinum-based chemotherapy combined with Herceptin is highly effective against HER2-positive, locally advanced breast cancer. The study is so significant that editors at the prestigious Journal of Clinical Oncology opted to publish the results early, online. Dr. Hurley has been a national leader in the study of locally advanced breast cancer for more than 15 years. “This is a natural progression of our research showing that platinum-based regimens can cure breast cancer,” said Hurley, who is also medical director of the oncology clinics at Jackson Memorial Hospital.

The five-year disease-free survival rate for patients with stage III locally advanced breast cancer is between 20 and 30 percent. But Dr. Hurley’s patients had an 85 percent survival rate at 43 months. “The fact of the matter is that seven relapsed but 41 did not,” said Hurley. “Considering these tumors were an average of 9 centimeters (3 ½ inches) and HER2 over-expressing, you would expect at four years that most of the patients would have relapsed.” The largest tumor in Dr. Hurley’s study was 35 centimeters – more than 13 inches.

Forty-eight patients were enrolled in this study. All had locally advanced breast cancer with tumors more than 5 cm in size and all tested positive for the presence of human epidermal growth factor receptor 2 (HER2). HER2 is a protein that occurs naturally in glandular cells like breast tissue. When it occurs in unusually high amounts it can fuel the proliferation of cancer. Each patient underwent three stages of therapy: a 12-week chemotherapy regimen of docetaxel, cisplatin and Herceptin to shrink the tumor; surgery to remove the remaining tumor; then a 12-week chemotherapy regimen of adriamycin and cyclophosphamide.

Every single patient responded to the therapy. Many showed visible tumor shrinkage within one day of treatment with cisplatin, docetaxel and herceptin chemotherapy.

Dr. Hurley began working with platinum-based chemotherapy in 1990 after she found more traditional regimens were not effective in her patient population. Across the United States, only about 6 percent of breast cancer patients present with locally advanced breast cancer – about 13,000 women a year. But nearly one in four of Dr. Hurley’s patients – 23 percent – have that diagnosis. The reason for this preponderance of locally advanced breast cancer in Miami is not known for certain, but Miami’s large minority population and high number of uninsured and underinsured patients are probably contributing factors. “I happened to be in the right place at the right time,” she said. “My research career started because there was a clinical problem that I didn’t know how to solve, so I set about trying to solve it.”
Hurley found three studies, one in bladder cancer and two in breast cancer, published in the late 1980s that all showed good results with platinum-based chemotherapy, so she began her own study at UM. Of the 75 patients enrolled, one in three had a complete pathologic response – elimination of the tumor from chemotherapy alone. Based on these promising results she has performed a set of nested studies evaluating platinum-based chemotherapy in the curative therapy of breast cancer. Subsequent studies have evaluated the addition of Taxotere and Herceptin to cisplatin and the modification of dosing schedule with even better results.

Publication of those studies caught the attention of Dennis J. Slamon, M.D., Ph.D., chief of the UCLA Oncology Center and the creator of Herceptin, who participated in the current study. He was sent tissue samples and voluntarily determined the HER2 status of each patient on the study. “This is the first study using Herceptin in the curative setting with long-term survival data,” said Hurley. Normally patients treated for HER2 positive tumors suffer a relapse very quickly – within 18 months. Those who do relapse have extremely poor prognoses. Of the 48 patients enrolled in this study, 41 are now beyond three years with no relapse.

Patients with breast cancer that over-expresses HER-2 can now enroll in a new trial at UM and JMH which speeds up the chemotherapy regimen. Studies have shown that “dose dense” chemotherapy, which is given every two weeks instead of every three weeks, may yield even better results. “Building on our previous research we hope to continue to improve the survival of women with HER2 over-expressing breast cancer,” said Hurley.

The current study is available online in the Journal of Clinical Oncology at this link: http://www.jco.org/cgi/content/abstr...2005.02.8886v1.

UM/Sylvester opened in 1992 to provide comprehensive cancer services and today serves as the hub for cancer-related research, diagnosis, and treatment at the University of Miami Leonard M. Miller School of Medicine. UM/Sylvester handles 1,400 inpatient admissions annually, performs 3,000 surgical procedures, and treats 3,000 new cancer patients. All UM/Sylvester physicians are on the faculty of the Miller School of Medicine, South Florida’s only academic medical center. In addition, UM/Sylvester physicians and scientists are engaged in 200 clinical trials and receive more than $31 million annually in research grants. UM/Sylvester at Deerfield Beach recently opened to better meet the needs of residents of Broward and Palm Beach counties. This 10,000-square-foot facility at I-95 and S.W. 10th Street offers appointments with physicians from six cancer specialties, complementary therapies from the Courtelis Center, and education and outreach events. http://www.sylvester.org.

Docetaxel, Cisplatin, and Trastuzumab As Primary Systemic Therapy for Human Epidermal Growth Factor Receptor 2-Positive Locally Advanced Breast Cancer

Judith Hurley *, Philomena Doliny , Isildinha Reis , Orlando Silva , Carmen Gomez-Fernandez , Pedro Velez , Giovanni Pauletti , Mark D. Pegram , and Dennis J. Slamon
From the Sylvester Cancer Center, Miller School of Medicine, University of Miami; Taylor Breast Center, Jackson Memorial Hospital, Miami, FL; and University of California at Los Angeles, Los Angeles, CA.

* To whom correspondence should be addressed. E-mail: jhurley@miami.edu


Purpose: To evaluate the efficacy and safety of docetaxel, cisplatin, and trastuzumab as primary systemic therapy for human epidermal growth factor receptor 2 (HER2) -positive, locally advanced breast cancer (LABC).

Patients and Methods: Forty-eight patients with immunohistochemistry-confirmed HER2-positive LABC or inflammatory breast cancer received 12 weeks of docetaxel, cisplatin, and trastuzumab with filgrastim, followed by surgery, adjuvant doxorubicin and cyclophosphamide, and locoregional radiotherapy with or without tamoxifen. The primary end point was pathologic complete response (pCR) in breast.

Results: Baseline mean tumor size was 9.2 cm (range, 4 to 32 cm). pCR occurred in breast in 11 patients (23%; 95% CI, 12% to 37%) and breast and axilla in eight patients (17%; 95% CI, 8% to 30%). pCR rates in breast (HER2 positive, seven of 30 patients, 23% v HER2 negative, four of 18 patients, 22%; P > .05) and breast and axilla (four of 30 patients, 13% v four of 18 patients, 22%, respectively; P > .05) were similar regardless of HER2 status by fluorescence in situ hybridization (FISH). At a median follow-up time of 43 months, 4-year progression-free survival (PFS) rate was 81% (95% CI, 64% to 90%); overall survival (OS) rate was 86% (95% CI, 71% to 94%). In patients with pCR in breast and axilla, PFS and OS rates were 100% (95% CI, inestimable). In patients without pCR, PFS rate was 76% (95% CI, 57% to 88%; P = .15, log-rank test), and OS rate was 83% (95% CI, 66% to 92%; P = .21). Survival rates were similar regardless of FISH status. There were only two grade 4 adverse events.

Conclusion: Twelve weeks of docetaxel, cisplatin, and trastuzumab is clinically active and leads to excellent survival in patients with large, HER2-positive tumors.

[Audrey]

Great news--I hadn't heard of this study--thanks for sharing!

[StephN]

"The five-year disease-free survival rate for patients with stage III locally advanced breast cancer is between 20 and 30 percent. But Dr. Hurley’s patients had an 85 percent survival rate at 43 months. “The fact of the matter is that seven relapsed but 41 did not,” said Hurley. “Considering these tumors were an average of 9 centimeters (3 ½ inches) and HER2 over-expressing, you would expect at four years that most of the patients would have relapsed.” The largest tumor in Dr. Hurley’s study was 35 centimeters – more than 13 inches."


The above is a quote from the article using Cisplatin in the treatment. I was considering a treatment regimen with this drug for adjuvent. It was recommended by one of the oncs I saw for 2nd or 3rd opinion. He knew I had agressive disease and thought this might be a good drug for me. We will never know if it might have worked better than Adria & Taxotere, which did NOT work on me.

What shocked me in the above was the size of the tumors. involved. I ask WHO could have 13 inch tumor and not be aware sooner? Must have been a very large person. Even with an average of 9 centimeters, this is much larger than almost anyone here has posted.

Most of us would have been dead by the time our tumors got that large, as the disease would be everywhere by then. The fact that these patients were
surviving for 4 years IS amazing.

[kk1]

Hi Steph;

Interesting point, as they say size is not everything. I had a small ~1cm non-palatable breast tumor that had already metastized to my liver-- contrast that this report where 13cm was still localized. As the kids say go figure!

Here in Miami we have a large population of uninsured people and a large immigrant population. UM runs the Miami-Dade county hospital (Jackson Memorial) as their teaching Hospital so all the Oncs and surgeons at UM/Sylvestor practice at Jackson, where they see many of the indigent population who delay treatment until things are desperate because they don't have access to earlier treatment. Most of us on this board are very fortunate to have access to the type of information and care we receive.

btw- Steph, Looks like am going to be in Seattle July 22nd would love to meet you for lunch iif your in town then.

KK1

[Audrey]

Steph, regarding tumor size--I think Her2+ tumors can get really large quickly in some cases. My tumor was 15 cm (!) and I'm only 5 ft. tall (100 lbs. at diagnosis). You ask who wouldn't notice a large tumor? It's not all just women in denial or ignoring palpable masses...My tumor was not detected by my ob-gyn, two breast surgeons, not visible on mammogram or noted on ultrasound. I presented with a bloody nipple discharge, had a nipple biopsy, which showed atypical cells/DCIS, then underwent a mastectomy. Only the pathologist's report showed invasive cancer and noted the large tumor size. When I asked everybody how they could have missed something so large, the surgeon noted that the tumor was not a large mass like a grapefruit, but more like a slender snake...Also, since I was younger (36) my breasts were very dense and this makes mammograms harder to read. I used to think I was doomed since the tumor was so large, but I've had a few friends in support groups who had very small tumors at diagnosis and have since passed away. You really can't tell one's future based on tumor size anymore. Anyway, this was all 5 years ago and I'm doing fine..

[jojo]

Hmmm, interesting...

Are these drugs the same thing? Aren't they both in the platinum <spell?> family?

[jhandley]

If you read "the her 2 story" you will see that Dennis Slamon wanted to do the phase 3 trials with a platinum drug because the phase 1 and 2 trials were done with cisplatin (I think from memory) and also lab tests had shown profound synergy with herceptin. Anyway he was overruled by the drug company who according to the book were a bit nervous about using a drug that wasn't active on its own against breast cancer. Apparently that is why they went with taxol. It has since been shown that the median time to progression in a phase 3 trial of herceptin/taxol/carboplatin versus just herceptin/taxol was more than doubled in a study of Stage IV patients.
I tried to get carboplatin added to my regime in Oct last year when these trial results came out but wasnt able to.
Jackie

[kk1]

JoJo;

Platinum agents, carboplatin (Paraplatin) or (less commonly) cisplatin (Platinol). At this time carboplatin is preferred over cisplatin in the combination because studies indicate that carboplatin is as effective as cisplatin but is less toxic and can be administered in a more convenient, outpatient regimen.

Taxanes, paclitaxel (Taxol) and docetaxel (Taxotere). Taxol was the first taxane develped and brought to market. The more recent synthetic version Taxotere has been showing improved efficacy so is gaining ground as the standard of care over the more traditional Taxol. Now we very recntly also have Abraxane which is just Taxol/paclitaxel packaged in little nanoparticles so it causes less side effects than Taxol, so can be given in high doses, and out performed Taxol in recent pahse III studies. At this point I have not seen any studies comparing Abraxane with Taxotere so who knows where the standard of care will go next.

KK1

[Christine MH-UK]

Hi kk1,

I read through the article and it seems like there was no year of herceptin given at the end. The cost accountants will love this one (I told a chemo nurse about it today and her reaction was basically, "good, no new drugs are involved").

Of course, the big concern is cardiotoxicity. According to the article "Eighteen patients refused postadjuvant chemotherapy MUGA scans because they were asymptomatic. Of the remaining 30 patients, 14 patients’ ejection fractions remained normal, whereas 10 patients (33%) had grade 1 cardiotoxicity, and six patients (20%) had grade 2 cardiotoxicity." What I don't know is whether that is good or bad.

[lu ann]

When I was at Cancer Treatment Centers of America, the oncologist wanted to give me taxotere, carboplatin, and herceptin. I decided to get chemo treatment from our local hospital instead of traveling to Zion, Illinois. My local oncologist agreed to use the same treatment suggested by C.T.C.A. I decided to use taxol instead of taxotere because less pre-meds (decadron) needed to be used. I have had the best results with this combination. My ca15-3 went from 345-115 after radiation and from 115-21 (34< normal) after taxol, carbo, and herceptin. I had this combo for 6 months. I then had navelbine/herceptin with an increase of tumor markers and gemsar/herceptin also with an increase. I will be starting xeloda without herceptin within the next couple of weeks.

Love and Blessings, Lu Ann.