Autologous and Allogeneic Stem-Cell Transplantation for Transformed Follicular Lymphoma: A Report of the Canadian Blood and Marrow Transplant Group.

Abstract

Purpose To determine whether autologous (auto) or allogeneic (allo) stem-cell transplantation (SCT) improves outcome in patients with transformed follicular lymphoma compared with rituximab-containing chemotherapy alone.

Patients and Methods This was a multicenter cohort study of patients with follicular lymphoma and subsequent biopsy-proven aggressive histology transformation. Patient, treatment, and outcome data were collected from each transplantation center and combined for analysis. A separate control group was composed of patients with transformation treated with rituximab-containing chemotherapy but not SCT. The primary end point was overall survival (OS) after transformation.

Results One hundred seventy-two patients were identified: 22 (13%) treated with alloSCT, 97 (56%) with autoSCT, and 53 (31%) with rituximab-containing chemotherapy. Five-year OS after transformation was 46% for patients treated with alloSCT, 65% with autoSCT, and 61% with rituximab-containing chemotherapy (P = .24). Five-year progression-free survival (PFS) after transformation was 46% for those treated with alloSCT, 55% with autoSCT, and 40% with rituximab-containing chemotherapy (P = .12). In multivariate analysis, patients treated with autoSCT had improved OS compared with those who received rituximab-containing chemotherapy (hazard ratio [HR], 0.13; 95% CI, 0.05 to 0.34; P < .001). On the other hand, there was no OS difference between those treated with alloSCT and rituximab-containing chemotherapy (HR, 0.44; 95% CI, 0.16 to 1.24; P = .12). OS and PFS after SCT were similar between those treated with autoSCT and alloSCT. Five-year transplantation-related mortality was 23% for those treated with alloSCT and 5% for autoSCT.

Conclusion Patients undergoing autoSCT had better outcomes than those treated with rituximab-containing chemotherapy alone. AlloSCT did not improve outcome compared with rituximab-containing chemotherapy and was associated with clinically significant toxicity.

Source: JCO

 

 

Maintenance Chemotherapy for Advanced Non–Small-Cell Lung Cancer: New Life for an Old Idea.

Abstract

Although well established for the treatment of certain hematologic malignancies, maintenance therapy has only recently become a treatment paradigm for advanced non–small-cell lung cancer. Maintenance therapy, which is designed to prolong a clinically favorable state after completion of a predefined number of induction chemotherapy cycles, has two principal paradigms. Continuation maintenance therapy entails the ongoing administration of a component of the initial chemotherapy regimen, generally the nonplatinum cytotoxic drug or a molecular targeted agent. With switch maintenance (also known as sequential therapy), a new and potentially non–cross-resistant agent is introduced immediately on completion of first-line chemotherapy. Potential rationales for maintenance therapy include increased exposure to effective therapies, decreasing chemotherapy resistance, optimizing efficacy of chemotherapeutic agents, antiangiogenic effects, and altering antitumor immunity. To date, switch maintenance therapy strategies with pemetrexed and erlotinib have demonstrated improved overall survival, resulting in US Food and Drug Administration approval for this indication. Recently, continuation maintenance with pemetrexed was found to prolong overall survival as well. Factors predicting benefit from maintenance chemotherapy include the degree of response to first-line therapy, performance status, the likelihood of receiving further therapy at the time of progression, and tumor histology and molecular characteristics. Several aspects of maintenance therapy have raised considerable debate in the thoracic oncology community, including clinical trial end points, the prevalence of second-line chemotherapy administration, the role of treatment-free intervals, quality of life, economic considerations, and whether progression-free survival is a worthy therapeutic goal in this disease setting.

Source: JCO

 

Turning Traditional Medicine Into Cancer Drugs.

Quite a few substances used in traditional medicine in China or other countries have received Food and Drug Administration (FDA) approval as cancer drugs… and their numbers are growing.  Some examples are:

Arsenic trioxide, made from arsenic sulfide ore, has been used therapeutically for more than 2,400 years. Following promising reports from China, the agent was tested in clinical trials and received FDA approval in 2000 for patients with acute promyelocytic leukemia who have not responded to other therapies or whose disease has recurred.

Camptothecin, isolated from the bark and stem of a tree native to China, was long used as a cancer treatment in traditional Chinese medicine. When preliminary clinical trials of the compound showed encouraging results in patients with leukemia, chemists made synthetic versions that retain its anticancer properties while reducing its harsh side effects. Two of these synthesized versions, or analogues, have been approved for the treatment of chronic lymphocytic leukemia.

Podophyllotoxin, isolated from the Mayapple plant that grows in forests in the eastern United States, has a long history as a medicinal agent. A gel made from the compound is used to treat certain kinds of warts, and a synthetic version is used to treat lung cancer, testicular cancer,lymphoma, and certain forms of leukemiaand sarcomas.

Vinca alkaloids were derived from the Madagascar periwinkle plant and, according to folklore, were useful in treating diabetes. Scientific testing found they had no antidiabetic properties but could extend the lives of mice with certain forms of leukemia. Synthesized forms of the alkaloids include two of the most common chemotherapy agents in use today, vincristine and vinblastine. Cancers treated with vinca alkaloid-derived drugs include acute leukemia, neuroblastoma,  Wilms tumor, Hodgkin and non-Hodgkin lymphomas,breast cancer, melanoma, and uterine cancer.

Homoharringtonine, which comes from an evergreen shrub indigenous to China called Plum Yew or Cowtail Pine, was approved by the FDA last year for the treatment of adult patients with chronic myelogenous leukemia (CML) who aren’t helped by agents known as kinase inhibitors.

Indirubin, extracted from the indigo plant, is part of a traditional Chinese preparation used to treat CML. Laboratory and animal studies suggest it may be an effective treatment for patients, but clinical trials have not yet been conducted.

Natural compounds from Chinese medicine currently being studied as potential cancer drugs include astragulus (a large family of herbs and shrubs); scutellaria (flowering plants of the mint family, used in traditional Chinese medicine to strengthen the immune system); and indigofera (a large family of flowering plants, used to alleviate pain).

Some naturally-derived agents are used as stand-alone treatments; others are part of combined therapies. Because some natural therapies can decrease the effect of chemotherapy drugs, it’s important for patients to inform their physicians of any alternative treatments they are using.

Source:Dana Faber

Induction chemotherapy followed by concurrent chemoradiotherapy (sequential chemoradiotherapy) versus concurrent chemoradiotherapy alone in locally advanced head and neck cancer (PARADIGM): a randomised phase 3 trial.

 

The relative efficacy of the addition of induction chemotherapy to chemoradiotherapy compared with chemoradiotherapy alone for patients with head and neck cancer is unclear. The PARADIGM study is a multicentre open-label phase 3 study comparing the use of docetaxel, cisplatin, and fluorouracil (TPF) induction chemotherapy followed by concurrent chemoradiotherapy with cisplatin-based concurrent chemoradiotherapy alone in patients with locally advanced head and neck cancer.
METHODS: Adult patients with previously untreated, non-metastatic, newly diagnosed head and neck cancer were eligible. Patients were eligible if their tumour was either unresectable or of low surgical curability on the basis of advanced tumour stage (3 or 4) or regional-node stage (2 or 3, except T1N2), or if they were a candidate for organ preservation. Patients were randomly assigned (in a 1:1 ratio) to receive either induction chemotherapy with three cycles of TPF followed by concurrent chemoradiotherapy with either docetaxel or carboplatin or concurrent chemoradiotherapy alone with two cycles of bolus cisplatin. A computer-generated randomisation schedule using minimisation was prepared and the treatment assignment was done centrally at one of the study sites. Patients, study staff, and investigators were not masked to group assignment. Stratification factors were WHO performance status, primary disease site, and stage. The primary endpoint was overall survival. Analysis was by intention to treat. Patient accrual was terminated in December, 2008, because of slow enrolment. The trial is registered with ClinicalTrials.gov, number NCT00095875.
FINDINGS: Between Aug 24, 2004, and Dec 29, 2008, we enrolled 145 patients across 16 sites. After a median follow-up of 49 months (IQR 39-63), 41 patients had died-20 in the induction chemotherapy followed by chemoradiotherapy group and 21 in the chemoradiotherapy alone group. 3-year overall survival was 73% (95% CI 60-82) in the induction therapy followed by chemoradiotherapy group and 78% (66-86) in the chemoradiotherapy alone group (hazard ratio 1.09, 95% CI 0.59-2.03; p=0.77). More patients had febrile neutropenia in the induction chemotherapy followed by chemoradiotherapy group (16 patients) than in the chemoradiotherapy alone group (one patient).
INTERPRETATION: Although survival results were good in both groups there was no difference noted between those patients treated with induction chemotherapy followed by chemoradiotherapy and those who received chemoradiotherapy alone. We cannot rule out the possibility of a difference in survival going undetected due to early termination of the trial. Clinicians should still use their best judgment, based on the available data, in the decision of how to best treat patients. The addition of induction chemotherapy remains an appropriate approach for advanced disease with high risk for local or distant failure.

Source: Lancet oncology

The cancer stem cell discovery which sheds light on regrowth.

When different kinds of cancer are tackled, tumors may shrink in reaction to treatments including chemotherapy, but there is often the possibility of them springing back.

Some scientists believe that regrowth occurs because chemotherapy fails to eradicate a small number of cells, known in the field tentatively as ‘cancer stem cells’. It may be the case that these kinds of cells perform the same function in all cancers that create solid tumor masses.

The suspicion of stem cell cancer cells has long been an aspect of research in the field, but the hypothesis has remained controversial — mainly due to the artificial environments that most studies have taken place in, where human cells are transplanted into mice.

Now, studies on three different kinds of cancerous tumor has suggested a key reason why certain types of cells play a part in regrowth – stem cells that fuel the cancer and are not killed by standard therapies.

Published in the journals Nature and Science, the new studies conducted by three independent teams of researchers believe that this discovery may be a breakthrough in the field of cancer research.

Conducting tests on mice, so-called tumor stem cells were identified in the brain, skin and gut. In one case, researchers were able to prove that treating glioblastoma — a fatal brain tumor — with chemotherapy left behind these kinds of cells, and eventually this sparked regrowth.

Luis F. Parada, a molecular geneticist hailing from the University of Texas Southwestern Medical Center in Dallas, and author of one of the studies, said:

“Everything has a soft underbelly once you understand it well. With all the modern molecular techniques and modern approaches we have, we should be able to find their soft underbelly.”

Each study used color markers to detect when tumor cells divided in the mouse hosts. By doing so, the researchers were able to detect which cells did not replicate — and whether old cells can fuel regrowth, or it has to be stem cell subsets.

Robert Weinberg, a biology professor at MIT who was not involved in the new studies said:

“What these three papers have done, through elegant strategies, is demonstrate, indeed there are cancer stem cells. It makes it more and more difficult for people to doubt the existence of cancer stem cells.”

Source: Smart planet

 

 

Preventing Thrombosis During Chemotherapy.

Prophylactic anticoagulation with the low-molecular-weight heparin semuloparin reduced the incidence of thromboembolic events without increasing the risk for major bleeding.

Venous thromboembolism (VTE) often complicates cancer and is related to patient performance status, tumor stage, and treatment. Many chemotherapeutic agents increase the risk for VTE, even in ambulatory outpatients. However, whether prophylactic anticoagulation diminishes VTE risk during chemotherapy is unclear.

To address this issue, an international team of investigators conducted an industry-supported, randomized, double-blind, placebo-controlled trial involving 3212 patients who were beginning to receive chemotherapy for cancers typically associated with an increased risk for VTE; 36% of patients had lung cancer, and 28.9% had colorectal cancer. Most tumors (66%) were metastatic; the remaining tumors were locally advanced. Patients with adequate renal function (creatinine clearance >30 mL/minute) received either the hemisynthetic low-molecular-weight heparin (LMWH) semuloparin (20 mg/day subcutaneously) or placebo for a median 3.5 months.

The primary outcome — any symptomatic deep venous thrombosis (DVT), nonfatal pulmonary embolism (PE), or death related to VTE — occurred in fewer semuloparin recipients than placebo recipients (1.2% vs. 3.4%; hazard ratio, 0.36; P<0.001). Semuloparin was also associated with significantly lower risk for DVT (odds ratio, 0.32; 95% confidence interval, 0.15–0.62) and PE (OR, 0.41; 95% CI, 0.19–0.85). However, overall survival was similar in both groups. Rates of major bleeding and nonmajor clinically relevant bleeding were low (about 2%), and other adverse events were also similar in both groups.

Comment: The decision to administer anticoagulant prophylaxis to patients receiving chemotherapy is informed by several factors: the nature of the chemotherapy, patient characteristics, tumor type and stage, and the safety and efficacy of available antithrombotic agents. This trial demonstrates that in carefully selected patients with high-risk tumors, LMWH — which is simple to administer without monitoring — safely reduced the incidence of VTE when given concomitantly with chemotherapy.

Source: Journal Watch Oncology and Hematology

 

Cancer Trials Can Lack Clear Information on Biopsies.

 Cancer drug trials often require participants to receive invasive procedures like biopsies, which are used to assess the drug’s effectiveness but have no therapeutic value – and can pose serious risks — for the patient.

Informed consent documents are supposed to inform study participants about these types of risks so they can make an educated decision on whether or not to participate in the trial, but a new study found this type of risk information to be seriously lacking.

Risks of Biopsies Not Clearly Stated

Writing in the Journal of Clinical Oncology, researchers stated:¹

“A better representation of the risks and benefits of research biopsies in study protocols and informed consents is needed.”

This was their conclusion after finding that more than 5 percent of biopsies in cancer drug trials may cause complications, but the informed consent documents did not adequately explain this. In fact, on average the consent documents had only 39 words addressing risks from invasive biopsies – less than the number of words used to address risks for simple blood draws.

Of the 745 tumor biopsies reviewed for the study, 39 resulted in complications, including lung air leaks, bleeding and other major effects that required hospitalization or surgery.

Whether you’re participating in a drug trial, or considering a biopsy for another medical reason, you should know that while biopsy risks are rarely discussed, there are risks, indeed.

Serious Biopsy Complications Every Patient Should Know

During a biopsy, a piece of tissue from a tumor or organ is removed so that it can be examined under a microscope, often to determine if it is cancerous. Needle biopsies, for instance, are widely used as part of the traditional allopathic approach to diagnosing breast cancer. But they may accidentally cause malignant cells to break away from a tumor, resulting in its spreading to other areas of your body.

According to a study from the John Wayne Cancer Institute, it appears that a needle biopsy may increase the spread of cancer by 50 percent compared to patients who receive excisional biopsies, also known as lumpectomies.²

The procedure also involves a serious risk of infection. For prostate gland biopsies, specialists have begun to worry about a recent, significant increase in hard-to-treat bloodstream infections that can require weeks of treatment.

Prostate biopsies inherently pose a risk for infection because:

• The needles that collect a tiny piece of prostate tissue can transport bacteria through your rectal wall into the prostate and bloodstream
• The needles can spread harmful bacteria present in your gut into your bloodstream

Pain, bleeding (that can be so severe it requires a blood transfusion or surgery to stop it), infection and accidental injury to a nearby organ are established risks that are present no matter what type of biopsy you receive. And then there is the issue of its questionable effectiveness.

In the case of prostate biopsies, an estimated one-third of men who receive “negative” results for prostate cancer actually do have prostate cancer that was missed by the biopsy. For breast biopsies, estimates suggest that 17 percent of D.C.I.S. (ductal carcinoma in situ) cases found through needle biopsy are misdiagnosed. And oftentimes it is an inaccurate mammogram (mammograms carry a first-time false positive rate of up to 6 percent) that leads to the breast biopsy in the first place, making the procedure completely unnecessary.

So, certainly if you’re considering taking part in a drug trial, you need to carefully assess whether the biopsy risks are worth it to you … and this is also true anytime you’re faced with a recommendation of a biopsy. You must measure the potential benefits against the risks in order to make an informed decision.

5,000 Combinations Of 100 Existing Cancer Drugs Tested To Find More Effective Treatments

Whereas biopsies are one of the go-to procedures conventional medicine uses to diagnose cancer, chemotherapy is the go-to procedure to treat it. But one of the reasons why conventional cancer treatment is such a dismal failure in the United States is because it relies on chemotherapy. Despite its reputation as the gold-standard in cancer treatment, chemotherapy has an average 5-year survival success rate of just over 2 percent for all cancers, according to a study published in the journal Clinical Oncology.³

The researchers concluded:

“ … it is clear that cytotoxic chemotherapy only makes a minor contribution to cancer survival. To justify the continued funding and availability of drugs used in cytotoxic chemotherapy, a rigorous evaluation of the cost-effectiveness and impact on quality of life is urgently required.”

It’s no secret among the cancer industry that these drugs are often ineffective, or that oftentimes the cancer patient survives not because of — but despite – the treatment. Moreover, it’s now common for treatments to use combinations of drugs, as many cancers have become resistant to single drugs, rendering them useless. Chemotherapy often supports the more chemo-resistant and malignant cell subpopulations within tumors (e.g. cancer stem cells), as it kills both the more benign cells and/or senescent cells within the tumor that keep it slow-growing, or even harmless.

As a result, this unleashes a more aggressive, treatment-resistant type of cancer to wreak havoc on the body.

A new study recently tested 5,000 combinations of the 100 cancer drugs approved for use in patients in an attempt to find more effective treatments.⁴ They plan to move several of their novel combinations into clinical trials as quickly as possible, but is this really going to benefit cancer patients?

Chemo Drugs Destroy Your Healthy Cells, Including Your Immune System

Chemotherapy drugs are, by their very nature, extremely toxic and typically work against your body’s natural ability to fight cancer by harming your immune system (often irreparably) instead of supporting it. Combining them into new formulations could cause any number of unforeseen consequences. Already, it’s known that certain chemo drugs become so toxic when combined that they would have to be used at such a low dose they would no longer work against the cancer!

And one of the biggest drawbacks to chemotherapy of any kind is the fact that it destroys healthy cells throughout your body right along with cancer cells, a “side effect” that often leads to accelerated death, not healing.

Another study, “The National Confidential Enquiry into Patient Outcome and Death (NCEPOD)”, found that more than four in 10 patients who received chemotherapy toward the end of life experienced potentially fatal effects. And after reviewing data from over 600 cancer patients who died within 30 days of receiving treatment, it was found that chemotherapy hastened or caused death in 27 percent of those cases.

In the last 30 years the global cancer burden has doubled, and it will likely double again between 2000 and 2020, and nearly triple by 2030 — unless people begin to take cancer prevention seriously. We CAN turn this trend around, but to do so the medical community must stop overlooking the methods that can actually have a significant impact.

Why I Strongly Advise Avoiding Chemotherapy

I strongly advise everyone to avoid taking any chemotherapy drugs. In my experience the people who survive the chemotherapy do it in spite of the therapy not because of it. More typically, once a person starts chemo it can lead to death. It is the one form of cancer therapy that I strongly advise most to avoid.

Why?

Because the way your body fights cancer normally is through a healthy immune system, and if you take drugs to target and destroy your immune system you tend to radically reduce your likelihood of long-term survival. This is not the case for surgery and radiation, which although also overused, do not impair your immune system and may debulk the tumor enough to give your immune system a chance to fight it.

Please also be aware that avoiding chemo comes with massive responsibility and the need to do something positive. Typically this involves a radical application of my advanced nutrition plan in addition to severely limiting protein and carbs and using high-quality fats as a source of calories. This would include foods like avocados, coconut oil, butter, nuts, olive and olive oil. This will tend to lower the mTOR pathway and optimize leptin and insulin signaling.

Four Must-Know Tips for Cancer Prevention

If you’re facing a health challenge, I recommend seeking out a qualified natural health consultant. When it comes to cancer, you’ll want to identify someone that is well known and respected for their work in treating cancer patients. If you don’t find someone locally then scour the Internet and make calls to plenty of patients that the practitioner has seen.

For the rest of you, focusing on cancer prevention is essential. Here are four advancements that have not yet been accepted by conventional medicine, but are extremely powerful cancer preventive tools nonetheless:

1.  Avoid Fructose and Sugar

It’s quite clear that if you want to avoid cancer, or are currently undergoing cancer treatment, you absolutely MUST avoid all forms of sugar — especially fructose — and this is largely due to its relation to insulin resistance.

According to Lewis Cantley, director of the Cancer Center at Beth Israel Deaconess Medical Center at Harvard Medical School, as much as 80 percent of all cancers are “driven by either mutations or environmental factors that work to enhance or mimic the effect of insulin on the incipient tumor cells,” Gary Taubes reported,⁵ adding:

“As it was explained to me by Craig Thompson, who has done much of this research and is now president of Memorial Sloan-Kettering Cancer Center in New York, the cells of many human cancers come to depend on insulin to provide the fuel (blood sugar) and materials they need to grow and multiply. Insulin and insulin-like growth factor (and related growth factors) also provide the signal, in effect, to do it.

The more insulin, the better they do.

Some cancers develop mutations that serve the purpose of increasing the influence of insulin on the cell; others take advantage of the elevated insulin levels that are common to metabolic syndrome, obesity and type 2 diabetes.

Some do both.

Thompson believes that many pre-cancerous cells would never acquire the mutations that turn them into malignant tumors if they weren’t being driven by insulin to take up more and more blood sugar and metabolize it.”

Some cancer centers, such as the Cancer Centers of America, have fully embraced this knowledge and place their patients on strict low-sugar, low-grain diets. But conventional medicine in general has been woefully lax when it comes to highlighting the health dangers of this additive.

As a standard recommendation, I strongly advise keeping your TOTAL fructose consumption below 25 grams per day, including fruits. But for most people it would also be wise to limit your fructose from fruit to 15 grams or less, as you’re virtually guaranteed to consume “hidden” sources of fructose if you drink beverages other than water and eat processed food.

2.  Optimize Vitamin D

There’s overwhelming evidence pointing to the fact that vitamin D deficiency plays a crucial role in cancer development. Researchers within this field have estimated that about 30 percent of cancer deaths — which amounts to 2 million worldwide and 200,000 in the United States — could be prevented each year simply by optimizing the vitamin D levels in the general population.

On a personal level, you can decrease your risk of cancer by MORE THAN HALF simply by optimizing your vitamin D levels with sun exposure. And if you are being treated for cancer it is likely that higher blood levels — probably around 80-90 ng/ml — would be beneficial.

If the notion that sun exposure actually prevents cancer is still new to you, I highly recommend you watch my one-hour vitamin D lecture to clear up any confusion. It’s important to understand that the risk of skin cancer from the sun comes only from excessive exposure.

3.  Decrease Protein

Ideally your protein level should be around one gram of protein per pound of lean body mass. Be very careful not to exceed this level and be assiduous about calculating and following this important recommendation. If you exceed this level of protein you will activate your mTOR pathway, which has been strongly correlated with promoting tumor growth.

4.  Exercise

If you are like most people, when you think of reducing your risk of cancer, exercise doesn’t immediately come to mind. However, there is some fairly compelling evidence that exercise can slash your risk of cancer. One of the primary ways exercise lowers your risk for cancer is by reducing elevated insulin and blood sugar levels, which creates a microenvironment that discourages the growth and spread of cancer cells.

If you have cancer, exercising during and after cancer treatment can reduce your risk of dying from cancer; reduce your risk of cancer recurrence; boost energy; and minimize the side effects of conventional cancer treatment.⁶

It’s important to include a large variety of techniques in your exercise routine, such as strength training, aerobics, core-building activities, and stretching. Most important of all, however, is to make sure you include high-intensity, burst-type exercise, such as Peak Fitness.

Source: Dr. Mercola

Statins as Anticancer Drugs?

In an observational study with limitations, statin use by cancer patients was associated with lower 3-year mortality.

In some basic science studies, statins inhibit cancer growth through various pathways. These observations raise the following question: Could statins lower cancer-related mortality? Danish researchers used national databases to address this question.

Among nearly 300,000 people who received cancer diagnoses between 1995 and 2007, 6% had used statins regularly before and after their diagnoses. During average follow-up of 3 years (but as long as 15 years in some cases), two thirds of the patients died. In analyses adjusted for several confounding variables, statin use was associated with a significant 15% drop in all-cause and cancer-related deaths. Mortality reductions were noted for most cancer types (although differences did not reach statistical significance for every type).

Comment: This observational study suggests that statins might influence tumor growth favorably in patients with cancer. In contrast, a recent meta-analysis of randomized trials showed that statins did not increase or decrease the incidence of cancer (PLoS One 2012; 7:e29849). An editorialist notes that the current analysis could not be controlled for several potentially important confounding factors and recommends caution in interpreting the findings. Until these results are confirmed or refuted by additional research, clinicians will have to decide whether to apply them to cancer patients; at the least, one might argue that patients who already are taking statins (and tolerating them) at the time of cancer diagnosis should continue.

Source: Journal Watch General Medicine

T-DM1 Prolongs Survival in Advanced HER2-Positive Breast Cancer.

The drug-antibody conjugate was more effective and less toxic than lapatinib plus capecitabine in patients previously treated with trastuzumab and a taxane.

We can expect that the next breast cancer drug soon to be approved by the FDA will be trastuzumab emtansine (T-DM1), an antibody-drug conjugate combining trastuzumab with a derivative of the cytotoxic maytansine via a stable linker molecule (JW Oncol Hematol Oct 2 2012). T-DM1 is more than just another new agent. It represents vindication for those who have worked on fusion molecules for the last 2 decades. Previous efforts with such molecules were often derailed because the linker was either unstable (resulting in systemic exposure to the toxin) or cytotoxic (resulting in prohibitive adverse effects). With T-DM1, intracellular drug delivery only to human epidermal growth factor receptor 2 (HER2)–overexpressing tumor cells has been observed.

Now, investigators report the results of the EMILIA study, an industry-sponsored, phase III, randomized, open-label trial involving 991 patients with HER2-positive, unresectable, locally advanced or metastatic breast cancer who were previously treated with trastuzumab and a taxane. Patients received either T-DM1 or lapatinib plus capecitabine (LC) and were stratified by world region, number of prior chemotherapy regimens for advanced disease, and presence or absence of visceral disease. Primary endpoints were progression-free survival (PFS), overall survival (OS), and safety; secondary endpoints included objective response rate, duration of response, and time to symptom progression.

Median PFS was significantly longer with T-DM1 versus LC (9.6 vs. 6.4 months; hazard ratio, 0.65; P<0.001), as was median OS (30.9 vs. 25.1 months; HR, 0.68; P<0.001). Overall response rate was also superior with T-DM1 versus LC (43.6% vs. 30.8%; P<0.001), as were results for all secondary endpoints. Rates of grade 3 or 4 adverse events were 40.8% with T-DM1 and 57.0% with LC.

Comment: The excitement surrounding the anticipated FDA approval of T-DM1 is justified given that the drug successfully targets HER2-overexpressing disease with potent antitumor activity minus the full complement of adverse effects associated with typical chemotherapy partnered with trastuzumab. Of course, the stage is set for exploring T-DM1 in combination with other anti-HER2 agents, including pertuzumab (JW Oncol Hematol Jan 24 2012). Because the toxicity of T-DM1 is quite modest, adjuvant trials are under way to compare the use of this compound with standard trastuzumab-based regimens.

Source: Journal Watch Oncology and Hematology

 

Researchers identify three subtypes of high-grade serous ovarian cancer.

Findings may indicate how patients will respond to treatment

New research led by Dana-Farber Cancer Institute scientists may soon enable doctors to determine which patients with high-grade serous ovarian cancer (HGSOC) – the most common cancer of the ovary – are most likely to benefit from a certain class of drugs.

Using technology able to pick out abnormalities in single units of the genetic code, the researchers sorted tumor samples from HGSOC patients into three subtypes based on the extent of a particular kind of genetic damage within the cells. Patients in the subtype with the highest levels of damage – representing one-third to one-half of all HGSOC patients – were the slowest to develop resistance to platinum chemotherapy treatment such as carboplatin. Overall, these patients lived longer without having their disease worsen than more did patients in the two other groups.

“Our findings suggest that, for the first time, we can determine which patients have the best chance of responding to specific categories of drugs for high-grade serous ovarian cancer,” says Dana-Farber’s Ursula Matulonis, MD, one of the senior authors of the study, which has been published online by the journal Clinical Cancer Research. “For this disease, one of the most difficult to treat of all gynecologic cancers, the study is an important step forward.”

J. Dirk Iglehart, MD, of Dana-Farber and Brigham and Women’s Hospital, is the paper’s other senior author, and Zhigang Wang, MD, PhD, of Dana-Farber, is the first author.

HGSOC cells have a high degree of “genomic instability,” their nuclei littered with large numbers of extra or missing chromosomes or chromosome fragments. One of the consequences of this havoc is a process known as loss of heterozygosity (LOH). LOH occurs in cells that lack the usual complement of two normal copies of each gene, having instead a normal and mutant copy of certain genes. When the normal gene in these mismatched pairs becomes inactive or mutated, the cell has no normal copy of the gene left – and is said to have lost heterozygosity.

In the study, investigators used single nucleotide polymorphism (SNP) arrays – technology that reads the elements of the genetic code one by one – to probe HGSOC tissue samples for instances of LOH. The samples tested fell neatly into three groups based on the patterns of LOH within them.

One of these groups was distinguished by a high level of LOH and a deleted segment of chromosome 13. When researchers reviewed the medical records of patients in this group, they found the patients were slow to develop resistance to chemotherapy drugs.

“Patients with the greatest burden of LOH had the longest progression-free survival – the period of time after treatment when their disease is not advancing,” says Wang. “This is the group which stands to derive the most from treatment with certain classes of drugs.”

LOH hampers cancer cells’ ability to survive, rendering the cells particularly dependent on proteins that repair damaged chromosomes. Drugs that target those repair proteins, including a class of agents known as PARP inhibitors, may be especially effective against HGSOC cells with high levels of LOH, the study authors assert.

The authors also found that LOH patterns in HGSOC were similar to those in triple-negative breast cancer, a form of breast cancer also characterized by a high level of chromosomal instability. The discovery suggests that agents effective in treating HGSOC might be effective against this type of breast cancer as well, the authors claim.

Source: http://www.dana-farber.org