low dose chemo
Low-dose Chemotherapy Protocol Relies on Normalization of Tumor Blood Supply – an article from Massachusetts General Hospital.
If you search metronomic chemotherapy at clinicaltrials.gov, you will find at least 178 citations. While most oncologists will tell you that either low dose chemotherapy does not work, or that there has not been a randomized trial comparing standard of care to low dose metronomic, this concept is attracting plenty of attention from the academicians.
While cytotoxic chemotherapy works only through direct killing of cancer cells (and normal cells), low dose metronomic chemotherapy targets tumor vasculature, improves the host anti-cancer immune response, improves blood supply to the tumor (thereby increasing chemotherapy delivery to the tumor, as well as oxygen delivery, which then turns off HIF-1 alpha), and improves the tumor stroma to favor a host anti-tumor response.
Unfortunately, one size never fits all, so even low dose metronomic chemotherapy needs to be altered (dose and frequency) according to tumor response. The data continues to mount, and in the near-future, maximum tolerated dose chemotherapy, in the treatment of solid tumors, will no longer be the norm.

 

July 8th, 2019

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breast cancer

New Research Finds That Routine Breast Cancer Tests Lead to Unnecessary Mastectomies and Chemotherapy – an article from Cancer News.

This article may temper the celebrity-endorsed enthusiasm for prophylactic mastectomies for those with BRCA mutations. In addition, another study out of Duke Cancer Institute followed women with a BRCA mutation who had been diagnosed with ovarian cancer, with one group having prophylactic mastectomies, and the other group receiving routine screening (mammograms/MRIs); you can read the article here.

Results: For women diagnosed at any age with BRCA 1 and 2 gene mutations and within the first four years after ovarian cancer diagnosis, prophylactic mastectomy was associated with a negligible gain in survival. For women diagnosed at age 60 or older, regardless of time since ovarian cancer diagnosis, the gain in survival months was also negligible. For women diagnosed at age 40 to 50 with BRCA 1 and 2 mutations and at least five years after an ovarian cancer diagnosis, the procedure was associated with a survival benefit of two to five months.

Bottom line: Although prophylactic mastectomy in BRCA gene mutation carriers has shown to decrease breast cancer incidence, the data does not confirm an increase in survival.

 

June 11th, 2019

Posted In: cancer care, Cancer Prevention

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xray
This is a groundbreaking article, as it safely increases the population who do not need to undergo chemotherapy, even by conventional guidelines. To reiterate what I have said in the past, conventional chemotherapy dosing probably adds the most benefit in the adjuvant setting, as opposed to metastatic disease, where it improves survival marginally.
Having said that, of course we do not want to use it in the adjuvant setting, if it does not improve progression-free or overall survival.
Bottom line: In the 50-75 year old age group, with ER+, Her-2 neg cancer and negative nodes, with an Oncotype Recurrence Score between 11 and 25, chemotherapy is NOT indicated. In women younger than 50, with Oncotype Recurrence Scores between 16 and 25, outcomes were only SLIGHTLY better in the chemotherapy group, so patients need to take that into consideration.

 

April 9th, 2019

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low dose chemo

“When Cancer Can’t Be Cured, Low-Dose Chemo Aims To Keep It In Check,” an article from CommonHealth, can be accessed here.

This article is interesting because it notes that an oncologist at Tufts Medical Center uses low dose metronomic chemotherapy. In addition, an oncologist at Mass. General Hospital believes it may potentiate the effectiveness of immunotherapy. And finally, Dr. Schilsky, the director of ASCO, says, “It’s an interesting theory. It’s supported to some extent by laboratory studies.”

Dr. Schilsky also stated “the highest quality trials that have been done so far have generally not proven low-dose chemo to be better than conventional chemo.” As stated in the article, there is no large study, which randomizes standard of care maximum tolerated dose chemotherapy against low dose metronomic chemotherapy.

Unfortunately, it is unlikely that a study like this will ever be done due to lack of funding. What I find extremely interesting is that Dr. Schilsky said that “the highest quality trials that have been done so far have generally not proven low-dose chemo to be better than conventional chemo.” I assume that when Dr. Schilsky uses the term “better,” he means affords the patient longer survival (although it is not clear what he actually means). But even if a trial were to be performed, and low dose chemotherapy did not allow patients to live longer than maximum tolerated dose, is it possible that the improved quality of life from low dose chemotherapy in fact makes it “better?”

December 6th, 2018

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low dose article2

Here is another publication on the use of low dose chemotherapy, but instead of being delivered in a metronomic fashion, one of the chemotherapy drugs was delivered in a continuous fashion. You can read the article on the National Institutes of Health website, by clicking the title below.

Low-Dose Continuous 5-Fluorouracil Combined with Leucovorin, nab-Paclitaxel, Oxaliplatin, and Bevacizumab for Patients with Advanced Pancreatic Cancer: A Retrospective Analysis

As I have previously mentioned, the longer the interval between chemotherapy dosing, the more likely cancer resistance will ensue.

In the current work, 1-year survival was 82%, versus 45% reported for FOLFIRINOX (standard of care), and median overall survival was 19 months, exceeding the 11.1 months for FOLFIRINOX. The authors conclude with the following, “In spite of the depressing statistics resulting from mostly negative trials, oncologists continue to accept the marginal benefits of currently sanctioned therapies for pancreatic cancer…There is no conclusive evidence that these treatment protocols are better than the 5FU-based regimens which were used in the 1980s and 1990s.”

Where and how did the concept of maximum tolerated dose chemotherapy (MTD) arise? MTD protocols were developed initially in the context of treating childhood leukemias and lymphomas; their extended clinical applications to the treatment of solid tumor malignancies were based largely on the therapeutic successes observed in the treatment of Hodgkin’s Disease and childhood ALL.

Therapeutic modeling in solid tumors was largely based on the growth parameters defined by the growth of leukemia cells. The primary therapeutic target in the leukemias/lymphomas is the abnormal cancer stem cell population of the bone marrow/lymph node. This target is more amenable to treatment with cytotoxic drugs that block cell cycle proliferation than are solid tumors, as the propagation of abnormally dividing cells comprises the primary cancer phenotype.

Solid tumor malignancies develop a phenotype that is a product not only of genetically induced cell cycle dysregulation, but also as a consequence of the abnormal microenvironment created by the tumor mass. The net result is a tumor whose proliferative capacity is generally restricted to its outer margins, thereby seriously limiting the potential efficacy of cancer drugs that target dividing cells.

Bottom line: We are still using chemotherapy dosing for solid tumors based on studies and trials treating leukemias/lymphomas, when in fact, these are two entirely different disease processes. It is time for a Wake-UP Call!

October 1st, 2018

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depression

Source Credit: This article was originally released by the the European Society for Medical Oncology in December, 2016.

A brain-boosting protein plays an important role in how well people respond to chemotherapy, researchers report at the ESMO Asia 2016 Congress in Singapore.

A study has found that cancer patients suffering depression have decreased amounts of brain-derived neurotophic factor (BDNF) in their blood. Low levels make people less responsive to cancer drugs and less tolerant of their side-effects.

Lead author Yufeng Wu, head of oncology, department of internal medicine, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China, said: “It’s crucial doctors pay more attention to the mood and emotional state of patients. “Depression can reduce the effects of chemotherapy and BDNF plays an important role in this process.”

Low mood is common among cancer patients, especially the terminally ill. BDNF is essential for healthy brain function and low levels have already been linked with mental illness. This study aimed to discover how depression influenced outcomes for people with advanced lung cancer.

Researchers recruited 186 newly diagnosed patients receiving chemotherapy. To assess their state of mind, they were asked to rate their depression levels the day before treatment began. Quality of life details, overall survival and other data were also collected. This allowed researchers to compare this information with the patients’ mood scores.

Results showed that those whose cancer had spread to other organs were the most depressed and this severely decreased their tolerance to chemotherapy. It was associated with vomiting, a reduction in white blood cells, and prolonged hospital stays. The impact of severe depression was even greater. It reduced the length of time that patients lived with the disease without it getting worse.

Researchers found that BDNF clearly boosted the number of tumour cells killed by chemotherapy. Patients with severe depression had lower levels of the protein in the blood so their bodies were not as effective at fighting cancer. This reduced their chance of surviving the disease.

“Our aim now is to prescribe drugs such as fluoxetine to depressed patients and study their sensitivity to chemotherapy,” added Wu. Commenting on the results of the research, Ravindran Kanesvaran, consultant medical oncologist and assistant professor, Duke-NUS Medical School, Singapore, said: “The link between depression and poor outcomes among these patients is significant and can be associated with the downregulation of brain derived neurotrophic factor.

“This finding can perhaps lead to new ways to treat depression in these patients which in turn may prolong their lives. Further research is needed to establish the effects of different anti-depressant drugs on BDNF levels.”

March 29th, 2017

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Two recent articles have prompted me to share my opinion about SACT (systemic anti-cancer therapy, i.e., cytotoxic chemotherapy) and the rate of deaths in cancer patients associated with this therapy. Based on years of data, “standard of care” does not work in many, if not most cases of advanced-stage cancer. The studies and cases brought forth by these articles and the studies they are based on, offer more proof that my beliefs have merit, with many of my research partners, colleagues, and scientists being in agreement.

These articles bring to light the significant rate of death in patients diagnosed with non-small cell lung cancer and patients with breast cancer, within 30 days of being treated with cytotoxic chemotherapy (SACT). One article by Yelena Sukhoterina reveals that 50% of cancer patients die within 30 days, at some hospitals.

Another article based on a British study in hospitals from 2012 to 2014, also shows a significant death rate among those diagnosed with non-small cell lung cancer and patients with breast cancer after 30 days of treatment, with higher rates noted after 30 days of first-time cytotoxic chemotherapy treatment. The patient deaths in the British study, in many cases, were attributed to “poor clinical decision making” and prompted this statement from the directors of this study:

“Patients dying within 30 days after beginning treatment with SACT are unlikely to have gained the survival or palliative benefits of the treatment, and in view of the side-effects sometimes caused by SACT, are more likely to have suffered harm.”

It is my experience that these treatments have failed to achieve a high level of consistent rates of disease-free survival in some of the most common cancers, including lung cancer and breast cancer. This is why I have long been a proponent of the concept of low dose “metronomic” chemotherapy. This method effectively kills cancer cells with lower doses of chemotherapy, while inhibiting angiogenesis (development of new blood vessels for the cancer), and stimulating an immune response (as opposed to inhibiting the immune system with maximum tolerated dose chemotherapy), which enables the patient to experience the benefits without the associated health risks of commonly used SACT.

It is my mission, with my research, testing and in-office patient care and evaluation, to alert the public at large, and help them understand that there are far less dangerous methods available now, to extend the lives of cancer patients.

With public awareness, we can all fight the battle of making the most effective treatments for patients available for all doctors and oncologists to use, without having “standard of care” issues prevent patients from getting the non-life threatening treatments they need and deserve.

To all doctors involved in the battle against cancer, I propose considering treatments that are not administered in “maximum tolerated doses.” From the data available, maximum tolerated doses are often responsible for cancer patients losing their fight, not to the cancer, but from the standard of care treatments.

The big problem associated with SACT is the evolution of resistance in cancer cells. Maximum tolerated dose chemotherapy causes accelerated Darwinian natural selection and evolution of the cancer cells, rapidly creating the most resistant and aggressive cancer, that is no longer amenable to treatment.

My approach of low dose metronomic chemotherapy is congruent with cancer scientists’ ideas and observations, that the increasing development of cancer-resistant clones can be delayed, by adopting a “minimum drug intensity” approach, rather than the maximum tolerated dose standard of care approach.

https://www.sciencedaily.com/releases/2016/02/160224164357.htm

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2669231/

September 26th, 2016

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