Combination therapy holds great promise to clear precancerous skin lesions

A combination of two FDA-approved drugs - a topical chemotherapy and an immune-system-activating compound - was able to rapidly clear actinic keratosis lesions from patients participating in a clinical trial. Standard treatment for this common skin condition, which can lead to the development of squamous cell carcinoma, takes up to a month and can elicit several unpleasant side effects. The report from Massachusetts General Hospital (MGH) investigators has been published online and will appear in the January issue of the Journal of Clinical Investigation.

fluorouracil (5-FU)      Calcipotriol 

"The high tumor clearance rate, short treatment duration and favorable side-effect profile highlight the remarkable effectiveness of this approach, compared with currently available treatments," says Shadmehr Demehri, MD, PhD, of the MGH Center for Cancer Immunology and the Cutaneous Biology Research Center, senior author of the report. "But more importantly, the unprecedented ability of this combination therapy to directly activate the adaptive immune system against skin cancer precursors holds great promise to establish an immune memory within treated skin capable of preventing future cancer development."

Caused by long-term exposure to sunlight, actinic keratosis is characterized by rough, scaly patches on the skin. Very common in older individuals with fair complexions, actinic keratosis is the third most common reason for consulting a dermatologist in the U.S. If untreated, actinic keratosis lesions can progress to squamous cell carcinoma, the second most common form of skin cancer. Current topical treatments for actinic keratosis cause side effects - such as pain, crusting and susceptibility to infection - and need to be applied for up to four weeks.

Calcipotriol, an FDA-approved treatment for psoriasis, induces expression in the skin of an immune system activator called TSLP. While overexpression of TSLP is associated with the allergic inflammation seen in asthma and eczema, it has been noted that individuals with these allergic conditions appear to be less susceptible to skin cancer. Other studies have supported the ability of TSLP to suppress skin cancer development, which led Demehri's team to investigate its potential against actinic keratosis.

Experiments with a mouse model of skin cancer development showed that twice-weekly application of calcipotriol both induced TSLP expression and delayed tumor development. When tumors did develop, they were fewer and smaller than in mice not treated with calcipotriol. An experiment in which calcipotriol was applied to the ears of mice while skin cancer was induced to develop on the backs of the animals resulted in elevated blood levels of TSLP and the suppression of tumor development, implying that brief TSLP-inducing treatment could lead to a lasting systemic antitumor immune response.

Since clinically available concentrations of calcipotriol have had limited effectiveness against actinic keratosis and produced no evidence of immune activation, the MGH team hypothesized that combining the available 0.005 percent calcipotriol ointment with 5 percent fluorouracil (5-FU) cream, a standard treatment for actinic keratosis, might amplify the immune-activating potential of calcipotriol. In a randomized, double-blinded clinical trial, 65 participants with multiple actinic keratosis lesions were treated with a combination of calcipotriol and 5-FU, while 67 received a control preparation of 5-FU mixed with petroleum jelly.

The preparations were applied twice a day to the entire affected sites of participants - face, scalp and arms - and because treatment with 5-FU alone requires seven or more days to have any effect against actinic keratosis, participants were treated for four days only. A day after treatment ended, the treated skin of those receiving calcipotriol plus 5-FU, including areas that did not contain clinically visible lesions, showed clear signs of inflammation, indicating immune system activation. Areas of inflammation were found to have a significant influx of lymphocytes - primarily T cells - at the sites of lesions.

Eight weeks after treatment, participants receiving the combined treatment had a significantly greater reduction in the number and size of actinic keratosis lesions - for example, an average of 88 percent reduction in facial lesions versus 26 percent reduction for those receiving the control preparation. Even participants with large "hypertrophic" lesions, which rarely respond to conventional topical treatments, saw significant reduction in the size of their lesion with combined treatment. Among participants receiving combined treatment who had previously been treated for actinic keratosis, 82 percent found the treatment to be more effective.

"As both medications used in our trial are already available clinically, they could readily be used by dermatologists to treat actinic keratosis, particular in patients for whom conventional treatments have failed," says Demehri, who is an assistant professor of Dermatology at Harvard Medical School. "The ultimate goal of our research is to use patients' own immune systems to prevent cancer, so we are very excited to determine whether our success in activating a T-cell-dominant immune response against a skin cancer precursor will protect the treated skin against future skin cancer development. We're planning to follow the participants in this trial over the coming years to address that important question."

Drug combination lengthens lives of metastatic colorectal cancer patients

                         fluoropyrimidine                    TAS-102

 Capecitabine

A drug developed 50 years ago and abandoned because it was considered to be too toxic has gained a second life in an international clinical trial. Research led by scientists at Dana-Farber Cancer Institute showed the drug and a potentiating agent lengthened the lives of patients with metastatic colorectal cancer, all of whom had exhausted available standard treatments.

In a paper published online today by the New England Journal of Medicine, investigators at Dana-Farber and research centers around the world found that the drug combination - given as a single pill known as TAS-102 - not only extended patients' overall survival, but also delayed the advance of the disease and did so with very few side effects.

According to the study authors, the results are especially impressive because half of the patients had just finished treatment with the standard class of chemotherapy agents - fluoropyrimidines (e.g. 5-fluorouracil [5-FU] or capecitabine [Xeloda]) but had failed to benefit from them. The fact that TAS-102 temporarily halted the disease in many of these patients suggests that it operates through a different biochemical pathway than 5-FU, and therefore may serve as an alternative to standard therapy.

"Colorectal cancer is the second most common cause of cancer deaths [after lung cancer] in the United States and is an enormous health problem around the world," said the study's lead author, Robert J. Mayer, MD, faculty vice president for academic affairs, medical oncologist and colorectal cancer researcher at Dana-Farber. "To have a well-tolerated, effective new drug in a cancer that is so prevalent is good news for patients."

The trial, a phase 3 study involving major cancer research institutions in Europe, the United States, Australia and Japan, enrolled 800 patients with metastatic colorectal cancer that was progressing despite previous treatment. Participants were randomly assigned to receive TAS-102 or a placebo pill...

More : http://www.nejm.org/doi/full/10.1056/NEJMoa1414325

Drug combination lengthens lives of metastatic colorectal cancer patients

Drug combination lengthens lives of metastatic colorectal cancer patients

                         fluoropyrimidine                    TAS-102

 Capecitabine

A drug developed 50 years ago and abandoned because it was considered to be too toxic has gained a second life in an international clinical trial. Research led by scientists at Dana-Farber Cancer Institute showed the drug and a potentiating agent lengthened the lives of patients with metastatic colorectal cancer, all of whom had exhausted available standard treatments.

In a paper published online today by the New England Journal of Medicine, investigators at Dana-Farber and research centers around the world found that the drug combination - given as a single pill known as TAS-102 - not only extended patients' overall survival, but also delayed the advance of the disease and did so with very few side effects.

According to the study authors, the results are especially impressive because half of the patients had just finished treatment with the standard class of chemotherapy agents - fluoropyrimidines (e.g. 5-fluorouracil [5-FU] or capecitabine [Xeloda]) but had failed to benefit from them. The fact that TAS-102 temporarily halted the disease in many of these patients suggests that it operates through a different biochemical pathway than 5-FU, and therefore may serve as an alternative to standard therapy.

"Colorectal cancer is the second most common cause of cancer deaths [after lung cancer] in the United States and is an enormous health problem around the world," said the study's lead author, Robert J. Mayer, MD, faculty vice president for academic affairs, medical oncologist and colorectal cancer researcher at Dana-Farber. "To have a well-tolerated, effective new drug in a cancer that is so prevalent is good news for patients."

The trial, a phase 3 study involving major cancer research institutions in Europe, the United States, Australia and Japan, enrolled 800 patients with metastatic colorectal cancer that was progressing despite previous treatment. Participants were randomly assigned to receive TAS-102 or a placebo pill...

More : http://www.nejm.org/doi/full/10.1056/NEJMoa1414325

Drug combination lengthens lives of metastatic colorectal cancer patients

EMA extends approval of Vectibix plus FOLFIRI as first-line treatment for wild-type RAS mCRC

Amgen (NASDAQ: AMGN) today announced that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion to extend the marketing authorization for Vectibix® (panitumumab) to include combination with FOLFIRI- FOLFIRI is a chemotherapy regimen for treatment of colorectal cancer. It is made up of the following drugs:

• FOL – folinic acid (leucovorin), a vitamin B derivative used as a "rescue" drug for high doses of the drug methotrexate, but increases the cytotoxicity of 5-fluorouracil;
• F – fluorouracil (5-FU), a pyrimidine analog and antimetabolite which incorporates into the DNA molecule and stops synthesis; and
• IRI – irinotecan (Camptosar), a topoisomerase inhibitor, which prevents DNA from uncoiling and duplicating.

 (an irinotecan-based chemotherapy) as first-line treatment in adult patients with wild-type RAS metastatic colorectal cancer (mCRC). About half of the patients with mCRC have wild-type RAS tumors.

"Adding Vectibix to chemotherapy as first-line treatment in patients with wild-type RASmetastatic colorectal cancer has been shown to result in better responses than chemotherapy alone," said Elliott M. Levy, M.D., senior vice president of Global Development at Amgen. "The CHMP recommendation is an important step toward increasing the treatment options for patients with this aggressive disease and helping improve outcomes in the European Union."

EMA extends approval of Vectibix plus FOLFIRI as first-line treatment for wild-type RAS mCRC

Addition of S-1 to cisplatin plus radiotherapy ‘favourable’ in NSCLC

In continuation of my update on cisplatin and 5-fluorouracil derivative S-1v

Research suggests that treatment with cisplatin plus S-1 together with thoracic radiotherapy is relatively efficacious and tolerable in patients with locally advanced non-small-cell lung cancer (NSCLC).

Although cisplatin-based chemotherapy with thoracic radiotherapy is a standard treatment for unresectable, locally advanced NSCLC, the outcomes are not satisfactory, explain Katsuyuki Hotta, from Okayama University Hospital in Japan, and colleagues. They investigated the effect of adding the 5-fluorouracil derivative S-1 to the standard treatment in a phase II trial, the primary endpoint of which was the response rate.

A total of 48 patients with stage III NSCLC received cisplatin plus S-1 (at a dose of 40 mg/m2 twice daily from days 1–14 and 29–42 of treatment) with concurrent thoracic irradiation, of whom 37 had a partial response, giving an overall response rate (ORR) of 77%.

Addition of S-1 to cisplatin plus radiotherapy ‘favourable’ in NSCLC

More Evidence for Oxaliplatin as Colon Cancer Chemotherapy

In continuation of my update on Oxaliplatin 

Adding oxaliplatin to a standard chemotherapy regimen boosts survival rates for patients with advanced colon cancer, according to a new study that bolsters previous research on the drug by looking at a broader group of patients.

In past studies, oxaliplatin, as an adjuvant to the established treatment of 5-fluorouracil (5-FU), improved survival by up to 23 percent. But the new study looked at a different group of colon cancer patients, who were older, sicker, more racially diverse and had never participated in a controlled clinical study.

To determine whether oxaliplatin would show a similar benefit among a "real-world" population of patients, the authors sifted through five cancer registries containing survival information on more than 4,000 people with stage 3 colon cancer. All were younger than 75, and all had begun chemotherapy -- either a standard regimen or in combination with oxaliplatin -- within four months of having surgery between 2004 and 2009.

Researchers lead by Dr.Hanna K. Sanoff compared their survival rates with those of nearly 8,300 patients who had participated in one of five different clinical trials using oxaliplatin.

The addition of oxaliplatin to standard chemotherapy protocols was found to be just as effective in prolonging survival among the community-based set of patients - including the elderly, minorities and those with additional complicating health issues  who were not enrolled in studies.

More....

ESPAC-3 trial (Fluorouracil and Folinic Acid) shows promising results to prevent pancreatic cancer

In continuation of my update on  drug discovery and 5-fluorouracil

A major international trial has shown a commonly used chemotherapy drug, 5-fluorouracil, and  Folinic Acid  is as effective at helping prevent pancreatic cancer returning after surgery as the more expensive standard chemotherapy treatment.

The results of the Cancer Research UK- funded study mean the cheaper drug - called 5-fluorouracil (5-FU) - could be prescribed in cases when the standard chemotherapy - gemcitabine - has failed, providing an extra lifeline for patients whose cancer comes back after surgery.

They also raise hopes that a new trial currently underway, looking at combining an oral version of 5-FU with the standard treatment of gemcitabine, could lead to a more effective treatment for pancreatic cancer patients who are eligible for surgery.

The trial, called European Study Group for Pancreatic Cancer (ESPAC)-3, is the largest of its kind and involved 159 centres in Europe, Australasia, Japan and Canada which between them recruited 1088 patients who had undergone surgery for pancreatic cancer.

One group had the standard chemotherapy treatment - gemcitabine. The second group had a cheaper widely available drug called 5-fluorouralcil (5-FU) that is commonly used in cancer treatment already.

The results mean that 5-FU should now also be considered one of the standard options for the treatment of patients with this disease.

They build on earlier trial results suggesting patients who had surgery and chemotherapy had better a chance of survival than patients who only had surgery. 

Finding out these two drugs are as effective as each other at preventing pancreatic cancer returning after surgery is important. It raises hopes that a new trial currently looking at giving two similar drugs together could be successful at preventing or at least delaying pancreatic cancer returning after surgery.

"Previous trial results involving advanced pancreatic cancer patients have shown this drug combination can give precious extra months or even years of life, so there is reason to be hopeful the survival benefit could be even more marked for patients who are eligible for surgery."

 Ref : http://jama.ama-assn.org/cgi/content/full/304/10/1073

Positive results from Phase 2 trial of picoplatin for colorectal cancer...

In continuation of my update on picoplatin,.......

Poniard Pharmaceuticals, Inc,  claims that Phase 2 trial  study met its primary objective, that is picoplatin in combination with 5-fluorouracil and leucovorin (FOLPI regimen) was associated with a statistically significant reduction in neurotoxicity (p <0.004) compared to oxaliplatin given in combination with 5-fluorouracil and leucovorin (FOLFOX regimen). More...

Picoplatin a better drug than oxaliplatin for colorectal cancer !

In one of my earlier blog, I did mention about the Cisplatin (Cisplatin doubles lung cancer survival time in mice !).

About Cis-platin & other drivatives:

Cisplatin, cisplatinum, or cis-diamminedichloroplatinum(II) is a platinum-based chemotherapy drug used to treat various types of cancers, (sarcomas, some carcinomas (small cell lung cancer, and ovarian cancer), lymphomas, and germ cell tumors. It was the first member of a class of anti-cancer drugs which now also includes carboplatin and oxaliplatin. These platinum complexes react in vivo, binding to and causing crosslinking of DNA which ultimately triggers apoptosis (programmed cell death).

Now its the turn of Picoplatin [see structure , Amminedichloro(2-methylpyridine)platinium)], Poniard Pharmaceuticals, Inc. has come up with some interesting results from its Phase 2 trial of picoplatin in patients with metastatic colorectal cancer (CRC). Picoplatin, given once every four weeks in combination with 5-fluorouracil and leucovorin in the FOLPI regimen, has comparable efficacy to oxaliplatin, given in combination with 5-fluorouracil and leucovorin in the modified FOLFOX-6 regimen, as a first-line therapy for CRC, as assessed by one-year survival rate, progression-free survival (PFS) and disease control. The company claims that, (from the updated proof-of-concept Phase 2 safety and efficacy results) picoplatin could be superior to oxaliplatin as a neuropathy-sparing alternative when used in combination as a first-line treatment for metastatic colorectal cancer.

Source : http://investor.poniard.com/ReleaseDetail.cfm?ReleaseID=424813.

Capecitabine combination therapy reduces early breast cancer recurrence...

Capecitabine, is an orally-administered chemo therapeutic agent used in the treatment of metastatic breast and colorectal cancers.

Mode of action :

Capecitabine is a prodrug, that is enzymatically converted to 5-fluorouracil in the tumor, where it inhibits DNA synthesis and slows growth of tumor tissue. The activation of capecitabine follows a pathway with three enzymatic steps and two intermediary metabolites, 5'-deoxy-5-fluorocytidine (5'-DFCR) and 5'-deoxy-5-fluorouridine (5'-DFUR), to form 5-fluorouracil. Its being used (& FDA approved) in the treatment of adjuvant in colorectal cancer, metastatic colorectal cancer and Metastatic breast cancer - used in combination with docetaxel, after failure of anthracycline-based treatment. Also as monotherapy, if the patient has failed paclitaxel-based treatment, and if anthracycline-based treatment has either failed or cannot be continued for other reasons.

Recently, Finnish Breast Cancer Group and published in The Lancet Oncology shows women at intermediate to high-risk of early breast cancer recurrence who received capecitabine as part of their chemotherapy regimen had a 34% reduction in the risk of the disease returning or death, compared with those taking the chemotherapy combination regimen without capecitabin. The pre-planned three-year interim analysis of a randomised, prospective trial compared adjuvant capecitabine in combination with docetaxel and cyclophosphamide plus epirubicin for the treatment of early breast cancer with the standard, non-capecitabine regimen (docetaxel, epirubicin, cyclophosphamide and fluorouracil). The analysis also found that patients taking the capecitabine-containing regimen were significantly less likely to have their cancer spread (distant metastasis) to another part of the body (a 36% reduction in risk was observed). This is the first phase III randomised trial to report efficacy of capecitabine combination therapy in the adjuvant treatment of early breast cancer.

Though capecitabine, has already been shown to be effective in patients with advanced breast cancer, but the most important conclusion the researchers have arrived is "capecitabine-containing regimen in the early stages of breast cancer may offer survival benefits for women".....

Source :http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045%2809%2970307-9/fulltext