Cancer Research & Treatment 2000-2009: A Listing of Some of the Most Cited Articles of that Decade & Highlights of Some of their Findings

By 2005, as expressed in a major review by Adams and Weiner,  it  had become clear that monoclonal antibodies have proven to be one of the most promising of new biological chemotherapies.  That term may seem an oxymoron in the old dichotomy which separated biologicals (such as vaccines derived from sera or killed cells) from chemotherapeutic agents (which were synthesized from common chemicals usually derived from petrochemicals or alcohols). But the new usage indicates that they are derived from cell culture methods and are then chemically stabilized so as to be able to be administered in reliable dosages.) The key to the effectiveness of monoclonal antibodies appears to be their ability dock onto receptors that are needed for cancer cells or tumors to thrive. In doing so, they displace growth factors or hormones, often leading to tumor regression. In addition, monoclonal antibodies often can be used with traditional cytotoxic chemotherapies, or radiation,  without interfering with their effects.

Epidermal growth factor receptors (EGFR) have been found in excess in a number of tumor classes, and drugs targeted against them ( e.g  erlotinib, Tarceva™) have worked with spotty success among some non-small-cell cancers of the lung or pancreas. But there  were no standards for pre-testing tissues to see if the tumors were, in fact, susceptible. This was an omission corrected by an expert panel (Eberhard, Giaccone and Johnson 2008) who were setting up clinical trials and needed to have benchmarks.

One of the happy but still puzzling situations encountered in oncology are a small number of types of  cancers that start out aggressively growing but then spontaneously become self limiting. A 2007 review by Bartek, Bartkova and Lukas discussed the DDR (DNA damage response)  with the idea that a new line of therapy might well involve, instead of trying with limited success to kill off all cancer cells, stimulating surviving cancer cells to initiate this DDR-induced quiescence.

Telomeres and telomerases were profiled in 2008 by the French team of DeCian, Lacroix, Douarre et al,   as representing a good therapeutic target because it is thought that many cancers result from a decrease in the ability of chromosome basically to keep  the ends of their chromosomes (their telomeres)  intact, or at least forestall the rate at which they fray and shrink.

Along similar lines, it was suggested in a 2005 review by Dean, Fojo, and Bates that the resilient pluripotential stem cells we virtually worship in biotechnology  as the hope for replacing many damaged cells and tissues in diseases like Parkinsonism, have a darker side, and it might be warranted to target them in some forms of cancer. The very traits that make them able to survive undifferentiated and less vulnerable, and then  later  to  take on many identities,  tend in cases like hematopoietic cancers (leukemia, lymphoma and multiple myeloma)  to  protect them from being killed during chemotherapy. Those stem cells may contain what the authors call an overabundance of adenosine trisphophate (ABC)  cassettes.  In some cases, ABC cassettes  promote resistance to chemotherapeutic agents by literally pumping them out of the stem cells  which, once the existing cancer cells have been killed off, may replace them as cancer cells, instead of as healthy tissue.

Transforming Growth Factor beta (TGF-beta) is an essential component of normal activities that involve the growth and branching out of healthy human cells into tissues and then into organs. In particular, helps them develop their own localized blood supply to keep them going. A 2005 study by Elliott and Blobe suggests that unfortunately very high levels of TGF-beta are  detectable in early cancer biopsies, and that monitoring these could help in staging cancers, and disrupting them, may cut off their growth.

While CAT scans and MRIs had long  become effective and routine in the diagnosis and staging of cancers, arguably the fastest rising technology of the 2000s  was F18- FDG PET (Fluorodeoxyglucose Positron Emission Tomography). The combination of trace radioactivity and glucose function enable not only a 3D visualization of location, but also provide information on metabolism at the site. According to Fletcher, Djulbegovic, Benjamin et al it served as an excellent tool for initial diagnosis of cancers of the head and neck, pancreas and unknown primary tumors, and was a good measure for scoring the staging or recurrence of breast, colon, esophageal, and other tumors initially diagnosed by other means.

 

Breast Cancer

Given the major advances made in understanding and treating several estrogen receptor (ER) dependent breast cancers, it surprised many that even  as  the decade waned that there was still a great deal of  tumor resistance to the usual hormone receptor blocking therapies. The thinking was that without these hormones having a home at which they could lodge, that the stimulus they provided to further breast tissue growth would be shut down and tumors would shrink and perhaps disappear. But in 2008  Arpino, Wiechman, Osborn and Schiff  explored  how human epithelial growth receptors  (HER)    provided what they termed  “cross-talk” with estrogens in search of a place to go, leading to  alternative pathways for  these  hormones to dock despite the shut down of ER.  This study  led towards further recognition of  an important subtype of breast cancer  ( HER-susceptible) requiring an alternative treatment with  newer drugs like transtuzumab (Herceptin™) to cut off that alternate route.

One of the most effective families of breast cancer chemotherapeutic agents, are the anthracyclines,  with doxorubicin, (Adriamycin™) probably being the best known. Nonetheless one of the most successful new class of breast cancer drugs of the 1980s and 1990s, particularly in the more aggressive breast cancers  have been the taxanes  (historically derived from rather rare yew bark, but now made by semi-synthetic methods that did not endanger the species and have since reduced their costs) . These taxanes were often administered only after the anthracyclines seemed to stop working, and the disease returned.  A 2008 meta-analysis by DeLaurentis, Cancello, D’Agostino et al, demonstrated that a concurrent combination therapy of anthracyclines and taxanes (as opposed to a sequential one) increased the intervals when  patients with  early but aggressive breast cancers patient  stayed in remission and raised their overall survival.

Colorectal Cancer

Testing the character of a tumor to determine the right course of treatment is standard for a wide variety of tumors, and two of the most common are IHC (ImmunoHistoCompatability) complex and its more recently developed competitor FISH (Fluorescent In-Situ Hybridization) are sometimes used for biopsies. In some cases, such as breast and lung cancers, a positive test on the IHC  is automatically sent for confirmation by the FISH, but it is not unknown for the two test to conflict on whether or not a therapeutic  attack based on the biopsy indicating a high level of Epidermal Growth Factor Receptors (EGFR) would be the best course. A 2005 study by Chung, Shia, Kemeny et al determined that no matter whether the IHC test was positive or negative, once a course of a more conventional chemotherapeutic agent such as iriniotecan (Camptesar™) had failed, then progression towards one of the newer EGFR inhibitors, such as cetuximab (Erbitux™) seems warranted, because many IHC negative tumors seemed to have responded to the Erbitux ™ despite that test.

In a 2007 paper Giantonio, Catalano, Meropol et al trialed three courses of treatment for colorectal cancer. One plan involved a traditional cocktail of oxaliplatin (Eloxatin™), Fluouracil (Adrucil™ and Fluoroplex™) and folinic acid (Leucovorin™), a combination known in chemotherapy circles as FOLFOX4. The second plan involved the use of newer anti-angiogenic drug bevacizumtab (Avastin™) on its own. A third plan combined FOLFOX4 and Avastin ™. The Best outcomes came form the addition of bevacizumab to oxaliplatin, fluorouracil, and leucovorin. This four-way combination   improves survival duration for patients with previously treated metastatic colorectal cancer, although as with many chemotherapeutic regiments: nausea, hypertension and some rectal bleding were side-effects that had to be managed.

 

Gastrointestinal  Cancer

One of the most common of stomach tumors as the gastrointestinal stromal tumors (the GISTs). GISTs are often  detected only when they become rather large by which time they tend to displace the alignment and sometimes the smooth function of  nearby organs in the area. While usually treated by surgical removal, and often with good results, they have long resisted follow-up chemotherapy. But by 2005, a consensus recommendation of European sarcoma societies had endorsed imatinib (Gleevec™) a drug previously used with some success in chronic myelogenous leukemia,  known to be a disruptor of tyrosine kinase, an enzyme absolutely essential to the progression of the cancer, as a post-surgical treatment.

Cancers of the Head and Neck

In 2008, Argiris, Karamouzis, Raben and Ferris reviewed the current state of sqamous cell head and neck cancer etiology and treatment. Certain traditional contributing factors such as tobacco use and heavy (and often concurrent) alcohol intake remained  at the top of the list, but human papilloma viruses became more and more often implicated, and became formalized as an important subtype. While a variety of traditional chemotherapeutic agents and radiation therapy continued  to be the first line of treatment (Fakhry, Westra, Cmelak et al 2008)  epidermal growth factor receptor inhibitors (e.g. cetuximab, Erbitux™,  showed increasing promise (Bonner, Harari, Giralt et al 2006, Burtness, Goldwasser, Flood et al 2005).   

 

Liver Lancer

In the western world, most liver cancer has been secondary to prolonged alcoholism, but in the Far East, where hepatitis remains especially endemic a substantial number of patients seem to develop it  after chronic viral infection. A  2009 protocol has been reported by Cheng, Kang, Chen et al for the prolonging of life of patients with advanced hepatocellular cancer ,  with a  drug that had previously been shown to have good results against kidney cancers,  sorafenib (Nexavar™). While the life extension offered is still only about  six months, this is an improvement over the 4 months common with placebo, or other therapies in use, with a relatively tolerable incidence of side-effects. 

A greater life extension was achieved in patients with gastroeneteropancreatic cancers. While slow-growing, most patients die within four years. But a radioactively labeled growth stopper, a somatostatin analog called lanreotide (Somatuline™) has extended the life of some patients up to six.

Lung Cancer

Lung cancers have a spotty record in terms of which drugs will lengthen life with the fewest side-effects, and most patients die within a fairly short time despite treatment. But in 2006, Cappuzzo, Hirsch, Rossi et al and in 2008, Hirsch, Herbst, Olsen et al reported that when patients with non-small-cell lung cancer (NSCLC)  had biopsies that included a fluorescent in-situ hybridization (FISH) test of the tissue, those patients who were positive for epidermal growth factor receptors (EGFR) could be treated better with cetuximab (Erbitux™) a drug otherwise used successfully for  colorectal and head and neck cancers. EGFR positive patients  whose treatment included Erbitux™ tended to live eight months longer than patients negative for EGFR treated with  a similar regimen.

Ovarian Cancer

Apart from the  Pap smear early detection method, ovarian cancer  has traditionally been found only when it had become painful, usually at an advanced stage with a  poor prognosis, and an uncertain chemotherapeutic path. In 2008, however, Garcia, Hirte, Fleming et al advanced the idea that a combination therapy of a very traditional (1950s) alkylating agent cyclophosphamide (Cytoxan™) and a newer monoclonal antibody bevacizumab (Avastin™)  that blocked angiogenesis in tumors (cutting off their blood supply) in colorectal cancers had excellent results blocking ovarian cancer recurrences and was well worth further exploration. A 2006 study in the New England Journal of Medicine  by Armstrong, Bundy, Wang et al reported that the use of a combination of some traditional chemotherapeutic agents delivered through differing routes can have significantly different results. As compared with the traditional administration of  paclitaxel and cisplatin via the intravenous route, intravenous paclitaxel plus direct intraperitoneal injections of cisplatin and paclitaxel improves survival in patients with optimally debulked stage III ovarian cancer, by a period of several months to years. This effect held true even though many patients disliked and even discontinued the direct injections owing to greater pain, nausea and other side effects.  The longer after the treatments concluded the more that patients reported that these side-effects dissipated, and in retrospect, seemed to make worthwhile their initial suffering.

Pancreatic Cancer

Pancreatic cancers have a very poor prognosis and most chemotherapeutic strategies have very limited life-prolonging potential. In 2008, Kulke, Lenz, Meropol et al  tried using sunitinib (Sutent™)  a drug that targets VEGF (vascular endothelial growth factors and their receptors) and PDGF (platelet derived growth factors) and which had  previously shown good results in fighting gastrointestinal stromal tumors and in renal cell carcinonoma. It  extended the life of pancreatic cancer patients whose tumors were of the neuroendocrine type for a whole year.  It has shown less promise in dealing with carcinoid tumors of the pancreas, but these began showing good response to somatostatin analogs like lanreotide (Somatuline™) as noted earlier.

Prostate Cancer

Most prostate cancers are slow moving, but certain subtypes become more aggressive and require treatment sooner than the norm. The treatment regimes often  include some combination of surgery, cytotoxic chemotherapy, radiation, and increasingly,  male hormone suppression.  While none of these treatments is without the potential for incontinence and impotence, androgen suppression has the added problem of a certain feminization of features and in some cases cognitive declines, bone thinning and increased cardiovacular risk A 2008 analysis by D’Amico, Chen, Renshaw et al reported  that in a study of 206 men with localized but unfavorable risk prostate cancer,  that androgen suppression did not markedly preserve life notably longer, and might be omitted if its addition to side-effects seemed to onerous for the patient to bear.

Skin Cancer

Melanomas are among the most common cancers, and they can become fatally invasive, if left untreated. Fortunately they can often be cut, frozen or burned off the skin, but the question remains whether or not the melanoma will recur despite what appears to be “clean edges.” Stage III melanomas are fairly advanced, and have a high rate of recurrence,  but there has been no consensus as to the best follow-up after surgical removal, and doing nothing but watchful waiting has been shown to be about as effective as other more aggressive therapies. Eggermont, Suciu, Santinami et al demonstrated in 2008 that a post melanoma removal treatment plan that included pegylated interferon alfa-2b (Peg Intron™) substantially increased recurrence-free survival rates.

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