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April 2005, Volume 55, Issue 4

Science Vision

A War From Within

Zulfiqar Mir  ( Staff Physician and Instructor, Little Rock Veterans Affairs Hospital/University of Arkansas for Medical Sciences, Arkansas, USA )

Circulating tumor cells may provide a useful insight in prognosticating metastatic breast cancer


No cancer is more feared by the women than carcinoma of breast and for good reason. It remains the most frequent type of cancer in women and also the leading cause of cancer deaths in women. Recent advances in the field of Oncology have provided excellent cure rates for Stage 1 and 2 disease. However the odds of achieving complete response for patients with metastatic breast cancer (MBC) remain extremely low. The conventional and well reported prognostic indicators of breast cancer in general, include the size of the primary carcinoma, lymph node involvement and their number involved by metastasis, the carcinoma's grade and histologic type, whether it shows lymphovascular invasion, the presence or absence of estrogen or progesterone receptors and the expression of ERBB2, a membrane bound protein which is intricately involved in the proliferation of the cancer.

However, MBC is incurable and its treatment remains palliative. Researchers have now identified a novel prognostic factor for newly diagnosed metastatic breast cancer. It is the presence (or absence) of circulating tumor cells (CTC). Thanks to the development of "immunomagnetic platforms", it is now possible to detect CTCs in extremely low numbers. A multicenter team studied the presence of CTCs in the blood samples of 177 patients with MBC. They concluded that the detection of CTCs is highly predictive of progression free survival and overall survival in MBC. This technology can aid in the appropriate patient stratification and design of tailored treatments in the future.

J Clin Oncol 2005;23:1420-30.

News flash: a vaccine for CML

Chronic Myelogenous Leukemia (CML) is a clonal disease of the hematopoietic stem cell, in which a reciprocal translocation forms the Philadelphia chromosome and creates a new fusion gene BCR-ABL. This gene is translated into a 210kDa protein (p210) which has abnormal tyrosine kinase activity that is central to the pathogenesis of the disease. The unleashed tyrosine kinase activates several pathways which lead to clonal expansion of the granulocyte precursors. The crucial role of BCR-ABL has been confirmed by the dramatic response of patients with CML after therapy with an inhibitor of ABL kinase called STI 571/Gleevec/Imatinib. Three cheers for yet another example of rational drug design from an understanding from the molecular basis of cancer.

However, while patients respond most of the time with even cytogenetic response to Imatinib, molecular remissions are rare. Subsequently obvious resistance to Imatinib as well as loss of response during treatment is of great concern. Hence the possible cure without bone-marrow transplant still seems a difficult goal for a tyrosine-kinase inhibitor approach alone.

Researchers have now postulated to target the p210 fusion protein with specific immunotherapy (with a vaccine). Infact this protein happens to have a unique amino acid sequence which can be targeted as a tumor specific antigen to which an immune response can be induced. This was the basis of a study which comes from Italy in which patients were given vaccinations with a peptide vaccine derived with this idea in mind. They report that all patients improved in their cytogenetic responses. Notably some of them had undetectable amounts of the target protein. They conclude that addition of such vaccines to conventional treatments in patients with CML might favor further reduction of residual disease and increase the number of patients reaching a molecular response.

Lancet 2005;365:

Closing in on Myelodysplastic syndromes

Ineffective erythropoiesis is the hallmark of Myelodysplastic syndromes (MDS). In patients with this syndrome, bone marrow is partly or wholly replaced by clones of a pleuripotent stem cell that retains the capacity to differentiate into RBCs, granulocytes and platelets but in a manner that is both ineffective and disordered. As a result the bone marrow is usually hypercellular or normocellular but the peripheral blood smear shows pancytopenia. This abnormal stem cell clone is unstable with a tendency to accumulate mutations and may give rise to acute myeloid leukemia.

Management of anemia in MDS is difficult as the pathophysiology is complex. Survival signals from the microenvironment of the bone marrow are compromised, owing in part to the presence of angiogenic molecules, disruption of the medullary architecture and excess production of inflammatory cytokines. A significant minority of patients become transfusion dependant.

It has been noted that Thalidomide, an inhibitor of angiogenesis and an immune modulator, restores erythropoiesis and reduces transfusion dependence in a significant percent of patients who have no response to conventional agents like erythropoietin to correct anemia. However, the drug has significant side effects.

Researchers studied a novel analogue of Thalidomide that is more potent but does not have the neurotoxic or teratogenic side effects of its ancestor. It is Lenalidomide. 43 transfusion dependant patients who had no response to erythropietin and/or with symptomatic anemia were given this drug and it became apparent that about 20 of those had a sustained independence from transfusion. Of 20 patients with karyotypic abnormalities (chromosomal abnormalities are present in upto 70% of MDS), 10 had a complete cytogenetic remission. Thus, Lenalidomide was shown to have hematologic activity in patients with low risk MDS who have no response to erythropoietin or who are unlikely to benefit from conventional therapy. Moving on….

N Eng J Med 2005;352:

Causing harm while treating Cancer

Prostate cancer is the commonest visceral cancer in males. It is predominantly a disease of older males with a peak incidence between the ages of 65 and 75 years of age. Cancer of the prostate does not develop in males castrated before puberty, indicating that androgens play a fundamental part in its development.

It comes as no surprise that androgen deprivation therapy can reduce morbidity, palliate metastasis and improve survival in locally advanced disease when combined with radiation therapy. And now, this therapy in the form of Gonadotropin releasing hormone agonists is increasingly being used in men with localized prostate cancer and in men with the level of PSA rises after prostatectomy. Interestingly, both are situations in which no survival benefit has been demonstrated. Hence it becomes increasingly important to have accurate data on the toxic effects of androgen deprivation.

Although the treatment is clearly linked with a loss in bone-mineral density (hypogonadism is a known cause of osteoporosis), the risk of actual incidence of fractures after androgen deprivation therapy has not been well studied.

Researchers studied the records of over fifty thousand patients in this regard. They found that about 20 % of patients who received androgen deprivation therapy ended up with a fracture which was significantly more than patients who had not received the same therapy. This makes a strong case for the prevention of osteoporosis with the use of Bisphosphonates which are inhibitors of osteoclasts. Also periodic measurements of bone density with the help of DEXA scans may be of value.

N Eng J Med 2005;352:

Redefining the role of Positron Emission Tomography in the management of Non Small Cell lung cancer

Bronchogenic carcinoma is without doubt one of the worst malignancies one can have. For therapeutic purposes, this is divided into broad groups: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). They key reason for this distinction is that virtually all SCLCs have metastasized by the time of diagnosis and hence are not amenable to curative surgery.

While treating NSCLC, tumor stage is considered the most important prognostic factor. It also is the most important guide in treatment decisions. However, it is not completely reliable. For example, although surgery is usually performed in patients with stage I and II disease and in selected patients with stage IIIa, approximately 50% of patients who undergo a complete and presumably curable resection suffer relapse. In addition, despite the use of different multimodal therapeutic strategies in patients with Stage III NSCLC, the overall survival is still unsatisfactory. Therefore, better ways to predict prognosis and guide therapy are needed.

The role of Positron Emission Tomography is already established in determining whether a solitary pulmonary nodule may be malignant. Furthermore, PET is rapidly emerging as a useful resource for staging, estimating therapeutic response and delineating radiologic targets. The whole premise is based on the fact that the more metabolically active (read: dangerous) the tumor is, the higher the standardized uptake value (SUV) by PET.

Researchers studied 162 patients with stage I to IIIb NSCLC. A cut off of 5 for the SUV for the primary tumor showed the best discriminative value. The SUV turned out to be a significant predictor of overall survival and prognosis.
J Clin Oncol 2005;23:1136-43.

And finally, on a more humanistic note…….

Doctor … Know thyself!

The news of metastatic and terminal cancer is devastating. The communication of this distressing news is emotionally demanding for both the doctor and the patient. Disclosure of a short life expectancy becomes an obvious source of stress and at times a contentious issue. With the debate previously focused on whether to tell the patient the prognosis, recently it has changed its focus towards what information to give and how to convey it.

These subjective things are always difficult to measure scientifically in terms of meaningful studies. This uphill task was taken up by the researchers from Australia. In this study, they tried to identify preferences for the process of prognostic discussion among patients with incurable metastatic cancer and variables associated with these preferences.

The results showed that 98% of patients wanted their doctor to be realistic, provide an opportunity to ask questions and acknowledge them as individuals when discussing prognosis. The issues which raised the hope of the patient were whether the doctor was offering the most uptodate treatment, whether he appeared to know all there is to know about the disease and whether he reassures the patients about the control of pain. The majority of patients indicated that the doctor appearing nervous, or giving information to the family first or mincing words would not facilitate hope.

All in all, the majority of patients preferred a realistic and individualized approach from the cancer specialist.

Needless to say, we desperately need a study like this to be done in our country.

J Clin Oncol 2005;23:1278-88.

Journal of the Pakistan Medical Association has agreed to receive and publish manuscripts in accordance with the principles of the following committees: