AZ Guide u Oncology

ACUTE PROMYELOCYTIC LEUKEMIA

Acute promyelocytic leukemia (APL) represents 10 to 15 percent of the cases of acute myeloid leukemia in adults.
This disease is characterized by a specific cytogenetic abnormality , a chromosomal translocation that disrupt the retinoic acid receptor a gene (RAR-a ) on chromosome 17 and the promyelocytic leukemia gene (PML), which encodes a transcription factor and is located on chromosome 15.
The resulting fusion gene, PML-RAR a , encodes a chineric protein that cause an arrest of maturation at the promyelocyte stage of myeloid cell development.

THERAPY

In the early years ’90 the introduction in therapy of all-trans-retinoic acid has more than doubled the survival expected with chemotherapy alone.
All-trans-retinoic acid has provided the first proof of the principle of "differentiation therapy", in which drugs induce the terminal differentiation of malignant cells that are then incapable of further proliferation

Two reports from China (1996 & 1997) have suggest that arsenic trioxide can induce complete remissions in patients with acute promyelocytic leukemia (APL).

Soignet SL et al. (N Engl J Med 1998; 339: 1341-1348) have evaluate arsenic trioxide in patients with APL who had relapsed.
The results show that low doses (ranging from 0.06 to 0.2 mg per kilogram of body weight per day until visible leukemic cells were eliminated from the bone narrow) of arsenic trioxide are effective and cause few serious adverse reactions.
The clinical response to arsenic trioxide is associated with the induction of "nonterminal" cytodifferentiation and the activation of cysteine proteases (caspases) that are characteristic of apoptosis.

• Anastrozole (1 mg daily) has given a higher two-year survival (56.1% vs 46.3%) and a longer median overall survival time (26.7 vs 22.5 months) than Megestrol [1997].

AROMATASE INHIBITORS

• Aromatase inhibitors block the production of oestrogen outside the ovaries and are indicated for the treatment of advanced Tamoxifen-refractory breast cancer in postmenopausal women.

See ANASTROZOLE
See LETROZOLE
See VOROZOLE

Axillary lymph nodes are important prognostic in patients with breast cancer.
However a high number of women presents:
postoperative complications
psychological distress.

A potential alternative to axillary lymphadenectomy is sentinel-node resection.
In 1977, Canabas proposed to remove sentinel lymph nodes (the first nodes that receive drainage from tumors) by limited surgery and to examine their ………… to determine whether more extensive lymphadenectomy should be performed.
443 patients with breast cancer were enrolled.
Before surgery, 1 mCi (37 M Bq) of technetium – 99m sulfur colloid was injected into the breast tissue surrounding the primary tumor or biopsy cavity.
The accuracy of the sentinel nodes was 97%; the specificity of the method was 100 percent, the negative predictive value was 96% and the sensitivity was 89%.
The multicenter Validation Study conclused saying that "the biopsy of sentinel nodes can be technically challenging and the success rate varies according to the surgeon and the characteristics of the patients.

[Krag D. et al, E Engl J Med 1998; 339: 941-946].

CPPS is a randomised controlled trial planned to study the effect on calcium on colon cancer.
930 people with a history of colorectal cancer were enrolled and they took 1200 mg calcium or placebo daily for 4 years.
When compared with the placebo group, patients taking calcium had a 15% reduction in adenoma recurrence and developed fewer polyps when adenomas recurred.

[November 1998]

ELECTROPORATION
DELIVERY OF ANTICANCER DRUGS

• Electroporation is the application of short (100 microseconds) high-voltage pulses to cells.
• Electroporation is a method widely used by biologists to transfer DNA into both eukaryotic and prokaryotic cells.
• Electroporation creates a voltage difference across the plasma membrane, creating a disturbance in the proteolipid organization of the membrane. It makes it permeable to large molecules (DNA, proteins).
• The treatment involves injecting the chemotherapeutic drug into the tomour, then applying the pulsed electric fields.
• In what kind of tumours does electroporation work well ?
  Electrochemotherapy is currently effective only on local tumours.
• Basal-cell carcinoma.
  The success with basal-cell carcinoma treated by electrochemotherapy is comparable to that with surgery. Electroporation is especially suited to areas such as the face.
  Electroporation is a tissue-saving procedure that leaves little or no visible scarring.

ENDOSTATIN

• Endostatin is
• an enzyme that cleaves plasminogen to release the antiangiogenic molecule angiostatin,
• a specific inhibitor of endothelial proliferation.
• In animal models Endostatin is a potent inhibitor of tumour growth.

u Antiangiogenic therapy of experimental cancer does not induce acquired drug resistance.

Boehm T et al.
Nature 1997, 390, 404-407
Repeated administration of Endostatin in three murine tumour types (Lewis lung carcinoma, fibrosarcoma and melanoma) causes tumour regression without leading to drug resistance.
Endostatin was administered until the tumours had regressed; treatment was stopped and tumours were allowed to re-grow before Endostatin therapy was resumed.
After also six round of therapy, tumours continued to respond to the treatment.
In contrast, drug resistance developed rapidly in tumours treated with standard cytotoxic chemotherapy.
This study shows the powerful control exerted by the vascular endothelial cell population over tumour cells.

LETROZOLE

• Letrozole is a non-steroidal aromatase inhibitor approved as a once-daily oral agent for advanced breast cancer in postmenopausal women whose disease has progressed despite anti-oestrogen therapy.
• The most commonly reported adverse effects with Letrozole are:

• musculoskeletal pain
• nausea
• headache
• arthralgia
• fatigue.

• Letrozole is indicated for the second-line treatment of advanced breast cancer where Tamoxifen has failed.

OVARIAN CANCER

Patients with ovarian cancer have the highest mortality rate among women with gynecologic cancers.
More than two thirds of patients with ovarian-cancer have widespread metastatic disease at initial diagnosis.
In the advanced disease, the 5-year survival rate is no more than 15%.

DIAGNOSIS

The CA125 is the most widely used biomarker for the detection of ovarian cancer, even though it is not highly sensitive and lacks specificity.
CA 125 is not consistently elevated in serum from patients with early-stage ovarian cancer and may be elevated in patients with benign gynecologic diseases.
Measurement of serum CA 125 in association to ultrasound screening as a second-line test confers higher specificity but detects only about half of stage I ovarian cancers.
In the ascitic fluid from patients with ovarian cancer has been purified a factor Ovarian Cancer Activating Factor (OCAF), a lysophosphatidic acid (LPA).
LPA has been shown to stimulate proliferation of ovarian cancer cells.
According to Cleveland’s researchers the plasma LPA levels may represent a potential biomarker for ovarian cancer and other gynecologic cancers.

[Xu Y, et al. JAMA 1998; 280: 719-723]

• A large-scale study of Trastuzumab in combination with chemotherapy in metastatic breast cancer (stage IV disease) showed a 53% better response rate, a 57% improvement in median duration of response and a 65% improvement in median duration in response in comparison with chemotherapy alone.
• Side effects were similar in both groups, except for an increased risk of cardiac dysfunction in women receiving Trastuzumab and Doxorubicin plus Cyclophosphamide.
• When administered alone, in women with metastatic disease that had not responded to one or two prior chemotherapy regimens, Trastuzumab has showen efficacy (16%) and good tolerability (fever and chills), with none of the commonly observed side-effects associated with chemotherapy.
• Trastuzumab is the first product targeted to an underlying genetic defect which cause cancer.
• The over-expression of HER2 is seen in 25-30% of metastatic breast cancer patients.
• HER2 protein is a cell-surface receptor that transmits growth signals to the cell nucleus.
• Trastuzumab is a humanized monoclonal antibody that appears to block these signals.
• Other cancers that could be potential Trastuzumab targets include: ovarian, peritoneum, gastric, endometrial, salivary gland, pancreatic, prostate, colorectal and non-small-cell lung cancer.
• Some patients with ovarian and gastric tumours seem to have very high HER2 levels and these two tumours may be the most probably candidates for an anti-HER2 therapy.
• New assays to test the overexpression of HER2 have been developed:
• HER2 DNA assay based on fluorescenze in situ hybridization or FISH;
• HER2 protein assay based on immunohistochemistry.

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