Course Of Cytotoxic Therapy Research Articles

INFLUENCE OF LONG-TERM CYTOTOXIC CHEMOTHERAPY ON THE CONDITION OF PERIPHERAL VENOUS CHANNEL

The necessity of long-term venous access in cancer patients appears at frequent and long-term courses of cytotoxic therapy. Peripheral veins of forearms are most often used for these aims. The conditions of peripheral venous channel in 32 cancer patients, who underwent the long-term treatment with antitumor preparations were analyzed in the article on own investigatory material. The methods of dopplerography, morphological and immunohystochemical studies were used. The qualitative and quantitative dopplerographic changes in forearm veins in different terms after chemotherapy start were revealed in most patients. The conclusion was made about unsuitability of forearm peripheral veins for the long term administration of cytostatics and the necessity to create the alternative vascular access that would correspond to the criteria of safety, reliability and long-term exploitation.

Clinical Significance of Hilar Hyalinosis in Glomeruli of Children with Idiopathic Nephrotic Syndrome

Introduction: Hilar hyalinosis (HH) of glomeruli has been thought for a long time to be a precursor or a variant of focal glomerulosclerosis (FGS). In view of its implications on treatment and prognosis of nephrotic syndrome, a retrospective study of hilar hyalinosis in children with the idiopathic nephrotic syndrome (INS), but without any other histologic evidence of FGS, was performed to determine the clinic-pathologic significance of this lesion. Methods: A total of 92 Children with INS who had kidney biopsies for frequent relapses, steroid dependency or resistance were included. Eight of them had a biopsy-proven diagnosis of either minimal change disease or mild IgM nephropathy with HH in 6-25% of glomeruli were compared to control group consisting of 84 children with either minimal change disease (n=57) or IgM nephropathy (n=27) but without HH. Results: Clinically HH patients presented with NS and followed a steroid-dependent relapsing course prior to biopsy. Around 75% of the HH patients received at least one course of cytotoxic therapy after biopsy. At last visit, 6 patients were in remission, 2 were protein-free but on medication. None had hypertension or renal insufficiency. Apart from having a shorter interval between presentation and biopsy (P<0.001) and a lower remission rate (P<0.05), control patients followed a similar course. Pathologically HH patients showed less mesangial change (P<0.001) than the controls but similar mean glomerular size and tubuloinerstitial damage. Conclusion: The results do not support the concept of HH being a precursor lesion of FGS. Kibara [10] have reported HH in the kidneys of children without clinical evidence of renal disease. In view of the possibility that Hilar and perihilar hyalinosis is a precursor or a variant of FGS with its implications for treatment and prognosis, a retrospective study of HH in children with the nephrotic syndrome (NS) but without any other histologic evidence of FGS was performed to determine the clinic-pathologic significance of this lesion.

Abstract 1210: Mifepristone abrogates repopulation of ovarian cancer cells in between courses of cisplatin treatment

Abstract Repopulation of cancer cells that escape cytotoxic chemotherapy is a critical factor that negatively impacts treatment success. Thus, any strategy that prevents this phenomenon from occurring would be beneficial for the outcome of the treatment. One such strategy to inhibit tumor cell repopulation is the use of cytostatic compounds among courses of cytotoxic therapy. In this study, we tested the hypothesis that mifepristone, a steroid compound displaying a potent cytostatic effect in ovarian cancer as recently demonstrated in our laboratory (Clin Cancer Res 2007, 13, 3370-3379), should be efficacious to induce cytostasis and to prevent ovarian cancer repopulation if given in between rounds of cisplatin therapy. We established an in vitro approach in which OV2008 cisplatin-sensitive ovarian cancer cells were exposed to three rounds of a cytotoxic dose (20 μM) of cisplatin for 1 h, twelve days apart. Every four days the number of cells, their viability, and their distribution within the cell cycle were assessed by micro-cytometry using exclusion fluorochromes and propidium iodide, respectively. Further, the colony-forming capacity of the viable cells was evaluated along the experiment. Although cisplatin killed the vast majority of OV2008 cells, there were cells that escaped cisplatin toxicity and repopulated the culture. This phenomenon occurred each one of the three times the cells were challenged by cisplatin during the 36 days the study lasted. Post-cisplatin repopulation was evidenced by the increase in number and clonogenic capacity of the viable cells, the normalization in the distribution of cells within the different phases of the cell cycle (S, G1 and G2/M), and the concomitant reduction in sub-diploid DNA content (as marker of cytotoxicity). Instead, when the cells were exposed to cisplatin for 1 h, but 5, 10 or 20 μM mifepristone was present in the culture medium after removal of the platinum agent, both number of cells and their clonogenic capacity were reduced in a dose-related manner. Remarkably, the cultures exposed to cisplatin for 1 h followed by chronic exposure to 20 μM mifepristone did not have remaining viable cells to allow performing the clonogenic survival assay by day 12 of the study, suggesting an added lethality to the cytostatic effect of mifepristone. In conclusion, this study demonstrates that presence of cytostatic concentrations of mifepristone prevents the repopulation of ovarian cancer cells surviving the lethality of cisplatin, and further suggests mifepristone may potentiate cisplatin toxicity. The scheduling of mifepristone between courses of cisplatin-based therapy for human ovarian cancer has potential for improving treatment success. Supported by NIH grant CA121991.

Malignant Peripheral Nerve Sheath Tumour Associated With Von Recklinghausen\'s Disease: Case Report

Only a few cases of malignant peripheral nerve sheath tumour (MPNST) associated with Von Recklinghausen's disease or type I neurofibromatosis (NF-1) have so far been reported worldwide, yet the primary disease (NF-I ) does not seem rare even in Africa. We present a case of a 40 year old woman with MPNST of the left thigh associated with NF-1. The diagnosis was based on clinical, radiological and histopathological evidence. She presented with a 25 year history of painless, multiple, generalized skin nodules and hyperpigmented spots. She also noticed a gradually progressive, painless, redundant mass on the left side of the forehead 16 years prior to presentation. Four months before presentation, she noticed another mass at the back of the left thigh, which increased rapidly in size. Examination revealed a middle aged woman with generalized subcutaneous nodules of various sizes (3mm - 2.5cm), multiple café-au-lait spots (2cm-4.5cm), a plexiform neurofibroma on the left side of the forehead measuring 6cm x 5cm x 5cm. There was a firm, non-pulsatile and non-tender mass (11.5cm x 9cm x 5cm) on the posterior aspect of the left upper thigh. The mass was more mobile longitudinally than transversely and was attached to the overlying skin at the summit, the regional Iymph nodes were not enlarged. Most investigations were essentially normal except a plain radiograph, which revealed a soft tissue mass on the left thigh without bony involvement. At surgery, a well localized soft tissue tumour, abutting on the sciatic nerve was widely resected without neural damage to the nerve. Histologic sections of a tru cut as well as the surgical specimens showed a tumour consisting of closely packed serpentine cells arranged in palisades; marked nuclear and cellular pleomorphism and hyperchromatism, many bizarre tumour giant cells, mitotic figures and foci of necroses. The patient received six courses of cytotoxic therapy and is well eleven months after surgery. It is presented to highlight the clinical and pathological features of NF-1 complicated with malignant transformation.

Urachal cyst presenting as abdomino-inguino-scrotal tumour

Background : This report describes the unusual presentation and management of an urachal cyst in a 3½ year old Nigerian male child. Before being referred, he had been managed as a bladder rhabdomyosarcoma, and given two courses of cytotoxic therapy. Methodology : Pre-operative diagnosis was inconclusive, including the use of Ultrasonography and micturating cysto-urethrogram (MCUG). Abdomino-inguino-scrotal exploration revealed a pre-peritoneal multi-septate cyst spanning from the umbilicus to the dome of the urinary bladder. In addition there was herniation of this cyst into the right inguino-scrotal space. The cyst yielded 1.7litres of straw coloured fluid. Results : Drainage of the cyst with total excision of the sac in continuity resulted in cure. The patient has remained symptom free at 2years of follow up. Conclusion : This rare presentation of a benign condition stands to caution all practitioners against the irrational use of cytotoxic therapy. Keywords : urachal cyst, abdomino-inguino-scrotal Journal of College of Medicine Vol. 10(2) 2005: 72-74

Effectiveness of Interferon-Alfa and Mid-Cycle Chemotherapy Added to an Anthracycline-Based Regimen in the Treatment of Aggressive Non-Hodgkin's Lymphoma

Interferon-alfa in combination with cytotoxic chemotherapy has been shown to be effective in treating certain types of non-Hodgkin's lymphoma (NHL) (1). However, there is no published data on upfront induction treatment of aggressive NHL with IFN-alfa containing regimens. Studies have also shown that one can overcome regrowth resistance by administering mid-cycle agents which slow tumor proliferation between courses of cytotoxic therapy (2). Based on this, we treated 32 consecutive patients between 1/93 and 9/96 with a regimen containing cyclophosphamide 750 mg/m2, mitoxantrone 12 mg/m2, and teniposide 60 mg/m2 IV on day 1 with prednisone 100 mg PO given on days 1–5. On day 15, patients received vincristine 1.4 mg/m2 (2 mg max.) and bleomycin 10 units/ m2 IV. Interferon-alfa-2b 5×l06 units/m2 SQ was administered on days 22–26. The median age was 55 (range 26–83), M:F ratio was 2.5:1, and the median International Prognostic Index was 2. 38% of patients had stages I-II and 62% had stages III-IV disease. Fifty-nine percent of the patients achieved a complete response, 22% a partial response, and 19% had progressive disease. The overall survival (OS) was 81% and the progression free survival (PFS) was 56% at 4.3 years. There were no severe (grade IV) hematologic, flu-like, GI and infectious toxicities from IFN-α. Leukopenia was the main severe toxicity related to the chemotherapy regimen (days 1–15), but not IFN-α. Severe infection secondary to the chemotherapy regimen occurred in one patient. Interferon-alfa-2b and mid-cycle chemotherapy added to an anthracycline based regimen is effective induction treatment for patients with aggressive NHL. The OS and PFS using this regimen, based on regrowth resistance, appears to be at least as or more effective than CHOP therapy for this group of patients. Severe toxicities were rare.

Infection prophylaxis in neutropenic patients with acute leukaemia--a randomized, comparative study with ofloxacin, ciprofloxacin and co-trimoxazole/colistin

Preliminary results are presented of an ongoing, prospective, randomized, study comparing ofloxacin, ciprofloxacin and co-trimoxazole/colistin for the prevention of infection in patients with acute leukaemia. The results for 59 patients (median age 47 years, range 21-72) included 88 episodes of neutropenia, each associated with a course of cytotoxic therapy. The main factor measured was the time elapsed from the beginning of neutropenia (neutrophils less than 500/microliter) until the first infectious febrile episode. The median time for the period was 12 days (range 1-56) for the cotrimoxazole/colistin group, 15 days (range 1-38) for the ofloxacin group and 20 days (range 1-36) for the ciprofloxacin group (differences not significant). Microbiologically proven major infections occurred in 10/27 treatment courses with co-trimoxazole/colistin 7/31 courses with ofloxacin and 7/30 courses with ciprofloxacin (P not significant). These were mostly due to Gram-positive cocci. There were no Gram-negative infections in the quinolone groups compared with one major Pseudomonas aeruginosa infection in the co-trimoxazole/colistin group. No Pneumocystis carinii infections were encountered. Adverse reactions associated with co-trimoxazole/colistin required discontinuation of medication in 11/27 treatment courses because of compliance problems, skin reactions or gastrointestinal intolerance. There were significantly fewer discontinuations in the ofloxacin (n = 2) and in the ciprofloxacin groups (n = 3). Major side effects of the quinolones included persistent icterus in one patient receiving ofloxacin and psychiatric symptoms in one patient receiving ciprofloxacin. It is concluded from these data that there were no statistically significant differences between the three treatment groups in respect of the prevention of infection.(ABSTRACT TRUNCATED AT 250 WORDS)

The magnitude of endocrine effects of adjuvant chemotherapy for premenopausal breast cancer patients

We analysed the incidence of amenorrhoea and its association with outcome in a cohort of 1127 premenopausal women with breast cancer randomized to International Trial V (formerly Ludwig V). For 552 patients without axillary lymph node involvement, one course of perioperative cytotoxic drugs was compared with no-adjuvant chemotherapy. For 575 patients with node-positive disease, a single course of cytotoxic chemotherapy was compared with a prolonged treatment (6 or 7 courses). Amenorrhoea was defined as having no menstrual bleeding for a 3-month interval within the first 9 months after surgery. Amenorrhoea was observed in 21% of the 199 patients with node-negative breast cancer who received no adjuvant therapy, 31% of the 353 node-negative patients who had a single course of cytotoxic therapy, 31% of the 188 patients with node-positive disease who had the same short-duration therapy, and 68% of the 387 node-positive patients who had a prolonged adjuvant therapy. Amenorrhoea was associated with an increased disease-free survival (DFS) only in the patients with prolonged cytotoxic therapy: 4-year DFS % (+/- s.e.) was 68% +/- 3% vs. 61% +/- 5% for the amenorrhoea and the no-amenorrhoea groups, respectively, (p = 0.05). In contrast, the comparison between prolonged therapy and one single course among node-positive patients showed a much larger treatment effect (4-year DFS 66% vs. 38%, p less than 0.0001). We conclude that although cytotoxics-induced amenorrhoea is associated with a better outcome, it is unlikely that this form of endocrine manipulation is the main mechanism of response to adjuvant systemic chemotherapy.

Beneficial effect of second courses of cytotoxic therapy in children with minimal change nephrotic syndrome.

Therapeutic guidelines are not available for children with minimal change nephrotic syndrome (MCNS) who experience frequent relapses or develop steroid resistance after a course of cytotoxic therapy. The records of nine children with biopsy-proven MCNS who received two courses of cytotoxic therapy with either chlorambucil or cyclophosphamide were reviewed to evaluate the length of remission, associated side-effects and long-term outcome. Initial cytotoxic therapy was given to five frequent-relapsing patients and four steroid-resistant patients 2-48 months (mean 16 months) following diagnosis of nephrotic syndrome. The second drug was given 4-85 months (mean 27 months) after the first. Steroid-resistant patients attained remissions of 0-81 months (mean 23 months) following the first agent and 13-67 months (mean 32 months) following the second. Frequent-relapsing patients experienced remissions of 0.5-24 months (mean 7.4 months) following the first cytotoxic drug and 3-72 months (mean 22 months) after the second. Remissions following the second agent were equal to or longer than those following the first in the seven patients who received both chlorambucil and cyclophosphamide. In the 19- to 128-month follow-up (mean 66 months), all four steroid-resistant patients experienced infrequent relapses which responded to prednisone. One frequent-relapsing patient remains in remission, three have chronic proteinuria and one still has a frequent-relapsing course. For the select group of patients who become frequent relapsing or steroid resistant after one course of cytotoxic therapy, a second course of cytotoxic therapy may allow time for catch-up growth, as well as improve steroid responsiveness once relapses occur.

Aberrant immunoglobulin synthesis in light chain amyloidosis. Free light chain and light chain fragment production by human bone marrow cells in short-term tissue culture.

Bone marrow cells obtained from 14 patients with light chain amyloid (AL) deposition were examined by biosynthetic labeling techniques. These analyses identified free monoclonal light chain (L-chain) synthesis even in those patients whose serum or urine contained no M protein or free L-chains or only an intact M protein. The experiments also identified a subset of patients whose plasma cells synthesized polypeptides bearing constant region antigenic determinants that migrated more rapidly than intact L-chains on polyacrylamide gels. Since most AL fibrils contain L-chain fragments rather than intact L-chains, these studies suggested that the genesis of the fibril components may reflect aberrant synthesis, proteolytic processing, or both. We also noted that in some individuals the pattern of Ig synthesis normalized after several courses of cytotoxic therapy. Thus, we could use bone marrow Ig synthesis as a sensitive biochemical parameter for monitoring therapy. Finally, the presence of aberrant synthetic products in these clones raised questions about their origin with respect to the normal processes of transcription, translation, and posttranslational modification in Ig-producing cells.

The syndrome of inappropriate secretion of antidiuretic hormone (SIADH) in small-cell lung cancer.

Review of clinical data from 350 patients with small-cell lung cancer (SCLC) revealed hyponatremia (sodium less than 130 mEq/L) attributable to the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) in 40 patients (11%). Although hyponatremia was severe in most instances (median, sodium 117 mEq/L), symptoms attributable to water intoxication were identified in only 27% of hyponatremic episodes. Development of SIADH showed no correlation with clinical stage, distribution of metastatic sites, sex, or histologic subtype of small-cell carcinoma. SIADH occurred most often with initial presentation (33 of 40), and resolved promptly (less than 3 weeks) with initiation of combination chemotherapy in 80% of evaluable patients. The presence of SIADH did not influence response to chemotherapy or overall survival as an independent variable. However, in five patients profound hyponatremia developed immediately following primary cytotoxic therapy (range, one to five days). Despite initial control of SIADH, dilutional hyponatremia recurred in 70% of patients with tumor progression. Our findings suggest that development of clinically demonstrable SIADH in patients with SCLC is dependent on functional properties of the neoplastic cells, rather than tumor burden or metastatic site. The potential for development of clinically significant hyponatremia early in the course of cytotoxic therapy emphasizes the need to closely monitor patients, particularly those receiving chemotherapy regimens requiring substantial intravenous hydration.

Renal oncocytoma associated with diffuse lymphoma

We report on a sixty-six-year-old man with a poorly differentiated, diffuse lymphomain whom bilateral multiple renal masses developed six months after starting chemotherapy. Computerized tomography and selective renal arteriograms were suggestive of either recurrence of lymphoma or renal cell carcinoma. Kidney biopsy revealed renal oncocytomas, benign renal tumors. The patient was spared further courses of cytotoxic therapy.

A randomised multicentre single blind comparison of a cannabinoid anti-emetic (Levonantradol) with chlorpromazine in patients receiving their first cytotoxic chemotherapy

One hundred and eight patients selected to receive combinations of highly emetic cytotoxic chemotherapy for malignant disease were included in a study of anti-emetic therapy. The patients were randomly allocated to receive levonantradol (0.5, 0.75 or 1 mg) or chlorpromazine (25 mg) prior to receiving their first course of cytotoxic therapy. The appropriate anti-emetic was administered 2 hr prior to the start of chemotherapy, 2 hr after chemotherapy and subsequently at 4-hourly intervals for a further 8 hr. The extent of anorexia, nausea and vomiting along with other side-effects were assessed at regular intervals by physicians and nursing staff during the 24 hr following chemotherapy. In addition, a self-assessment questionnaire was completed by the patients. Levonantradol (0.5 mg) was superior to chlorpromazine (25 mg) as an anti-emetic. Both were reasonably well tolerated, although at this dose of levonantradol 22% of patients experienced dysphoric reactions. At higher doses of levonantradol the proportion of patients experiencing these reactions rose to 50%, but without a concomitant increase in anti-emetic activity. Neither drug achieved satisfactory control of vomiting in patients receiving combinations containing cis-platinum. We conclude that levonantradol (0.5 mg) is a more effective anti-emetic than chlorpromazine (25 mg) in patients receiving cytotoxic chemotherapy. However, its use cannot be recommended due to its high incidence of unacceptable central nervous system side-effects.

Metoclopramide. An updated review of its pharmacological properties and clinical use.

Since previously reviewed in the Journal (Vol. 12, No. 2), metoclopramide has been confirmed as an effective drug in treating and preventing various types of vomiting and as a useful agent in oesophageal reflux disease, gastroparesis, dyspepsia, and in a variety of functional gastrointestinal disorders. Of considerable importance is the recent evidence of its efficacy when administered intravenously in high dosages in preventing severe vomiting associated with cisplatin. Good results have been achieved in patients not previously treated with cisplatin, but further studies are needed to determine its level of efficacy in patients who have experienced severe vomiting during earlier courses of cytotoxic therapy. Side effects consisting of mild sedation, diarrhoea and reversible extrapyramidal reactions have occurred, but are tolerated by many patients.

Temporary resolution of geographic tongue with cytotoxic therapy.

SYNOPSISGeographic tongue had been present prior to the development of lymphosarcoma in a boy aged 7 years. The lymphosarcoma was treated with cyclical courses of cytotoxic therapy (M.O.P.P.), consisting of nitrogen mustard, vincristine, procarbazine and prednisolone, with initial remission, but later recurrence. Remission and recurrence of the geographic tongue occurred in a cyclical fashion, and could be correlated with courses of MOPP. This association has not apparently been described.These changes are documented, and the possible causes of this phenomenon are considered, but the multiple components of MOPP make it difficult to ascribe the changes to one component or function of therapy.