Cancer Chemotherapy in the Elderly

Sekine, Ikuo; Fukuda, Haruhiko; Kunitoh, Hideo; Saijo, Nagahiro

doi:10.1093/jjco/28.8.463

Cited by 41 publications

(27 citation statements)

References 138 publications

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“…We found that a low dose of cisplatin causes necrosis in old cells whereas a high dose induces apoptosis. Actinomycin D is widely used in cancer therapy; however, its severe toxicity in old patients has been reported (52). We found that while in young cells actinomycin D induces apoptosis, in old cells it results in massive necrosis.…”

Section: Discussionmentioning

confidence: 73%

“…Cisplatin is one of the most effective and widely used anticancer drugs, and it is considered to have acceptable toxicity for old patients (35,38). No increased toxicity was observed in the elderly when the cisplatin dose was increased (52,58), and it was suggested that its toxicity was inversely dependent on the dose administered. We found that a low dose of cisplatin causes necrosis in old cells whereas a high dose induces apoptosis.…”

Section: Discussionmentioning

confidence: 99%

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Change of the Death Pathway in Senescent Human Fibroblasts in Response to DNA Damage Is Caused by an Inability To Stabilize p53

Seluanov

Gorbunova

Falcovitz

et al. 2001

Molecular and Cellular Biology

149

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The cellular function of p53 is complex. It is well known that p53 plays a key role in cellular response to DNA damage. Moreover, p53 was implicated in cellular senescence, and it was demonstrated that p53 undergoes modification in senescent cells. However, it is not known how these modifications affect the ability of senescent cells to respond to DNA damage. To address this question, we studied the responses of cultured young and old normal diploid human fibroblasts to a variety of genotoxic stresses. Young fibroblasts were able to undergo p53-dependent and p53-independent apoptosis. In contrast, senescent fibroblasts were unable to undergo p53-dependent apoptosis, whereas p53-independent apoptosis was only slightly reduced. Interestingly, instead of undergoing p53-dependent apoptosis, senescent fibroblasts underwent necrosis. Furthermore, we found that old cells were unable to stabilize p53 in response to DNA damage. Exogenous expression or stabilization of p53 with proteasome inhibitors in old fibroblasts restored their ability to undergo apoptosis. Our results suggest that stabilization of p53 in response to DNA damage is impaired in old fibroblasts, resulting in induction of necrosis. The role of this phenomenon in normal aging and anticancer therapy is discussed.

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Section: Discussionmentioning

confidence: 73%

Section: Discussionmentioning

confidence: 99%

Change of the Death Pathway in Senescent Human Fibroblasts in Response to DNA Damage Is Caused by an Inability To Stabilize p53

Seluanov

Gorbunova

Falcovitz

et al. 2001

Molecular and Cellular Biology

149

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“…This resulted in the omission of a median of 3 bleomycin doses in 20.8% of patients aged 40 years compared with the omission of a median of 2.5 bleomycin doses in 10.6% of the control group (Table 2). Some studies have reported increased bleomycin-related toxicity in older patients with testicular GCC, 15,16 and 1 report even suggested that bleomycin should not be used routinely in patients aged 40 years who have testicular GCC because of an increased risk of bleomycin-induced pulmonary toxicity. 17 However, this was not supported by the current study, in which the majority of patients aged 40 years tolerated full doses of bleomycin if their lung function was monitored carefully.…”

Section: Discussionmentioning

confidence: 99%

Survival and toxicity in patients with disseminated germ cell cancer aged 40 years and older

Thomsen

Bandak

Thomsen

et al. 2013

Cancer

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BACKGROUND: Germ-cell cancer (GCC) patients aged 40 years have a two-fold higher GCC-specific mortality. It has been hypothesized that reduced treatment intensity combined with increased treatment related toxicity could be the explanation. The objective was to analyze chemotherapy intensity, treatment related toxicity and survival in patients aged 40 years treated with standard chemotherapy for GCC compared with a younger control group that received similar treatment during the same period. METHODS: From 1984 to 2011, 135 patients aged 40 years with disseminated GCC treated with bleomycin, etoposide and cisplatin (BEP). A control-group of 135 patients aged 18-35 years was randomly selected matched on year of BEP treatment. Cumulated doses of BEP as well as bone marrow toxicity, renal-and lung functions were recorded before, during and after termination of treatment. All patients were followed until death or October 1, 2011. RESULTS: The cumulated doses of BEP were comparable between the two groups, however, more patients aged 40 years were reduced in bleomycin doses based on a decrease in carbon monoxide diffusion capacity corrected for haemoglobin (P 5 0.03). No differences between the two groups were found regarding bone marrow toxicity or mean percentage changes in lung-or renal function. Patients aged 40 year had increased cancer specific mortality, HR 5 4.8 (P 5 0.005). In particular patients with disease progression after first line chemotherapy had increased mortality (P 5 0.015). Moreover, the 5-year overall survival for patients aged 40 years was 82.5% compared to the expected 5-year survival of the background population of 96.3% (P <0.001). CONCLUSIONS: Treatment related toxicity could not explain the increased cancer specific mortality in patients aged 40 years compared to a younger control-group, and while there were no differences in the administrated doses of cisplatin/ etoposide, a decreased number of bleomycin doses were administered in the older patients. Apart from this, the inferior prognosis could be related to tumour biology, increased co-morbidity, or more severe toxicity in relation to second line treatment. Cancer 2014;120:43-51.

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“…Because renal function decreases physiologically with aging, (16) cisplatin use in elderly patients remains controversial. Some authors of clinical studies for patients aged 70 years or older have concluded that the use of cisplatin at moderate doses (60-100 mg/m 2 ) should be encouraged in these patients, just as it is in younger patients.…”

Section: Discussionmentioning

confidence: 99%

Bodyweight change during the first 5 days of chemotherapy as an indicator of cisplatin renal toxicity

Sekine¹,

Yamada²,

Nokihara³

et al. 2007

Cancer Science

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To determine whether bodyweight (BW) loss, daily urine volume (UV) or furosemide use are associated with cisplatin nephrotoxicity, performance status, serum chemistries before treatment, average daily UV, maximum BW loss and use of furosemide on days 1-5 of chemotherapy were evaluated retrospectively in chemotherapy-naive patients with thoracic malignancies who had received 80 mg/m 2 cisplatin. Associations between these parameters and the worst serum creatinine levels (group 1, grade 0 -1; and group 2, grade 2 -3) during the first cycle were evaluated. Of the 417 patients (327 men and 90 women; median age, 59 years), 390 were categorized into group 1 and 27 were categorized into group 2. More women and older patients were observed in group 2 than in group 1 (11.1 vs 5.2%, P = 0.044, and 65 vs 59 years, P = 0.041, respectively). The median average daily UV was 3902 mL in group 1 and 3600 mL in group 2 (P = 0.021). A maximum BW loss ≥ ≥ ≥ ≥2.1 kg was noted in 4.4% of patients in group 1 and 18.5% of patients in group 2 (P = 0.006). Furosemide was used in 206 (49.4%) patients. The median total dose of furosemide in groups 1 and 2 were 0 mg and 26 mg, respectively (P = 0.024). A multivariate analysis showed that a maximum BW loss ≥ ≥ ≥ ≥2.1 kg and the total furosemide dose were significantly associated with group category. In conclusion, BW loss and total furosemide dose were associated with cisplatin nephrotoxicity. (Cancer Sci 2007; 98: 1408-1412) C isplatin alone or in combination with other chemotherapeutic agents has been the most frequently used chemotherapy regimen against a variety of solid tumors for 30 years because of its significant therapeutic effects.(1) In spite of intensive efforts to devise platinum analogs and the successful development of carboplatin, cisplatin remains a key agent in the treatment of germ cell tumors, head and neck cancer and bladder cancer, as shown in several randomized controlled trials comparing the two platinum agents.(2) In addition, cisplatin has a significant role in the treatment of lung and ovarian cancers, although carboplatin is becoming increasingly used against these cancers as an alternative chemotherapeutic agent. (3,4) Cisplatin nephrotoxicity has been a major dose-limiting toxicity for this drug in most drug administration schedules. (5) Although the exact mechanism is unclear, high concentrations of platinum and widespread necrosis were observed in the proximal tubules of the kidney. This tubular impairment secondarily leads to a reduction in renal blood flow and glomerular filtration rate, potentiating primary tubular damage. This vicious circle causes a delayed deterioration in renal function, as an increase in the serum creatinine level typically appears 6-7 days after cisplatin administration in humans.(5,6) The standard prophylaxis for cisplatin nephrotoxicity is a normal saline infusion of 1-4 L with osmotic diuresis on the day of cisplatin administration. (5) Although this vigorous hydration diminishes life-threatening renal toxicity, 7-40% of patients s...

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Cancer Chemotherapy in the Elderly

Cited by 41 publications

References 138 publications

Change of the Death Pathway in Senescent Human Fibroblasts in Response to DNA Damage Is Caused by an Inability To Stabilize p53

Change of the Death Pathway in Senescent Human Fibroblasts in Response to DNA Damage Is Caused by an Inability To Stabilize p53

Survival and toxicity in patients with disseminated germ cell cancer aged 40 years and older

Bodyweight change during the first 5 days of chemotherapy as an indicator of cisplatin renal toxicity

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