Reversible mechlorethamine-associated hearing loss in a patient with Hodgkin's disease

Mechlorethamine, when administered in massive doses (0.6-1.5 mg/kg) to cancer patients in several early studies, caused severe irreversible hearing loss. There have been no reports of ototoxicity with doses of 0.4 mg/kg or less. The authors describe a 36-year-old man who developed profound sensorineural hearing loss during his first cycle of MOPP chemotherapy for Hodgkin's disease. Cyclophosphamide was substituted for mechlorethamine in subsequent cycles and his hearing deficit resolved. This is the first reported case of reversible ototoxicity associated with currently recommended doses of mechlorethamine.     

Oxaliplatin-Related Ocular Toxicity

We report the case of a 52-year-old woman with advanced colorectal cancer who was treated with oxaliplatin on a FOLFOX schedule. After 3 cycles of chemotherapy, she started to complain of visual loss, altered color vision and neurological symptoms. Due to the suspicion of ocular and neurological toxicity, antineoplastic treatment was stopped. Her visual field showed a concentric bilateral scotoma and the electrooculogram test revealed severe impairment of the retinal pigment epithelium. Visual acuity, color vision and visual field recovered completely 8 months later, although electrooculogram remained abnormal. Ocular toxicity has been reported as an infrequent adverse event of oxaliplatin. Findings in this case indicate toxicity of this chemotherapeutic agent on the retinal pigment epithelium, which has not been reported before. This damage could be permanent, and it thus differs from previously described oxaliplatin-induced ocular toxicities, which are usually transient and reversible. With increasing use of oxaliplatin as first-line treatment in advanced colorectal cancer, we have to be aware of this possible toxicity.     

Irreversible sensorineural hearing loss due to Imatinib

OBJECTIVE: We report probably the first case of bilateral irreversible sensorineural hearing loss caused by Imatinib. METHOD: A review of the world literature, concerning Imatinib toxicity is presented. RESULTS: We report a case of bilateral irreversible sensorineural hearing loss, in a 19-year-old male patient of chronic myeloid leukemia after 3 months of Imatinib therapy. Audiometric evaluation documented the findings. CONCLUSION: To the best of our knowledge, this is the first case report of Imatinib induced sensorineural hearing loss. This case indicates that treating oncologists should keep in mind that this drug too can produce ototoxicity.     

Hemolysis and thrombocytopenia following oxaliplatin administration

Oxaliplatin is a platinum derivative with an overall excellent safety profile that has a major role in the treatment of colorectal cancer. With a proven role now in the adjuvant setting, rare but potentially life‐threatening toxicities become a more significant issue. We report here a case of significant postinfusion hemolysis and thrombocytopenia in a patient undergoing adjuvant chemotherapy for stage III colon cancer, and review the literature. Six cases of hemolysis following oxaliplatin treatment have previously been reported, all in the setting of advanced colorectal cancer, with one case resulting in death. In three of the seven reports (including the present case), warning signs of low grade hemolysis were apparent during preceding cycles, with fever and/or back pain during the infusion being the most common feature. Our case appears to be the first reported with a direct antiglobulin test‐negative hemolysis with thrombocytopenia, with each of the previous reports postulating an autoimmune basis. Hemolysis and/or thrombocytopenia are potentially life‐threatening complications of oxaliplatin chemotherapy. With the increasing use of oxaliplatin in the adjuvant setting, clinicians need to be aware of this entity and the possible clinical warning signs that may be evident in preceding cycles.     

Cisplatin-induced ototoxicity in osteosarcoma patients: a report from the late effects surveillance system

The aim of this study was to analyze cisplatin-induced ototoxicity in a recent study trial. Seventy-four patients who had received cisplatin for the treatment of osteosarcoma (median cumulative dose: 360 mg/m2) were investigated prospectively for ototoxicity in a multicenter trial. Hearing function was tested by audiometry. We evaluated the incidence and dependencies of hearing loss. After cessation of therapy, 51% of the patients showed a hearing loss of >20 dB in the frequency range of 4-8 kHz. Only in one patient a hearing loss was found at 2 kHz, and in none at 1 kHz. At a cumulative cisplatin dose of < or = 240 mg/m2, almost no ototoxicity was found. Incidence and magnitude of hearing loss increased significantly with a higher cumulative dose. Furthermore, hearing thresholds were significantly poorer in children <12 years. A further follow-up investigation showed only a marginal change in hearing function. We conclude that ototoxicity is moderate in our group of patients and probably irreversible.     

Capecitabine in combination with oxaliplatin as first-line therapy for advanced gastric cancer: a case report

Gastric cancer is one of the most common cancers worldwilde. The five-year survival for stage IV gastric cancer is around 5-10% in Western countries. Advanced gastric cancer is sensitive to numerous agents, but there is no generally accepted standard regimen. Here we report on a case of advanced gastric cancer occurring in a 72-year-old man who underwent treatment with capecitabine plus oxaliplatin, achieving a complete response.     

Cisplatin ototoxicity in gynecologic cancer patients. A preliminary report

The ototoxicity associated with long-term cisplatin therapy in gynecologic cancer patients was investigated. Twenty-three of 31 patients developed hearing loss and 21 patients reported the onset of tinnitus. The hearing loss was bilateral, cochlear, and permanent. The tinnitus was transient and not predictive of change in hearing level. The likelihood of developing hearing loss appeared to be greatest in patients older than 40 years and in patients with preexisting hearing loss. The amount of change did not appear to be related to the degree of preexisting hearing loss.     

Analysis of risk factors for cisplatin-induced ototoxicity in patients with testicular cancer.

This study evaluates the degree and relevance of persisting ototoxicity after cisplatin-based standard-dose chemotherapy for testicular cancer, with emphasis on identification of potential factors for an increased risk of this late sequel. Hearing thresholds of 86 patients with a median age of 31 years (range 21-53 years) and a median follow-up time of 58 months (range 15-159 months) were assessed by conventional pure-tone audiometry. Interviews were conducted evaluating the patients'' history with special regard to audiological risk factors, as well as circumstances of ototoxic symptoms. Details concerning treatment and patient variables were extracted retrospectively from the patients'' charts. An additional screening programme assessed current body functions, blood parameters and other late toxicities. Symptomatic ototoxicity persisted in 20% of patients (59% tinnitus, 18% hearing loss, 23% both), while 10% had experienced completely reversible ototoxic symptoms for a duration of 1-18 months after treatment. Symptoms were bilateral in 81% of patients. Hearing thresholds were compatible with cisplatin-induced hearing loss in 42% of audiograms performed. Subjective (history) and objective (audiogram) findings were not always consistent. The following statistically significant risk factors for ototoxicity were established: high cumulative dose of cisplatin (P < 0.0001); history of noise exposure (P = 0.006). Additionally, high doses of vincristine (P = 0.001) seemed to result in reversible ototoxic symptoms. No other independent risk factors were identified. In conclusion, persisting ototoxicity represents a clinical sequel for approximately 20% of testicular cancer patients treated at standard dose but may affect more than 50% of patients receiving cumulative doses of cisplatin > 400 mg m(-2). Previous noise exposure may also result in a threefold increased risk for cisplatin ototoxicity. Future studies should use these risk factors as important stratification criteria for trials aiming at the evaluation and prevention of cisplatin-induced ototoxicity.     

Irreversible ototoxicity associated with difluoromethylornithine.

Difluoromethylornithine (DFMO) is a potent, irreversible inhibitor of ornithine decarboxylase, the rate-limiting enzyme in the synthesis of polyamines that promote cellular proliferation. DFMO has been tested as a potential cancer therapeutic and chemopreventive agent in clinical trials. Reversible hearing loss is a recognized toxicity of DFMO that usually occurs at doses above 2 g/m(2)/d, and generally when the cumulative dose exceeds 250 g/m(2). In a recently completed Barrett's esophagus chemoprevention trial, a participant developed a 15-dB decrease in hearing at frequencies of 250, 2,000, and 3,000 Hz in the right ear and a > or =20-dB decrease in hearing at 4,000 to 6,000 Hz in the left ear after taking 0.5 g/m(2)/d DFMO for approximately 13 weeks (cumulative dose of 45 g/m(2)). The threshold shifts persisted 7 months after DFMO was discontinued. There was no obvious impact on the participant's clinical hearing, but these findings were consistent with irreversible hearing loss. This is the first case reported of irreversible ototoxicity in a clinical trial participant receiving DFMO and, thus, trial participants should be made aware of this small but important risk.     

Bilateral hearing loss during vincristine therapy: a case report

Vincristine sulfate is a chemotherapeutic agent used in different cancer therapies. It is also the first choice of treatment for peripheral T-cell lymphoma with cyclophosphamide and adriamycin. Sudden hearing loss during vincristine therapy is a very rare event. This is a case of a 16-year old girl who developed sudden bilateral hearing loss related to vincristine therapy.     

Bilateral irreversible hearing loss associated with the combination of carboplatin and paclitaxel chemotherapy: a unusual side effect

The regimen with paclitaxel and platinum compound (carboplatin or cisplatin) is the standard chemotherapy for patients with advanced ovarian cancer. Ototoxity for carboplatin and paclitaxel alone or combined is rarely observed. We report the case of a 35-year old female with advanced ovarian cancer who developed sudden bilateral sensorineural hearing loss related to paclitaxel and carboplatin based chemotherapy. This uncommon adverse effect of carboplatin and paclitaxel alone or combined is discussed and the literature reviewed. Hearing monitoring should be mandatory to evaluate the real incidence of clinical and sub-clinical hearing modification induced by carboplatin and paclitaxel based chemotherapy.     

替吉奥胶囊联合奥沙利铂治疗晚期食管癌的临床观察

目的观察替吉奥胶囊联合奥沙利铂治疗晚期食管癌患者的疗效和不良反应。方法 27例晚期食管癌患者采用替吉奥胶囊联合奥沙利铂方案治疗,每3周重复1次,治疗3个周期后评价疗效。结果 27例患者均完成6个周期化疗。其中完全缓解1例（3.7%）,部分缓解12例（44.4%）,近期有效率48.1%。主要不良反应为血液学毒性、胃肠道反应和感觉神经毒性,无化疗相关性死亡。结论替吉奥胶囊联合奥沙利铂治疗晚期食管癌,疗效肯定,患者耐受性良好,可作为晚期食管癌患者化疗的选择方案。     

Irinotecan versus oxaliplatin for adjuvant colon cancer therapy: Why do the results differ?

Chemotherapy for colon cancer has evolved substantially over the past 5 years with the addition of new drugs such as oxaliplatin and irinotecan. Though chemotherapy regimens based on oxaliplatin and irinotecan are considered to be equivalent in the advanced-disease setting, oxaliplatin-based regimens appear more effective in adjuvant therapy after resection. The MOSAIC and NSABP C-07 trials demonstrated survival improvement with the addition of oxaliplatin, whereas the CALGB 89803, ACCORD-02, and PETACC-3 trials did not reveal the same benefit with irinotecan. This discrepancy may stem from differences in the mechanism of action, drug resistance, toxicity, or trial design. These results challenge the conventional wisdom that agents effective in the advanced setting will work postoperatively. With the availability of new, targeted agents, it is clear that the results of randomized phase 3 trials must be analyzed before extrapolating efficacy from the metastatic setting to the adjuvant setting in colon cancer.     

Novel chemotherapeutic agents for gastrointestinal cancers.

Although 5-fluorouracil has been the most commonly prescribed chemotherapy agent in the treatment of patients with gastrointestinal malignancies, new agents discussed herein provide options for the treatment of patients with colorectal, gastric, and pancreas cancer. Irinotecan was recently approved for the treatment of patients with colorectal cancer refractory to 5-fluorouracil. It has also been evaluated in chemotherapy-na?ve patients both alone and in combination with 5-fluorouracil plus leucovorin or with oxaliplatin. Evaluated primarily in patients with colorectal cancer, oxaliplatin, a novel platinum compound, is an active agent. In combination with 5-fluorouracil and leucovorin, oxaliplatin provides a higher response rate than 5-fluorouracil and leucovorin alone. Furthermore, when oxaliplatin was added to the same 5-fluorouracil-based regimen in which patients had disease progression, clinical activity was observed. Other agents discussed herein are raltitrexed and the oral fluorinated pyrimidines, including uracil:tegafur plus leucovorin, capecitabine, eniluracil plus oral 5-fluorouracil, and S-1. Gemcitabine has been demonstrated to be more effective than 5-fluorouracil in the alleviation of disease-specific symptoms in patients with advanced pancreatic cancer. Gemcitabine also confers a modest survival advantage. Combinations of these novel compounds are evaluated in gastrointestinal malignancies in the advanced disease setting and in adjuvant therapy programs.     

COAST (Cisplatin ototoxicity attenuated by aspirin trial): A phase II double-blind,randomised controlled trial to establish if aspirin reduces cisplatin induced hearing-loss

BackgroundCisplatin is one of the most ototoxic chemotherapy drugs, resulting in a permanent and irreversible hearing loss in up to 50% of patients. Cisplatin and gentamicin are thought to damage hearing through a common mechanism, involving reactive oxygen species in the inner ear. Aspirin has been shown to minimise gentamicin-induced ototoxicity. We, therefore, tested the hypothesis that aspirin could also reduce ototoxicity from cisplatin-based chemotherapy.MethodsA total of 94 patients receiving cisplatin-based chemotherapy for multiple cancer types were recruited into a phase II, double-blind, placebo-controlled trial and randomised in a ratio of 1:1 to receive aspirin 975 mg tid and omeprazole 20 mg od, or matched placebos from the day before, to 2 days after, their cisplatin dose(s), for each treatment cycle. Patients underwent pure tone audiometry before and at 7 and 90 days after their final cisplatin dose. The primary end-point was combined hearing loss (cHL), the summed hearing loss at 6 kHz and 8 kHz, in both ears.ResultsAlthough aspirin was well tolerated, it did not protect hearing in patients receiving cisplatin (p-value = 0.233, 20% one-sided level of significance). In the aspirin arm, patients demonstrated mean cHL of 49 dB (standard deviation [SD] 61.41) following cisplatin compared with placebo patients who demonstrated mean cHL of 36 dB (SD 50.85). Women had greater average hearing loss than men, and patients treated for head and neck malignancy experienced the greatest cHL.ConclusionsAspirin did not protect from cisplatin-related ototoxicity. Cisplatin and gentamicin may therefore have distinct ototoxic mechanisms, or cisplatin-induced ototoxicity may be refractory to the aspirin regimen used here.     

A case of interstitial lung diseases in patient treated with oxaliplatin, 5-fluorouracil and leucovorin (FOLFOX)

FOLFOX/bevacizumab has been shown to be a promising chemotherapeutic regimen for advanced or metastatic colorectral cancer. We reported a case of intestinal lung diseases occurring in association with the use of this combination chemotherapy. The patient presented here is a 71-year-old man with lung metastasis of rectal cancer who was treated with FOLFOX4/ bevacizumab. He complained of high fever in the eleventh course of a FOLFOX4/bevacizumab regimen. Chemotherapy was stopped. But fourteen days after, he suffered from dyspnea and soon went into respiratory failure of WHO grade 3 with severe hypoxemia. He was diagnosed with interstitial pneumonitis. Corticosteroid therapy consisting of metylprednisolone(1 g/day) for tree days was significantly effective in treatment of respiratory failure. Drug-induced interstitial pneumonitis was suspected from chest X-ray and CT. We performed DLST of oxaliplatin, l-levofolinate, 5-FU and bevacizumab for him. He was positive for oxaliplatin and l-levofolinate and 5-FU, and negative for bevacizumab. Interstitial pneumonitis induced by FOLFOX/bevacizumab chemotherapy is rare, but six patients had developed, one of whom died in post-marketing surveillance. The possibility of interstitial pneumonitis should always be considered when a patient presents with a respiratory disorder while undergoing systemic chemotherapy.     

Recommendations for cancer prevention trials using potentially ototoxic test agents.

PURPOSE: Preventive oncology applies pharmacologic agents to reverse, retard, or halt progression of neoplastic cells to invasive malignancy, a process that may require administration of agents over long periods of time. Although ototoxicity may be a tolerable side effect of anticancer or antimicrobial therapy, even modest ototoxicity may not be acceptable in agents developed for preventive oncology that are routinely administered to subjects who neither are, nor necessarily will become, clinically ill. MATERIALS AND METHODS: Age-related shifts in hearing may occur over the course of longterm or open-ended therapy; consequently, age-adjusted norms enable researchers to better distinguish hearing loss caused by drugs from that caused by aging. Norms for hearing sensitivity are derived from the Baltimore Longitudinal Study of Aging and are the basis for the proposed audiologic monitoring recommendations. RESULTS: Audiologic monitoring recommendations are presented that standardize patient selection, adverse event reporting, posttreatment follow-up, and audiologic testing for potentially ototoxic investigational agents. CONCLUSION: These recommendations are applicable to trials of investigational agents as well as various classes of drugs used in routine clinical care.     

Phase II study of capecitabine and oxaliplatin as first-line treatment in advanced colorectal cancer.

BACKGROUND: Capecitabine and oxaliplatin are both active anticancer agents in the treatment of patients with advanced colorectal cancer. The aim of this phase II study is to determine the efficacy and tolerability of combining oxaliplatin with capecitabine in the treatment of advanced non-pretreated colorectal cancer. PATIENTS AND METHODS: Forty-three chemotherapy-na?ve patients were enrolled. Capecitabine 2500 mg/m(2)/day was administered orally twice a day continuously for 14 days and oxaliplatin 120 mg/m(2) was administered as a 2-h infusion on day 1, repeated every 3 weeks. RESULTS: Forty-three patients were assessable for toxicity and 39 for clinical activity: the main toxicity was grade 3 or 4 diarrhea, which occurred in 28% of the patients. The response rates were 44% [95% confidence interval (CI), 29.3% to 59.0%] and 48.7% (95% CI 33.0% to 64.4%) (intention-to-treat and per protocol analysis, respectively). The median overall survival was 20 months (95% CI 12-28). CONCLUSIONS: Combining capecitabine and oxaliplatin yields promising activity in advanced colorectal cancer; therefore, the capecitabine dose we utilized is probably too high. The main toxicity is diarrhea, which is manageable with appropriate dose reductions.This combination may be preferable compared to a standard combination with infusional fluorouracil/leucovorin as it is more convenient and practical with similar efficacy. Thus, phase III trials are needed to clarify its role in the treatment of chemotherapy-na?ve advanced colorectal cancer patients.     

New chemotherapeutic advances in pancreatic, colorectal, and gastric cancers

Pancreatic, gastric, and colorectal cancers are major causes of morbidity and mortality worldwide. When curative surgical resection is not an option, these malignancies tend to respond very poorly to chemotherapy and carry a dismal prognosis. There is, therefore, an urgent need for novel treatment strategies for these cancers. Great strides have been made in colon cancer treatment with the recent introduction of several novel agents, including capecitabine, irinotecan, and oxaliplatin either alone or in combination regimens. Treatment of advanced colon cancer, however, remains essentially palliative, and treatment-related toxicity remains a significant problem. The treatment of advanced gastric and pancreatic cancer has also seen the introduction of new agents, such as gemcitabine and irinotecan; however, the impact of these agents on survival has been small, and toxicity continues to be a major obstacle. The search for new chemotherapeutic agents and treatment strategies will need to focus on improving outcomes and safety and tolerability profiles. To date, several new agents have shown promise, including pemetrexed, G17DT, bevacizumab, and other targeted agents. Further research into their optimal use either alone or in combination regimens should be a priority.