Symptomatic hyponatremia induced by low-dose cyclophosphamide in patient with systemic lupus erythematosus: A case report.

RATIONALE: Cyclophosphamide (CY) is an alkylating agent used widely to treat cancer and autoimmune diseases. Hyponatremia is a common adverse effect of high-dose and moderate-dose of intravenous CY, but is rare in patients treated with low-dose (<15 mg/kg). PATIENT CONCERNS: A 52-year-old woman with new-onset systemic lupus erythematosus (SLE) was treated with low-dose cyclophosphamide (8 mg/kg, CY), but showed sudden headaches, disorientation and weakness. Laboratory examinations revealed severe isovolumic hyponatremia along with low-serum osmolality and high urine osmolality. DIAGNOSIS: The acute hyponatremia was consistent with the syndrome of inappropriate antidiuretic hormone secretion (SIADH) and was an adverse event of low-dose CY, with no evidence of endocrine, cancer, pulmonary, or cerebral abnormalities relevant to the SIADH. INTERVENTION: The hyponatremia was resolved after the supplementation of NaCl solution. OUTCOMES: The hyponatremia was resolved without any complications. LESSONS: Hyponatremia induced by low-dose CY should be recognized as an underlying life-threatening complication in clinical practice.

Use of Copeptin Levels to Predict the Resolution of Transient Postoperative SIADH.

BACKGROUND: Copeptin levels reflect vasopressin activity and help classify osmoregulatory disorders. There is limited pediatric experience using copeptin to diagnose and manage diabetes insipidus, syndrome of inappropriate antidiuretic hormone secretion (SIADH), and bi- or tri-phasic postsurgical osmoregulatory disorders. In this report, we describe serial copeptin levels in an infant who developed transient SIADH after neurosurgery. CASE DESCRIPTION: A 4-month-old infant with no prior pituitary dysfunction underwent endoscopic fenestration of a large arachnoid cyst (3.5 × 4.7 × 3.8 cm). He developed SIADH on postoperative day 4 with seizures, hyponatremia (sodium 121 mmol/L), and concentrated urine (535 mOsm/kg). His initial copeptin level was inappropriately high in the context of his hyponatremia. Copeptin levels decreased as his SIADH resolved. Serial copeptin levels correlated to the infant's increased ability to dilute urine. CONCLUSION: Copeptin levels in this infant are consistent with levels described in adults and older children. Obtaining copeptin levels may improve providers' ability to quickly diagnose and manage SIADH amongst other heterogeneous causes of hyponatremia. Lastly, trending copeptin levels improved providers' ability to monitor SIADH progression, and may allow preemptive fluid titration for children with bi- or tri-phasic shifts in osmoregulation after neurological procedures.

Risk factors for sodium overcorrection in non-hypovolemic hyponatremia patients treated with tolvaptan.

PURPOSE: In this study, the risk factors associated with sodium overcorrection were investigated with an optimal cutoff for baseline serum sodium for use in daily clinical practice. METHODS: Electronic medical records of patients who received tolvaptan for non-hypovolemic hyponatremia were reviewed. Demographic and clinical data including age, sex, weight, height, comorbidity, cause of hyponatremia, hypertonic saline use, and comedication were collected. Baseline laboratory parameters measured included serum sodium, serum potassium, serum creatinine, blood urea nitrogen, serum tonicity, ALT, AST, and urine osmolality. The primary outcome was the overcorrection of serum sodium, which was defined as an increase in serum sodium by more than 10 mmol/L in 24 h. RESULTS: From a total of 77 patients included in the analysis, 24 (31.2%) showed sodium overcorrection (> 10 mmol/L/24 h); 2 (2.6%) in heart failure cohort, 17 (22.1%) in SIADH cohort, and 5 (6.5%) in unknown cause cohort. More than half of patients (51.9%) were administered hypertonic saline prior to tolvaptan. Hypertension, cancer, diuretics, baseline serum sodium, and SIADH were associated with the risk of overcorrection in the univariable analysis. Significant factors for the overcorrection from multivariable analysis were lower body mass index, presence of cancer (adjusted odds ratio, 10.87; 95% CI, 1.23-96.44), and lower serum sodium at baseline (adjusted odds ratio, 0.76 for every 1 mEq/L increase; 95% CI, 0.61-0.94). CONCLUSION: The overcorrection of hyponatremia in non-hypovolemic patients treated with tolvaptan was significantly associated with lower body mass index, presence of cancer, and lower serum sodium at baseline. In subgroup analysis using SIADH patients, baseline sodium and cancer were found to be significant factors of overcorrection.

Small cell carcinoma of the bladder presenting with paraneoplastic syndrome of inappropriate antidiuretic hormone.

Small cell carcinoma (SCC) of the bladder is a rare malignancy, representing less than 1% of bladder cancers diagnosed annually in the USA. In contrast to SCC of the lung, paraneoplastic syndromes are rarely documented in cases of extrapulmonary SCCs, particularly those of genitourinary origin. We present a case of SCC of the bladder presenting with paraneoplastic syndrome of inappropriate antidiuretic hormone, which resolved after treatment with sequential chemoradiation.

[CME: Paraneoplastic Endocrine Syndromes]. / CME: Paraneoplastische endokrine Syndrome.

CME: Paraneoplastic Endocrine Syndromes Abstract. Paraneoplastic endocrine syndromes are caused by ectopic hormone production by malignant tumor cells. Knowledge of paraneoplastic endocrine syndromes may allow a timely diagnosis of the underlying cancer at a treatable stage and, on the other hand, appropriate treatment of the endocrine manifestations reduces morbidity and mortality of the affected patients. The most common endocrine syndromes are paraneoplastic hypercalcaemia, caused by the secretion of PTHrP, and hyponatremia, caused by the inadequate secretion of ADH. Although there may be clinical symptoms like fatigue, nausea/vomiting and renal insufficiency for hypercalcaemia and gait disturbances and mental alterations for hyponatremia, the diagnosis must be confirmed by laboratory testing and prompt the search for associated tumors.

[Study of diagnostic value of natremia in a cohort of patients with hypercalcemia]. / Etude de la valeur diagnostique de la natrémie dans une cohorte de patients hypercalcémiques.

INTRODUCTION: Hypercalcemia is a common pathological condition in clinical practice. The two most common causes are primary hyperparathyroidism and cancer. SIADH is often encountered in cancer cases and is the most common cause of hyponatremia. The aim of this study is to evaluate serum sodium levels in a cohort of patients with hypercalcemia and consider its predictive value in determining the origin of this hypercalcemia. MATERIALS AND METHODS: We performed a retrospective study on a series of 15.284 blood tests among adult patients with hypercalcemia. After selection, the study population had 151 patients. We studied mainly serum sodium and etiology of hypercalcemia in our population. RESULTS: We observed a statistically significant association between the presence of hyponatremia and the neoplastic etiology of hypercalcemia. This association persisted after exclusion of patients under treatment with loop diuretics. Conversely, there was no association between hypernatremia and cancer-related hypercalcemia. Among 151 patients with hypercalcemia, 16 presented hyponatremia and 7 with hypernatremia. SIADH was the main cause of hyponatremia. We performed univariate and multivariate logistic regression showing the association between the presence of cancer and the presence of hyponatremia. CONCLUSION: Our study shows that there is an association between the presence of hyponatremia and neoplastic origin of hypercalcemia. Besides, the association described between hyponatremia and cancer is not faulted by the presence of hypercalcemia, a potential cause of acquired nephrogenic diabetes insipidus.

INTRODUCTION: L'hypercalcémie est une condition pathologique courante en pratique clinique. Les deux causes les plus fréquentes sont l'hyperparathyroïdie primaire et le cancer. Le syndrome de sécrétion inappropriée de l'hormone antidiurétique (SIADH) est souvent rencontré dans les cas de cancer, et constitue la cause la plus fréquente d'hyponatrémie. Le but de cette étude est d'évaluer la natrémie dans une cohorte de patients atteints d'hypercalcémie et d'apprécier sa valeur prédictive dans la détermination de l'origine de cette hypercalcémie. Matériel et méthode : Nous avons réalisé une étude rétrospective sur une série de 15.284 analyses sanguines chez des patients adultes hypercalcémiques. Après sélection, la population de l'étude comptait 151 patients. Nous avons étudié principalement la natrémie et l'étiologie de l'hypercalcémie au sein de notre population. Résultats : Nous avons observé une association statistiquement significative entre la présence d'une hyponatrémie et l'étiologie néoplasique de l'hypercalcémie. Cette association persistait après l'exclusion des patients sous traitement par diurétiques de l'anse. Par contre, il n'existait pas d'association entre l'hypernatrémie et l'origine cancéreuse de l'hypercalcémie. Sur 151 patients hypercalcémiques, 16 étaient hyponatrémiques et 7 étaient hypernatrémiques. Un SIADH représentait la cause principale des cas d'hyponatrémie. Nous avons réalisé une régression logistique uni- et multivariée montrant l'association entre l'existence d'un cancer et la présence d'une hyponatrémie. CONCLUSION: Notre étude montre qu'il existe une association entre la présence d'une hyponatrémie et l'étiologie néoplasique de l'hypercalcémie. Par ailleurs, l'association classiquement décrite entre hyponatrémie et cancer n'est pas prise en défaut par la présence d'une hypercalcémie, cause potentielle de diabète insipide néphrogénique acquis.

Low-dose tolvaptan PK/PD: comparison of patients with hyponatremia due to syndrome of inappropriate antidiuretic hormone secretion to healthy adults.

PURPOSE: Tolvaptan (TLV) is indicated to treat hyponatremia due to syndrome of inappropriate diuretic hormone (SIADH) in Europe. Treatment is to be initiated at 15 mg QD but post-approval reporting indicates increasing use of 7.5 mg as the starting dose. Physicians believe 7.5 mg is effective and has a lower incidence of overly rapid correction of serum sodium. METHODS: Single TLV doses of 3.75, 7.5, and 15 mg were administered to 14 healthy adults in a crossover design and to 29 subjects ≥18 years with SIADH and serum sodium between 120 and 133 mmol/L in a parallel-group design. Pharmacodynamics and TLV plasma concentrations were assessed for 24 h post-dose. RESULTS: In SIADH subjects, corrections of serum sodium (Δ of ≥8 mmol/L in the first 8 h or ≥12 mmol/L in the first 24 h) were observed in one, one, and two subjects in the 3.75-, 7.5-, and 15-mg dose groups. Fluid balance (FB) for 0-6 h post-dose was correlated (r 2 = 0.37) with maximum increases in serum sodium; subjects with large corrections had large (~1 L) negative FB. Compared to healthy adults, subjects with SIADH did not drink in response to their negative FB and had larger increases in serum sodium at 24 h. Median time of maximum increase in healthy adults was 6 h, with no rapid corrections, and FB was near 0 mL by 24 h. CONCLUSION: Starting titration with 7.5 mg TLV will not eliminate the risk of rapid corrections in serum sodium. Monitoring FB may indicate that a subject is at risk for over correction.

Tolvaptan use in cancer patients with hyponatremia due to the syndrome of inappropriate antidiuretic hormone: a post hoc analysis of the SALT-1 and SALT-2 trials.

Hyponatremia is a common electrolyte disorder in cancer patients and has been associated with poor prognosis. A frequent cause of cancer-related hyponatremia is the syndrome of inappropriate antidiuretic hormone (SIADH). This study was a post hoc subgroup analysis of the SALT-1 (Study of Ascending Levels of Tolvaptan in Hyponatremia) and SALT-2 clinical trials. Hyponatremic subjects with SIADH and cancer received the oral selective vasopressin V2-receptor antagonist tolvaptan (n = 12) or matching placebo (n = 16) once-daily for 30 days. The initial tolvaptan dose (15 mg) was titrated over 4 days to 30 or 60 mg per day, as needed, according to serum sodium level and tolerability. Baseline serum sodium levels in the SIADH/cancer cohort of the SALT trials was 130 and 128 mEq/L for tolvaptan and placebo, respectively. Mean change from baseline in average daily serum sodium AUC for tolvaptan relative to placebo was 5.0 versus -0.3 mEq/L (P < 0.0001) at day 4, and 6.9 versus 1.0 mEq/L (P < 0.0001) at day 30; the observed treatment effects were similar to those in the overall SIADH population (i.e., with and without cancer) at both time points. Serum sodium normalization was observed in 6/12 and 0/13 subjects at day 4 and 7/8 and 2/6 subjects at day 30 in the tolvaptan and placebo groups, respectively (P < 0.05 for both). Common treatment-emergent AEs for tolvaptan were consistent with previously reported results. In this post hoc study of the SALT trial population, oral tolvaptan was an effective and safe therapy for the treatment of hyponatremia in subjects with SIADH and cancer.

The V2 receptor antagonist tolvaptan raises cytosolic calcium and prevents AQP2 trafficking and function: an in vitro and in vivo assessment.

Tolvaptan, a selective vasopressin V2 receptor antagonist, is a new generation diuretic. Its clinical efficacy is in principle due to impaired vasopressin-regulated water reabsorption via aquaporin-2 (AQP2). Nevertheless, no direct in vitro evidence that tolvaptan prevents AQP2-mediated water transport, nor that this pathway is targeted in vivo in patients with syndrome of inappropriate antidiuresis (SIAD) has been provided. The effects of tolvaptan on the vasopressin-cAMP/PKA signalling cascade were investigated in MDCK cells expressing endogenous V2R and in mouse kidney. In MDCK, tolvaptan prevented dDAVP-induced increase in ser256-AQP2 and osmotic water permeability. A similar effect on ser256-AQP2 was found in V1aR -/- mice, thus confirming the V2R selectively. Of note, calcium calibration in MDCK showed that tolvaptan per se caused calcium mobilization from the endoplasmic reticulum resulting in a significant increase in basal intracellular calcium. This effect was only observed in cells expressing the V2R, indicating that it requires the tolvaptan-V2R interaction. Consistent with this finding, tolvaptan partially reduced the increase in ser256-AQP2 and the water permeability in response to forskolin, a direct activator of adenylyl cyclase (AC), suggesting that the increase in intracellular calcium is associated with an inhibition of the calcium-inhibitable AC type VI. Furthermore, tolvaptan treatment reduced AQP2 excretion in two SIAD patients and normalized plasma sodium concentration. These data represent the first detailed demonstration of the central role of AQP2 blockade in the aquaretic effect of tolvaptan and underscore a novel effect in raising intracellular calcium that can be of significant clinical relevance.

Medication-induced SIADH: distribution and characterization according to medication class.

AIMS: The aims of the current study were to determine the distribution of aetiologies for the drug-induced syndrome of inappropriate antidiuretic hormone secretion (SIADH) in hospitalized patients, and to characterize them according to the different drug groups. METHODS: A single-centre retrospective study was carried out, including all patients diagnosed with SIADH in a large community hospital and tertiary centre between 1 January 2007 and 1 January 2013 who were treated with drugs known to be associated with SIADH. Two physicians reviewed every patient's medical file for predetermined relevant clinical data. RESULTS: The study cohort included 198 patients who had SIADH and received drugs associated with SIADH. Most patients [146 (73.7%)] were diagnosed with drug-associated SIADH, while 52 (26.3%) were diagnosed with SIADH due to other aetiologies. The Naranjo algorithm differentiated well between the two groups (P < 0.001). Five drug classes (antidepressants, anticonvulsants, antipsychotic agents, cytotoxic agents and pain medications) were implicated in 82.3% of patients diagnosed with drug-associated SIADH. Specific serotonin reuptake inhibitors and carbamazepine were commonly implicated. There were no clinically significant differences in the characteristics or severity of SIADH according to drug class. CONCLUSIONS: The clinical characteristics of SIADH caused by different drugs are comparable. Patients with SIADH treated with drugs from five common medication classes will probably be diagnosed with drug-induced SIADH. Physicians should be aware of the significance of these medication classes as SIADH aetiologies.

Severe Hyponatremia in a Single-Center Series of 84 Homogenously Treated Children With Acute Lymphoblastic Leukemia.

Electrolyte abnormalities are hallmark metabolic disturbances during the treatment of acute lymphoblastic leukemia (ALL). Hyponatremia is an ominous laboratory sign in the setting of neoplasia. We analyzed the incidence, risk factors, associations, specific interventions and outcomes of severe hyponatremia in a single-center series of children with ALL. The incidence of severe hyponatremia, defined as serum sodium levels below 130 mmol/L on at least 2 of 3 consecutive days, was 11.9%. History of hyponatremia episode is associated with neurologic complications (P=0.023) and the presence of overt central nervous system leukemia (CNS3) at diagnosis (P=0.005). Most observed hyponatremia episodes resolved relatively quickly, rarely requiring specific treatment. All but 1 hyponatremia episodes occurred in the induction or reinduction phases, but none before the administration of cytotoxic drugs, pointing to the role of therapy complications rather than leukemia per se. Most patients received vincristine shortly before hyponatremia onset, and vincristine has been previously strongly implicated in hyponatremia. We also suggest a role for imatinib. Although every patient with severe hyponatremia requires swift and thorough diagnostics a serious sequelae in the setting of pediatric ALL is rare. Hyponatremia association with neurotoxicity likely points to vincristine hypersensitivity in the subgroup of patients with both complications.

Identifying Different Causes of Hyponatremia With Fractional Excretion of Uric Acid.

BACKGROUND: There is controversy over the prevalence of the syndrome of inappropriate antidiuretic hormone secretion (SIADH) and cerebral or renal salt wasting (RSW), 2 syndromes with identical common clinical and laboratory parameters but different therapies. The traditional approach to the hyponatremic patient relies on volume assessment, but there are limitations to this method. METHODS: We used an algorithm that relies on fractional excretion of urate (FEurate) to evaluate patients with hyponatremia and present 4 illustrative cases. RESULTS: Overall, 2 patients had increased FEurate [normal: 4-11%], as is seen in SIADH and RSW. A diagnosis of SIADH was made in 1 patient by correcting the hyponatremia with 1.5% saline and observing a characteristic normalization of an elevated FEurate that is characteristic of SIADH as compared to FEurate being persistently increased in RSW. A patient with T-cell lymphoma had symmetrical leg edema due to lymphomatous obstruction of the inferior vena cava, postural hypotension, pleural effusion, ascites, decreased cardiac output and urine sodium level of 10mmol/L. Saline-induced excretion of dilute urines and undetectable plasma antidiuretic hormone were consistent with RSW. Furosemide, given for presumed heart failure, induced a profound diuresis that required large volumes of fluid resuscitation. A normal FEurate identified a reset osmostat in a transplant patient with a slowly developing pneumocystis carinii pneumonia. A volume-depleted hyponatremic patient with Addison׳s disease had a low FEurate of 1.4%. CONCLUSIONS: These illustrative cases suggest that an approach to hyponatremia using FEurate may be a useful alternative to traditional volume-based approaches.

Immature ovarian teratoma with hyponatremia and low serum vasopressin level.

Hyponatremia is often caused by the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). Hypersecretion of vasopressin from malignant tumors can be considered a cause of SIADH. Most of these ectopic productions of vasopressin are complications of small cell lung cancer. Cases concomitant with ovarian tumors are very rare, and a specific causative substance from the ovary is often unknown. A 16-year-old woman was diagnosed with an ovarian tumor. She developed hyponatremia that was resistant to medical treatment, but immediately improved after surgical resection of the tumor. Her diagnosis was SIADH caused by an ovarian tumor; however, her serum vasopressin level was normal. It is possible that a vasopressin-like substance causing SIADH was secreted by either nervous system tissue within an immature teratoma or small cell lung cancer. We should be cautious when SIADH is a complication of an ovarian tumor.

Malignancy associated SIADH: Characterization and clinical implications.

PURPOSE: To determine the distribution of etiologies for the syndrome of inappropriate antidiuretic hormone secretion (SIADH) in hospitalized patients with active malignancies and to characterize them according to the different etiologies. METHODS: A single center retrospective study including all patients with active malignancies diagnosed with SIADH in a large community hospital and tertiary center between 1 January 2007 and 1 January 2013. Two physicians reviewed every patient's medical file for predetermined relevant clinical data. RESULTS: The study cohort included 204 patients. 74.4% of those with solid tumors had metastatic disease. Most patients (149, 73%) had malignancy associated SIADH, while 55 (27%) had SIADH due to other etiologies. All of the major malignancy types were implicated in SIADH. Patients with breast cancer without lung or brain involvement were significantly less likely to be diagnosed with malignancy associated SIADH compared with other malignancies [Odds ratio (OR) 0.031, 95% CI 0.003-0.25, p < 0.001]. Patients with malignancy associated SIADH had lower serum sodium concentrations on short-term follow-up (p = 0.024) and significantly shorter median survival (58 vs. 910 days, p < 0.001). Short-term hyponatremia correction was associated with better survival. CONCLUSIONS: SIADH is associated with most malignancy types. Physicians caring for patients with breast cancer without lung or brain involvement diagnosed with SIADH without an obvious etiology should consider obtaining lung and brain imaging to rule out undiagnosed metastatic spread. Patients with malignancy associated SIADH have considerably worse outcomes compared to cancer patient with SIADH due to other etiologies. Short-term sodium concentration can be used as a prognostic marker for these patients.

A young boy with recurrent headache, lethargy, and hyponatremia.

BACKGROUND: To investigate and differentiate the causes of hyponatremia in an 8-y old boy. METHODS: An 8-y boy presented with headache, vomiting, and diplopia. Magnetic resonance imaging of the brain confirmed a mass in the pineal region. Pathology report demonstrated a mixed germ cell tumor with a yolk sac component. A multi-agent chemotherapy and radiation regimen was initiated. He developed hyponatremia, with sodium concentrations varying from 116 to 133 mEq/l. RESULTS: Serum levels of sodium, chloride, phosphorous, uric acid, and osmolality were low. Serum α-fetoprotein, ß-HCG, and lactate dehydrogenase were highly elevated. Urine sodium and osmolality were increased. CONCLUSIONS: These presentations suggest that the patient has cerebral salt-wasting syndrome caused by intracranial germ cell tumor. Recognition and differentiation of cerebral salt-wasting syndrome from other disorders are essential.

Hyponatremia in cancer patients.

Hyponatremia is the most frequent electrolyte disorder in hospitalized patients but also a well known poor prognostic factor in cancer patients. Syndrome of inappropriate secretion of antidiuretic hormone (SIADH) is often misdiagnosed by oncologist because of difficulties in the interpretation of laboratory tests. Etiology is heterogeneous but the predominant cause is represented by the unbalance between excessive presence of water and serum sodium deficiency. Ectopic production of arginine vasopressin (AVP) develops more frequently in small cell lung cancer but it is not so rare in other malignancies. Neurological impairment may range from subclinical to life-threating symptoms depending by the rate of serum sodium deficiency. Appropriate diagnosis is essential to set a proper therapy. When hyponatremia is caused by SIADH, hypertonic saline infusion is indicated for acute presentation whereas fluid restriction is preferred in case of chronic asymptomatic evolution. Other options include vaptans, vasopressin receptor antagonists, targeted specifically for the correction of euvolemic hyponatremia. The aim of this brief report is to provide concise and specific informations for the management of SIADH in oncology clinical practice.

[Severe hyponatremia during chemotherapy for small cell carcinoma]. / Hyponatrémie sévère sous chimiothérapie du carcinome à petites cellules.

INTRODUCTION: The small cell lung cancer (SCLC) is a rapidly progressive malignancy with a poor prognosis. Its chemosensitivity mandates prompt treatment. Hyponatremia occurs frequently in patients with small cell lung cancer due to the syndrome of inappropriate antidiuretic hormone (SIADH). We report a case of severe hyponatremia induced by chemotherapy that required management in intensive care. OBSERVATION: A 68-year-old patient was undergoing treatment for small cell cancer, invading the right lung. On the second day of the first cycle of treatment (cisplatine-vepeside), the patient became comatose and required transfer to an intensive care unit. The coma was due to severe hyponatremia (107 mmol/L) and improved with specific treatment. The patient had similar episodes on the second day of each chemotherapy treatment but with less and less severe clinical manifestations. Hyponatremia due to chemotherapy in SCLC is not commonly known; a relation between hyponatremia intensity and the tumor size is suspected. CONCLUSION: This clinical case highlights the possibility of severe hyponatremia during small cell lung cancer chemotherapy. Hyponatremia may be related to the reduction in tumor size. Monitoring of electrolytes on day 2 of chemotherapy is advised.

Inappropriate antidiuretic hormone secretion due to squamous cell lung cancer.

The syndrome of inappropriate secretion of antidiuretic hormone is a disorder of impaired water excretion caused by the inability to suppress secretion of antidiuretic hormone. It has been commonly associated with small cell carcinoma. The association of this syndrome with squamous cell lung carcinoma has rarely been reported, with only 4 cases over the past two decades in the English literature. We describe the case of a 75-year-old Caucasian male who developed the syndrome after a right pneumonectomy for down-staged squamous cell lung cancer previously treated with neoadjuvant platinum-based chemotherapy and radiotherapy.