Fabiana Letizia Cecere

Medical treatment of advanced non-small cell lung cancer in elderly patients: A review of the role of chemotherapy and targeted agents

Lung cancer is the leading cause of cancer related mortality worldwide. Non-small cell lung cancer (NSCLC) accounts for 85% of all cases. Half of the patients at diagnosis of NSCLC are over seventy years old; therefore, the elderly represent a large subgroup of patients affected by advanced NSCLC in our clinical practice. Nevertheless, the elderly are under-represented in clinical trials. Given the fact that old age is frequently associated with several comorbidities, poor general conditions and physiologic reduction in organ function, clinicians must carefully choose the best treatment option for elderly patients with advanced NSCLC, always taking into account the expected risks and benefits. In this paper we perform a review of literature evidence regarding the medical treatment of elderly patients affected by advanced NSCLC, encompassing single-agent chemotherapy, doublet chemotherapy and targeted agents. We conclude that single-agent chemotherapy with a third generation agent (vinorelbine, taxanes, gemcitabine) represents a valid treatment option for elderly patients who are not eligible for a combination chemotherapy due to clinical features such as comorbidities, poor performance status and inadequate organ function. Platinum-based doublet chemotherapy shows similar efficacy in elderly patients as compared to their younger counterpart, despite greater treatment related toxicity and it is indicated in elderly patients with ECOG PS: 0-2, adequate organ function and no major comorbidities. Elderly patients affected by epidermal growth factor receptor (EGFR) mutated NSCLC benefit mostly from a tyrosine kinase inhibitor of EGFR (erlotinib, gefitinib) which is associated with a good toxicity profile. Currently there are no available data to strongly support the use of bevacizumab in combination with first line chemotherapy in the treatment of older adults. Elderly patients affected by NSCLC harboring the EML4-ALK translocation could benefit mostly from a treatment with an oral inhibitor of such a rearrangement (crizotinib).

Phase II trial of customized first line chemotherapy according to ERCC1 and RRM1 SNPs in patients with advanced non-small-cell lung cancer.

OBJECTIVESnCustomized chemotherapy has several advantages: patients are more likely to be treated with the most effective agents and can be spared the toxicity of ineffective drugs. Based on the literature, excision repair cross complementation group 1 (ERCC1) and ribonucleotide reductase M1 (RRM1) genes represent predictive biomarkers of response to platinum compound and gemcitabine, in NSCLC.nnnMATERIALS AND METHODSnWe had planned a phase II trial (Simon design) to evaluate combination chemotherapy according to single nucleotide polymorphisms (SNPs) of ERCC1 (118T/C and 8092C/A) and RRM1 (-37C/A and -524T/C) in naïve patients affected by advanced NSCLC. ERCC1 and RRM1 SNPs assessment was performed in peripheral blood lymphocytes (PBLs). Combination chemotherapy was selected based on ERCC1 and RRM1 SNPs: we assume that patients with one or two C alleles at position 118 and with one or two A alleles at position 8092 in ERCC1 gene would correspond to Cisplatin non-responder and than with two A alleles at -37 and two C alleles at -524 in RRM1 gene to gemcitabine non-responder. Four schedules were provided: cisplatin+gemcitabine, cisplatin+docetaxel, gemcitabine+docetaxel; docetaxel+vinorelbine. Primary endpoint was overall response (ORR) in the intention-to-treat population.nnnRESULTSn42 patients were enrolled from January 2010 to November 2011; 40 patients received at least 1 cycle of chemotherapy; median age was 66 years (range: 47-72); 36(90%) had stage IV, 4(10%) IIIB; 23(58%) had adenocarcinoma, 14(35%) squamous carcinoma. Twenty-five (62%) patients received treatment A, 3(8%) treatment B, 11(28%) treatment C, 1(23%) treatment D. ORR was 55%, analysis in squamous patients subgroups showed 71.4% ORR. The median follow-up was 19.7 months, PFS was 23 weeks (95% CI = 15-26) and OS was 40.4 weeks (95% CI = 32-55). Treatment was well tolerated.nnnCONCLUSIONnWe observed an increase of ORR in NSCLC patients when they were treated with chemotherapy according to ERCC1 and RRM1 SNPs status.

Gender differences: implications for clinical trials and practice.

Lung cancer has been the leading cause of cancer death among men in the United States and throughout the world for years, and since 1988, it has become the number one cause of cancer death among women. More women die annually of lung cancer than of breast, ovarian, and uterine cancers combined. More than 81,000 new cases of lung cancer were diagnosed in American women in 2006.1 It is estimated that 72,000 women will die of progressive lung cancer, accounting for 26% of all cancer deaths in women.1 Lung cancer, rare in women in the early 1900s, has progressively reached epidemic proportion. In the past 30 years, there has been a fourfold increase in lung cancer, referred to as a “contemporary epidemic.”2 The increase in the incidence of lung cancer among women is primarily the result of an increase in their tobacco use. Just as in men, most (85–90%) lung cancers among women are considered to be caused by smoking. Women began smoking in significant numbers in the 1940s, and although overall smoking rates have declined since reaching a peak in the 1970s, the current prevalence of smoking among women is still alarmingly high (22% in 2004).3 There is considerable controversy over the relative risk (RR) for lung cancer among women versus men at any given level of tobacco exposure. Several case control studies from the 1990s have argued that women are more susceptible to the carcinogens in cigarette smoke than men. Recently, Henschke and Miettinene evaluated the absolute risk for lung cancer in a high-risk population of women and men older than 40 years and with at least a 10-pack-year tobacco history who underwent baseline computed tomography (CT) screening for lung cancer. After adjusting for age and smoking history, the risk for lung cancer among women versus men was 2.7.4 However, an analysis of the Nurses’ Health Study of more than 60,000 women and the Health Professionals Follow-up Study of more than 25,000 men failed to find an increased lung cancer risk among women.5 Regardless of sex differences in the RR of lung cancer among smokers, lung cancer seems to be a different disease in women. Moreover, multiple studies suggest that women may be more susceptible than men to the carcinogenic effects of cigarette smoke as a result of genetic, metabolic, and hormonal factors.

Severe rhabdomyolysis associated with pemetrexed-based chemotherapy.

Pemetrexed is an antifolate metabolite that inhibits several enzymes involved in the folate pathway. It has activity against various solid tumours, and has been approved for treatment of malignant pleural mesothelioma on the basis of fi ndings from a randomised phase III trial. The main toxic eff ects noted for pemetrexed have been rash, myelosuppression, diarrhoea, mucositis, and reversible elevation of liver enzymes—eff ects that are preventable partly by vitamin supplementation. A 68-year-old man with malignant pleural mesothelioma had extrapleural pneumonectomy followed by external mediastinal radiotherapy (50 Gy total dose, completed in March, 2003). Because of distant disease progression involving supradiaphragmatic and infradiaphragmatic lymph nodes and a biopsy-confi rmed metastatic nodule in the mammary gland, he received 500 mg/m2 pemetrexed, given as an intravenous infusion over 10 min followed at least 45 min later by carboplatin (AUC [area under the curve] 5, given as an intravenous infusion over 60 min) in the setting of an expanded access trial in January, 2004. As requested per protocol, he was given full vitamin supplementation (ie, 400 μg folic acid a day orally and 1 mg vitamin B12 as one intramuscular injection every 9 weeks), starting 14 days before fi rst trial treatment. The patient was given 4 mg dexamethasone twice a day intramuscularly on the day before chemotherapy and the day after chemo therapy; on the day of chemotherapy, he received 16 mg dexamethasone, 50 mg ranitidine, and 8 mg ondansetron intravenously. No acute toxic eff ects were reported. On day 2 after chemotherapy, he developed severe and gradually worsening myalgias, weakness of the arms and legs, and abdominal tenderness. On day 4 after chemotherapy, he was therefore admitted to the accident and emergency department. Physical examination showed a severely ill patient with weakness in both arms and both legs. Laboratory tests on admission showed substantially increased serum concentrations of creatine kinase (21 530 U/L), myoglobin (3000 μg/L), aspartate aminotransferase (453 U/L), and alanine aminotransferase (159 U/L); serum electrolytes and renal-function tests were normal. The patient was diagnosed with rhabdomyolysis. The patient was treated with vigorous fl uid replacement with the addition of sodium bicarbonate, methylprednisolone, and furosemide. On the third day in hospital, concentration of creatine kinase decreased to 1835 U/L, and the weakness improved slowly during the following weeks. However, the patient was unable to do his normal daily activities, and 1 month later he was transferred to a long-term hospital clinic for muscular rehabilitation, at which stage serum concentrations of creatine kinase and transaminases were normal. Drug-induced rhabdomyolysis is a fairly common and potentially life-threatening syndrome associated with several drugs, including chemotherapeutic agents. In patients with cancer, rhabdomyolysis has been reported in association with exposure to high-dose interferon alfa, vancomycin after high-dose chemotherapy with peripheralblood stem-cell transplantation, and the combination of cyproterone and statins. To our knowledge, this is the fi rst report of severe and life-threatening rhabdomyolysis during pemetrexed-based chemotherapy. Moreover, to our knowledge, no cases of rhabdomyolysis have been reported as a consequence of exposure to other structurally related drugs such as methotrexate and raltitrexed. The causal association of rhabdomyolysis with pemetrexed in our patient is suggested by a temporal relation and by the absence of concomitant exposure to any other drugs potentially involved with this clinical syndrome, including statins. Although to our knowledge no cases of rhabdomyolysis have been reported with carboplatin-based regimens, with the exception of a patient with a testicular germ-cell tumour given high-dose ifosfamide, carboplatin, and etoposide and peripheralblood stem-cell transplantation, we cannot presently rule out its involvement in the pathogenesis of this particular patient. Nevertheless, we think that clinicians should be aware of this possible, although rare, complication of pemetrexed-based treatment to recognise promptly and treat successfully the potentially life-threatening disorder of rhabdomyolysis.

Adjuvant Chemotherapy for Non-small Cell Lung Cancer

Cisplatin must be considered the treatment standard for lung cancer chemotherapy, whatever the disease setting, at least in the Western world. After the seminal meta-analysis published in 1995, 12 randomized clinical trials (RCTs) exploring the benefits of adjuvant cisplatin-based chemotherapy have been completed, published, or presented. Although all these RCTs differ in patient features, two common suggestions emerge when the stage is taken into account: a significant benefit for chemotherapy is demonstrated for stage II and IIIA patients and none of these trials showed any significant benefit for adjuvant chemotherapy in stage IB patients. Ten years after this meta-analysis, a further individual patient data-pooled analysis exploring the eventual benefits of adjuvant cisplatin-based chemotherapy after surgery for early stage non-small cell lung cancer in the more recent RCTs has been presented. The 5-year overall survival benefit in favor of cisplatin-based chemotherapy was 5.3% (48.8% versus 43.3%, p = 0.004), with a relative risk reduction of 11%. These results confirm those reported by previous meta-analyses performed according to a literature-based approach. Advances are emerging in the selection of those patients who are likely to benefit more from such treatment. In this respect, the customized therapy based on molecular/genetic patient and disease features constitutes a new avenue to pursue.

Severe rhabdomyolysis during sunitinib treatment of metastatic renal cell carcinoma. A report of two cases

Here, we report two cases of severe rhabdomyolysis, regarding patients with metastatic renal cell cancer (RCC) receiving treatment with sunitinib. The first case was a 74-year-old woman with lung and bone metastases from RCC diagnosed in 2007. Neither comorbities were present nor concomitant treatments were given. Karnofsky performance status (KPS) was 100. Cardiac, hepatic, bone marrow and thyroid function were within the normal range. Serum creatinine was normal. The left ventricular ejection fraction (LVEF) at baseline was 65%. The patient started first-line treatment with sunitinib at the dose of 37.5 mg/day on a schedule of 4/2. No major toxic effects were registered until the day 26 of the third course when the patient presented severe weakness, asthenia, oliguria with renal failure along with marked elevation of transaminases, lactate dehydrogenase (LDH), creatine–phosphokinase (CPK) and myoglobin (Table 1). No alteration of the thyroid function was present. No sign of cardiac damage was observed on electrocardiogram, while the echocardiogram showed a marked decrease of LVEF to 28%. Acute myocardial infarction was ruled out as a cause of the elevated CPK levels, and a diagnosis of rhabdomyolysis was established. After 3 days, a right pleural effusion, anuria and hypotension together with a dramatic rise in the levels of myoglobin and CPK were detected. Then, the patient presented coma and died few hours later. The second case was a 77-year-old man with multiple lung metastases from RCC diagnosed in 2004. At start of treatment with sunitinib (50 mg/day, schedule 4/2), his KPS was 100% and no alterations in the cardiologic and hematologic tests were present. Serum creatinine was within normal range. At fourth cycle, an asymptomatic hypothyroidism was detected. Thyroid replacement treatment was started and sunitinib therapy continued. At the end of the fifth cycle, the patient presented generalized impairment in carrying out normal daily activities (KPS of 40); marked asthenia; jaundice; thrombocytopenia and increased values of creatinine, transaminases and CPK. Bilateral pleural effusion and ascites were detected, as well as imaging suggestive of cirrhotic liver. On day 3, the patient developed anuria; severe dyspnea and an increase of transaminases; bilirubin, myoglobin, CPK and LDH (Table 1). A computed tomography scan suggested an acute heart failure together with ground glass areas in lungs, bilateral pleural effusion and liver stasis. The echocardiogram showed an LVEF of 28% with diffuse hypokinesia. The patient underwent hemodialysis until spontaneous diuresis and normalization of renal function tests was attained. During the following weeks, the patient recovered and all laboratory tests normalized. An improvement of cardiac function was seen (LVEF: 34%) and 6 months later, the patient is alive with a stable disease and an LVEF of 50%. These two cases are suggestive of rhabdomyolysis secondary to sunitinib therapy. Cases of rhabdomyolysis had already been described [1–5]. Acute kidney failure is the most serious complication of rhabdomyolysis. In our cases, the severity and the outcome may be related both to the multiorgan failure and to the fact that both patients were nephrectomized. Sunitinib is a standard of care for patients affected with mRCC with good or intermediate prognosis and is considered as a safe and effective treatment, although cardiovascular events have received increased attention. It has been suggested that the cardiotoxicity may be the result of a direct effect of this drug on the myocytes. The observation of two cases of acute rhabdomyolysis with multiorgan failure suggests that the damage may be directed to all striated muscles, including myocytes, and that the cardiotoxicity could be an epiphenomenon of a wider effect. This could partly explain the Table 1. Laboratory tests monitoring

Outcomes of First-Generation EGFR-TKIs Against Non-Small-Cell Lung Cancer Harboring Uncommon EGFR Mutations: A Post Hoc Analysis of the BE-POSITIVE Study

Background Beyond progression after tyrosine kinase inhibitor in EGFR‐positive non‐small‐cell lung cancer patients (BE‐POSITIVE) was the first Italian multicenter observational study that reported the outcomes of first‐generation epidermal growth factor receptor (EGFR)‐tyrosine kinase inhibitors (TKIs) in a “real‐life” Caucasian EGFR‐mutated non‐small‐cell lung cancer (NSCLC) population. The sharing of multi‐institutional experiences represents a crucial strategy to enrich knowledge about uncommon EGFR mutations. Therefore, we performed a post hoc analysis of the BE‐POSITIVE study. Patients and Methods Data of advanced NSCLC patients with uncommon EGFR mutations who received first‐line first‐generation EGFR‐TKIs in 24 Italian Hospitals were collected. In this analysis we aimed to evaluate overall survival (OS), progression‐free survival (PFS), and overall response rate (ORR) of EGFR‐TKIs in NSCLC patients harboring uncommon EGFR mutations. Results Thirty‐five patients harboring uncommon EGFR mutations (any mutation other than deletion 19 or substitution of leucine by arginine at codon 858) were included of the original 312 EGFR‐mutated cases. Most of them were female (n = 20, 57.1%), former smokers (n = 23, 65.7%), with adenocarcinoma (n = 31, 88.6%). The most frequent EGFR mutations were G719X (n = 6, 17.2%) and L861Q (n = 5, 14.2%). The population presented an ORR of 25.7%, a median PFS of 5.19 months, and a median OS of 14.49 months. When stratified according to type of EGFR mutation, median OS ranged from 3.65 months for unspecified mutations to 21.29 for double EGFR mutations. Median PFS ranged from 1.77 months for unspecified mutations to 20.83 months for concomitant EGFR‐anaplastic lymphoma kinase alteration. ORR varied from 0% in exon 18, 20 and double gene alteration to 66.6% in exon 19. Conclusion Our study supports the existence of a strong outcome heterogeneity within patients harboring uncommon EGFR mutations, which needs to be clarified to achieve a real personalized treatment strategy. Micro‐Abstract Non‐small‐cell lung cancer harboring uncommon epidermal growth factor receptor (EGFR) mutations (any mutation other than deletion 19 or substitution of leucine by arginine at codon 858) presents a variable sensitivity to EGFR‐tyrosine kinase inhibitors. With the final aim to enrich knowledge about uncommon EGFR mutations, we performed a post hoc analysis of the beyond progression after tyrosine kinase inhibitor in EGFR‐positive non‐small‐cell lung cancer patients (BE‐POSITIVE) trial. Thirty‐five patients were included of the original 312 EGFR‐mutated cases. The results of our analysis support the existence of a strong heterogeneity within patients harboring uncommon EGFR mutations, which implies the necessity to stratify the subgroups of rare mutations in individual entities with different clinical perspectives.

BE-POSITIVE: Beyond progression after tyrosine kinase inhibitor in EGFR- positive non small cell lung cancer patients: Results from a multicenter Italian observational study.

OBJECTIVESnNon-small-cell-lung-cancer (NSCLC) patients harbouring epidermal growth factor receptor (EGFR) mutations develop drug resistance after 9-12 months of EGFR tyrosine kinase inhibitors (TKIs) therapy pointing out the issue of the second-line treatment choice.nnnMATERIALS AND METHODSnFrom June 2009 until May 2013 patients affected by advanced NSCLC harbouring EGFR mutations receiving first-line TKI were collected mainly retrospectively in 24 Italian Centers. Primary objective was to describe the percentage of EGFR mutated patients receiving second-line therapy after progression to first-line EGFR-TKIs assessing the type, the activity in terms of objective response rate (ORR), efficacy in terms of progression free survival (PFS) and overall survival (OS), and safety of second-line treatment. Secondary objective was to describe the efficacy of first-line EGFR-TKIs.nnnRESULTSn312 patients were included. Most of them were females (203, 65.1%), never smokers (200, 64.1%), with adenocarcinoma histology (290, 92.9%). The most common mutations were EGFR exon 19 deletion and L858R, detected in 186 and 97 cases (59.6% and 31.1%), respectively. At data cut-off, 274 patients (95.1%) received any second-line treatment (including best supportive care or local treatments only). A total of 163 patients received second-line systemic therapy with an ORR of 20.9% (95% CI:14.62-27.10), a median PFS and OS of 4.7 (95% CI:3.81-5.26) and 24.5 (95% CI:21.65-27.37) months, respectively. Grade 3-4 hematological and non-hematological toxicities were reported in 9% and 6.3% of 144 patients treated with chemotherapy while non-hematological toxicity was reported in 4 cases of the 17 patients receiving second-line target agents.nnnCONCLUSIONSnBE-Positive is the first multicenter observational study reporting outcomes of therapies in a real-life Caucasian EGFR-mutated population, highlighting the need of further researches about new treatment strategies in this setting.

Pegylated liposomal doxorubicin (PLD) and gemcitabine (G) in metastatic breast cancer (MBC) patients: A phase II study

813 Background: PLD and G have recently demonstrated a clinical efficacy in MBC in mono-chemotherapy. We conducted a phase II clinical trial to determine the activity and safety of the two drugs in combination either in untreated or previously treated metastatic breast cancer women. Patients (pts) received PLD 25 mg/m2 i.v on day 1 plus G 800 mg/m2 i.v. on day 1 and 8 of each 21-day cycle.nnnMETHODSnTwenty-eight pts were entered into the study between January 2003 and December 2003. Median age: 55 years (range 33-71), median PS (WHO): 0 (0-2), predominant metastatic sites: lung (13 pts), liver (8 pts), bone (5 pts) and soft tissues (2 pts). The median number of previous chemotherapies given for metastatic disease was 1 (range 1-2). Fifteen women were chemotherapy naïve. Eleven pts (39%) were treated with anthracycline-containing regimen with a median anthacycline dose of 480 mg/m2. A median of 5 cycles were administered (range 1-8).nnnRESULTSnTwenty-one pts (1 early death, 6 too early) were assessable for response: 10 achieved partial response (47.6%), 5 (23.8%) stable disease, while 6 women (28.6%) experienced progressive disease. Among pretreated with anthacycline, 36% had a response. Among responders, 70% were chemotherapy naïve while 30% had previously received 1st or 2nd line chemotherapy. Median duration of response and time to progression were 6 months (range 4-9) and 5.8 months (range 1-9), respectively. Only grade 3-4 neutropenia was observed in 11 pts (39%); one case (3.5%) of febrile neutropenia occurred. Grade 3 mucositis and peripheral paresthesia were observed in 3 (11%) and 1 (3.5%) pts, respectively; one pt (3.5%) had a grade 2 hand-foot syndrome; seven pts (25 %) complained of moderate/severe asthenia. No case of cardiotoxicity or LVEF reduction was observed, even among pts previously treated with anthacyclines.nnnCONCLUSIONSnThe combination of PLD and G shows activity and a good tolerability. It seems to be no evidence of cross-resistance between classic anthracyclines and PLD. This regimen seems to be adequate even for heavily treated and elderly women. No significant financial relationships to disclose.

Aromatase inhibitors in post-menopausal metastatic breast carcinoma

To summarise the advances in the hormonal treatment of post-menopausal metastatic breast cancer, this paper reviews the published literature regarding the randomised trials comparing aromatase inhibitors (AIs) versus tamoxifen as a first-line therapeutic choice, or AIs versus megestrole acetate (MEG) as a second-line option. The pooled analysis of these authors on AI versus MEG as a second-line option for post-menopausal metastatic breast cancer suggested that AIs do not add any significant benefit over MEG in terms of overall response rate (ORR) and time to progression. According to the Cochrane Database, use of an AI as a second-line therapy versus any other endocrine therapy (mostly MEG) has shown a significant benefit in terms of overall survival, but not for progression-free survival, clinical benefit (CB) or ORR. Concerning the authors’ comparisons between AIs versus tamoxifen as a first-line endocrine option in post-menopausal women with metastatic breast carcinoma, AIs seem to be superior to tamoxifen, with a significant benefit in terms of ORR, CB and time to progression being observed in favour of AIs over tamoxifen with fixed effects estimates. According to the Cochrane Database, there was an advantage to the use of AIs over tamoxifen in terms of progression-free survival and CB, but not for overall survival or ORR. With regards to toxicity, AIs show similar levels of hot flushes and arthralgia, increased risks of nausea, diarrhoea and vomiting, but a decreased risk of vaginal bleeding and thromboembolic events compared with other endocrine therapies. Weight gain, dyspnoea and peripheral oedema seem to be more frequent with MEG. At present, there is no proved overall survival difference in patients who are treated first with an AI and then with tamoxifen compared with the opposite sequence. In the metastatic setting, results are limited and are based on retrospective analyses.