Fatal Pulmonary Toxicity Research Articles

Preliminary Results of Developing Imaging Complexity Biomarkers for the Incidence of Severe Radiation Pneumonitis Following Radiotherapy in Non-Small Cell Lung Cancer Patients with Underlying Idiopathic Pulmonary Fibrosis.

Background: Idiopathic pulmonary fibrosis (IPF) has the potential to cause fatal pulmonary toxicity after radiotherapy and can increase the morbidity and mortality of non-small-cell lung cancer (NSCLC) patients. In this context, we aimed to develop imaging complexity biomarkers to predict the incidence of severe pulmonary toxicity in patients with NSCLC who have underlying IPF and are treated with radiotherapy. Methods: We retrospectively reviewed the medical records of 19 patients with NSCLC who had underlying IPF and were treated with radiotherapy at the Korea University Guro Hospital between March 2018 and December 2022. To quantify the morphometric complexity of the lung parenchyma, box-counting fractal dimensions and lacunarity analyses were performed on pre-radiotherapy simulation chest computed tomography scans. Results: Of the 19 patients, the incidence of grade 3 or higher radiation pneumonitis was observed in 8 (42.1%). After adjusting for age, sex, smoking status, histology, and diffusing capacity of the lung for carbon monoxide, eight patients with a lower fractal dimension showed a significantly higher hazard ratio of 7.755 (1.168-51.51) for grade 3 or higher pneumonitis than those with a higher fractal dimension. Patients with lower lacunarity exhibited significantly lower hazards in all models, both with and without adjustments. The lower-than-median lacunarity group also showed significantly lower incidence curves for all models built in this study. Conclusions: We devised a technique for quantifying morphometric complexity in NSCLC patients with IPF on radiotherapy and discovered lacunarity as a potential imaging biomarker for grade 3 or higher pneumonitis.

Bleomycin induces senescence and repression of DNA repair via downregulation of Rad51

BackgroundBleomycin, a potent antitumor agent, is limited in clinical use due to the potential for fatal pulmonary toxicity. The accelerated DNA damage and senescence in alveolar epithelial cells (AECs) is considered a key factor in the development of lung pathology. Understanding the mechanisms for bleomycin-induced lung injury is crucial for mitigating its adverse effects.MethodsHuman lung epithelial (A549) cells were exposed to bleomycin and subsequently assessed for cellular senescence, DNA damage, and double-strand break (DSB) repair. The impact of Rad51 overexpression on DSB repair and senescence in AECs was evaluated in vitro. Additionally, bleomycin was intratracheally administered in C57BL/6 mice to establish a pulmonary fibrosis model.ResultsBleomycin exposure induced dose- and time-dependent accumulation of senescence hallmarks and DNA lesions in AECs. These effects are probably due to the inhibition of Rad51 expression, consequently suppressing homologous recombination (HR) repair. Mechanistic studies revealed that bleomycin-mediated transcriptional inhibition of Rad51 might primarily result from E2F1 depletion. Furthermore, the genetic supplement of Rad51 substantially mitigated bleomycin-mediated effects on DSB repair and senescence in AECs. Notably, decreased Rad51 expression was also observed in the bleomycin‐induced mouse pulmonary fibrosis model.ConclusionsOur works suggest that the inhibition of Rad51 plays a pivotal role in bleomycin-induced AECs senescence and lung injury, offering potential strategies to alleviate the pulmonary toxicity of bleomycin.

RITUXIMAB INDUCED LUNG DISEASE IN A MANTLE CELL LYMPHOMA PATIENT RECEIVING MAINTENANCE: CASE PRESENTATION

Rituximab-induced lung disease (R-ILD) is a rare entity that should be considered in patients treated with rituximab who present with dyspnea, fever, and cough but no clear evidence of infection. We describe the clinical presentation, management, and response to rechallenge in one mantle cell lymphoma patient who developed R-ILD during maintenance rituximab. Case report 66 years old male with history of mantle cell lymphoma (MCL), who had been treated with RCHOP and underwent autologous stem cell transplantation (ASCT), was diagnosed with relapse 5 years after ASCT. Six courses of rituximab-bendamustine resulted in 2nd complete response and 2-monthly rituximab maintenance was initiated.10 days after 3rd rituximab , he presented with a 1 week history of progressive exertional dyspnea and cough. He was tachypneic and hypoxemic. Thorax HRCT showed peripheral bilateral patchy ground glass opacities and nodular opacities. Bronchoalveolar lavage identified no bacterial,viral or fungal pathogen. With presumptive diagnosis of late R-ILD, methylprednisolone(MP) 1 mg/kg/day was started. In absence of rapidly progressing respiratory failure and fever, the patient was evaulated as non severe R-ILD. Thus, rechallenge with rituximab is being considered due to the risk of relapse of MCL. Discussion: Reported rate of possible R-ILD is <0.03% in over 540,000 patients. Pulmonary complications of rituximab are hypersensitivity pneumonitis, ARDS, interstitial pneumonitis, organizing pneumonia, pulmonary fibrosis, and alveolar haemorrhage. Symptoms of R-ILD are dyspnea, fever, and hypoxemia and HRCT findings include focal alveolar densities, ground glass opacities and alveolar opacification. Time to symptom onset ranges from 1 day to several weeks after 1st infusion with mean mean duration of 3 months. Our patient had received rituximab prior to relapse and developed R-ILD after 9 doses of rituximab for relapse, which is a rare finding. All other causes of potential lung injury had to be meticulously excluded. ILD is a rare but potentially fatal pulmonary toxicity due to rituximab. As the symptoms at presentation are nonspecific, physicians must maintain a high index of suspicion to recognize it early and initiate treatment to avoid severe morbidity and mortality.

Pulmonary toxicities of molecular targeted antineoplastic agents: a single-center 10-year experience.

Background/AimsA better understanding of cancer cell biology has led to the discovery and development of several new targeted agents for cancer. These drugs are widely used in cancer treatment and have good toxicity profiles. However, some patients are extremely sensitive to these drugs and can develop severe toxicities. Among the toxicities, pulmonary complications are infrequent with most targeted therapies. This study aimed to identify the radiologic pulmonary complications in various targeted therapies and to analyze the characteristics of patients with pulmonary toxicity.MethodsWe retrospectively reviewed the medical records and chest image findings of 644 patients who were treated with targeted antineoplastic agents at Soonchunhyang University Hospital between May 2005 and September 2014.ResultsOf these 644 patients, 90 (14.0%) developed pulmonary complications as noted on chest computed tomography. Among these patients, 15 (2.3%) developed drug-related pulmonary toxicities. Treatment with targeted agents was discontinued in all patients, while 11 patients were simultaneously treated with glucocorticoids. Three patients died of drug-related pulmonary toxicity.ConclusionsDuring targeted therapy, clinicians should assess for pulmonary toxicities and symptoms that occur with dyspnea. If drug-induced pulmonary toxicities are suspected, imaging studies should be performed immediately, and the possibility of variable radiological patterns should be considered. Discontinuing the use of implicated causative agents and treatment with glucocorticoids resulted in an improvement in both symptoms and imaging findings, but some patients still experienced fatal pulmonary toxicities.

High incidence of radiation pneumonitis in lung cancer patients with chronic silicosis treated with radiotherapy.

Silica is an independent risk factor for lung cancer in addition to smoking. Chronic silicosis is one of the most common and serious occupational diseases associated with poor prognosis. However, the role of radiotherapy is unclear in patients with chronic silicosis. We conducted a retrospective study to evaluate efficacy and safety in lung cancer patients with chronic silicosis, especially focusing on the incidence of radiation pneumonitis (RP). Lung cancer patients with chronic silicosis who had been treated with radiotherapy from 2005 to 2018 in our hospital were enrolled in this retrospective study. RP was graded according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE), version 3.0. Of the 22 patients, ten (45.5%) developed RP ≥2. Two RP-related deaths (9.1%) occurred within 3 months after radiotherapy. Dosimetric factors V5, V10, V15, V20 and mean lung dose (MLD) were significantly higher in patients who had RP >2 (P < 0.05). The median overall survival times in patients with RP ≤2 and RP>2 were 11.5 months and 7.1 months, respectively. Radiotherapy is associated with excessive and fatal pulmonary toxicity in lung cancer patients with chronic silicosis.

Brentuximab Vedotin in Combination with Nivolumab, Doxorubucin, and Dacarbazine in Newly Diagnosed Patients with Advanced Stage Hodgkin Lymphoma

Brentuximab Vedotin in Combination with Nivolumab, Doxorubucin, and Dacarbazine in Newly Diagnosed Patients with Advanced Stage Hodgkin Lymphoma

Intensity modulated radiation therapy after extra-pleural pneumonectomy for malignant pleural mesothelioma is feasible without fatal pulmonary toxicity and provides good survival.

To analyze patterns of failure, toxicity, relapse-free survival (RFS), and overall survival (OS) in malignant pleural mesothelioma (MPM) patients treated with intensity-modulated radiation therapy following extrapleural pneumonectomy (EPP). We reviewed 18 charts of patients with MPM from 2005 to 2014 who underwent EPP followed by hemithoracic intensity-modulated radiation therapy. Intensity-modulated radiation therapy dose delivery adhered to published lung dose constraints. Kaplan-Meier curves were used to assess the RFS and OS. Median survival times are reported for both RFS and OS. Median age was 65 years (range: 40-76 years). Chemotherapy was administered in four neo-adjuvant and seven adjuvant patients. Pathological American Joint Committee on Cancer stages II, III, IV, surgical margin, lympho-vascular space, pericardium, and chest wall involvement were seen in 3, 12, 3, 9, 7, 12 and 3 patients, respectively. The majority of the patients received 45 Gy in 25 fractions. The mean lung dose was 7.14 Gy (range: 5 Gy-9.3 Gy). The mean V20 was 2.23%. At a median follow-up of 3 years, eight patients were alive (44%); 10 experienced relapse (56%). Median RFS and OS were 24.4 months (95% CI: >16.3 months) and 38.2 months (95% CI: 17.4-78.1 months), respectively. Acute toxicities were fatigue, dermatitis, nausea, esophagitis/dysphagia, cough, and dyspnea on exertion. No grade III, IV, or fatal pulmonary toxicities were observed. Intensity-modulated radiation therapy following EPP for MPM resulted in RFS and OS comparable to the published literature without significant toxicity.

Toxicity Burden of Bleomycin Treatment in Hodgkin Lymphoma: A Systematic Literature Review

Introduction: Bleomycin has been a component of chemotherapeutic regimens for decades, typically among young individuals who may survive for long periods. Yet, toxicity from bleomycin may result in short-term and long-term health problems. The study objectives were to characterize the occurrence and severity of bleomycin toxicities and identify risk factors for bleomycin toxicity among patients with Hodgkin lymphoma.Methods: A systematic literature review of the burden of bleomycin treatment in cancer patients was conducted using the PRISMA checklist. PubMed, EMBASE, and Cochrane Database were searched for English language articles between 1980 and March 2016 providing data on bleomycin toxicity in studies with >10 patients.Results: Overall, 18 original research articles of good to moderate quality were included in the systematic review for patients with Hodgkin lymphoma. Pulmonary toxicity ranged from dyspnea, pulmonary fibrosis, and pneumonitis, to acute respiratory distress syndrome and respiratory tract disorders or infections. For Hodgkin lymphoma, the proportion of patients experiencing pulmonary toxicity was >5% in 12 of 17 studies, with 8 studies reporting toxicity in 13% - 28% of patients. Other studies (n=5) reported that 0% - 4.7% of patients experienced pulmonary toxicity. About 4% -5% of Hodgkin lymphoma patients had fatal pulmonary toxicity. Skin toxicity ranged from skin rash to dermatitis and erythema, with 1% - 5% of Hodgkin lymphoma patients experiencing skin toxicity after bleomycin exposure.In the 4 studies that investigated risk factors for bleomycin-induced pulmonary toxicity among patients with Hodgkin lymphoma, low albumin level (<40 g/dL), treatment with anthracycline containing chemotherapy regimens and use of colony granulocyte stimulating factor concomitant with bleomycin were reported to be significant risk factors. No significant difference was found between patients with and without pulmonary toxicity in terms of exposure to radiation therapy, cumulative bleomycin dose, smoking history, or underlying lung involvement.Conclusions: Long-term pulmonary toxicity was not consistently evaluated in the studies and may understate the true burden on patients. Many patients treated with bleomycin may experience toxicity and sometimes fatal toxicity. Since Hodgkin lymphoma is a highly curable malignant disease and to further improve patient outcomes, attention needs to be focused on reducing treatment-related toxicities, particularly long-term morbidity and death associated with pulmonary events. DisclosuresFox:Seattle Genetics: Research Funding. Josephson:Seattle Genetics: Employment. Richhariya:Seattle Genetics, Inc.: Employment.

Abstract 3843: Pulmonary toxicities of molecular targeted antineoplastic agents

Abstract Background A better understanding of cancer cell biology has suggested many new targets for cancer drug discovery and development. And these drugs are widely used in treating cancer and usually have good toxicity profiles. But some patients are exquisitely sensitive to these drugs and can develop particular and severe toxicities. Among the toxicities, pulmonary toxicities are infrequent with most commonly used targeted therapies. The aim of this study was to review the pulmonary toxicities caused by molecular targeted agents and analyze the various radiologic findings and clinical outcomes in these patients group. Methods We retrospectively reviewed the medical records and chest image findings of 549 patients who were treated by molecular targeted anti-neoplastic agents at Soonchunhyang University Hospital between May 2003 and September 2012. Patients who had chest image findings that suspected infection, pulmonary hemorrhage caused by other cause and primary disease progression were excluded. Results Of these 549 patients, 364 patients performed chest CT or HRCT during targeted agent therapy. Thirty-four patients (6.2%) with drug induced pulmonary toxicities confirmed by radiologist and oncologist were identified. The most common targeted agent that induced pulmonary toxicities was gefitinib (9/34 patients), followed by rituximab, imatinib, erlotinib, cetuximab, trastuzumab, bevacizumab, bortezomib, and dasatinib. Pneumonitis (44.1%) and pleural effusion (32.4%) were common radiological findings. Dyspnea was the main presenting initial symptom and proportion in symptomatic patients (18/34 patients, 52.9%) was mostly 83.3% (15/18 patients). Sixteen patients stopped being treated with targeted agents, 11 patients were simultaneously treated with glucocorticoids. Sixteen patients did not receive any other treatment and were observed with regular follow ups. Of 34 patients, 20 patients (58.8%) resolved pulmonary toxicity from chest CT imaging. There were four patients (11.7%) who died from drug related pulmonary toxicity. Conclusion Pulmonary toxicities caused by targeted agents are rare but important to recognize. Dyspnea appears to be the main presenting symptom. In conclusion, we should be aware of pulmonary toxicities and symptoms presenting dyspnea during targeted agent therapy. If we suspect drug induced pulmonary toxicities, we should perform immediate imaging studies and keep a possibility of variable radiological patterns in mind. The cessation of the implicated causative targeted agents and treatment with systemic glucocorticoids resulted in an improvement both in symptoms and image findings, but fatal pulmonary toxicities occurred in some patients. Citation Format: Seug Yun Yoon, Namsu Lee, Sook-Ja Kim, Hee-Jeong Cheong, Kyoung Ha Kim, Jong-Ho Won. Pulmonary toxicities of molecular targeted antineoplastic agents. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3843. doi:10.1158/1538-7445.AM2014-3843

Rituximab Induced Interstitial Lung Disease in Patients with Non-Hodgkin’s Lymphoma: A Clinical Study of Six Cases and Review of the Literature

Background. Rituximab-induced lung disease (R-ILD) is a rare entity that should be considered in patients treated with rituximab who present with dyspnea, fever, and cough but no clear evidence of infection. Aim. The aim of this prospective longitudinal study is to describe the clinical presentation, management, and response to rechallenge in patients diagnosed with rituximab induced ILD over a period of one year. Results. Out of sixteen patients with CD20 positive non-Hodgkin’s lymphoma who received rituximab along with standard chemotherapy, six patients developed features suggestive of R-ILD. Four (66.6%) of these patients had diffuse large B cell lymphoma. The median time of presentation of R-ILD was after the 3rd cycle of chemotherapy. Three patients (50%) presented with acute onset of high fever, dyspnea, and dry cough while the remaining three presented with insidious onset of dyspnea and dry cough. An infectious etiology for the respiratory illness was ruled out in all patients with an exhaustive work-up. Four patients (66.6%) responded to corticosteroid treatment and supplemental oxygen. One patient required mechanical ventilation and succumbed to ILD while another required prolonged supplemental oxygen. Two (33.3%) of patients were successfully rechallenged with rituximab under cover of corticosteroids. Conclusions. Rituximab induced lung disease is a rare but potentially fatal pulmonary toxicity which requires a high index of suspicion for early diagnosis and treatment.

Fatal Nitrofurantoin-Induced Pulmonary Toxicity: A Potentially Preventable Medical Error

Nitrofurantoin is a commonly prescribed urinary antiseptic both for acute treatment and prophylaxis against recurrent urinary tract infections. It is known for its safety, efficacy, tolerability and cost-effectiveness. Rarely, nitrofurantoin can cause acute and chronic lung and liver diseases. Acute pulmonary toxicity due to nitrofurantoin is more common than its chronic form and is probably a hypersensitivity reaction to the drug. In contrast, the chronic pulmonary toxicity appears to be due to cumulative drug exposure leading to chronic inflammation and fibrosis and is therefore an irreversible process. What predisposes to the rare and severe form of acute pulmonary toxicity is unknown. In this case, it appears that renal impairment may have played a role as a predisposing factor.

Amiodarone-Induced Pulmonary Toxicity—A Fatal Case Report and Literature Review

Amiodarone is a widely used and very potent antiarrhythmic substance. Among its adverse effects, pulmonary toxicity is the most dangerous without a causal treatment option. Due to a very long half-life, accumulation can only be prevented by strict adherence to certain dosage patterns. In this review, we outline different safe and proven dosing schemes of amiodarone and compare the incidence and description of pulmonary toxicity. Reason for this is a case of fatal pulmonary toxicity due to a subacute iatrogenic overdosing of amiodarone in a 74-year-old male patient with known severe coronary artery disease, congestive heart failure and ectopic atrial tachycardia with reduced function of kidneys and liver but without preexisting lung disease. Within 30 days, the patient received 32.2 g of amiodarone instead of 15.6 g as planned. Despite early corticosteroid treatment after fast exclusion of all other differential diagnoses, the patient died another month later in our intensive care unit from respiratory failure due to bipulmonal pneumonitis.

Short-term onset of fatal pulmonary toxicity in a patient treated with intravenous amiodarone for post-operative atrial fibrillation

A 77year-old man was admitted to our Institution with the diagnosis of adenocarcinoma of the cardia. The patient had no history of pulmonary or cardiac disease. In the past he had been a heavy smoker, he had undergone distal gastric resection for duodenal ulcer, but he did not complain of any pulmonary symptoms.

Pulmonary toxicity among cancer patients treated with a combination of docetaxel and gemcitabine: a meta-analysis of clinical trials

The combination of docetaxel and gemcitabine was tested in several studies in patients with lung, breast, and pancreatic cancers and other tumor entities. Some studies reported cases of severe or even fatal pulmonary toxicity that led to early termination of some trials. We created a meta-analysis model of published studies to identify explanatory factors for docetaxel-gemcitabine-dependent pulmonary toxicity. We searched MEDLINE/Pubmed, EMBASE, and Cochrane Clinical Trials database for prospective full-text studies that used a schedule of docetaxel and gemcitabine to treat a malignant disease. We performed a meta-analysis for proportions using the arcsine transformation and a meta-regression using a generalized linear mixed model based on a binomial distribution and a logit link. We included 103 trials with 113 treatment arms comprising 5,065 patients (major entities included non-small cell lung cancer (n = 2,550), breast cancer (n = 1,119), pancreatic cancer (n = 466), and urothelial cancer (n = 161)). For the incidence of severe lung toxicity (common toxicity criteria [CTC] grades 3-5), we found a combined estimate of 2.70% (95% CI 2.26, 3.14). The estimate for the proportion of fatal cases was 0.35% (95% CI 0.21, 0.58). We found that the sequence of the chemotherapy schedule had no influence on the incidence of severe pulmonary adverse events (F-test F = 0.65, df = 3,113, P = 0.58) nor did the study phase, treatment line or ethnicity of the participants. We found that patients with breast cancer, compared to lung cancer patients, developed severe lung toxicity less frequently (OR = 0.18, 95% CI (0.09, 0.36)). We could not demonstrate that a particular chemotherapy sequence of docetaxel-gemcitabine is associated with excess pulmonary toxicity. Patients with lung cancer are at a higher risk for severe pulmonary side effects with docetaxel-gemcitabine than are patients with breast cancer.

Fatal interstitial lung disease associated with gemcitabine and erlotinib therapy for lung cancer

Gemcitabine in combination with the oral epidermal growth factor receptor tyrosine kinase inhibitor, erlotinib, is a treatment option for patients with advanced pancreatic cancer. Lung toxicity has been described for each of these drugs. A 59-year-old man with advanced non-small-cell lung cancer developed acute respiratory failure with bilateral interstitial lung disease 4 weeks after the onset of second-line combination therapy that included gemcitabine and erlotinib. Despite discontinuation of gemcitabine and erlotinib, treatment with corticosteroids was ineffective and the patient gradually deteriorated and died with progressive respiratory failure 2 months after the start of the gemcitabine/erlotinib combination. It was concluded that a synergistic effect between gemcitabine and erlotinib could have been responsible for this fatal pulmonary toxicity. Physicians should be aware of the potential severe lung toxicity of this combination. The potential role of corticosteroids in the management of this toxicity is unknown.

Alternatives to Standard BEP x 3 in Good-Prognosis Germ Cell Tumors--You Bet Your Life

Curing systemic cancer is rare and precious. In treating adult patients with systemic malignancies, rarely do medical oncologists have the opportunity to operate at the favorable asymptote of the therapeutic curve, perhaps only in early-stage favorable Hodgkin lymphoma and good-prognosis testicular cancer. In both cases, expectations for a cure with standard therapy routinely exceed 95% in clinical trials and in large population-based experiences. This situation has not changed for either disease for many years. Particularly in such rare diseases, it is logistically and statistically impossible to demonstrate any strategy that will improve cure rates. Indeed, in good-prognosis testicular cancer, there have been a number of attempts to demonstrate only equivalence to the standard bleomycin, etoposide, and cisplatin (BEP) chemotherapy regimen (in hopes of defining a regimen that might have some toxicity advantages). In 20 years of attempts to decrease standard BEP doses, and as reported by Grimison et al. (1) in this issue of the Journal, virtually all efforts have fallen short of the standard BEP effectiveness bar (2–7). Not curing one patient with a good-prognosis disseminated germ cell tumor costs, on average, 40 years of productive highquality life. What clinical trial questions are of sufficient magnitude to jeopardize the meaty therapeutic gains of standard BEP? One could certainly argue that few of the attempts to date to improve the toxicity profile of three cycles of standard BEP (BEP × 3) while trying to maintain efficacy was worth the effort. Like the challenge of proving equivalent therapeutic punch, proving that any testicular cancer chemotherapeutic regimen is better tolerated than standard BEP × 3 is difficult precisely because in the modern era with the brief 9-week schedule, low cumulative doses, and modern supportive care, BEP × 3 is generally well tolerated with largely only short-term toxicity. The results of clinical trials on the toxicity side of the equation have shown mostly clinically insignificant and often evanescent improvements in toxicity, in particular, slightly fewer low-grade cutaneous and vascular side effects. Adding an additional cycle of cisplatin in an attempt to accommodate less than full doses of bleomycin or etoposide may, in aggregate, be adding long-term toxicity as seen in this 8-year follow-up study by Grimison et al. (1). A careful review of modern trials and large experiences with good-prognosis testicular cancer treatment reveals that the current delivery of standard BEP for three cycles only is nearly devoid of serious or fatal pulmonary toxicity, etoposideinduced leukemia, or death from neutropenic complications. BEP in the standard dose and schedule that was described more than 25 years ago has been a remarkably effective, remarkably safe, 9-week, largely outpatient regimen. When given by skilled and attentive chemotherapists with appropriate modern supportive care, patients are reliably cured and quickly return to full and productive activities with few long-term physical sequelae of their treatment. The primacy of BEP × 3 for treatment of good-prognosis disseminated germ cell tumors is now well embedded in emerging guidelines for the management of testicular cancer in both Europe and Canada (8,9). The results of the last 20 years of attempts to improve upon standard BEP, with consistent failure of alternative regimens to maintain the curative potential of BEP × 3, should call into question any deviations from the precise doses and schedule of this regimen in routine clinical practice. There is now sufficient evidence to say that deviation from standard BEP × 3 is a potentially life-threatening decision and, therefore, requires a corresponding life-threatening reason to drop bleomycin or to extend the 21-day schedule or to tinker with the etoposide dose. In addition, in terms of routine clinical practice, there must be a compelling medical reason to use etoposide and cisplatin for four cycles rather than BEP × 3 (eg, advanced age, substantial renal insuffi ciency, demonstrable clinically significant pulmonary compromise), and these two regimens should not be viewed as equally effective options. This question has been addressed formally by a randomized trial conducted in France (7), in which it was concluded that

Pulmonary toxicities of biologics: a review

With the advancement of research in cancer treatment more and more drugs are being introduced for the treatment of cancer. In this review study, we have tried to look at some of the relatively newly introduced drugs, commonly referred to as biologics. The aim of this study was to review the very rare but fatal pulmonary toxicities (mostly interstitial lung disease) caused by these drugs. The drugs that were reviewed are rituximab, cetuximab, bevacizumab, alemtuzumab, and trastuzumab. This review basically aims at presenting a basic introduction (mechanism of action and indications of use) of these drugs followed by a summary of the incidence, various clinical presentations, diagnosis, treatment options, and outcome of patients around the world who presented with pulmonary toxicities caused by these drugs.

Pulmonary Toxicity after a Quick Course of Combinatorial Vincristine, Bleomycin, and Cisplatin Neoadjuvant Chemotherapy in Cervical Cancer

Pulmonary toxicity is one of the most serious adverse effects associated with a quick course of vincristine, bleomycin, and cisplatin neoadjuvant chemotherapy (NAC-VBP). The aim of this study was to evaluate pulmonary toxicity related to a quick course NAC-VBP. A total of consecutive 61 patients, who underwent at most 3 cycles of NAC-VBP every 10 days in the International Federation of Gynecology and Obstetrics (FIGO) stage IB-IIB cervical cancer from 1995 to 2007, were retrospectively analyzed. Of the 61 study subjects, 7 (11.5%) were identified to have pulmonary toxicity and 2 (3.3%) died of pulmonary fibrosis progression despite aggressive treatment and the use of a multidisciplinary approach. No factor predisposing pulmonary toxicity was identified. Initial symptoms were non-specific, but bronchiolitis obliterans organizing pneumonia and interstitial pneumonitis were characteristic findings by high-resolution computed tomography of the chest. The benefit of steroid therapy was uncertain and was associated with steroid-induced diabetes mellitus requiring insulin therapy in two patients. Fatal pulmonary toxicity is a major concern of a quick course NAC-VBP. In conclusion, these patients require special monitoring for bleomycin-induced pulmonary toxicity.

Fatal gemcitabine-induced pulmonary toxicity in metastatic gallbladder adenocarcinoma

Gemcitabine is a chemotherapy agent that may cause unpredictable side effects. In this report, we describe a fatal gemcitabine-induced pulmonary toxicity in a patient with gallbladder metastatic adenocarcinoma. A 72-year-old patient was submitted to an elective laparoscopic cholecystectomy, and a tubular adenocarcinoma in the gallbladder was incidentally diagnosed. CT scan and ultrasound before the surgery did not show any tumor. After the surgery a Pet scan was positive for a hot-spot in the left colon. The colonic lesion was conveniently removed and the histology evaluation confirmed the diagnosis of adenocarcinoma tubular. The patient was then submitted to three sections of 1,600 mg/m2 of gemcitabine with intervals of 1 week. Three weeks later he developed severe respiratory distress. A helicoidal CT scan showed diffuse and severe interstitial pneumonitis, and lung biopsy confirmed accelerated usual interstitial pneumonia consistent with drug-induced toxicity. The patient presented unfavorable evolution with progressive worsening of respiratory function, hypotension, and renal failure. He died 1 month later in spite of methylprednisolone pulse therapy, large spectrum antimicrobial therapy, and full support of respiratory, hemodynamic and renal systems. Gemcitabine-induced pulmonary toxicity is usually a dramatic condition. Physicians should suspect pulmonary toxicity in patients with respiratory distress after gemcitabine chemotherapy, mainly in elderly patients.

Patterns of Local and Nodal Failure in Malignant Pleural Mesothelioma After Extrapleural Pneumonectomy and Photon-Electron Radiotherapy

Multimodality therapy including extrapleural pneumonectomy (EPP), chemotherapy, and radiotherapy (RT) is often recommended for fit patients with early stage malignant pleural mesothelioma. Planning RT after an EPP is difficult due to the large target area, the high doses required to prevent recurrence, and the proximity of critical structures. We studied patterns of local and nodal recurrence in patients treated at our institution with EPP and RT, and whether advanced treatment planning techniques, such as intensity modulated radiotherapy (IMRT), could have been of potential benefit. From 1993 to 2008, 86 patients with malignant pleural mesothelioma underwent EPP followed by hemithoracic RT (median dose: 54 Gy). The RT technique included a combination of photons and electrons to maximize dose to the target, whereas minimizing dose to normal tissues. After treatment, patients were followed with serial imaging and patterns of local and nodal failure were studied. Median follow-up time for 78 analyzed patients was 17 months. Eight percent were in stage I, 35% stage II, 55% stage III, and 2% stage IV. Ten percent of all patients developed late grade 3 pulmonary toxicity and no patient died of RT. Fifteen patients failed in local and/or nodal sites and did not have a distant component to their failure pattern. Of these 15 patients, 10 failed in regions of dose inhomogeneity and could have possibly benefited from IMRT. The photon-electron technique was tolerable, but IMRT may provide better target coverage in some patients. IMRT's advantages must be balanced against the increased risk of fatal pulmonary toxicity.