Bleomycin-containing Regimens Research Articles

Incidence of pulmonary toxicity in bleomycin-containing regimens for testicular cancer with and without the use of growth factor.

The concurrent use of bleomycin and granulocyte colony-stimulating factors (G-CSFs) has historically been debated as a risk factor for bleomycin-induced pulmonary toxicity in patients with both testicular cancer and Hodgkin's lymphoma. The purpose of this study is to evaluate the incidence of pulmonary toxicity in patients with testicular cancer who were treated with bleomycin and pegfilgrastim concurrently. This is a retrospective study that includes male patients over the age of 18 years old diagnosed with testicular cancer who received bleomycin-containing chemotherapy regimens with and without the use of G-CSF agents. There were a total of 33 patients identified as receiving bleomycin, with 30 of those patients having received concurrent G-CSF therapy. Of the patients who received G-CSF therapy, 11 patients (36.6%) experienced pulmonary toxicity leading to discontinuation of bleomycin or changes in chemotherapy regimens altogether. There were no major differences in patient demographics or risk factors between those who received G-CSF and developed pulmonary toxicity and those who received G-CSF but did not develop pulmonary toxicity. Further studies are needed in order to fully assess the risk of pulmonary toxicity with this chemotherapy regimen.

The Risk-Benefit Balance of Treatments for Hodgkin Lymphoma Reported in the Randomised and Non-Randomised Trial Setting: A Systematic Review

Introduction: Hodgkin lymphoma (HL) is a cancer that originates in the lymphocytes. Current standard of care (SOC) therapies include combination chemotherapy and/or radiotherapy regimens. However, optimising treatment to obtain high efficacy with low toxicity remains a challenge. A systematic literature review (SLR) was conducted to identify relevant clinical evidence for front line treatments in the management of patients with advanced Hodgkin lymphoma (HL) (defined as stage IIb, III, and IV).Methods: A SLR was performed in July 2016 to summarise the efficacy and safety of front-line treatments for the management of patients with advanced HL.Results: In total, 70 unique studies, 38 randomised controlled trials (RCTs) and 32 non-RCTs, were identified and included in the review. Of the 38 included RCTs, nine were open-label trials, while the remaining 29 trials did not report details of blinding. Most patients with advanced HL reported durable remissions following front-line SOC treatment (ABVD and escBEACOPP) (Table 1); however, these treatment options are associated with adverse events. Further, up to 30% of advanced HL patients relapse after frontline treatment, indicating an unmet need for new therapies. The incidence of secondary malignancy at long-term follow-up after HL treatment remains a major adverse effect. Nine of the included studies reported secondary malignancy in 1.7-8.3% of patients, with acute myeloid leukaemia and non-Hodgkin lymphoma the most commonly observed secondary malignancies. However, the follow-up across these studies ranged from 5 to 8 years and the incidence of secondary malignancy are potentially underestimated due to limited follow-up. A single study reported that the cumulative incidence of secondary malignancies was 48.5% at 40 years follow-up. The risk of secondary malignancy was increased in patients receiving combined modalities compared with chemotherapy or radiotherapy alone and the risk is greater in men compared with women. The risk of second malignancy increases after initial therapy and remains elevated at ≥35 years after treatment. In the majority of studies radiotherapy was administered either as adjuvant or consolidation therapy. The most commonly reported adverse effects observed in patients receiving radiotherapy were nausea/vomiting, infections, secondary malignancy, and toxicities related to cardiovascular and pulmonary systems. Pulmonary toxicity was reported in up to 36% of patients across 23 studies with bleomycin-containing regimens. Discontinuation or dose reduction of bleomycin was associated with a decrease in the incidence of pulmonary toxicity; however, the impact of bleomycin dose reductions on efficacy outcomes was not statistically significant. Neutropenia and febrile neutropenia are also dose-limiting events that occur during chemotherapy in patients with malignant lymphoma. Granulocyte colony-stimulating factor, a haematopoietic growth factor which prevents neutropenia/febrile neutropenia, was used for primary or secondary prophylaxis in 7 and 5 of the studies included in the SLR, respectively.Conclusion: Failure rates of up to 30% and serious adverse events are reported following treatment with current standard of care therapies in newly diagnosed patients with advanced HL. Therefore, there exists an unmet medical need for an effective and well-tolerated therapy in HL. [Display omitted] DisclosuresDalal:Takeda Pharmaceuticals International Co: Employment, Equity Ownership. Mitchell:DRG Abacus: Employment. McCloskey:DRG Abacus: Employment. Zagadailov:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Gautam:Takeda Pharmaceuticals International Co: Employment, Equity Ownership.

The Role of Hypertension and Renin-angiotensin-aldosterone System Inhibitors in Bleomycin-induced Lung Injury

IntroductionThe risk factors for bleomycin-induced lung injury (BLI), a fatal complication of cancer chemotherapy, are not well-established. The renin-angiotensin-aldosterone system (RAAS) has recently been suggested to play a role in the development of lung injury. This study clarified the impact of hypertension (HTN) and the administration of RAAS inhibitors on BLI occurrence in patients treated with bleomycin-containing regimens. Patients and MethodsWe retrospectively analyzed the data of 190 patients treated with a bleomycin-containing regimen for Hodgkin lymphoma or germ cell tumors at our institutions from 2004 to 2018. ResultsOverall, 190 patients received bleomycin, and symptomatic BLI occurred in 21 (11.1%) cases. In the multivariate analysis, age ≥ 65 years (odd ratio, 10.90; 95% confidence interval, 3.72-32.20; P < .001) and history of HTN (odds ratio, 3.32; 95% confidence interval, 1.07-10.30; P = .04) were found to be significant risk factors for BLI onset. BLI occurred in 3.6% (n = 5) of patients with no risk, 11.8% (n = 2) of those whose only risk factor was HTN, 31.6% (n = 6) of those whose only risk factor was age ≥ 65 years, and 57.1% (n = 8) of those with both risk factors (P < .001). BLI-induced mortality rates in each group were 0.0% (n = 0), 5.9% (n = 1), 10.5% (n = 2), and 42.9% (n = 6) (P < .001), respectively. Among 31 patients with HTN, BLI incidence was 12.5% in patients who were administered RAAS inhibitors and 53.3% in those who were not (P = .02). ConclusionOlder age and history of HTN were independent risk factors for the development of BLI, and the administration of RAAS inhibitors might reduce the onset of BLI.

Outcome of elderly patients with classical Hodgkin lymphoma (HL) in British Columbia.

8031 Background: Outcomes in elderly patients (pts) with Hodgkin lymphoma (HL) have traditionally been poor. We evaluated the survival of elderly pts (&gt;60 years [y]) with classical HL in British Columbia (BC). Methods: All pts aged &gt;60 y newly diagnosed with classical HL from 1961 to 2019 were identified in the BC Cancer Lymphoid Cancer Database. Limited stage was defined as non-bulky (&lt;10 cm) stage 1A/IB or 2A (before 2000 1B = advanced stage), with the remainder considered advanced stage. Results: Following exclusions (HIV positive n=4, incomplete data n=21, prior or concurrent other lymphoproliferative disease n=67), 713 pts were identified. With a median follow up of 6.0 y (0.1 - 24.0 y) in living pts, there has been an improvement in 5 y DSS/OS (both p&lt;.001) by decade comparison: 1960s (n=52) 25%/17%; 1970s (n=75) 38%/31%; 1980s (n=90) 51%/43%; 1990s (n=115) 53%/42%; 2000s (n=180) 66%/57%; 2010s (n=201) 63%/53%. To account for advances in diagnosis, staging, supportive care, and therapy in the modern era, we evaluated the outcome of pts diagnosed since 01/1995. A total of 368 pts were treated with curative intent (Table). Most pts received multi-agent chemotherapy (n=359, 98%: ABVD[like] n=351, alkylator-based n=7, CHOP n=1), 8 pts had radiotherapy (RT) alone, and 1 pt had surgery (primary CNS HL). The 5 y DSS, PFS, and OS were 74%, 57%, and 62%, respectively. Increasing age was associated with inferior outcomes (5 y DSS/PFS/OS): 61-70 y (81%/70%/74%), 71-80 y (69%/47%/52%), and &gt;80 y (59%/27%/31%) (DSS p=.011; PFS p&lt;.0001; OS p&lt;.0001). Of 318 pts that received bleomycin, 60 (19%) developed pulmonary toxicity, including 22 cases that occurred after cycles 1 and 2. Overall, 24/368 pts (7%) died of acute treatment toxicity (pulmonary [bleomycin n=10, radiation n=1], infection n=10, cardiac n=3). There was no association between age and developing bleomycin (p=.80) or lethal treatment toxicities (p=.74). Conclusions: The outcome of elderly pts with HL has improved in recent decades. However, treatment related toxicity remains a concern and use of multi-agent chemotherapy, particularly bleomycin-containing regimens, should be undertaken with caution. [Table: see text]

Current Treatment Options for Older Patients with Hodgkin Lymphoma.

Older adults with Hodgkin lymphoma (HL), commonly defined as age ≥ 60years, represent approximately 20% of the total HL population. Historically, they have significantly inferior outcomes compared with younger patients. The cause of this is multifactorial, including biologic differences (e.g., mixed cellularity and EBV-related disease); high incidence of advanced stage disease; and frequency of comorbidities and decreased organ reserve leading to poorer tolerability of therapy with increased toxicity, including treatment-related mortality. Pretreatment evaluation for older HL patients should entail a geriatric assessment (GA), with evaluation of functional status and comorbidities (e.g., geriatric cumulative illness rating scale, CIRS-G) to determine fitness. Furthermore, treatment selection should be based in part on GA, with fit older patients receiving curative chemotherapy-based regimens and unfit or frail patients considering less intensive or non-chemotherapy-based platforms. Additionally, there may be consideration for pre-phase of therapy (e.g., pulse steroids) in order to improve performance status. The inclusion of anthracycline therapy appears important, while bleomycin-containing regimens (e.g., ABVD) may be associated with prohibitive pulmonary toxicity, and intensive therapies such as BEACOPP are too toxic. benefit ratio/benefit ratio, a priori omission of bleomycin may also be considered (i.e., AVD), especially for patients older than 70years of age. In addition, newer regimens for older HL patients integrating novel therapeutic agents into frontline treatment have emerged as effective and tolerable options. Data incorporating brentuximab vedotin sequentially before and after AVD chemotherapy represent the best-reported outcomes in older HL patients to date. In the relapsed/refractory setting, salvage chemotherapy regimens followed by autologous stem cell transplantation should be considered for fit patients, while less intensive treatment, including the use of novel targeted agents, is an option for unfit or frail patients. In this review, we examine the epidemiology, importance of GA, and current treatment options for older HL patients.

Bleomycin in Hodgkin's Lymphoma - A Boon or a Bane? - A Retrospective Study of Bleomycin Pulmonary Toxicity in Hodgkin's Lymphoma.

Introduction:Hodgkin's lymphoma (HL) is one of the most curable malignancies with cure rates of above 85% across all stages. Bleomycin containing regimen is routinely employed in the treatment of HL. Pulmonary toxicity due to this drug is the most feared side effect in these regimens where the mortality rate is approximately 2%–3%. We have conducted this study to assess the genetic susceptibility among the Indian HL patients to bleomycin pulmonary toxicity (BPT).Materials and Methods:In a retrospective study conducted at a tertiary care hospital from South India between January 2013 and May 2019, we reviewed 100 HL patients who were treated with bleomycin-containing regimen (adriamycin, bleomycin, vinblastine, and dacarbazine or cyclophosphamide, vincristine, procarbazine, and prednisone/adriamycin, bleomycin, and vinblastine) for BPT.Results:A total of 100 patients with HL who had received bleomycin-containing regimen were analyzed, which included 23 females and 77 males. Twenty-nine patients had BPT and five deaths were attributed to the same. Radiology reports showed that 15 patients had acute BPT and eight patients had chronic changes. Four patients had rare findings of bleomycin-induced lung damage and computed tomography of the chest could not be done for two patients, whose chest X-ray showed features suggestive of BPT.Conclusion:The incidence of bleomycin induced pulmonary toxicity and mortality was significantly higher in our study compared to that of other Western studies. This could be probably due to the increased susceptibility of the Indian patients to bleomycin induced lung damage. In a highly curable cancer such as HL, it is unacceptable to have such a high life-threating toxicity. Hence, an alternative chemotherapy regimen without bleomycin is to be explored which would prevent toxicity and hence the compromise on survival.

Clinical Characteristics and Treatment Outcomes of Patients with Primary Mediastinal Germ Cell Tumors: 10-Years' Experience at a Single Institution with a Bleomycin-Containing Regimen

Background: Cisplatin-based chemotherapy followed by surgical resection of the residual tumor remains the standard of care for patients with mediastinal germ cell tumors (MGCTs). To prevent pulmonary complications, a non-bleomycin-containing regimen is generally preferred. This study aims to review the clinical characteristics and outcomes of these patients. Methods: A retrospective chart review was undertaken in patients treated for MGCTs between 2003 and 2013. Results: A total of 40 patients were enrolled; 7 patients were diagnosed with seminoma, while 33 patients had non-seminoma. 92% of patients received chemotherapy as a first treatment modality: 87% bleomycin, etoposide and cisplatin; 13% etoposide and cisplatin, with an objective response rate of 61.3%. Among these, 44% achieved a complete serological response. 17 patients underwent surgical resection of the residual tumor. No patient suffered from pulmonary complications after surgery. The 5-year overall survival (OS) was 71.4 and 27.3% in seminoma and non-seminoma patients, respectively (p = 0.051). For those who received chemotherapy followed by surgical resection with no viable tumor or only mature teratoma detected, the 5-year OS was 72.7% compared with 20.7% in patients not treated with surgery (p = 0.02). Conclusion: Our study confirmed the importance of a multimodality approach with primary chemotherapy followed by surgical resection of the residual tumor. A bleomycin-containing regimen can be safely used in this setting.

Bleomycin-Induced Pneumonitis in the Treatment of Ovarian Sex Cord-Stromal Tumors: A Systematic Review and Meta-analysis.

Adult ovarian sex cord-stromal tumors (SCSTs) are a rare histological subtype of ovarian cancer associated with a favorable prognosis. Bleomycin-containing regimens are standards of care, although pneumonitis may cause potentially fatal dose-limiting toxicity. We aimed to evaluate the safety of bleomycin in SCST treatment. We performed a systematic literature review of all studies of bleomycin therapy for SCSTs that were referenced in MEDLINE (PubMed), EMBASE, and Cochrane Central Register of Controlled Trials and published from 1986 to 2014. Eight studies totaling 221 patients were included. Rates of pneumonitis (7.7%; 95% confidence interval, 4.2-11.2) and mortality (1.8%; 95% confidence interval, 0.1-3.6) related to bleomycin were significant. However, these results were very similar to those reported for men who were treated with bleomycin for a male germ cell tumor, suggesting that women with ovarian SCSTs are not particularly vulnerable to bleomycin lung toxicity. The main risk factors of bleomycin-induced pneumonitis are high cumulative bleomycin dose (>400 U or mg), age older than 40 years, and impaired renal function. Whether granulocyte colony-stimulating factor is a risk factor remains controversial. Bleomycin-induced pneumonitis frequently occurs in patients with SCSTs and lacks effective treatment. Prevention lies in limiting cumulative bleomycin dose, monitoring pulmonary function during treatment, discontinuing bleomycin at the onset of pulmonary symptoms or if pulmonary function is impaired, and avoiding bleomycin in older patients.

Older patients and risk of developing and dying from bleomycin-induced lung toxicity.

8584 Background: Bleomycin-induced pneumonitis (BIP) has been well described in classical Hodgkin lymphoma (cHL) patients treated with bleomycin-containing chemotherapy regimens. The incidence of acute and subacute pulmonary toxicity varies widely and multiple factors contribute to mortality in patients with BIP. We therefore reviewed the outcome of cHL patients treated at a single institution to further define the incidence of BIP and to identify major contributors to BIP-associated morbidity and mortality. Methods: One hundred sixty-one pediatric and adult patients who were treated with bleomycin-containing chemotherapy for newly diagnosed cHL between January 2000 and December 2012 were eligible for this retrospective review. BIP was defined by fever, pulmonary symptoms, pulmonary infiltrates, or a decline in DLCO, with no evidence of an infectious etiology. Results: BIP was observed in 43.5 % (n=70) of patients. Age >/=45 years was associated with both an increased incidence (p= <0.0001) and increased severity (p=0.0005) of lung toxicity. ABVD regimen as initial therapy (p= <0.001), obesity (p=0.0331) and the presence of at least one cardiac or respiratory comorbidity (p=0.0088) was also associated with the development of BIP. Higher BMI was associated with earlier onset of lung toxicity. No significant increase in pulmonary toxicity was noted with co-administration of G-CSF (p=0.7249). Bleomycin related mortality rate was 4.97 % (n=8) when all patients were considered and 11.43 % (8/70) in patients who developed pulmonary symptoms. Seventy five percent (6/8) of those who died were older than 60 years. Conclusions: The risk of BIP is significant in cHL with the use of bleomycin-containing regimens. Age >/= 45 years appears to increase the risk of BIP and is associated with increased mortality. These findings highlight the need for testing novel treatment combinations in cHL patients that omit bleomycin.

Clinical characteristics and outcomes of patients with primary mediastinal germ cell tumors.

389 Background: Mediastinal germ cell tumors (MGCTs) account for 20% of all mediastinal tumors. Cisplatin-based chemotherapy followed by surgical resection of residual tumor remains the standard of care. To prevent pulmonary complications secondary to extensive thoracic surgery, non-bleomycin containing regimen is generally preferred. This study aims to review clinical characteristics and outcomes of these patients. Methods: A retrospective chart review was undertaken in patients with MGCTs treated in our institution between 1993 and 2013. Results: A total of 40 patients were enrolled with a median age of 24. Only one patient is female. Stratified by histology; eight patients (20%) had pure seminoma, 25 patients (62.5%) had pure non-seminoma, four patients (10%) had mixed seminoma and non-seminoma, and three patients (7.5%) had malignant transformation (two adenocarcinoma, one sarcoma). Median tumor size was 13 centimeters. Ninety-two percent of patients received chemotherapy as a first treatment modality, whereas 8% underwent upfront surgery. All patients received cisplatin-based chemotherapy: Eighty seven percent bleomycin, etoposide and cisplatin; 13% etoposide and cisplatin. Seventy-two percent of patients completed four planned cycles of chemotherapy. Thirty-one patients were able to assess radiological response: 3.2% complete response, 58.1% partial response, 29.0% stable disease, and 9.7% progressive disease. Forty-four percent of patients achieved completely serological response with chemotherapy. Seventeen patients underwent surgical resection of residual tumor. Among these, viable tumor was seen in 35% (6 out of 17 patients). No patients complicated with clinically significant pulmonary complications after thoracic surgery. The five year overall survival (OS) of patients with seminoma was 72.9% as compared with 19.9% in those with non-seminoma (p=0.012). For those who received chemotherapy followed by surgical resection with no viable tumor or only mature teratoma detected (N=11), the five year OS was 64.9%. Conclusions: Our study confirmed the importance of multi-modality approaches with primary chemotherapy followed by surgical resection of residual tumor. Bleomycin-containing regimen can be safely used in this setting.

How Can Outcomes Be Improved for Older Patients With Hodgkin Lymphoma?

Older age has consistently been identified as an independent adverse prognostic factor for Hodgkin lymphoma (HL) survival in population-based studies and clinical trials in the last several decades. In the 1970s and 1980s, 5-year event-free survival or freedom from treatment failure rates for older (or elderly) patients with HL, most commonly defined as age 60 years, ranged from 30% to 40% with 5-year overall survival (OS) rates of 40% to 50%. These rates are markedly inferior compared with patients with HL younger than age 60 years with 5-year event-free survival of 70% to 75% and OS greater than 80% to 85%. An important question is: have outcomes improved for older patients with HL with refined therapeutic regimens and enhanced supportive care measures in the contemporary era? In a 2008 SEER database analysis, Brenner et al reported improved HL survival over time across all age groups, including older patients. The 5-year survival rates for patients age 60 years increased from 1980 to 1984 through 2000 to 2004 (35% to 59%, respectively). However, the survival rates were exceptionally low from 1980 to 1984, and they still remained significantly lower ( 30% to 35%) in the latter time period compared with younger populations. Recent prospective data in advanced-stage HL confirmed this. Outcomes for patients with HL age 60 years on the phase III study E2496 (treated with ABVD [doxorubicin, bleomycin, vinblastine, and dacarbazine] or Stanford V) seemed improved with historical controls but remained much lower compared with patients younger than age 60 years (5-year failure-free survival [FFS] and OS: 48% and 58%, respectively, v 74% and 90%, respectively). Notably, these survival disparities cannot be explained merely by the advanced age of patients. In a recent retrospective analysis of older patients with HL treated in the current era, we reported 5-year progression-free survival (PFS) and OS of 44% and 58%, respectively, which were significantly inferior compared with an ageand sex-matched population (Fig 1). The cause of poor outcomes for older patients with HL is likely multifactorial, including presence of comorbidities and decreased organ reserve leading to increased toxicity and poor tolerability of therapy, which compromises chemotherapy dose-intensity and contributes to treatment-related mortality (TRM). BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) in the “baseline” form has been shown to be too toxic with a reported TRM rate of 21% in patients with HL age 66 to 75 years. Many bleomycin-containing regimens, including ABVD, are poorly tolerated; this is partly from the risk of the potentially lethal adverse event, bleomycin lung toxicity (BLT). The incidence of BLT in the literature is variable, including up to 46%. Older age is a well-described risk factor associated with BLT in addition to cumulative bleomycin dose, renal insufficiency, pulmonary radiation, and high fractions of inspired oxygen. The incidence of BLT in our Chicago series of patients with HL age 60 years was 32% with an associated mortality rate of 25%. Furthermore, the rate of BLT was much higher in patients who received granulocytestimulating growth factor versus those who did not (ie, 38% v 0%, respectively; P .001), which supports prior data suggesting granulocyte-stimulating growth factor increases the risk of BLT. Several sources of evidence have also suggested that HL in older 0 HL population General US population Ov er al l S ur vi va l ( % )

Frontline Therapy with Brentuximab Vedotin Combined with ABVD or AVD in Patients with Newly Diagnosed Advanced Stage Hodgkin Lymphoma

Frontline Therapy with Brentuximab Vedotin Combined with ABVD or AVD in Patients with Newly Diagnosed Advanced Stage Hodgkin Lymphoma

Treatment of Visceral, Unresectable, or Bulky/Unresectable Regional Metastases of Penile Cancer

To review the treatment strategies among patients with Stage IV penile cancer to describe potentially curative or palliative therapy. The International Consultation on Urologic Disease for Penile Cancer subcommittee on the treatment of Stage IV penile cancer reviewed reports related to the topics of advanced penile cancer and metastatic penile cancer alone and combined with chemotherapy, radiotherapy, and inguinal lymphadenectomy. The reports were rated as to their level of evidence using the criteria of the Oxford Centre for evidence-based medicine. Treatment recommendations were made by consensus, with the appropriate grades determined from the level of evidence. The incidence of Stage IV disease using the current or modified TNM or Jackson descriptions was 0%-14%. Cisplatin-containing regimens were the most active, with patients exhibiting an average response and survival rate of 26% (range 15%-32%) and 5.5 months (range 4.7-7), respectively. Bleomycin-containing regimens were associated with significant pulmonary toxicity. The role of radiotherapy for advanced penile cancer has been largely palliative. Data have suggested that surgical consolidation among patients exhibiting an objective response to chemotherapy could be associated with durable survival. Treatment with a cisplatin-containing regimen in Stage IV penile cancer should be considered and might facilitate curative resection. The use of bleomycin was associated with a high level of toxicity and should be discouraged as first-line therapy. Surgical consolidation to achieve disease-free status or palliation should be considered in fit patients with an objective response to systemic chemotherapy. Palliative radiotherapy to inguinal or skeletal metastases might be of benefit.

Refining the Optimal Chemotherapy Regimen in Good Prognosis Germ Cell Cancer: Interpretation of the Current Body of Knowledge

Refining the Optimal Chemotherapy Regimen in Good Prognosis Germ Cell Cancer: Interpretation of the Current Body of Knowledge

Pulmonary epithelial permeability in patients treated with bleomycin containing chemotherapy detected by technetium-99m diethylene triamine penta-acetic acid aerosol (99mTc-DTPA) scintigraphy

To evaluate pulmonary epithelial permeability using 99mTc-DTPA scintigraphy in patients treated with bleomycin-containing regimens. Twelve non-smoking chemotherapy-naïve patients with no clinical or radiological evidence of pulmonary disease and treated with bleomycin-containing chemotherapy were tested with 99mTc-DTPA scintigraphy before the first cycle and every 3 weeks until the third month after the end of chemotherapy (total cumulative dose of bleomycin 347.9 mg). Pretreatment values (T1/2 74.93 minutes) of 99mTc-DTPA scintigraphy were significantly higher than those obtained after the total dose of bleomycin (T1/2 51.00 minutes) (p < 0.001). This difference was more important in the later evaluations especially, on the third week and third month measures after discontinuing treatment (p < 0.001). All the tests of Within-Subjects Effects were significant (p < 0.001). Comparing pretreatment and post-treatment scintigraphies the mean T1/2 99mTc-DTPA values decreased as the bleomycin dose increased. We conclude that cumulative bleomycin doses are related to increased pulmonary epithelial permeability at a dose of 256.5 mg. However, whether this is related to clinical toxicity is uncertain and large, multi-center prospective studies are needed.

G-CSF Administration Increases Pulmonary Toxicity for Hodgkin's Disease Patients Treated with Bleomycin-Containing Chemotherapy.

Background: In Hodgkin's Disease (HD), G-CSF has been used to maintain maximum dose intensity by avoiding neutropenia and treatment delays. Pre-clinical data and anecdotal reports have shown an association between G-CSF administration and bleomycin pulmonary toxicity (BPT). This complication may cause access morbidity and have a detrimental impact on survival in this otherwise good prognosis population. We embarked on a retrospective analysis to determine if G-CSF increased the incidence of this complication or had an impact on outcomes.Methods: We reviewed all patients managed for HD at Mayo Clinic, Rochester, from January 1986 to February 2003. BPT was defined by the presence of pulmonary symptoms, bilateral interstitial infiltrates, and no evidence for an infectious etiology. Patients who received G-CSF support with one or more of their bleomycin-containing chemotherapy cycles were considered as being treated with G-CSF.Results: A retrospective review identified 141 patients with HD treated with a bleomycin-containing regimen. The mean age of patients at diagnosis was 34 years. Fifty four percent were males. The histology was nodular sclerosing in 85%. The Hasenclever index was 0 in 15%, 1 in 35%, 2 in 24%, 3 in 16%, 4 in 9%, and ≥ 5 in 1%. The G-CSF and non G-CSF groups were balanced for poor prognosis risk factors including Hasenclever index. Frontline chemotherapy included ABVD in 57%, MOPP-ABV(D) in 33%, COPP-ABV in 8%, BEACOPP in 3%, and Stanford V in 2%. Forty one percent of patients received radiation. The 5-year overall survival (OS) and progression free survival (PFS) for all patients were 87% and 79% respectively. G-CSF was administered to 52% (74/141) of patients. BPT occurred in 18% of patients (25/141). A higher rate of BPT was observed in patients receiving G-CSF, 26% (19/74) versus 9% (6/67) in non G-CSF patients (p=0.0141). In this population, G-CSF administration was the only factor associated with an increased risk of BPT. There was no difference between the two groups for BPT associated risk factors including radiation, bleomycin dose, renal insufficiency, smoking history, and underlying lung disease. Additionally these risk factors showed no correlation with the development of BPT. The mortality from BPT was 4.2% (6/141) in all patients and 24% (6/25) in patients who developed the pulmonary syndrome. Of the 6 patients who died acutely, 83% (5/6) received G-CSF. CR rates were equal between the G-CSF and non G-CSF groups at 92% and 94% respectively. Five year OS and PFS were equal between the G-CSF and non G-CSF groups at 82% versus 89% (p=0.473) and 74% versus 84% (p=0.152) respectively.Conclusion: G-CSF administration increases the incidence of pulmonary toxicity in HD patients treated with bleomycin based chemotherapy. The major impact was on treatment related morbidity as 5-year OS and PFS were equal between the G-CSF and non G-CSF groups.

Bleomycin Pulmonary Toxicity Does Impact on Hodgkin's Disease Outcome.

Background: Bleomycin-containing chemotherapy regimens have become the mainstay of treatment in Hodgkin's Disease (HD). The risk of bleomycin pulmonary toxicity (BPT) ranges from 0–46% and mortality rates range from 0–27%. Although there is no excepted standard treatment for BPT, corticosteroid treatment, withholding bleomycin from subsequent chemotherapy, and proceeding with a non-bleomycin containing regimen is the most common approach. We reviewed our experience to better delineate outcome and appropriate treatment in these patients.Methods: We reviewed all patients managed for HD at Mayo Clinic, Rochester, from January 1986 to February 2003. BPT was defined by the presence of pulmonary symptoms, bilateral interstitial infiltrates, and no evidence for an infectious etiology.Results: A retrospective review identified 141 patients with HD treated with a bleomycin-containing regimen. The mean age of patients at diagnosis was 34 years. Fifty four percent were males. The histology was nodular sclerosing in 85%. The Hasenclever index was 0 in 15%, 1 in 35%, 2 in 24%, 3 in 16%, 4 in 9%, and >5 in 1%. Frontline chemotherapy included ABVD in 57%, MOPP-ABV(D) in 33%, COPP-ABV in 8%, BEACOPP in 3%, and Stanford V in 2%. Forty one percent of patients received radiation. The 5-year overall survival (OS) and progression free survival (PFS) for all patients were 87% and 79% respectively. BPT was observed in 18% of patients (25/141). There was a significant decrease in OS, 63% in patients with BPT versus 90% in non-BPT patients at 5 years (p=0.0013). The mortality from BPT was 4.2% (6/141) in all patients and 24% (6/25) in patients who developed the pulmonary syndrome. These 6 patients all died within 9 months of their HD diagnosis from BPT. The Hasenclever index was 3 or less in 5 of these 6 patients. CR rates were equal at 91% and 93% in BPT and non-BPT patients respectively (p=0.299). Twenty two percent (31/141) of patients, either symptomatic or asymptomatic, had bleomycin omitted at any time from their regimen with no difference in OS or PFS, 83% versus 88% (p=0.369) and 82% versus 78% (p=0.853) respectively. The mean bleomycin dose was 84 mg/m2 (range of 20–180 mg/m2). Bleomycin dose had no impact on OS or PFS. In BPT patients subsequent non-bleomycin therapy included AVD 44%, MOPP-AV 31%, or no further chemotherapy 25%. The five-year OS was equal between the AVD and MOPP-AV groups at 91%. However in patients who received no further chemotherapy 5-year OS was 30% (p=0.0001).Conclusion: Bleomycin pulmonary toxicity (BPT) results in a significant decrease in OS survival at 5 years in patients being treated for Hodgkin's Disease. In patients who do not die acutely from pulmonary toxicity both OS and PFS appear equal despite the omission of bleomycin.

Predicting the risk of bleomycin lung toxicity in patients with germ-cell tumours

Bleomycin pulmonary toxicity (BPT) has been known since the early clinical trials of bleomycin in the 1960s. Postulated risk factors include cumulative bleomycin dose, reduced glomerular filtration rate (GFR), raised creatinine, older age and supplemental oxygen exposure. From our prospectively collected testicular cancer research database, we reviewed 835 patients treated at the Royal Marsden NHS Trust (Sutton, UK) with bleomycin-containing regimens for germ-cell tumours between January 1982 and December 1999, to identify those with BPT. Fifty-seven (6.8%) patients had BPT, ranging from X-ray/CT (computed tomography) changes to dyspnoea. There were eight deaths (1% of patients treated) directly attributed to BPT. The median time from the start of bleomycin administration to documented lung toxicity was 4.2 months (range 1.2-8.2). On multivariate analysis, the factors independently predicting for increased risk of BPT were GFR <80 ml/min [hazard ratio (HR) 3.3], age >40 years (HR 2.3), stage IV disease at presentation (HR 2.6) and cumulative dose of bleomycin >300,000 IU (HR 3.5). Patients with poor renal function are at high risk of BPT, especially if they are aged >40 years, have stage IV disease at presentation or receive >300,000 IU of bleomycin. In such cases alternative drug regimens or dose restriction should be considered.

The role of cisplatin/bleomycin-based chemotherapy in the treatment of poorly differentiated carcinoma of unknown primary site.

Between 1978 and 1990, 173 patients with poorly differentiated carcinoma or poorly differentiated adenocarcinoma of unknown primary site were treated with bleomycin-containing regimens at Vanderbilt University Medical Center. Patients were prospectively identified based on light microscopy findings. The median age of patients was 39 years; 78% were male and 76% had metastatic tumors in two or more sites. Dominant tumor location was the mediastinum, retroperitoneum, or peripheral lymph nodes in 82 patients (47%). Between 1978 and 1985, patients received cisplatin 20 mg/m2 intravenously (IV) days 1 through 5, vinblastine 0.15 mg/kg IV days 1 and 2, and bleomycin 30 U IV weekly. In 1986, etoposide 100 mg/m2 IV days 1 through 5 replaced vinblastine in the regimen. Responding patients received four courses of therapy at 3-week intervals. One hundred thirteen patients (65%) had a major response to therapy, including 47 (27%) complete responses. At present, 27 patients are disease free at a median of 78 months posttherapy (range, 11 to 142 months); an additional patient was lost to follow-up while in complete response. Median survival of the entire group was 11 months, with a 12-year actuarial disease-free survival of 16%. Combination chemotherapy with cisplatin/bleomycin and either vinblastine or etoposide is highly active in patients with poorly differentiated carcinoma of unknown primary site and is curative in a minority of these patients. A trial of this therapy should be considered in all such patients.

Pulmonary Emboli in Patients Receiving Chemotherapy for Non-Hodgkin's Lymphoma

Combination chemotherapy has dramatically improved the prognosis of patients with intermediate and high grade histologic subtypes of non-Hodgkin's lymphomas. Treatment-related complications, however, are considerable, and a common problem encountered is respiratory distress or respiratory insufficiency. Usually these difficulties have been attributed to infectious etiologies or to chemotherapy-induced interstitial fibrosis, most often involving bleomycin. We describe five patients presenting with respiratory problems several weeks after the initiation of chemotherapy. These patients, who represent 3 percent of all patients treated with a single bleomycin-containing regimen for intermediate or high grade non-Hodgkin's lymphoma, were all initially thought to have chemotherapy-induced interstitial fibrosis but were found on subsequent evaluation to have pulmonary emboli. Of the three patients in whom pulmonary emboli were diagnosed antemortem, two had symptoms suggestive of pulmonary emboli and all were successfully treated and remained well and free of lymphoma for over 24 months. Two additional patients were diagnosed at autopsy. We suggest that pulmonary emboli may contribute significantly to the morbidity and mortality of patients undergoing chemotherapy for non-Hodgkin's lymphoma and recommend that patients presenting with respiratory difficulties be evaluated for pulmonary emboli.