Hyperthermic intrathoracic chemotherapy for the treatment of malignant pleural effusion caused by breast and ovarian cancer: A systematic literature review and pooled analysis.

OBJECTIVES: Breast and ovarian cancer account for over 30% of malignant pleural effusions (MPEs). Treatment of the metastatic disease requires control of the MPE. Even though primarily symptomatic, the treatment of the MPE can potentially affect the oncological course of the disease. The aim of this review is to analyze the effectiveness of intrathoracic chemotherapy in the treatment of MPE caused by breast and ovarian cancer. METHODS: A systematic literature research was conducted up until May 2021. Studies published in English on patients undergoing either surgical or interventional intrapleural chemotherapy were included. RESULTS: Thirteen studies with a total of 497 patients were included. Analysis was performed on 169 patients with MPE due to breast cancer and eight patients with MPE secondary to ovarian cancer. The pooled success rates of intrathoracic chemotherapy for controlling the MPE were 59.1% and 87.5%, respectively. A survival analysis was not possible with the available data. The overall toxicity of the treatment was low. CONCLUSIONS: Intrathoracic chemotherapy achieves symptomatic control of the MPE in 59.1% of patients with metastatic breast cancer and 87.5% of patients with metastatic ovarian cancer. This is inferior to other forms of surgical pleurodesis. Data from small case series and studies on intraperitoneal chemotherapy show promising results. However, formal oncological studies on the use of intrathoracic chemotherapy for metastatic breast or ovarian cancer are lacking. Further prospective pilot studies are needed to assess the therapeutic oncological effects of this treatment.

Does cytoreduction surgery and hyperthermic intrathoracic chemotherapy prolong survival in patients with N0-N1 nonsmall cell lung cancer and malignant pleural effusion?

INTRODUCTION: Debulking surgery and hyperthermic intrathoracic chemotherapy (HITHOC) has been successfully used in the treatment of thoracic tumours. Few authors report on the feasibility of its use in patients with lung cancer and malignant pleural effusion. The aim of this study was to evaluate the efficacy and results of debulking surgery and HITHOC in the treatment of selected patients with nonsmall cell lung cancer (NSCLC) and malignant pleural effusion. METHODS: A systematic review was conducted in MEDLINE in accordance with PRISMA guidelines. The word search included: "hyperthermic intrathoracic chemotherapy and/or HITHOC or hyperthermic intrapleural". Inclusion criteria were only those studies reporting a sufficient amount of data on HITHOC and surgery for lung cancer. Single case reports and review articles were excluded. RESULTS: 20 articles were selected as they related to the topic of HITHOC and lung cancer. Most were from China (n=8) and Japan (n=6). Only four out of the 20 articles had sufficient data for this review. In total, data for 21 patients were collected. Debulking surgery ranged from wedge resection to pneumonectomy and pleurectomy. Mean survival was 27 months and median survival was 18 months (range 1-74 months). 13 patients out of 21 (62%) were alive at 1 year and six (28.5%) were alive at 2 years. 10 patients were still alive at the time of the respective publication in the 21 patients included. Systemic toxicity and treatment-related mortality were nil. There were insufficient data to perform a meta-analysis. CONCLUSION: Although reported survival in this systematic review is encouraging, available evidence concerning debulking surgery and HITHOC in N0-N1 NSCLC with malignant pleural effusion is weak. Better evidence in the form of a randomised controlled trial is mandatory.

A meta-analysis of elemene versus DDP intrapleural injection in the treatment of malignant pleural effusion caused by lung cancer.

OBJECTIVE: The objective of this study was to evaluate the clinical efficacy of elemene versus DDP intrapleural injection in the treatment of malignant pleural effusion caused by lung cancer by meta-analysis. MATERIALS AND METHODS: PubMed (1960 ~ 2016.4), EMBASE (1980 ~ 2016.4), and CNKI (1979 ~ 2016.4) databases were searched to identify the clinical studies of elemene intrapleural injection in the treatment of lung cancer malignant pleural effusion. The odds ratio (OR) was used to evaluate the clinical efficacy of elemene in the treatment of pleural effusion compared to cisplatin (DDP). RESULTS: Seven hundred and Thirty-two subjects with 14 studies were finally included in this meta-analysis. Meta-analysis demonstrated that the objective response rate in elemene group was much higher than that in DDP group (OR = 1.34, 95% confidence interval: 1.07 ~ 1.69, P < 0.05). The Begg's funnel plot and Egger's line regression test showed no statistical publication bias. CONCLUSION: High clinical efficacy of elemene in the treatment of lung cancer malignant pleural effusion was found compared to DDP.

Povidone-iodine pleurodesis versus talc pleurodesis in preventing recurrence of malignant pleural effusion.

BACKGROUND: Malignant pleural effusions continue to be a common problem in patients with metastatic disease, leading to a significant reduction in quality of life with progressive dyspnea, dry cough, chest pain and reduced physical activity. This study was conducted to compare the efficacy, safety, and outcome of Talc Powder Pleurodesis (TPP) with Povidone-iodine Pleurodesis (PIP) through a chest drain as a palliative preventive treatment of recurrent malignant pleural effusion. METHODS: A total of 39 neoplastic patients with recurrent malignant pleural effusion were enrolled in a prospective randomized trial. Twenty-one patients received Talc pleurodesis (group A), and eighteen patients (group B) received Povidone-iodine pleurodesis. The continuous variables were expressed as mean values ± standard deviation (SD) and compared using the unpaired t-test. The discrete variables were expressed as percentage and compared using the chi-square test (χ(2)) test. p-values of less than 0.05 were considered significant. RESULTS: Our study included 11 males and 28 females, the mean age was (71.0 ± 5.0) years for group A and (70.9 ± 5.1) years for group B (non-significant). Post-procedure analgesic requirements were recorded in both groups. Four patients in each group had fever (>38°C) within 48 hours of the procedure. Both groups achieved good symptomatic relief. There were no in-hospital deaths. The mean post-procedure hospital stay was (4.7 ± 1.2) days for group A and (4.2 ± 1.0) for group B (non-significant). At follow-up recurrence of significant pleural effusion requiring intervention was noted in four and five patients in group A and group B, respectively (non-significant difference). CONCLUSION: Povidone-iodine pleurodesis can be considered as a good alternative to Talc pleurodesis for recurrent malignant pleural effusion. The drug is available, cost effective, safe and can be administered through an intercostal drain and repeated if necessary.

Notable decrease of malignant pleural effusion after treatment with sorafenib in radioiodine-refractory follicular thyroid carcinoma.

BACKGROUND: Malignant pleural effusion (MPE) caused by metastatic differentiated thyroid carcinoma (DTC) is usually associated with a rapid fatal outcome and should be recognized as a grim prognostic indicator. A standard therapeutic strategy has not been established for this situation. Here, we report a radioiodine-refractory follicular thyroid carcinoma (FTC) patient in whom a notable decrease of MPE was achieved after treatment with sorafenib. PATIENT FINDINGS: A 50-year-old patient underwent a total thyroidectomy and resection of recurrence for poorly differentiated FTC followed by radioiodine therapy with a negative whole body scan. One year later, dissection of the inferior lobe of the left lung was performed because two fluorodeoxyglucose-avid nodules were identified; pathological examination revealed a metastatic poorly differentiated FTC. Half a year later, he was referred to our clinic because of cough, thoracic pain, nausea, and loss of appetite. Chest computed tomography showed right lung multiple nodules, left pleural effusion, and left lung collapse with left-sided pleural thickening. We treated him with sorafenib. Clinical and radiographic assessments were performed periodically. SUMMARY: Symptoms and signs improved dramatically and continuously after initiation of sorafenib treatment. A duration of more than 12 weeks of apparent reduction of pleural effusion was achieved, which was confirmed by consecutive computed tomography examinations. Despite grade 1 alopecia, no other obvious treatment-related adverse events occurred. CONCLUSIONS: As a grim prognostic indicator for patients with DTC, no standard treatment recommendation for pleural effusion exists. Targeted therapy using sorafenib may be an effective therapeutic strategy in the treatment of MPE caused by FTC.

Effects of a simple intraoperative intrathoracic hyperthermotherapy for lung cancer with malignant pleural effusion or dissemination.

We examined the effect of a simple intraoperative intrathoracic hyperthermotherapy (IIH) and a simple intraoperative intrathoracic hyperthermo-chemotherapy (IIHC) on malignant pleural effusion and/or dissemination with primary non-small lung cancer. This study included 19 patients who had malignant pleural effusion and/or dissemination recognized for the first time at the time of surgery. We performed surgical procedures on the primary lesions and then the additional therapies followed. Seven patients received IIH (group A), five patients underwent IIHC (group B), and seven patients did not have any additional therapy (group C). There was no death during the follow-up period (9-35 months) in the group A. The median survival time was 41 months in the group B and 25 months in the group C. The group A was completely free of pleural effusion and one patient in the group B suffered from pleural effusion 26 months after surgery, although the median term of freedom from pleural effusion was three months in the group C. In patients with malignant pleural effusion and/or dissemination with primary non-small lung cancer, not only IIHC but also IIH might be beneficial in the prevention of pleural effusion instead of the improvement in prognosis.

Recurrent pleural effusion: who benefits from a tunneled pleural catheter?

Recurrent malignant pleural effusion (MPE) is a common concomitant phenomenon of malignant disease, which can worsen the patient's quality of life and lead to significant morbidity. Tunneled indwelling pleural catheters (TIPC) offer new modalities in patients with recurrent MPE and impaired dilatability of the lung. We report on our experience with 100 consecutive patients suffering from recurrent benign (n = 12) and malignant pleural effusion (n = 88) who were treated with TIPC. The catheter was placed during a VATS procedure or under local anesthesia in an open technique. The median residence time of the TIPC was 70 days; spontaneous pleurodesis was achieved in 29 patients. The rate of complications was low: pleura empyema (n = 4), accidental dislodgement (n = 2), malfunction of the drainage (n = 3). In conclusion, TIPC is a useful method for the palliative treatment of patients with recurrent malignant or nonmalignant pleural effusions and 3 groups of patients seem to benefit most: a) patients with the intraoperative finding of a trapped lung in diagnostic VATS procedure; b) patients after a history of repeated pleuracenteses or previously failed attempts at pleurodesis; c) patients in a reduced condition with a limited lifespan due to underlying disease.

Management of malignant pleural effusion associated with trapped lung syndrome.

Management of recurrent malignant pleural effusion associated with trapped lung syndrome remains problematic. An alternative treatment using a pleural catheter has been advocated. Between August 1999 and August 2002, 127 patients underwent thoracoscopy for malignant pleural effusion. Of these, 52 (41%) with trapped lung were managed by insertion of a pleural catheter. Mean age was 66 years (range, 42-89 years). The most frequent diagnosis was breast cancer. Spontaneous pleurodesis (drainage < 10 mL) occurred in 25 (48%) patients whose catheter was removed after 30 to 255 days (mean, 93.8 days). Symptomatic relief was achieved in 49 (94%) patients. Mean dyspnea score improved significantly from 3.0 to 1.9. Complications comprised catheter blockage, surgical emphysema, cellulitis, and loculated effusion in 2 patients each. Mean length of hospital stay was 3 days (range, 1-16 days). Median survival was 126 days (range, 10-175 days). We conclude that long-term placement of a pleural catheter provides effective palliation for malignant pleural effusion associated with trapped lung syndrome.

[A patient with advanced breast cancer refractory to chemotherapy accompanied by carcinomatous pleurisy and multiple bone metastasis that responded to combination therapy with high-dose toremifene and docetaxel].

The patient was a 76-year-old woman, who found a mass in her left breast around summer of 2003 but ignored it. She visited our hospital in April 2004 because of dyspnea and low-back pain. As there was a mass accompanied by partial ulceration all over the left precordium and bilateral pleural effusion, she was admitted for further evaluation and treatment. The patient was judged to be almost in a life-threatening condition, and thus thoracentesis was performed to remove pleural fluid, and chemotherapy with FEC was also performed. In addition, the patient was placed on oral exemestane (EXE). After four courses of therapy with FEC were completed, the drug was changed to paclitaxel (PTX) and chemotherapy was continued for another 3 months. It was confirmed that the tumor size had been reduced markedly and that the volume of pleural effusion had not increased. The patient was in a state of remission for a short time, but subsequently the tumor size increased again and the tumor bled continually in small amounts. The chemotherapeutic drug was changed to capecitabine, while EXE, which had been continued, was withdrawn and oral administration of 120 mg/day of toremifene (TOR) was started. However, the tumor size was not reduced. TOR was continued, while capecitabine was changed to docetaxel (DOC). Then, the tumor size was reduced again, until the breast became almost flat after 3 months and the patient no longer bled from the tumor. The volume of pleural effusion did not increase, nor did the patient have any more dyspnea. At present, she has been in a state of remission and is living at home with a certain QOL.

[A case of recurrent breast cancer with carcinomatous pleurisy successfully treated with combined chemoendocrine-therapy of CTF (CPA, THP and 5-FU) and anastrozole following instillation therapy 12 years after radical mastectomy].

A 52-year-old female underwent radical mastectomy at the age of 41 for left breast cancer (n0, positive for ER). After a few years of adjuvant TAM therapy, follow-up was stopped at the age of 50 with no recurrence. She had suffered from symptoms of cold since January 2001 and came to our hospital complaining dyspnea on February 11. CXP showed pleural effusion of the entire thoracic cavity and she was admitted to the hospital immediately. Pleural exudate cytodiagnosis showed carcinomatous pleurisy; however, dyspnea and thoracic effusion were improved by continuous thoracic drainage and instillation therapy. Various examinations demonstrated that the carcinomatous pleurisy was due to recurrent breast cancer. They also showed local recurrence, left supraclavicular lymph node metastasis and multiple bone metastasis. Thus, combined chemoendocrine-therapy of CTF (CPA, THP and 5-FU) and anastrozole was administered. After 6 cycles of CTF, the carcinomatous pleurisy, local recurrence and left supraclavicular lymph node metastasis were diagnosed as CR by CXP, chest CT and US and multiple bone metastasis were diagnosed as PR by bone scintigram. The patient continues to be treated on an outpatient basis with no recurrence about one year after the beginning of the treatment (6 months after CTF 6 cycles) and she is taking anastrozole continuously.

[A case of pleural effusion in a patient with malignant lymphoma diagnosed by thoracoscopy with local anesthesia].

A 47-year-old woman was admitted for examination of massive right pleural effusion on chest radiography, together with chief complaints of dry cough and body weight loss. Exudative effusion was aspirated by thoracentesis, revealing many lymphocytes and a high level of adenosine deaminase. Thoracoscopy with local anesthesia was performed. Elevated white lesions and miliary nodules were observed, and these lesions were examined by thoracoscopic biopsy, leading to a diagnosis of malignant lymphoma. Treatment with chemotherapy (THP-COP) resulted in partial remission. Thoracoscopy with local anesthesia in cases of pleural effusion with malignant lymphoma can be a safe and useful procedure for diagnosis.

Malignant pleural mesothelioma.

Malignant pleural mesothelioma remains a difficult tumor to treat, much less cure. Currently, the best chance for long-term survival lies with early diagnosis and aggressive surgical extirpation, but given the typically long delay between the onset of symptoms and diagnosis, this is only possible with a high index of suspicion and an aggressive diagnosis workup. Early referral to a tertiary center experienced in the treatment of MPM may be important for several reasons: (1) decreased risk of tumor spread along multiple thoracenesis/biopsy tracts, (2) the availability of specialized pathologic assays for definitive diagnosis, (3) the availability of critical staging modalities (aggressive mediastinoscopy +/- thoracoscopy, MRI scans performed according to specific mesothelioma protocols, and perhaps PET scans), (4) surgical experience with pleurectomy/decortication and/or extrapleural pneumonectomy, that may decrease morbidity and mortality, and (5) the availability of novel adjuvant protocols. Single-modality therapy is unlikely to result in long-term survival. Aggressive surgery is required for optimal debulking, and extrapleural pneumonectomy may offer better local control compared with pleurectomy/ecortication. Delivery of optimal radiation schedules, which may involve large fractions as well as large total doses, is limited by the presence of nearby dose-limiting structures. Current chemotherapy is severely lacking in producing objective responses and improved survival although gemcitabine and IL-2 may be active agents to be combined with radiation and/or other agents. Hyperthermia, photodynamic therapy, intracavitary therapy, and gene therapy are all relatively new techniques under active investigation that should be supported by enrollment in on-going protocols. Predictably, many of these techniques provide greater benefit when used in the setting of adjuvant protocols or minimal residual disease, emphasizing the importance of multimodality therapy.

[Treatment of pleural effusion caused by lung carcinoma with circular intrapleural hyperthermic perfusion and its mechanism].

OBJECTIVE: To assess the comprehensive effectiveness of intrapleural hyperthermic perfusion in treatment of malignant pleural effusion (MPE) caused by lung carcinoma and to explore its nechanism. METHODS: 45 patients with MPE caused by lung carcinoma underwent circular intrapleural hyperthermic perfusion with 43 warmed normal saline for 60 minutes. Response of pleural effusion and the original lung tumor, sife-effects, life qualty and survival time of the patients were followed up. Flow cytometry, optical microscopy, electron microscopy, and TUNEL method were used to compare the cytology and biochemistry of pleural effusion and cancer cells planted to the surface of pleura before and after the therapy. RESULTS: The control rate of pleural effusion was 100% (CR 93.3%, PR 6.7%). No recurrence of pleural effusion was observed in 44 cases. Pleural effusion reoccured 12 months after the thermotherapy in one case. The time without pleural effusion lasted 16.5 months on average with the longest time of 40 months. CT performed one month after the thermotherapy in 13 cases showed that the primary focus in lung dwindled in 13 cases, and remained unchanged in 5 cases. Neither operative death nor post-operative complication was found. The life quality was improved in all the cases. The medium survival time was 16.8 months. One-year survival rate was 87%. One case survived more than 3 years, 4 cases survives more than 2 years (29, 30, 31, and 40 months respectively). Carcinoembryonic antigen decreased to normal and no carcinoma cell was found in pleural effusion. Flow cytometry showed that the tumor heteroploid peak diasappeared. Pyknosis and disintegration of nuclei, and apoptotic bodies of tumor cells planted on the surface of pleura were found by optical and electron microscopy. TUNEL showed apoptotic cells with brilliant yellow fluorescence. CONCLUSION: (1) Circular intrapleural hyperthermic perfusion is a new, safe, and effective treatment for MPE. (2) Apoptosis-mediated cytocidal function, improvement of body immunity after hyperthermic perfusion and continuous wash of the perfusion fluid are important mechanisms of intrapleural hyperthermic perfusion in treatment of MPE caused by lung carcinoma.

[Anesthetic management of patients with malignant pleural effusion undergoing hyperthermic perfusion under thoracoscopy].

Nine patients with malignant pleural effusion due to lung cancer had been scheduled for hyperthermic treatment with warmed distilled water (40 degrees C) under thoracoscopy. This treatment aims to produce adhesion of the lungs to reduce pleural effusion. To evaluate the risk of general anesthesia for patients with lung cancer at the end stage, we examined the problems of perioperative management. Seven out of nine patients were classified into ASA physical status > or = III and seven patients into Hugh Jones > or = III Shapiro's score was > or = 5 in four patients. The average %VC was 60 +/- 16 and % FEV1.0 was 41 +/- 18% (means +/- SE). A double lumen endotracheal tube was inserted and anesthesia was maintained with inhalational anesthetics. In two cases, one-lung ventilation could not be maintained because of severe hypoxemia during hyperthermic perfusion. Hypertension occurred in three cases and hypotension in one by direct heat stimulation of the cardiopulmonary system. Although their preoperative risk was poor, there were no major complications and the quality of life was improved. We stress that careful anesthetic management is important for avoiding hypoxemia and hemodynamic instability during this treatment.

Malignant pleural effusions treated with high dose intrapleural doxycycline: clinical efficacy and tolerance.

Chronic malignant pleural effusion may be treated by instillating products in the pleural space to induce pleurodesis. We used intrapleural doxycycline at doses greater than 2000 mg in 16 malignant pleural effusion (14 patients). Patient survival ranged from 1 day to 19.5 months. Mean drainage duration was 7.5 days (range, 5-10 days). Pain (moderate n=7; severe n=2) was the most frequent side-effect with hypotension (moderate n=3; severe n=1). Five cases were not evaluable at one month because of death during the month following treatment (n=3) or during treatment (n=2). At one month follow-up, success was defined as no pleural effusion (n=5), partial response as minimal effusion (n=4) and we considered that treatment had failed if pleural drainage was necessary (n=2). Five patients died within one month and 5 had more than 3 months survival (4 without recurrence).

Thoracic complications in patients undergoing intraperitoneal heated chemotherapy with mitomycin following cytoreductive surgery.

BACKGROUND: The purpose of this study was to determine the incidence and severity of thoracic reactions in patients undergoing intraperitoneal heated chemotherapy (IPHC). METHODS: Forty-two patients who had intraperitoneal disseminated malignancies were treated with cytoreductive surgery (CS) and IPHC. The primary malignancies included carcinoma of the colon (n = 17), stomach (n = 6), appendix (n = 6), pseudomyxoma peritonei (n = 3), mesothelium (n = 2), ovaries (n = 2), jejunum (n = 2), gallbladder (n = 1), urachus (n = 1), and peritoneal carcinomatosis (n = 2). After CS, IPHC with mitomycin (MMC) was administered by perfusion at 40.5 degrees C. After IPHC, multiple radiographs of the chest were reviewed in comparison to the control group. RESULTS: Thoracic complications occurred in 36 patients (86%), including atelectasis in 32 patients (76%), pleural effusions in 27 (64%), pulmonary edema in 10 (24%), pneumonia in 2 (5%), and pneumothorax in 2 (5%). The incidence of thoracic complications in the IPHC group was significantly higher than that of patients in the control group (P < .05). Correlations between the prevalence of pleural effusion and the dose of MMC, duration of procedure, and presence of thrombocytopenia were not significant (P > .05). CONCLUSIONS: Bibasilar atelectasis and pleural effusions are common findings after IPHC with MMC, but most of them do not necessarily warrant intervention.