Background: We have performed the cisplatin-based intrapleural hyperthermic chemotherapy (IPHC) for advanced lung cancer with pleural effusion and for malignant pleural mesothelioma (MPM). Retrospectively, the outcomes of the IPHC were evaluated. Methods: For 14 years from February, 2000 to February, 2014, we performed 14 cases of IPHC including 8 lung cancers (staged-IV) and 6 MPMs (staged-III: 5; IV: 1). We divided these cases in two groups; the lung cancer group (LC group) and MPM group, and assessed the perioperative factors, toxicities, and effectiveness. Results: The patient age averaged 66.5 ± 11.1 years old (11 males and 3 females). The pathology was 7 pulmonary adenocarcinomas, 1 pulmonary angiosarcoma, and 6 epithelial type MPMs. The regimens of the IPHC were CDDP (300 mg) plus saline (n = 12), CDDP (100 mg) plus saline (n = 1), and CDDP (300 mg) plus distilled water (n = 1). The operation and IPHC time was 204 ± 70 and 59 ± 19 minutes, respectively. Intraoperative complication was observed in 2 lung injuries due to exfoliation of the pleural adhesion in the LC group. Blood loss was 292 ± 365 ml. The postoperative complication, i.e. , subcutaneous emphysema, was observed as grade 2 pulmonary fistula (7.1%, 1/14), which was significantly observed in the LC group (1/8, 12.5%) compared to the MPM group (0/8, 0%) (p = 0.040). The hematological toxicity of more than grade 3 was observed in only one case of anemia (7.1%, 1/14) and in the LC group (25%, 1/8). The grade 3 anemia (25%, 1/8) and grade 2 neutropenia (25%, 1/8) in the LC group were significantly observed compared to those in the MPM group (0%, 0/6), respectively (p = 0.040). The postoperative cytology of the malignant cells in the pleural effusion resulted in the negative (n = 6), positive (n = 7), and not evaluated (n = 1), and the control rate was calculated to be 46.2% (6/13). There was no significant difference between the two groups (p = 0.083), that is, 42.9% (3/7) in the LC group and 50.0% (3/6) in the MPM group. For the postoperative amounts of the pleural effusion, reduction (n = 10), unchanged (n = 3), and not evaluated (n = 1), the control rate was calculated to be 76.9% (10/13). There was a significant difference between the two groups (p = 0.042), that is, 71.4% (5/7) in the LC group and 83.3% (5/6) in the MPM group. Conclusion: The IPHC treatment resulted in no major complications, and fewer adverse events of more than grade 3. The outcome of the IPHC was safety, and a very effective control of the malignant cells and pleural effusion.
In Japan, seventy thousand lung cancer patients have died every year; the number of dead was mostly due to malignancies, 80% of which consisted of non-small cell carcinoma. In recent years, the Japanese population has become aged and the number of elder lung cancer patients has increased.
By the seventh edition of the tumor-node-metastasis (TNM) staging system for lung cancer [
Based on the basic scientific study about the anti-cancer effect of intrapleural hyperthermic chemotherapy (IPHC), our study group has performed the IPHC treatment since 1980. From 1988, our IPHC was indicated for lung cancers with dissemination with a resectable case of primary lung cancer with no lymphatic metastasis and no distal metastasis, which was possible for single-lung ventilation under general anesthesia. Our conventional IPHC treatment has been performed in clinical practice [
Regarding the benefits of the IPHC treatment, in addition to the tumor-cytotoxic effects with hyperthermic escalated efficacy, the palliation of dyspnea and improvement of the QOL are expected, that is, the control of the pleural effusion, shortening of the thoracic drainage period, lengthening the outpatient palliative therapy at home, and preserving the patient’s QOL.
We have summarized our 14-year experience and retrospectively evaluated our conventional IPHC treatment for thoracic malignancies (lung cancers and malignant pleural mesothelioma) and now report the clinical outcome about the perioperative factors, complications, adverse events, effectiveness, and safety.
For 14 years from February, 2000 to February, 2014, we performed 14 cases of conventional IPHC treatment, which consisted of 8 lung cancers and 6 malignant pleural mesotheliomas (MPM). The pathological stages were 8 in the IV-stage for lung cancers and 5 in the III- and 1 in the IV-stage for MPM. The profiles of the preoperative patients’ characteristics are summarized in
We performed IPHC (43˚C, 120 min, 200 mg/m2 of cisplatin), the therapy of which was based on the modified methods from the previous reports of Matsuzaki et al. [
protect the reperfusion pulmonary injury.
We studied the preoperative, intraoperative, and postoperative factors, and evaluated the treatment outcomes regarding the safety and effectiveness of the IPHC. The profiles of the preoperative, intraoperative, and postoperative patients’ characteristics are summarized in
As the intraoperative factors, regimens of IPHC treatment, operating time, IPHC time, blood loss, blood transfusion, intraoperative urine, intraoperative urine per hour, and intraoperative complication were compared in the two groups. As the postoperative factors, the drain detention period, postoperative complications, and post-treatment therapy were evaluated and compared in the two groups.
The adverse events were retrospectively examined, which were based on the patient’s medical records upon physical examination, toxic effects, and laboratory data of the blood cell counts and blood chemistry. The adverse events and their outcomes were evaluated after completion of the IPHC treatment according to the Common Terminology Criteria for Adverse Events Version 4.0 (CTCAE v4.0). The CTCAE v4.0 displays Grades 1 through 5 with unique clinical descriptions of severity for each adverse event (AE) based on this general guideline: Grade 1, mild AE; Grade 2, moderate AE; Grade 3, severe AE; Grade 4, life-threatening or disabling AE; Grade 5, death related to AE.
To evaluate the effectiveness of the IPHC treatment, the postoperative status of the pleural effusion was examined. The residual of the malignant cells in the postoperatively drained pleural effusion was diagnosed by postoperative cytology, that is, diagnosed with a negative or positive finding, or defined based on the cytological malignancy classification. Regarding the postoperative accumulated amount of the pleural effusion, as a height from the back chest bottom by chest CT scanning, which was measured, the degree of the accumulated pleural effusion after the IPHC treatment was compared to the preoperative status at the same slice level of the CT scanning and evaluated as reduction, unchanged, or increased. The effectiveness of the IPHC treatment was represented as the rate of the controlled cases of the reduced pleural effusion in all the cases.
The results are presented as the mean standard deviation (SD) or as a percentage. Comparisons of the results between the continuous variables were analyzed using the independent samples t test, and between categorical variables with chi-square statistics. The ethics committee of the University of Miyazaki Hospital approved this protocol.
Case | Age | Gender | Site | Diagnosis | Histology | Classification | Stage |
---|---|---|---|---|---|---|---|
1 | 73 | M | R | Advanced LC | Ad | N2M1a | IV |
2 | 71 | M | L | Postoperative recurrence | Ad | N3M1a | IV |
3 | 74 | M | L | Postoperative recurrence | Ad | N2M1a | IV |
4 | 59 | M | R | Intraoperatively-found dissemination | Ad | NxM1a | IV |
5 | 68 | M | R | Advanced LC | Ad | NxM1a | IV |
6 | 76 | M | R | Postoperative recurrence | Ad | N1M1a | IV |
7 | 45 | M | R | Advanced LC | Ad | N1M1a | IV |
8 | 48 | M | L | Advanced LC | Pa | N2M1a | IV |
9 | 60 | M | L | MPM | Epi | T3N0 | III |
10 | 65 | F | L | MPM | Epi | T3N1 | III |
11 | 75 | F | R | MPM | Epi | T4N2 | IV |
12 | 74 | F | L | MPM | Epi | T3N0 | III |
13 | 72 | M | R | MPM | Epi | T3N0 | III |
14 | 71 | M | R | MPM | Epi | T2N1 | III |
Case 1 - 8: Lung Cancer group; Case 9 - 14: Malignant pleural mesothelioma group; LC: Lung cancer; Pa: Pulmonary angiosarcoma; Epi: Epithelial; MPM: Malignant pleural mesothelioma; Ad: Adenocarcinoma.
The preoperative factors | Total (n = 14) | LC group (n = 8) | MPM group (n = 6) | p value | ||
---|---|---|---|---|---|---|
Age | Mean ± SD | 66.5 ± 11.1 | 63.7 ± 13.0 | 71.5 ± 4.5 | 0.143 | |
(range) | (45 - 75) | (45 - 73) | (60 - 75) | |||
Gender | Male | 11 | 8 | 3 | ||
Female | 3 | 0 | 3 | 0.427 | ||
Site | Left | 6 | 3 | 3 | ||
Right | 8 | 5 | 3 | 0.043 | ||
Histology | NSCLC | Ad | 7 | 7 | ||
Pa | 1 | 1 | ||||
MPM | Epi | 6 | 6 | |||
Stage | NSCLC | IV | 8 | 8 | ||
MPM | III | 5 | 5 | |||
IV | 1 | 1 | ||||
Lung function | VC (L) | 2.5 ± 0.9 | 2.7 ± 1.0 | 2.3 ± 0.8 | 0.263 | |
%VC (%) | 79.2 ± 20.4 | 76.3 ± 21.6 | 83.1 ± 19.7 | 0.154 | ||
FEV1 (L) | 1.8 ± 0.6 | 1.9 ± 0.7 | 1.7 ± 0.6 | 0.406 | ||
%FEV1 (%) | 76.2 ± 9.4 | 75.7 ± 12.6 | 76.9 ± 3.1 | 0.454 |
LC: Lung cancer; MPM: Malignant pleural mesothelioma; Epi: Epithelial; NSCLC: Non-small cell lung cancer; Ad: Adenocarcinoma; Pa: Pulmonary angiosarcoma; VC: Vital capacity; FEV1: Forced expiratory volume in 1 second.
Case | IPHC regimen | Operative time | IPHC time | Blood loss (ml) | Blood transfusion | Intraoperative urine (ml) | Urine (ml)/hr | Intraoperative complications |
---|---|---|---|---|---|---|---|---|
1 | CDDP 300 mg + saline | 152 | 30 | 170 | − | 1370 | 541 | Lung injury* |
2 | CDDP 300 mg + saline | 80 | 30 | 400 | + | 600 | 450 | − |
3 | CDDP 100 mg + saline | 131 | 30 | 550 | − | 990 | 453 | − |
4 | CDDP 300 mg + saline | 227 | 90 | 300 | − | 800 | 211 | − |
5 | CDDP 300 mg + saline | 288 | 90 | 50 | − | 380 | 79 | Lung injury* |
6 | CDDP 300 mg + saline | 169 | 60 | 0 | − | 370 | 131 | − |
7 | CDDP 300 mg + saline | 310 | 60 | 180 | − | 1380 | 267 | − |
8 | CDDP 300 mg + distilled water | 152 | 60 | 0 | + | 1480 | 584 | − |
9 | CDDP 300 mg + saline | 200 | 60 | 0 | − | 970 | 291 | − |
10 | CDDP 300 mg + saline | 291 | 70 | 1010 | − | 2860 | 590 | − |
11 | CDDP 300 mg + saline | 261 | 60 | 1030 | − | 2150 | 494 | − |
12 | CDDP 300 mg + saline | 135 | 60 | 0 | − | 200 | 89 | − |
13 | CDDP 300 mg + saline | 230 | 60 | 100 | − | 1950 | 509 | − |
14 | CDDP 300 mg + saline | 230 | 60 | 100 | − | 850 | 222 | − |
Case 1 - 8: Lung cancer group; Case 9 - 14: Malignant pleural mesothelioma group.
The intraoperative factors (n = 14) | Total (n = 14) | LC group (n = 8) | MPM group (n = 6) | p value | |
---|---|---|---|---|---|
IPHC regimen | CDDP 300 mg + saline | 12 | 6 | 6 | |
CDDP 100 mg + saline | 1 | 1 | |||
CDDP 300 mg + distilled water | 1 | 1 | |||
Operative time (min) | 204 ± 70 | 189 ± 80 | 225 ± 54 | 0.211 | |
IPHC time (min) | 59 ± 19 | 56 ± 25 | 62 ± 4 | 0.313 | |
Blood loss (ml) | 292 ± 365 | 206 ± 199 | 428 ± 542 | 0.154 | |
Blood transfusion | + | 2 (14.3%, 2/14) | 2 (25%, 2/8) | 0 | 0.147 |
− | 12 | 6 | 6 | ||
Intraoperative urine (ml) | 1168 ± 757 | 921 ± 454 | 1497 ± 987 | 0.058 | |
Intraoperative urine (ml/hour) | 351 ± 186 | 340 ± 192 | 366 ± 195 | 0.317 | |
Intraoperative complication | Lung injury* | 2 | 2 | 0 | 0.147 |
IPHC: Intrapleural hyperthermic chemotherapy; *Pleural adhesion.
exfoliation of the pleural adhesion. These parameters of the intraoperative factors showed no significant difference between the two groups.
Case | Drain detention period (day) | Postoperative complications | Post-treatment therapy |
---|---|---|---|
1 | 8 | − | GEM + CBDCA |
2 | 10 | − | Gefitinib |
3 | 12 | − | Gefitinib, Vinorelbine |
4 | 9 | − | Gefitinib |
5 | 8 | Air leak* | Gefitinib |
6 | 13 | − | − |
7 | 6 | − | Docetaxel, Chemotherapy |
8 | 14 | − | − |
9 | − | − | |
10 | 5 | − | CPT-11 + Epirubicin |
11 | 8 | − | CPT-11 + Epirubicin, GEM + CBDCA |
12 | 14 | − | − |
13 | 14 | − | CDDP (50 mg) + OK432 (5KE), Irinotecan + Epirubicin |
14 | 8 | − | − |
*Subcutaneous emphysema.
The postoperative factors (n = 14) | Total (n = 14) | LC group (n = 8) | MPM group (n = 6) | p value | |
---|---|---|---|---|---|
Drain detention period (day) | 9.9 ± 3.1 | 10.0 ± 2.8 | 9.8 ± 4.0 | 0.453 | |
Postoperative complications* | − | 13 | 7 | 6 | |
+ | 1 (7.1%, 1/14) | 1 (12.5%, 1/8) | 0 | 0.040 |
*Pulmonary fistula (G2).
IPHC, which was observed in one case of hematological toxicity of more than grade 3 in total (7.1%, 1/14). In the LC group, there was one case of grade 3 anemia (25%, 1/8), which was significantly observed in the LG group compared to that in the MPM group (0%, 0/6) (p = 0.040). Regarding the grade 2 hematological toxicity of neutropenia, there was one case in the LC group (25%, 1/8), which was also significantly observed in the LG groups compared to that in the MPM group (0%, 0/6) (p = 0.040). Regarding the grade 2 anemia, there was four cases in total (28.6%, 4/14), 2 cases were observed in the LC group and the others in the MPM group (p = 0.107). On the other hand, there were no non-hematological toxicities of more than grade 3. There was observed in three cases of grade 2 appetite loss (50%, 3/6) and three cases of grade 2 (50%, 3/6) in the MPM group.
Case | Hematological toxicitites | Non-hematological toxicities | |||||||
---|---|---|---|---|---|---|---|---|---|
Neutropenia | Anemia | Thrombocytopenia | Appetite loss | Nausea | Vomitting | Diarrhea | Liver dysfunction | ||
1 | − | G1 | − | − | − | − | − | − | |
2 | G2 | G3 | − | − | − | − | − | − | |
3 | − | G2 | − | − | − | − | − | − | |
4 | − | G1 | − | − | − | − | − | − | |
5 | − | G1 | − | − | − | − | − | − | |
6 | − | G1 | − | − | − | − | − | − | |
7 | G1 | G1 | − | − | − | − | − | − | |
8 | − | G2 | − | − | − | − | − | G1 | |
9 | − | − | − | − | − | − | − | G1 | |
10 | − | G2 | − | G2 | G2 | − | − | − | |
11 | − | G2 | − | G2 | G2 | − | − | G1 | |
12 | − | G1 | − | − | − | − | − | − | |
13 | − | G1 | − | G2 | G2 | − | − | G1 | |
14 | − | G1 | − | − | − | − | − | G1 | |
Case 1 - 8: Lung cancer group; Case 9 - 14: Malignant pleural mesothelioma group.
Adverse events | Total (n = 14) | LC group (n = 8) | MPM group (n = 6) | p value |
---|---|---|---|---|
Hematological toxicities (≥G3) | 1 (7.1%, 1/14) | 1 (25%, 1/8) | 0 (0%, 0/6) | 0.040 |
Neutropenia (G2) | 1 | 1 | 0 | 0.040 |
Anemia (G3) | 1 | 1 | 0 | 0.040 |
Anemia (G2) | 4 | 2 | 2 | 0.107 |
Non-hematological toxicities (≥G3) | 0 | 0 | ||
Appetite loss (G2) | 3 | 3 | 0.384 | |
Nausea (G2) | 3 | 3 | 0.384 |
Case | Postoperative cytology | Control of malignant cells | Amount of pleual effusion |
---|---|---|---|
1 | Class IIIb | + | Reduction |
2 | Not performed | − | Unchanged |
3 | Class III | + | Reduction |
4 | Negative | + | Reduction |
5 | Positive | − | Unchanged |
6 | Positive | − | Reduction |
7 | Class V | − | Reduction |
8 | Negative | not evaluated | Not evaluated |
9 | Negative | + | Reduction |
10 | Class II | + | Reduction |
11 | Class III | − | Reduction |
12 | Negative | + | Reduction |
13 | Class V | − | Unchanged |
14 | Class IV | − | Reduction |
Case 1 - 8: Lung cancer group; Case 9 - 14: Malignant pleural mesothelioma group.
Evaluation items | Total (n = 14) | LC group (n = 8) | MPM group (n = 6) | p value | |
---|---|---|---|---|---|
Cytology of pleural effusion | Negative | 6 | 3 | 3 | |
Positive | 7 | 4 | 3 | ||
Not evaluated | 1 | 1 | |||
Control rate of malignant cells | 46.2% (6/13) | 42.9% (3/7) | 50.0% (3/6) | 0.083 | |
Postoperative pleural effusion | Reduction | 10 | 5 | 5 | |
Unchanged | 3 | 2 | 1 | ||
Not evaluated | 1 | 1 | |||
Control rate of pleural effusion | 76.9% (10/13) | 71.4% (5/7) | 83.3% (5/6) | 0.042 |
chest drain, and by the measurement of the amount of pleural effusion at the same slice level of chest CT scanning, and by the status of the malignant cells in the pleural effusion after the IPHC treatment. The cytology of the malignant cells in the pleural effusion resulted in a negative (n = 6), positive (n = 7), and not evaluated (n = 1). The control rate of the malignant cells was calculated to be 46.2% (6/13). There was no significant difference between the two groups (p = 0.083), that is, 42.9% (3/7) in the LC group and 50.0% (3/6) in the MPM group. For the assessment of the postoperative amounts of the pleural effusion, the levels were reduction (n = 10), unchanged (n = 3), and not evaluated (n = 1). The control rate of the pleural effusion was calculated to be 76.9% (10/13). There was a significant difference between the two groups (p = 0.042), that is, 71.4% (5/7) in the LC group and 83.3% (5/6) in the MPM group.
In 2010, the Japan Lung Cancer Society, the Japanese Association for Chest Surgery, and the Japanese Association for Thoracic Surgery performed a survey of the lung cancers surgically resected in 2004 [
The recent intensive chemotherapy for advanced non-small cell lung carcinoma has been performed using the platinum doublet regimen, which is an effective treatment that showed an extended survival confirmed by the evidence of some meta-analyses [
The extended survival of advanced lung cancer patients has become 3 times (more than 2 - 3 years) longer than ever, and symptom-management of carcinomatosis pleuritis and malignant pleural effusion have become an important issue. IPHC would be one of the optimal palliative therapies used to improve the QOL for untreatable advanced cancer. As one of the multimodal therapies, IPHC should be one of the most expected modalities for an aggressive palliation therapy such as intrathoracic local control of the tumor, control of the pleural effusion, and preserving the good QOL during survival.
The targeted cases of this IPHC treatment were thoracic malignances with dissemination such as unresectable advanced lung cancer with malignant effusion along with carcinomatous pleuritis, intrathoracic recurring cases after primary lung cancer surgery, MPM, sarcoma tumors, metastatic intrapleural tumors due to breast and colon cancers, and other cancers. We introduced the use of IPHC for special diseases except lung cancer, which was disseminated intrapleural angiosarcoma and there was no effective chemotherapeutic treatment except surgery. We performed a palliative pneumonectomy of the unresectable pulmonary angiosarcoma [
The theory and mechanism of the effectiveness of the IPHC is described below. The anti-cancer effectiveness of hyperthermia are generally denoted as, 1) tumor cells have a high hyperthermic sensitivity compared to those of normal cells, 2) tumor tissue has a high hyperthermic sensitivity selectively dependent on the specificity of the surrounding tissue-environment (low pH, hypoxic, fragility of tumor angiogenesis), 3) a high hyperthermic sensitivity in the latter phase of the synthesis in the cell cycle, and 4) enhancement of the sensitivity of the anti- cancer drug for cancer cells, which had been performed as a combination therapy with radiation and chemotherapy.
Regarding the concentration of cisplatin in the tumor tissue, the local administered method showed a 2- to 3-fold higher level compared to that of the intravenously dripped infusion [
No updated evidence has recently been reported by a restrictive clinical trial regarding the therapy of IPHC. A conventional IPHC is a monotherapy of the hyperthermic perfusion of cisplatin into the intrathoracic cavity, which had been performed as a treatment for thoracic malignant diseases with dissemination in clinical practice. To manage the malignant pleural effusion, there were some methods, which were known as a repetition of the intrapleural drainage puncture, pleurodesis with a chest tube and thoracoscopy, detention of the intrapleural catheter tube, an intrapleuroperitoneal shunt, pleurectomy, intrapleural hypotonic cisplatin lavage, and our conventional IPHC treatment.
For the unresectable advanced and terminal staged patients with carcinomatosis pleuritis with malignant pleural effusion, the objective was to reduce the worse symptoms of dyspnea, which decreased the QOL of the patient. In this situation, there were many intrathoracic punctures and/or intrapleural drainage for palliation of the symptoms. Even though the patient was discharged with palliation of the clinical symptoms, however, because of re-accumulation of the pleural effusion, repeated management of pleural effusion should be needed. The patient’s QOL and activity of daily living have become worse, resulting in extended hospitalization and shortening of being at home. Regarding the benefit of IPHC treatment, even though this therapy has a surgical invasive aspect, however, not only the hyperthermic and anticancer effectiveness but also the palliation of dyspnea-symptoms and improvement of the QOL occurred. The efficacy of the IPHC treatment has an effect on the control of the pleural effusion, shortening of the drain detention period, and extension of outpatient care, that resulted in preserving of the patient’s good QOL.
In the past, our study group reported the first outcome of the IPHC treatments for thoracic malignant diseases with pleural dissemination with effusion, which were performed from 1988 to 1993 (n = 12) [
Regarding the limitation of our present study, we recognized the small sample size, the non-prospective study, the retrospective analysis of the old medical records, no evaluation of long-term outcomes, such as overall survival, assessment of short-term outcomes, such as cytology and amount of pleural effusion, no evaluation of the QOL outcome, and no study of the effectiveness of any post-treatment treatment.
Recently, there has not been a distinct clinical phase-II study and no update as new evidence of the IPHC treatment. The regimen has become the old-fashioned single use of cisplatin and its hyperthermic perfusion of the intrapleural space. A new next-generation IPHC and its accurate evidence should be expected. We developed a new next-generation IPHC, whose regimen is constructed of platinum doublet chemotherapy with the new 3rd generation cytotoxic drugs, that is, the additional oral medication of a S-1 drug. As the optimal aggressive palliation therapy, our new clinical trial, the next-generation IPHC is a hybrid chemotherapy combined with oral S-1 medication plus conventional cisplatin-based IPHC for the advanced thoracic malignancies with pleural effusion. We have reported the first case, and its preliminary feasibility, safety, efficacy, and good preserving of the QOL [
IPHC treatment resulted in no major complications, fewer adverse events of more than grade 3, which we could safely perform. We obtained a high effectiveness of the IPHC treatment, which resulted in both a high post- treatment control rate of pleural effusion (76.9%) and a control rate of malignant cells in the pleura effusion (46.2%).
This study was supported by a Grant-in-Aid for Clinical Research from the Miyazaki University Hospital.
Takanori Ayabe,Masaki Tomita,Eiichi Chosa,Hiroki Mori,Kunihide Nakamura, (2016) Clinical Outcomes, Safety and Efficacy of Intrapleural Hyperthermic Chemotherapy for Thoracic Malignant Diseases with Pleural Effusion. Journal of Cancer Therapy,07,203-215. doi: 10.4236/jct.2016.73021
IPHC: Intrapleural Hyperthermic Chemotherapy
LC: Lung Cancer
MPM: Malignant Pleural Mesothelioma
CDDP: Cisplatin
TNM: Tumor-Node-Metastasis
QOL: Quality of Life