Two weeks of hydrogen inhalation can significantly reverse adaptive and innate immune system senescence patients with advanced non-small cell lung cancer: a self-controlled study.

Following standard treatments, the traditional model for enhancing anti-tumor immunity involves performing immune reconstitution (e.g., adoptive immune cell therapies or immunoenhancing drugs) to prevent recurrence. For patients with advanced non-small cell lung cancer, we report here on two objectives, the immunosenescence for advanced non-small cell lung cancer and hydrogen gas inhalation for immune reconstitution. From July 1st to September 25th, 2019, 20 non-small cell lung cancer patients were enrolled to evaluate the immunosenescence of peripheral blood lymphocyte subsets, including T cell, natural killer/natural killer T cell and gamma delta T cell. Two weeks of hydrogen inhalation was performed during the waiting period for treatment-related examination. All patients inhaled a mixture of hydrogen (66.7%) and oxygen (33.3%) with a gas flow rate of 3 L/min for 4 hours each day. None of the patients received any standard treatment during the hydrogen inhalation period. After pretreatment testing, major indexes of immunosenescence were observed. The abnormally higher indexes included exhausted cytotoxic T cells, senescent cytotoxic T cells, and killer Vδ1 cells. After 2 weeks of hydrogen therapy, the number of exhausted and senescent cytotoxic T cells decreased to within the normal range, and there was an increase in killer Vδ1 cells. The abnormally lower indexes included functional helper and cytotoxic T cells, Th1, total natural killer T cells, natural killer, and Vδ2 cells. After 2 weeks of hydrogen therapy, all six cell subsets increased to within the normal range. The current data indicate that the immunosenescence of advanced non-small cell lung cancer involves nearly all lymphocyte subsets, and 2 weeks of hydrogen treatment can significantly improve most of these indexes. The study was approved by the Ethics Committee of Fuda Cancer Hospital, Jinan University in China (approval No. Fuda20181207) on December 7th, 2018, and was registered on ClinicalTrials.gov (ID: NCT03818347) on January 24th, 2019.

A narrative review of hydrogen oncology: from real world survey to real world evidence.

The use of hydrogen for cancer control has made great progress in cytology and animal experiments. With the increasing number of hydrogen products on the market, larger numbers of advanced cancer patients have participated in clinical trials or received treatment at home after purchase. Our study reported a real-world survey from 82 patients with good cancer control using hydrogen products, including real world evidence from patients who received ineffective traditional treatment, patients who received traditional treatment that failed, or patients who refused traditional treatment. Two typical cases were reported herein. Subsequently, we included studies on the mechanism of hydrogen oncology. The mechanism of cancer control using hydrogen includes the inhibition of tumor cells and the activation of exhausted lymphocytes. Large-scale real world evidence has shown clinical value, and yet remains to be further developed and researched.

Hydrogen therapy can be used to control tumor progression and alleviate the adverse events of medications in patients with advanced non-small cell lung cancer.

Chemotherapy, targeted therapy, and immunotherapy are used against advanced non-small cell lung cancer. A clinically efficacious method for relieving the adverse events associated of such therapies is lacking. Fifty-eight adult patients were enrolled in our trial to relieve pulmonary symptoms or the adverse events of drugs. Twenty patients who refused drug treatment were assigned equally and randomly to a hydrogen (H2)-only group and a control group. According to the results of tumor-gene mutations and drug-sensitivity tests, 10, 18, and 10 patients were enrolled into chemotherapy, targeted therapy, and immunotherapy groups in which these therapies were combined with H2-therapy, respectively. Patients underwent H2 inhalation for 4-5 hours per day for 5 months or stopped when cancer recurrence. Before study initiation, the demographics (except for tumor-mutation genes) and pulmonary symptoms (except for moderate cough) of the five groups showed no significant difference. During the first 5 months of treatment, the prevalence of symptoms of the control group increased gradually, whereas that of the four treatment groups decreased gradually. After 16 months of follow-up, progression-free survival of the control group was lower than that of the H2-only group, and significantly lower than that of H2 + chemotherapy, H2 + targeted therapy, and H2 + immunotherapy groups. In the combined-therapy groups, most drug-associated adverse events decreased gradually or even disappeared. H2 inhalation was first discovered in the clinic that can be used to control tumor progression and alleviate the adverse events of medications for patients with advanced non-small cell lung cancer. This study was approved by the Ethics Committee of Fuda Cancer Hospital of Jinan University on December 7, 2018 (approval No. Fuda20181207), and was registered at ClinicalTrials.gov (Identifier: NCT03818347) on January 28, 2019.

"Real world survey" of hydrogen-controlled cancer: a follow-up report of 82 advanced cancer patients.

Advanced cancer treatment is a huge challenge and new ideas and strategies are required. Hydrogen exerts antioxidant and anti-inflammatory effects that may be exploited to control cancer, the occurrence and progression of which is closely related to peroxidation and inflammation. We conducted a prospective follow-up study of 82 patients with stage III and IV cancer treated with hydrogen inhalation using the "real world evidence" method. After 3-46 months of follow-up, 12 patients died in stage IV. After 4 weeks of hydrogen inhalation, patients reported significant improvements in fatigue, insomnia, anorexia and pain. Furthermore, 41.5% of patients had improved physical status, with the best effect achieved in lung cancer patients and the poorest in patients with pancreatic and gynecologic cancers. Of the 58 cases with one or more abnormal tumor markers elevated, the markers were decreased at 13-45 days (median 23 days) after hydrogen inhalation in 36.2%. The greatest marker decrease was in achieved lung cancer and the lowest in pancreatic and hepatic malignancies. Of the 80 cases with tumors visible in imaging, the total disease control rate was 57.5%, with complete and partial remission appearing at 21-80 days (median 55 days) after hydrogen inhalation. The disease control rate was significantly higher in stage III patients than in stage IV patients (83.0% and 47.7%, respectively), with the lowest disease control rate in pancreatic cancer patients. No hematological toxicity was observed although minor adverse reactions that resolved spontaneously were seen in individual cases. In patients with advanced cancer, inhaled hydrogen can improve patients' quality-of-life and control cancer progression. Hydrogen inhalation is a simple, low-cost treatment with few adverse reactions that warrants further investigation as a strategy for clinical rehabilitation of patients with advanced cancer. The study protocol received ethical approval from the Ethics Committee of Fuda Cancer Hospital of Jinan University on December 7, 2018 (approval number: Fuda20181207).

Hydrogen gas therapy induced shrinkage of metastatic gallbladder cancer: A case report.

BACKGROUND: We present the case of a 72-year-old female patient with gallbladder cancer (GBC) who developed in situ recurrence and liver metastases 9 mo after irreversible electroporation ablation and oral tegafur (a fluoropyrimidine derivative) chemotherapy, which failed to control the progression of the disease. The patient further developed metastases in the lymph nodes around the head of the pancreas. The patient had severe anemia, requiring weekly blood transfusions. The gallbladder tumor invaded the descending part of the duodenum, causing intestinal leakage and hepatic colonic adhesion. CASE SUMMARY: The patient refused other treatments and began daily hydrogen inhalation therapy. After 1 mo of treatment, the gallbladder and liver tumors continued to progress, and intestinal obstruction occurred. After continuous hydrogen therapy and symptomatic treatments including gastrointestinal decompression and intravenous nutrition support, the intestinal obstruction was gradually relieved. Three months after hydrogen therapy, the metastases in the abdominal cavity gradually reduced in size, her anemia and hypoalbuminemia were corrected, lymphocyte and tumor marker levels returned to normal, and the patient was able to resume normal life. CONCLUSION: This is the first report of an efficacy and safety study about hydrogen therapy in patient with metastatic GBC and a critical general condition, who has remained stable for more than 4 months.

Using circulating tumor cells to evaluate the efficacy of irreversible electroporation for unresectasble pancreatic cancer.

We used circulating tumor cells (CTCs) as biomarkers to evaluate the efficacy of pre-irreversible electroporation (IRE) and post-IRE for unresectable pancreatic cancer (PC). Real-time qPCR was used to detect potential biomarker genes in CTCs, and magnetic-activated cell sorting (MACS) and fluorescence-activated cell sorting (FACS) were performed on 43 patients with PC who underwent IRE. Some patients experienced adverse reactions within 30 days of the operation, including arrhythmia (6.9%), intraoperative transient change of blood pressure (25.5%), cough (11.6%), nausea and vomiting (23.3%), ascites (25.6%), fever (9.3%), and pain of puncture point (60.5%). The number of CTCs decreased significantly with postoperative time (P < 0.01). Delta cycle threshold values for the CTC-related genes CEA, Ep-CAM, and CK19 increased significantly after IRE. Furthermore, the expression of CEA, Ep-CAM, and CK19 decreased significantly with time after IRE (P < 0.01). Detecting CTCs by RT-qPCR and FACS combined with MACS has significant diagnostic and prognostic value for evaluating the efficacy of IRE in patients with unresectable PC.

MiR-187 overexpression inhibits cervical cancer progression by targeting HPV16 E6.

Aberrantly expressed microRNAs contribute to the initiation and progression of human cancer. MiRNA-187 has been reported in nasopharyngeal, renal, pancreatic, prostate, and esophageal cancer, and acts as a tumor suppressor or oncogene. However, the underlying function of miRNA-187 in cervical cancer remains largely unexplored. In the present study, we demonstrated significantly miRNA-187 down-regulation in cervical cancer tissues and cell lines compared to their normal counterparts. Kaplan-Meier analysis revealed that decreased miRNA-187 was closely associated with shorter overall survival and relapse-free survival. Gain- and loss-of-function studies showed that miRNA-187 suppressed cervical cancer cell proliferation, migration, and invasion, and promoted cervical cancer cell apoptosis. Furthermore, luciferase reporter assay determined that human papillomavirus 16 E6 was a direct functional target of miRNA-187. Taken together, our findings indicate the essential role of miRNA-187 in suppressing cervical cancer progression and indicate a novel link between miRNA-187 and human papillomavirus 16 E6 in cervical cancer.

Circulating tumor cell as a biomarker for evaluating allogenic NK cell immunotherapy on stage IV non-small cell lung cancer.

In this study, we determined the number of peripheral blood circulating tumor cells (CTCs) pre- and post-NK in patients with stage IV non- small cell lung cancer (NSCLC) as a reference for understanding the relevance of any changes to the efficacy of NK cells therapy. The patients were given one to three courses of immunotherapy. CTC numbers and CTC-related gene expression were measured in the peripheral blood of 31 patients with stage IV NSCLC at 1day before and 7 and 30d after NK cells therapy using magnetic activated cell sorting (MACS) and fluorescence activated cell sorting (FACS) combined with real-time quantitative PCR (RT-qPCR). Throughout the research, fever was the most common reaction (34.6%). The number of CTCs was 18.11±5.813, 15.13±5.984 and 10.32±5.623, respectively, and this decreased significantly over time. ΔCt values for the CTC-related genes CEA, MAGE-3 and CK18 increased significantly after NK cells infusion. The expression of CEA, CK18 and MAGE-3 decreased significantly with time after NK. CTC was a useful biomarker for evaluating the efficacy of NK cells therapy on stage IV NSCLC.

Clinical efficacy of percutaneous cryoablation combined with allogenic NK cell immunotherapy for advanced non-small cell lung cancer.

In this study, the safety and clinical efficacy of cryosurgery combined with allogenic NK cell immunotherapy for the treatment of advanced non-small cell lung cancer (NSCLC) were evaluated. From July 2016 to March 2017, we enrolled 60 patients who met the enrollment criteria and divided them into two groups: (1) the simple cryoablation group (n = 30) and (2) the cryoablation combined with allogenic NK cell group (n = 30). The changes in immune function, quality of life, and clinical response were evaluated. We found that allogenic NK cells combined with cryosurgical treatment for advanced NSCLC have a synergistic effect, which not only enhancing the immune function of patients, improving the quality of life, and significantly increasing the response rate (RR) and disease control rate (DCR) compared to cryoablation group. This study is the first clinical trial of allogenic NK cells combined with cryosurgery for the treatment of advanced NSCLC and preliminaily its safety and efficacy.

The Safety and Efficacy of Irreversible Electroporation for Large Hepatocellular Carcinoma.

This study aimed to investigate the safety and effectiveness of irreversible electroporation ablation for unresectable large liver cancer. Fourteen patients were enrolled: 8 with large hepatocellular carcinoma (tumor diameter: 5.1-11.5 cm) and 6 with medium hepatocellular carcinoma (tumor diameter: 3.0-4.1 cm). All patients received percutaneous irreversible electroporation ablation. Ablation time and the incidence of complications were assessed by a t test. Post-irreversible electroporation and regular contrast-enhanced computerized tomography scans were performed to investigate the effect of tumor size (large vs medium) on irreversible electroporation treatment efficacy; 4-table data were assessed using a Fisher exact test. The 14 patients completed irreversible electroporation ablation successfully. In the large hepatocellular carcinoma group, no major complications occurred in the perioperative period. Minor complications comprised bloating, hypokalemia, edema, low white blood cells, and blood clotting abnormalities. All complications were mild and improved after symptomatic treatment. The frequency of minor complications was not significantly different ( P > .05) compared with the medium hepatocellular carcinoma group. The average follow-up time was 2.8 ± 2.1 months and complete ablation was achieved in 25% (2/8; residual = 75%). For the patients with medium hepatocellular carcinoma, the mean follow-up time was 4.3 ± 3.2 months; the rate of complete ablation was 66.6% (4/6; residual rate = 33.3%). The complete ablation rate was not statistically different between the 2 groups ( P > .05). Irreversible electroporation ablation for unresectable large hepatocellular carcinoma is safe, with no major complications. Short-term efficacy is relatively good; however, long-term efficacy remains to be explored.

Advances in cryoablation for pancreatic cancer.

Pancreatic carcinoma is a common cancer of the digestive system with a poor prognosis. It is characterized by insidious onset, rapid progression, a high degree of malignancy and early metastasis. At present, radical surgery is considered the only curative option for treatment, however, the majority of patients with pancreatic cancer are diagnosed too late to undergo surgery. The sensitivity of pancreatic cancer to chemotherapy or radiotherapy is also poor. As a result, there is no standard treatment for patients with advanced pancreatic cancer. Cryoablation is generally considered to be an effective palliative treatment for pancreatic cancer. It has the advantages of minimal invasion and improved targeting, and is potentially safe with less pain to the patients. It is especially suitable in patients with unresectable pancreatic cancer. However, our initial findings suggest that cryotherapy combined with 125-iodine seed implantation, immunotherapy or various other treatments for advanced pancreatic cancer can improve survival in patients with unresectable or metastatic pancreatic cancer. Although these findings require further in-depth study, the initial results are encouraging. This paper reviews the safety and efficacy of cryoablation, including combined approaches, in the treatment of pancreatic cancer.

Percutaneous imaging-guided cryoablation for lung cancer.

Percutaneous cryoablation under imaging guidance has been proved to be a safe and effective method for ablation and debulking of tumors, providing radical cure or palliation, as the case may be, for patients with different stages of disease. The local control rate is high with cryoablation, and the complications are usually controllable, making it a reasonable choice in lung cancer treatment. In this paper the technique and mechanism of action of cryoablation are summarized, and studies performed on the application of percutaneous cryoablation in various stages of lung cancer are reviewed. Its emerging application in the treatment of pure ground-glass nodules (GGNs) is also introduced.

Prospective study of the safety and efficacy of a pancreatic cancer stem cell vaccine.

INTRODUCTION: In this trial, we isolated and cultured pancreatic cancer stem cells (CSCs) to produce a vaccine and prospectively evaluated its safety and efficacy in low-, medium-, and high-dose groups. MATERIAL AND METHODS: Between February and October 2014, we enrolled 90 patients who met the enrollment criteria and assigned them to three groups (n = 30). CSC-specific and CSC-non-specific immunity pre- and post-vaccination were compared by Dunnett's multiple comparison test (one-way ANOVA). The data are presented as the mean±standard deviation. Local and systemic adverse events were recorded in the nursing records and compared using the Chi-square test. All statistical analyses were conducted using GraphPad software (GraphPad, San Diego, CA, USA). RESULTS: Throughout the trial, an injection site reaction was the most common reaction (54 %), and fever was least common (9 %). The incidence of these side effects did not vary among the three groups. When the pre- and post-vaccination immunity was compared, we found that both CSC-nonspecific and CSC-specific responses were significantly increased in the high-dose group. CONCLUSION: This study is the first clinical trial of a pancreatic CSC vaccine and preliminarily proves its safety and efficacy.

Safety and efficacy study of lung cancer stem cell vaccine.

In this trial, lung cancer stem cells (CSCs) were separated and cultured to produce a vaccine; its safety and efficacy were prospectively evaluated in low-, medium-, and high-dose groups. Between February and September 2014, we enrolled 90 patients who met the enrollment criteria and assigned them to three groups (n = 30). Throughout the trial, injection site reaction was the most common reaction (63 %), and fever was least common (16 %); however, there was no difference among the three groups. When the immune responses pre- and post-vaccination were compared, we found that the CSC-nonspecific and CSC-specific responses were both significantly enhanced in the medium- and high-dose groups. This study is the first clinical trial of a lung CSC vaccine and preliminarily proves its safety and efficacy.

Percutaneous Cryoablation for Liver Cancer.

Based on the primary tumor site, liver cancer can be divided into two categories: (1) primary liver cancer and (2) metastatic cancer to the liver from a distant primary site. Guided cryoablation via many imaging methods induces iceball formation and tumor necrosisand is an attractive option for treating unresectable hepatocellular carcinoma (HCC) and metastatic liver cancer. There are several advantages to using cryoablation for the treatment of liver cancer: it can be performed percutaneously, intraoperatively, and laparoscopically; iceball formation can be monitored; it has little impact on nearby large blood vessels; and it induces a cryo-immunological response in situ. Clinically, primary research has shown that percutaneous cryoablation of liver cancer is relatively safe and efficient, and it can be combined with other methods, such as radiation therapy, chemotherapy, and immunology, to control disease. Although research is preliminary, cryosurgery is fast becoming an alternative treatment method for HCC or liver tumors. Here, we review the mechanisms of liver tumor cryoablation, cryoablation program selection, clinical efficiency, and complications following treatment.

Combination treatment with comprehensive cryoablation and immunotherapy in metastatic hepatocellular cancer.

AIM: To retrospectively assess the effect of comprehensive cryosurgery (ablation of intra- and extra-hepatic tumors) plus dendritic cell-cytokine-induced killer cell immunotherapy in metastatic hepatocellular cancer. METHODS: We divided 45 patients into cryo-immunotherapy (21 patients), cryotherapy (n = 12), immunotherapy (n = 5) and untreated (n = 7) groups. Overall survival (OS) after diagnosis of metastatic hepatocellular cancer was assessed after an 8-year follow-up. RESULTS: Median OS was higher following cryo-immunotherapy (32 mo) or cryotherapy (17.5 mo; P < 0.05) than in the untreated group (3 mo) and was higher in the cryo-immunotherapy group than in the cryotherapy group (P < 0.05). In the cryo-immunotherapy group, median OS was higher after multiple treatments (36.5 mo) than after a single treatment (21 mo; P < 0.05). CONCLUSION: Cryotherapy and, especially, cryo-immunotherapy significantly increased OS in metastatic hepatocellular cancer patients. Multiple cryo-immunotherapy was associated with a better prognosis than single cryo-immunotherapy.

Intraperitoneal perfusion of cytokine-induced killer cells with local hyperthermia for advanced hepatocellular carcinoma.

AIM: To study the effect and tolerance of intraperitoneal perfusion of cytokine-induced killer (CIK) cells in combination with local radio frequency (RF) hyperthermia in patients with advanced primary hepatocellular carcinoma (HCC). METHODS: Patients with advanced primary HCC were included in this study. CIK cells were perfused intraperitoneal twice a week, using 3.2 × 109 to 3.6 × 109 cells each session. Local RF hyperthermia was performed 2 h after intraperitoneal perfusion. Following an interval of one month, the next course of treatment was administered. Patients received treatment until disease progression. Tumor size, immune indices (CD3⁺, CD4⁺, CD3⁺CD8⁺, CD3⁺CD56⁺), alpha-fetoprotein (AFP) level, abdominal circumference and adverse events were recorded. Time to progression and overall survival (OS) were calculated. RESULTS: From June 2010 to July 2011, 31 patients diagnosed with advanced primary HCC received intraperitoneal perfusion of CIK cells in combination with local RF hyperthermia in our study. Patients received an average of 4.2 ± 0.6 treatment courses (range, 1-8 courses). Patients were followed up for 8.3 ± 0.7 mo (range, 2-12 mo). Following combination treatment, CD4⁺, CD3⁺CD8⁺ and CD3⁺CD56⁺ cells increased from 35.78% ± 3.51%, 24.61% ± 4.19% and 5.94% ± 0.87% to 45.83% ± 2.48% (P = 0.016), 39.67% ± 3.38% (P = 0.008) and 10.72% ± 0.67% (P = 0.001), respectively. AFP decreased from 167.67 ± 22.44 to 99.89 ± 22.05 ng/mL (P = 0.001) and abdominal circumference decreased from 97.50 ± 3.45 cm to 87.17 ± 4.40 cm (P = 0.002). The disease control rate was 67.7%. The most common adverse events were low fever and slight abdominal erubescence, which resolved without treatment. The median time to progression was 6.1 mo. The 3-, 6- and 9-mo and 1-year survival rates were 93.5%, 77.4%, 41.9% and 17.4%, respectively. The median OS was 8.5 mo. CONCLUSION: Intraperitoneal perfusion of CIK cells in combination with local RF hyperthermia is safe, can efficiently improve immunological status, and may prolong survival in HCC patients.

Prevention of needle-tract seeding by two-step freezing after lung cancer biopsy.

Fine-needle aspiration biopsy is a method to detect malignancy for undetermined pulmonary nodules, but has the potential to spread malignant cells from the tumor to the pleural cavity or chest wall. We developed a two-step freezing method to avoid needle-tract seeding, by use of percutaneous cryoablation after biopsy but before the biopsy needle was removed. A man aged 72 years was admitted because of a large mass in right upper lobe. After biopsy, the patient underwent surgery. Pathological assessment of the resected tumor showed that tissue around the biopsy probe and cryoprobe had been killed before needle withdrawal.

[Percutaneous cryoablation and (125)I seed implantation combined with chemotherapy for advanced pancreatic cancer: report of 67 cases].

OBJECTIVE: To assess the efficacy and safety of percutaneous cryoablation (PCC) and (125)I seed implantation combined with chemotherapy for advanced pancreatic cancer. METHODS: Sixty-seven patients with advanced pancreatic cancer (6 in stage III, 61 in stage IV) received PCC and (125)I seed implantation combined with concomitant gemcitabine hydrochloride and DDP chemotherapy. The clinical benefit response (CBR), survival rate and therapy-related complications were assessed. RESULTS: All patients except one were followed up over 1 year. The 6-month and 1-year survival rates were 84.8% and 33.4%, respectively. The median progression free survival were 6.3 months and 5.5 months in the group stage III and group stage IV (P > 0.05), respectively, while the overall survival was 9.1 months in the group stage III and 11.0 months in the group stage IV (P > 0.05). CR,PR and SD were achieved in 5, 8, 54 patients, respectively. Fifty-four and 50 in the 67 patients experienced a ≥ 50% reduction of pain score and analgesic consumption, respectively, 18 patients experienced a ≥ 2 kg weight gaining, and KPS was increasing from 71.2 ± 0.4 to (90.0 ± 0.3, P < 0.05), the overall benefit rate was 80.6%. No serious therapy-related complications except pancreatic fistula accompanied abdominal hemorrhage, bile leakage, acute pancreatitis and needle track seeding in 1, 1, 2 and 1 case, respectively. CONCLUSION: Percutaneous cryoablation and (125)I seed implantation combined with chemotherapy are effective and safe for the treatment of advanced pancreatic cancer.

Radical treatment of stage IV pancreatic cancer by the combination of cryosurgery and iodine-125 seed implantation.

AIM: To investigate the therapeutic effect of radical treatment and palliative treatment in stage IV pancreatic cancer patients. METHODS: 81 patients were enrolled in the study. Radical treatment was performed on 51 patients, while 30 patients were put under palliative treatment. The procedural safety and interval survival for stage IV pancreatic cancer (IS-IV) was assessed by almost 2.5 years of follow-ups. The IS-IV of patients under the two kinds of treatment, and the effects of treatment timing and frequency on IS-IV, were compared. RESULTS: The IS-IV of patients who received radical treatment was significantly longer than those who received palliative treatment (P < 0.001). The IS-IV of patients who received delayed radical or palliative treatment was longer than those who received accordingly timely treatment (P = 0.0034 and 0.0415, respectively). Multiple treatments can play an important role in improving the IS-IV of patients who received radical treatment (P = 0.0389), but not for those who received palliative treatment (P = 0.99). CONCLUSION: The effect of radical treatment was significantly more obvious than that of palliative treatment, and multiple radical treatments may contribute more to patients than a single radical treatment.