An update on the treatment of CNS metastases in small cell lung cancer

Brain metastases occur frequently and are a significant threat to the quality of life in patients with small cell lung carcinoma. The primary treatment modality has historically been whole brain radiation, which can provide a moderate extension of life and improvement in neurologic symptoms. Despite increasing interest in the use of alternative therapeutic agents-primarily chemotherapy-these have yet to be demonstrated to be superior to radiation in management of brain metastasis. Prophylactic cranial irradiation prevents or delays the occurrence of brain metastases in patients with small cell lung carcinoma. Until recently, this benefit has been thought to be primarily restricted to a minority of patients with limited stage disease. A large European trial, however, has now shown a survival benefit to the use of prophylactic cranial irradiation in patients who have any response to systemic chemotherapy. This finding should significantly shift management practices for this aggressive disease for most patients.     

Prophylactic cranial irradiation for lung cancer patients at high risk for development of cerebral metastasis: results of a prospective randomized trial conducted by the Radiation Therapy Oncology Group.

Beginning in February 1984, 187 evaluable patients with adenocarcinoma or large cell carcinoma of the lung clinically confined to the chest were randomized to receive either conventionally fractionated thoracic irradiation alone or thoracic irradiation with concurrent, prophylactic cranial irradiation. The study population included 161 patients treated for medically or surgically inoperable primary cancers, and 26 patients undergoing adjuvant postoperative mediastinal irradiation following attempted curative resection of primary cancers found to have metastasized to hilar or mediastinal lymph nodes. Elective brain irradiation was not effective in preventing the clinical appearance of brain metastases, although the time to develop brain metastases appears to have been delayed. Eighteen of 94 patients (19%) randomized to chest irradiation alone have developed brain metastases as opposed to 8/93 patients (9%) randomized to receive prophylactic cranial irradiation (p = .10). No survival difference was observed between the treatment arms. Among the 26 patients undergoing prior resection of all gross intrathoracic disease, brain metastases were observed in 3/12 patients (25%) receiving adjuvant chest irradiation alone, compared to none of 14 receiving prophylactic cranial irradiation (p = .06). In the absence of fully reliable therapy for the primary disease, and without effective systemic therapy preventing dissemination to other, extrathoracic sites, prophylactic cranial irradiation for inoperable non-small cell lung cancer cannot be justified in routine clinical practice. Further investigation in the adjuvant, postoperative setting may be warranted.     

Neurologic dysfunction in patients treated for small cell carcinoma of the lung: a clinical and radiological study

The neurologic dysfunction in 7 patients treated for small cell carcinoma (SCC) of the lung by combination chemotherapy and prophylactic brain irradiation was evaluated. The disease appeared to be a diffuse encephalopathy frequently affecting the higher cortical functions. Five out of seven patients had progressive dysfunction leading to death in 1 to 26 months; one patient had stabilization of symptoms followed by death in 21 months, probably from the neurologic disease as well as SCC; one patient's symptoms improved. The clinical course of the neurologic disorder seemed different from the known reactions to brain irradiation and from the other neurologic syndromes associated with lung cancer. The relative contributions of cranial irradiation and treatment with chemotherapeutic agents in producing the neurotoxicity are not known. Computed tomographic (CT) brain scans done after the onset of symptoms did not show any focal signs or necrosis. However, there was a suggestion of progressive increase in intracranial fluid volume on the scans. The incidence of the disorder, 10.2% among a group of 49 patients, suggests the need for prospective studies to evaluate the problem.     

Zerebrale Metastasierung: Prophylaxe und Behandlung

Small cell lung cancer (SCLC) is characterized by a high prevalence of brain metastases, which affect more than half of the patients during the course of the disease. Since the meta-analysis of the late 1990s prophylactic cranial irradiation is a key element in multimodal therapy of limited disease SCLC with complete remission after chemotherapy. Recently, moreover, a multicenter phase III study in patients with advanced disease demonstrated a survival advantage following prophylactic radiotherapy to the brain. In the palliation of cerebral metastases whole brain radiotherapy remains the standard of treatment. The poor survival rates, however, strongly support the need for effective prophylaxis.     

The prognostic factors of lung cancer patients with brain metastases treated with radiotherapy

Purpose: To analyze the prognostic factors of lung cancer with brain metastases (BM) and evaluate the role of cranial irradiation on survival. Methods and materials: From 1987 to 1994, 159 lung cancer patients with CT scan documented BM were reviewed. All of them underwent cranial irradiation (median radiation dose: 30 Gy). Chemotherapy and surgery of BM were performed in 21 and 10 cases, respectively. Results: Overall median survival was 3.5 months and one year survival rate was 10.69%. Univariate analysis showed that the significant factors were performance status, age, total radiation dose to brain, BM as the first metastasis, neurosurgery, symptoms of urine/stool incontinence, and synchronous BM. Multivariate analysis indicated that (1) performance status (p=0.0002), (2) total radiation dose (p=0.0032), (3) BM as the first metastasis (p=0.0449), (4) neurosurgery (p = 0.0233), (5) symptoms of urine/stool incontinence (p = 0.0002), and (6) the presence of a midline shift on cranial CT scans (p = 0.0063) were significant prognostic factors. Conclusion: The prognosis of BM in lung cancer patients is extremely poor. Radiotherapy appears as an effective means of palliation with 75% overall symptomatic response rate. Higher radiation dose ( 30 Gy) and neurosurgery are associated with longer survival. Good performance status, BM as the first metastasis, absence of sphincter dysfunction, and midline shift on CT scans are favorable prognostic predictors. The role of midline shift is very interesting and needs to be explored further.     

Hirnmetastasen

Brain metastases are a frequent complication in solid tumors with a major worsening of the prognosis. With improved treatment of the primary tumor site and improved neuroradiological diagnosis, the incidence is apparently increasing. The incidence of brain metastases after complete remission in small cell lung cancer is reported to be approximately 30%. After prophylactic cranial irradiation the incidence is reduced to approximately 5%. Furthermore, there is an absolute increase in overall survival of 5.4%. An accepted moderate fractionation scheme with minimal morbidity is 30 Gy in 3 weeks. The therapeutic aim in patients with brain metastases is palliation. Symptomatic response rates of 80% are reported after therapeutic cranial irradiation and overall survival could be prolonged. New strategies to improve the still discouraging results are urgently needed. One candidate may be the combination of radiotherapy and chemotherapy.     

Neurologic disorders in patients with small cell lung cancer

In a series of 641 patients with small cell lung cancer, 189 (29.5%) had at least one neurologic disorder either at the time of presentation or during the subsequent clinical course of the cancer. The total number of neurologic disorders was 210, which included brain metastases (75.7%), meningeal carcinomatosis (6.7%), intramedullary metastases (2.4%), epidural metastases (11.0%), hyponatremia producing CNS symptoms (3.3%), and Eaton-Lambert syndrome (1.0%). The most common signs and symptoms were motor dysfunction and confusion. The overall survival of patients with any neurologic disorder was compared to that of patients without neurologic problems. There was no difference between the survival curves for the first year and a half, but patients without neurologic complications had a greater probability of long-term survival (log-rank P = 0.03). There were no statistically significant differences when this comparison was made according to stage of disease. When a neurologic disorder related to cancer occurred, the survival time from the date of that diagnosis was usually short. The neurologic disorder was the immediate cause of death in the majority of cases. In patients who achieved a complete remission, the administration of prophylactic cranial irradiation (PCI) significantly reduced the risk of developing brain metastases as the initial site of the relapse (log-rank P = 0.0034). After adjustment for performance status and extent of disease, the survival of complete responders treated with and without PCI was not significantly different. We conclude that neurologic complications are a frequent and serious problem in patients with SCLC.     

Combined modality treatment of regional small cell undifferentiated carcinoma of the lung: a cooperative study of the RTOG and ECOG

Between 1975 and 1979, 271 patients with regional small cell undifferentiated (including oat cell) carcinoma of the lung were entered into a study involving treatment by radiation therapy (4500 cGy (rad) in five weeks) to the primary tumor, mediastinum and supraclavicular lymph nodes, and a randomization to receive or not receive prophylactic treatment of the brain (3000 cGy in two weeks) and a randomization to prophylactic or delayed chemotherapy (cyclophosphamide and CCNU). Analysis of the data indicates that the median survival for responders (53 weeks) was significantly longer than that of the non-responders and partial responders (37 and 34 weeks). Median survival by treatment arm was 48 weeks for thoracic irradiation (TI), brain irradiation (BI), and early chemotherapy (CT), 44 weeks for TI alone, 41 weeks for TI and CT, 38 weeks for TI and BI. Regional complete and partial tumor responses were 52 and 25% for prophylactic chemotherapy and 44 and 35% for delayed chemotherapy. The site of first failure was regional in 12%, regional and distant simultaneously in 21%, and distant only in 46%. Elective brain irradiation significantly reduced the incidence of brain metastases from 21 and 5%, but did not improve survival.     

Non-small cell lung cancer and silent brain metastasis. Survival and prognostic factors

The detection of silent brain metastasis is becoming increasingly common in patients with non-small cell lung cancer (NSCLC). The aim of this study was to evaluate clinical course, prognostic significance, and treatment efficacy in patients with asymptomatic brain metastasis. A retrospective study of patients with cytologically and histologically diagnosed NSCLC and brain metastasis detected by cranial computed tomography or magnetic resonance imaging was performed. We compared 12 neurologically asymptomatic patients to 69 symptomatic patients and analyzed overall survival, clinical course, and prognostic factors (age, sex, performance status, histologic type, TNM stage, number and size of brain metastases, clinical neurologic status, and treatment of primary tumor and brain metastasis). The strongest favorable prognostic factor was active treatment of both the primary tumor (surgery, chemotherapy and/or thoracic radiotherapy) and brain metastasis (neurosurgery and/or whole brain radiotherapy). Neurologically asymptomatic patients had significantly longer survival times than did symptomatic patients (median survival of 7.5 and 4 months, respectively). Control of clinical neurologic status during follow-up was achieved in a greater proportion of asymptomatic patients (80%) than symptomatic patients (40%). We conclude that it is important to detect brain metastasis in patients with NSCLC before neurologic signs or symptoms develop, as early detection improves prognosis and provides patients with the opportunity of receiving timely and more effective treatment.     

Brain metastases in small cell lung cancer

Small cell lung cancer (SCLC) accounts for approximately 20% of all cases of lung cancer. It tends to disseminate earlier in the course of its natural history than non-small cell lung cancer and is clinically more aggressive. Approximately 10% of patients present with brain metastases at the time of initial diagnosis, and an additional 40% to 50% will develop brain metastases some time during the course of their disease. The prognosis of patients with brain metastases from SCLC is poor despite years of research. The standard of care remains appropriate medical management followed by whole brain radiation therapy. Current research is evaluating novel agents in an attempt to improve the survival and quality of life in these patients. However, the most effective treatment for brain metastases from SCLC is the prevention of the development of clinically detectable disease. For patients with a complete response to initial treatment, prophylactic cranial irradiation is an effective method of prevention.     

Ultra-rapid high dose irradiation schedules for the palliation of brain metastases: final results of the first two studies by the Radiation Therapy Oncology Group

Between January, 1971, and February, 1976, the Radiation Therapy Oncology Group entered 1902 evaluable patients into two sequential Phase III national cooperative trials to study the effectiveness of different time dose radiotherapy schemes on the palliation of patients with brain metastases. Each trial included an optional arm into which patients were randomized to receive 1000 rad/1 fraction (26 patients, First study) or 1200 rad/2 fractions (33 patients, Second study). Comparisons were made with 143 control patients randomized by the same participating institutions to receive a more protracted course of irradiation (2000, 3000 or 4000 rad/1–4 wks). Response of patients receiving ultra-rapid treatment, as assessed by the percent who had improvement in neurologic function, was comparable to that of patients receiving the more protracted schedules. Promptness of neurologic function improvement, treatment morbidity and median survival were also comparable to those of patients receiving 2000 to 4000 rad. However, the duration of improvement, time to progression of neurologic status and rate of complete disappearance of neurologic symptoms were generally less for those patients who received 1000 or 1200 rad. These results suggest that ultra-rapid, high dose irradiation schedules may not be so effective as higher dose schedules in the palliation of patients with brain metastases.     

Radiotherapy of brain metastases of breast cancer

Twenty-two patients with brain metastases of breast cancer treated by irradiation between 1974 and 1983 were reviewed. Significant neurologic improvement was obtained in 80%. The median duration of symptomatic palliation caused by irradiation and the median survival from the diagnosis of brain metastases were 3.0 months and 5.0 months, respectively. As a favorable prognosis can be expected for patients showing good performance, minor neurologic disorders, a long latent period between the first treatment of the primary lesion and the onset of the brain metastasis, and without extracranial metastases, irradiation with more than 40 Gy is recommended. Sequential CT examinations were useful to judge the effectiveness of treatment.     

The role of radiotherapy in lung cancer: where is the evidence?

Radiotherapy is one of the main treatment modalities in lung cancer, contributing to both its cure and palliation. Thoracic irradiation has traditionally been considered the mainstay of treatment in inoperable stage III non-small cell lung cancer. However, despite technical developments and the addition of chemotherapy, the curative potential of radiotherapy in this subset of patients is disappointingly poor. The role of radiotherapy as an adjunct to pulmonary resection (preoperative and postoperative) is questionable, but well-designed and executed phase III studies are lacking. An important application of radiotherapy is palliation of tumor-related symptoms in the chest and in metastatic sites, such as bones and brain. In small cell lung cancer, routine applications of radiotherapy include chest radiotherapy in limited disease and prophylactic cranial irradiation in complete responders to chemotherapy, each increasing survival by about 5%.     

Prophylactic cranial irradiation for limited non-small cell lung cancer

Seventy-three patients with biopsy-proven limited non-small cell lung cancer (NSCLC) were entered on a combined modality study at the University of Washington. Seventy-five percent (55 of 73) of the patients had a histologic diagnosis of adenocarcinoma or large cell carcinoma, whereas 25% (18 of 73) had squamous cell carcinoma. After two cycles of chemotherapy, patients without evidence of progressive disease received prophylactic cranial irradiation (PCI) and chest radiotherapy, followed by two additional cycles of chemotherapy. Brain computed tomography (CT) scans were performed at 3-month intervals after completion of therapy in all patients, and were additionally performed whenever signs or symptoms developed suggesting neurologic dysfunction or recurrent brain disease. Sixty-five patients were treated with PCI. No clinical or CT evidence of recurrence in the brain has developed in patients who completed PCI. PCI appears to be effective in greatly reducing the incidence of brain relapse in patients with limited NSCLC.     

Palliative radiotherapy for metastatic malignant melanoma: brain metastases, bone metastases, and spinal cord compression

The records of all patients receiving palliative radiotherapy for malignant melanoma metastatic to brain, to bone, or with spinal cord compression were reviewed. The median survival of 77 patients with brain metastases from the initiation of radiotherapy was 14 weeks. A statistically improved survival was observed only in the 10 patients who underwent subtotal to total resection of a solitary brain metastasis prior to radiotherapy (median = 36 weeks). No improved survival was observed in the 12 patients with a solitary brain metastasis treated by radiotherapy alone (median = 16 weeks). Multivariate analysis revealed that fraction size, total dose, patient age, sex, and duration of the interval between initial diagnosis and appearance of brain metastases did not significantly influence survival, but the use of chemotherapy was associated with a decreased survival. Twenty six patients with symptomatic and radiographic evidence of 39 bone metastases showed a palliative response rate of 85%. 18 of 20 bony lesions treated with high-dose-per-fraction (greater than or equal to 400 cGy) and 15 of 19 bony lesions treated with conventional fractionation (less than or equal to 300 cGy) were palliated. Total dose, patient age, sex, interval between initial diagnosis of malignant melanoma and the appearance of bone metastases, prior or concurrent chemotherapy, or lesion location did not significantly influence palliation. Seventeen patients were identified with symptomatic and myelographic evidence of spinal cord compression. Complete palliation was observed in 47% (8/17) and partial palliation was observed in 24% (4/17). The overall palliation response rate for neurologic symptoms due to spinal cord compression of 71% appeared to be independent of fraction size and total dose.     

小细胞肺癌预防性脑照射的临床研究

目的 探讨性全脑照射（ＰＣＩ）对局限期小细胞肺癌（ＳＣＬＣ）脑转移率和生存率的影响。方法 １９９０年１月～１９９５年１２月间,５１例经化疗加放疗后完全缓解的局限期ＳＣＬＣ患者被承机分为脑照射组（２６例）和对照组（２５例）。脑照射组患者接受ＰＣＩ２５．２～３０．６Ｇｙ。结果 脑照射组患者的脑转移率为３．８％,明显你芋对照组的２８．０％（Ｐ〈０．０５）。脑照射组患者和,１,２,３年生存率分别为８４．６     

Prophylactic cranial irradiation in small-cell lung cancer

Prophylactic cranial irradiation is now known to improve survival to a significant degree in small-cell lung cancer (SCLC) patients; this is in addition to its established role in preventing the disabling symptoms of brain metastases. New information indicates that it confers a survival benefit for limited or extensive stage SCLC patients gaining a complete response in the chest. A review of causes of cerebral dysfunction as a complication indicates that such problems can be due to suboptimal radiation fractionation, chemotherapy, or an inappropriate combination of prophylactic brain irradiation with chemotherapy. Optimum treatment with prophylactic brain irradiation has been shown not to cause adverse effects with detailed psychometric testing. Several additional sources of information can be drawn together to suggest a dose-response pattern for prophylactic brain irradiation, leading to the recommendation that a dose of 25-36 Gy is optimal, delivered in 2-3 Gy daily fractions after the completion of chest irradiation and chemotherapy. This will be better defined in future clinical trials.     

Factors affecting the risk of brain metastases after definitive chemoradiation for locally advanced non-small-cell lung carcinoma.

PURPOSE: As therapy for locally advanced non-small-cell lung carcinoma (NSCLC) improves, brain metastases (BM) may become a greater problem. We analyzed our chemoradiation experience for patients at highest risk for the brain as the first failure site. METHODS: Records for 150 consecutive patients with stage II/III NSCLC treated definitively with chemoradiation from June 1992 to June 1998 at the University of Pennsylvania were reviewed. Most patients (89%) received cisplatin, paclitaxel, or both. All had negative brain imaging before treatment. Posttreatment brain imaging was performed for suspicious symptoms. Incidence of BM was examined as a function of age, sex, histology, stage, performance status, weight loss, tumor location, surgery, radiation dose, initial radiation field, chemotherapy regimen, and chemotherapy timing. RESULTS: Crude and 2-year actuarial rates of BM were 19% and 30%, respectively. Among pretreatment parameters, stage IIIB was associated with a higher risk of BM (P <.04) versus stage II/IIIA. Histology alone was not significant (P <.12), although patients with IIIB nonsquamous tumors had an exceptionally high 2-year BM rate of 42% (P <.01 v all others). Examining treatment-related parameters, crude and 2-year actuarial risk of BM were 27% and 39%, respectively, in patients receiving chemotherapy before radiotherapy and 15% and 20%, respectively, when radiotherapy was not delayed (P <.05). On multivariate analysis, timing of chemotherapy (P <.01) and stage IIIA versus IIIB (P <.01) remained significant. CONCLUSION: Patients with later stage, nonsquamous NSCLC, particularly those receiving induction chemotherapy, have sufficiently common BM rates to justify future trials including prophylactic cranial irradiation.     

Combination therapy of small cell anaplastic carcinoma of the lung and the role of prophylactic whole brain irradiation--report of 39 cases

A series of 39 cases of small cell anaplastic carcinoma of the lung treated by combination of chemotherapy and radiotherapy is reported. The role of prophylactic whole brain irradiation in this combination is emphasized. Apart from 2 cases whose treatment was interrupted, the chief symptoms of the other 37 were significantly improved by irradiation. The response rate was over 86% and the median survival was 8 months. The 2-year survival rates of the patients with or without brain irradiation (group A and B) were 26.7% and 9.1% respectively. None of the group A patients (15 cases) developed brain metastasis while 4 (18%) of the group B patients (22 cases) did. The results prove the validity of the prophylactic whole brain irradiation. In this series, the mortality of liver metastasis amounted to 38%. The authors believe that prophylactic liver irradiation may reduce the metastases into the liver and prolong the survival.     

Radiotherapy for palliation of symptoms in incurable cancer

Approximately one half of prescribed radiotherapy is given for palliation of symptoms due to incurable cancer. Distressing symptoms including pain, bleeding, and obstruction can often be relieved with minimal toxic effects.Painful osseous metastasis is common in oncologic practice. Ninety percent of patients with symptomatic bone metastases obtain some pain relief with a lowdose, brief course of palliative radiotherapy. One half of the responding patients may experience complete pain relief. A single dose of 800 cGy in the setting of painful bone metastasis may provide pain control comparable to more protracted treatment at a higher dose of radiation. Patients with lytic disease in weight-bearing bones, particularly in the presence of cortical destruction, should be considered for prophylactic surgical stabilization of their condition. Routinely a brief, fractionated course of radiotherapy is given postoperatively.Pain due to multiple bone metastases uncontrolled by analgesics can be managed with single doses of half-body irradiation. Doses of 600 cGy delivered to the upper half-body (above the umbilicus to the middle of the femur) will provide some pain relief in 73% of patients. Half-body techniques have been investigated as prophylactic treatment, as a complement to localfield irradiation, and as fractionated rather than singledose therapy. Although intravenous administration of strontium 89 has been associated with myelosuppression, this treatment has been shown (a) to relieve pain due to bone metastasis and (b) to delay development of new painful sites.Recent data from phase III trials demonstrated that bisphosphonates have a role in reducing skeletal morbidity due to bone metastasis. Bone pain was reduced, and the incidence of pathologic fracture and the need for future radiotherapy were decreased.Radiotherapy relieves clinical symptoms in 70% to 90% of patients with brain metastases. Brief treatment schedules (e.g., 2000 cGy in five fractions over 1 week) are as effective as more prolonged therapy. Patients with solitary brain metastasis and no extracranial disease or controlled extracranial disease should be considered for surgical resection, because phase III data indicate enhanced survival with such an approach. Whole-brain radiotherapy is routinely administered postoperatively. A phase III study is examining the impact of accelerated fractionated doses of radiotherapy (two treatments per day) on survival of patients with brain metastases.Stereotaxic radiosurgical treatment is becoming increasingly available and permits delivery of radiation to metastatic intracranial tumor with minimal exposure of normal surrounding brain. This treatment is most commonly used at the time of a solitary recurrence of disease in patients who previously received whole-brain radiotherapy. A role for this modality in newly diagnosed brain metastases remains to be defined.Chest symptoms are common in patients with locally advanced lung cancer and are effectively palliated with one 1000 cGy or two 850 cGy one fraction doses of radiation to the thoracic inlet and mediastinum. Chest pain and hemoptysis are more effectively palliated than cough and dyspnea. In patients with stage III cancer there is no compelling evidence that radiotherapy confers a survival advantage, and it may be reasonable to administer thoracic radiotherapy only when the patient has significant symptoms and the goal is to achieve control of these symptoms.Approximately 75% of the cases of superior vena cava syndrome are due to lung cancer, and small-cell lung cancer is the most common histologic type. A histologic diagnosis should be obtained before treatment is started, because detection of lymphoma or small-cell carcinoma would necessitate systemic therapy. Eighty percent of the patients with superior vena cava syndrome due to malignant disease achieve symptom relief with a brief, fractionated, palliative course of radiotherapy to the thoracic inlet and mediastinum.Spinal cord compression requires emergency radiotherapy. This condition must be diagnosed and treated early to prevent irreversible neurologic injury. Central back pain usually precedes neurologic deficit, which can evolve to paraplegia within hours or days. Magnetic resonance imaging gives the most complete information when symptoms suggest spinal cord compression. The best predictor of neurologic outcome is pretreatment neurologic status. There are no data to demonstrate a difference in neurologic outcome when spinal cord compression is managed with radiotherapy alone or with laminectomy followed by radiotherapy. In specific clinical situations, initial surgical treatment is preferred to radiotherapy.Abdominal pain secondary to hepatic distention from metastatic disease is relieved by radiotherapy to the whole liver in 75% to 90% of patients. One half of the patients may obtain complete pain relief. Doses of 2000 to 3000 cGy in 200 to 300 cGy fractions are used.Metastases to the eye are the most common malignant intraocular tumors. Palliative radiotherapy is effective in relieving visual symptoms produced by uveal metastases or at least in preventing further deterioration. In symptomatic adrenal metastasis, radiotherapy appears to be effective in palliating pain, with minimal morbidity, in the majority of patients.Recurrent gynecologic and colorectal cancers can cause severe pelvic symptoms including pain, bleeding, and discharge. Brief courses of pelvic radiotherapy, including a single dose of 1000 cGy, have been shown to control these symptoms, with minimal morbidity, for a substantial proportion of the remaining survival time. In ovarian cancer, radiotherapy is effective in control of pain, bleeding, and discharge, despite resistance of the disease to cisplatin-based chemotherapy.