Methods of treating female non-smokers with non-small cell lung cancer

Abstract

A method of treating a female patient suffering from non-small cell lung cancer comprises the step of administering to the patient in need thereof a composition of 2, 2 '-dithiobisethionate or a pharmaceutically acceptable salt thereof. The methods may include other major thread therapies.

Description

[0001] This application is a divisional application of the application with the filing date of March 8, 2020, application number 202080034238.X, and invention title "Methods for Treating Female Non-Smokers with Non-Small Cell Lung Cancer". Technical Field

[0002] This application relates to pharmaceutical compositions, methods, and kits for treating cancer and other medical conditions. More specifically, this application relates to pharmaceutical compositions, methods, and kits comprising agents for treating non-small cell lung cancer, advanced non-small cell lung cancer, adenocarcinoma, and other medical conditions, particularly in females and female non-smokers or never-smokers. Background Art

[0003] Tavocept or disodium 2'-dithio-bis-ethane (CAS number 16208-51-8) is a water-soluble small molecule (about 326 Da), which can be administered intravenously and has the following structure:

[0004] Tavocept showed a positive subgroup response with a significant improvement in overall survival rate, but did not meet the clinical efficacy endpoints.

[0006] Worldwide, lung cancer is the most common cancer in terms of incidence and mortality. Lung cancer is the leading cause of cancer death in both men and women globally, and the cost of lung cancer treatment in the United States in 2015 was $13.4 billion. The American Cancer Society estimates that out of the 234,030 new lung cancer cases in the United States in 2018, 112,350 were in females. Non-small cell lung cancer is the most common form of lung cancer (accounting for about 85% of lung cancers), and adenocarcinoma, squamous cell carcinoma, and large cell carcinoma are the three subtypes, arranged in decreasing order of prevalence. Approximately 10 - 15% of lung cancers occur in never-smokers, making lung cancer one of the leading causes of cancer-related death in never-smokers. Given the significant impact of this disease, it is surprising that there is little information on the descriptive epidemiology of lung cancer in never-smokers. General demographics are largely under-informed because neither cancer registries nor routinely collected death certificates provide reliable information on lifetime smoking history. In addition, reports on smoking from close relatives or medical records are incomplete and often unreliable. Only large-scale cohort studies can measure the age- and sex-specific lung cancer rates in never-smokers with reasonable precision, and these studies typically study mortality rather than incidence. Currently, there is no approved therapy specifically for non-smokers with signs of non-small cell lung cancer or NSCLC.

[0007] Approximately 40% of non-small cell lung cancers are adenocarcinomas, and more than half are women. Today, most people diagnosed with lung cancer are not active smokers, and contrary to the recent overall decline in lung cancer, lung cancer has increased significantly in one group: women who do not smoke. Over time, the prevalence of lung cancer in non-smokers has been increasing, with more than half occurring in current non-smokers.

[0008] Recent data suggest that by 2030, the global female lung cancer mortality rate is expected to increase by 43% and exceed deaths due to breast cancer. It is thought that lung cancer in female non-smokers is a different cancer type, but there are few studies that characterize this population. This population remains underserved, and lung cancer in female non-smokers should be classified as a rare disease. The poor prognosis of advanced non-small cell lung cancer (NSCLC) may be due to tumor resistance to chemotherapy.

[0009] Therefore, there is a need for the treatment of non-smoking female NSCLC patients with adenocarcinoma. This application is specifically directed to this need. BRIEF DESCRIPTION OF THE DRAWINGS

[0010] Figure 1 Shows a retrospective subgroup analysis of NSCLC adenocarcinoma patients receiving cisplatin and / or paclitaxel;

[0011] Figure 2 Shows that among non-smokers receiving 2,2'-dithiobis(ethyl sulfonate), the percentage of patients experiencing treatment failure is the lowest; and

[0012] Figure 3 Shows that among female non-smokers receiving 2,2'-dithiobis(ethyl sulfonate), the percentage of patients experiencing treatment failure is the lowest. SUMMARY OF THE INVENTION

[0013] This application provides methods, devices, and compositions for dispensing a combination of a cell division inhibitor and disodium 2,2'-dithiobis(ethylsulfonate) to patients with non-small cell lung cancer, adenocarcinoma.

[0014] One aspect of the present application provides a combination therapy of disodium 2'-dithiobisethylate for treating non-small cell lung cancer, especially in female non-smokers. In some embodiments, the therapy includes one or more chemotherapeutic agents selected from camptothecin derivatives, paclitaxel, docetaxel, epothilone B, 5-FU, gemcitabine, oxaliplatin, cisplatinum, carboplatin, melphalam, dacarbazine, temozolomide, doxorubicin, imatinib, erlotinib, bevacizumab, cetuximab, and Raf kinase inhibitors.

[0015] Another aspect includes a method of treating advanced and / or metastatic non-small cell lung cancer in female patients, the method comprising administering a pharmaceutical composition of 2,2'-dithio-bis-ethane sulfonate or a pharmaceutically acceptable salt thereof and a second therapeutic agent to a patient with non-small cell lung cancer who has received second-line or higher-line therapy. The non-small cell lung cancer may be lung adenocarcinoma.

[0016] Another aspect includes a method of treating a female patient with non-small cell lung cancer, comprising the step of administering to a patient in need thereof a composition of 2,2'-dithio-bis-ethane sulfonate or a pharmaceutically acceptable salt thereof. The patient may be a non-smoker or a never-smoker. The method may further comprise the step of co-administering to a patient in need thereof a second therapeutic agent useful for treating non-small cell lung cancer.

[0017] Another aspect includes a method of treating a female non-smoking patient with or susceptible to non-small cell lung cancer, comprising the step of determining whether the patient is a non-smoker; and the step of administering to the non-smoker a composition of 2,2'-dithio-bis-ethane sulfonate or a pharmaceutically acceptable salt thereof. The method may include the second therapeutic agent paclitaxel or cisplatin. Additionally, the method may further comprise the step of co-administering to a patient in need thereof a second therapeutic agent useful for treating non-small cell lung cancer. The second therapeutic agent may be selected from camptothecin derivatives, paclitaxel, docetaxel, epothilone B, 5-FU, gemcitabine, oxaliplatin, cisplatin, carboplatin, melphalam, dacarbazine, temozolomide, doxorubicin, imatinib, erlotinib, bevacizumab, and cetuximab.

[0018] Another aspect includes a method that includes determining whether the non-small cell lung cancer is an ALK, ROS, MET, or EGFR mutation-positive non-small cell lung cancer. In an example, the non-small cell lung cancer includes ALK and ROS1 gene fusions / rearrangements, EGFR gene mutations / deletions, and MET / HGFR gene amplifications.

[0019] Details of the present application are set forth in the following drawings and description. Other features, objects, and advantages of the present application will be apparent from the description and claims. Detailed Description

[0020] One embodiment includes a method for increasing the survival time of a patient with non-small cell lung cancer or a female patient with non-small cell lung cancer, wherein a therapeutically effective amount of 2,2'-dithiobis(ethanesulfonate) or a salt thereof is administered to a patient with non-small cell lung cancer. In an example, 2,2'-dithiobis(ethanesulfonate) or a salt thereof can be administered before, simultaneously with, or after the administration of one or more chemotherapeutic agents. In an example, the female patient is a non-smoker. In another specific embodiment, the method is for treating a female non-smoking patient with non-small cell lung cancer.

[0021] The composition contains a therapeutically effective dose of a compound of formula (I) that affects oxidative metabolism, including but not limited to the disodium salt of 2,2'-dithiobis(ethanesulfonate) or a pharmaceutically acceptable salt or analogue thereof. The disodium salt of 2,2'-dithiobis(ethanesulfonate) is also referred to in the literature as 2,2'-dithiobis(ethanesulfonate). Various salts and analogues of 2,2'-dithiobis(ethanesulfonate) and other disulfides can also be synthesized as outlined in U.S. Patent No. 5,808,160, U.S. Patent No. 6,160,167, and U.S. Patent No. 6,504,049, the disclosures of which are incorporated herein by reference in their entirety. In addition, the composition of the present application further contains a medically sufficient dose of a metabolite of disodium 2,2'-dithio-bis-ethane sulfonate, which is known as sodium 2-mercapto ethanesulfonate.

[0022] In another embodiment, any of the above-described treatment methods further comprises the step of co-administering to the patient one or more second therapeutic agents. The choice of the agent combination or the second therapeutic agent can be made from any second therapeutic agent known to be useful for co-administration with 2,2'-dithiobis(ethanesulfonate) or its salts. The choice of the second therapeutic agent also depends on the particular disease or condition to be treated. Examples of second therapeutic agents useful in the methods of the present application are those described above for the compositions comprising a combination of a compound of the present application and a second therapeutic agent.

[0023] In another embodiment, the second therapeutic agent is one or more chemotherapeutic agents selected from camptothecin derivatives, paclitaxel, docetaxel, epothilone B, 5-FU, gemcitabine, oxaliplatin, cisplatin, carboplatin, melphalan, dacarbazine, temozolomide, doxorubicin, imatinib, erlotinib, bevacizumab, cetuximab, and Raf kinase inhibitors.

[0024] In another embodiment, the second therapeutic agent is one or more chemotherapeutic agents selected from paclitaxel or cisplatin.

[0025] The methods described herein also include methods in which a patient is identified as in need of a particular specified treatment. The identification of a patient in need of such treatment can be determined by the patient or a health care professional and can be subjective (e.g., an opinion) or objective (e.g., determinable by a test or diagnostic method). 2,2'-Dithiobis(ethanesulfonate) can target molecular pathways that are more common in female non-smokers compared to any other group. Genetic alterations in c-Met (also known as tyrosine protein kinase Met / MET mesenchymal-epithelial transition) / hepatocyte growth factor receptor (HGFR) / anaplastic lymphoma kinase (ALK), ROS-1 (orphan receptor tyrosine kinase), and epidermal growth factor receptor (EGFR) are more common in non-smokers, most commonly in females, and present as advanced adenocarcinoma. In certain embodiments, one or more tests for EGFR and c-Met / ALK status can be used to screen patients first. A relatively high percentage of adenocarcinoma patients appear to have EGFR gene mutants or are c-Met / ALK positive or ROS-1. A method of treating advanced and / or metastatic non-small cell lung cancer in female patients, the method comprising: administering to a patient with non-small cell lung cancer who has received second-line or higher-line therapy a pharmaceutical composition comprising 2,2'-dithiobis(ethanesulfonate) or a pharmaceutically acceptable salt thereof and a second therapeutic agent.

[0026] In one embodiment, the effective amount of the compounds of the present application can range from 10 - 40 grams per dose. In one embodiment, the effective amount of the compounds of the present application can range from 1 - 500 grams per dose. In some embodiments, the effective amount can range from 0.01 - 10 grams per dose. In other embodiments, the effective amount ranges from 10 - 60 grams per dose. It is not necessary to provide equal doses daily or weekly.

[0027] As will be appreciated by those skilled in the art, the therapeutically effective dose can vary depending on the disease being treated, the severity of the disease, the route of administration, the age and general health of the patient, the use of excipients, and the likelihood of co - use with other therapies (such as the use of other medicaments and the judgment of the treating physician). For example, guidance for selecting an effective dose can be determined by referring to the prescribing information of 2,2'-dithiobis(ethyl sulfonate) or journals discussing it.

[0028] Compositions suitable for parenteral administration include aqueous and non - aqueous sterile injection solutions, which may contain antioxidants, buffers, bacteriostatic agents, and solutes that render the formulation isotonic with the blood of the intended recipient; and aqueous and non - aqueous sterile suspensions, which may include suspending agents and thickening agents. The formulations may be presented in unit - dose or multi - dose containers, such as sealed ampoules and vials, and may be stored under lyophilized (freeze - dried) conditions, requiring only the immediate addition of a sterile liquid carrier, such as water for injection, prior to use. Immediate injection solutions and suspensions may be prepared from sterile powders, granules, and tablets.

[0029] Such injection solutions can be, for example, in the form of sterile injectable aqueous or oily suspensions. The suspension can be formulated using suitable dispersing or wetting agents (such as Tween 80) and suspending agents according to techniques known in the art. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non - toxic parenterally acceptable diluent or solvent, such as a solution in 1,3 - butanediol. Among acceptable carriers and solvents, mannitol, water, Ringer's solution, and isotonic sodium chloride solution can be used. In addition, a sterile fixed oil is commonly used as a solvent or suspending medium. For this purpose, any mild fixed oil can be used, including synthetic monoglycerides or diglycerides of glycerol. Fatty acids, such as oleic acid and its glyceride derivatives, can be used in the preparation of injectables, as can pharmaceutically acceptable natural oils, such as olive oil or castor oil, especially in their polyoxyethylated forms. These oil solutions or suspensions can also contain long - chain alcohol diluents or dispersing agents.

[0030] Alternatively, for 2,2'-dithiobis(ethyl sulfonate), formulations that protect the compound from oxidation in an acidic environment and allow intestinal absorption can be used for oral administration.

[0031] "Non-smoker" means an individual who is not a smoker at the time of assessment. This includes individuals who have never smoked and individuals who smoked in the past but have not used tobacco products in the past year. In one example, the term "non-smoker" means a person with a smoking history of 15 packs per year or less, or who has not smoked for more than 25 years. A person of ordinary skill in the art can select the appropriate category by routine experimentation alone. In certain embodiments, the subject is a non-smoker. "Never smoker" means an adult who has never smoked or who has smoked fewer than 100 cigarettes in their lifetime.

[0032] As used herein, the term "effective amount" means the amount of an agent required to alleviate at least one or more symptoms of a disease or disorder and refers to a sufficient amount of a pharmacological composition to provide the desired effect. Thus, the term "therapeutically effective amount" means the amount of an agent that is sufficient to provide a particular effect when administered to a typical subject. In various circumstances, the effective amount as used herein also includes an amount sufficient to delay the development of disease symptoms, alter the course of disease symptoms (e.g., but not limited to slowing the progression of disease symptoms) or reverse disease symptoms. Thus, it is generally not feasible to specify an exact "effective amount". However, for any given situation, the appropriate "effective amount" can be determined by a person of ordinary skill in the art using routine experimentation alone.

[0033] The dosage range for administering an agent according to the methods described herein depends, for example, on the form of the drug, its potency, and the degree to which it is desired to reduce the symptoms, markers, or indicators of the condition described herein, e.g., the percentage reduction in tumor growth desired. The dosage should not be so large as to cause adverse side effects. Generally, the dosage will vary with the age, condition, and sex of the patient and can be determined by a person skilled in the art. In the case of any complications, the dosage can also be adjusted by an individual physician.

[0034] The efficacy of the agents described herein in treating, for example, the conditions described herein or inducing the responses described herein (such as lung cancer) can be determined by a skilled clinician. However, as used herein, the term "treatment" is considered "effective treatment" in the following cases: if one or more signs or symptoms of the condition described herein are changed in a beneficial way, other clinically acceptable symptoms are improved or enhanced, or the desired response (such as at least a 10% induction) is induced after treatment according to the methods described herein. Efficacy can be evaluated, for example, by measuring markers, indicators, symptoms, and / or the incidence of the condition being treated according to the methods described herein or any other suitable measurable parameter (such as tumor size and / or growth rate). Efficacy can also be measured by the lack of deterioration or the need for medical intervention (i.e., the progression of the disease stops) in an individual evaluated in the hospital. Methods for measuring these metrics are known to those of skill in the art and / or described herein. Treatment includes any treatment of a disease in an individual or animal (some non-limiting examples include humans or animals) and includes: (1) inhibiting the disease, such as preventing the worsening of symptoms (such as pain or inflammation); or (2) reducing the severity of the disease, such as causing the symptoms to subside. An effective amount for treating a disease refers to an amount that, when administered to a subject in need thereof, is sufficient to obtain effective treatment of the disease as defined by the terms herein. The efficacy of an agent can be determined by evaluating physical indicators of the condition or the desired response. Monitoring the efficacy of administration and / or treatment by measuring any one or any combination of these parameters is well within the capabilities of those of skill in the art. The efficacy can be evaluated using an animal model of the condition described herein, such as treating lung cancer in a mouse model. When using an experimental animal model, the efficacy of treatment is confirmed when a statistically significant change in a marker (such as tumor size and / or growth rate) is observed. A method for treating advanced and / or metastatic non-small cell lung cancer in a female patient, the method comprising: administering to a human patient with non-small cell lung cancer who has received second-line or higher-line therapy a pharmaceutical composition comprising 2,2'-dithiobis(ethanesulfonate) or a pharmaceutically acceptable salt thereof and a second therapeutic agent.

[0035] As used herein, the term "pharmaceutically acceptable" refers to components that are within the scope of reasonable medical judgment, suitable for contact with the tissues of humans and other mammals without undue toxicity, irritation, allergic response, etc., and commensurate with a reasonable benefit / risk ratio. "Pharmaceutically acceptable salts" refer to any non-toxic salts that can directly or indirectly provide the compounds of the present application when administered to a recipient. "Pharmaceutically acceptable counterions" are the ionic portions of the salts that are non-toxic when released from the salts upon administration to a recipient.

[0036] The term "treatment" is used, including therapeutic treatment and prophylactic treatment (reducing the likelihood of development). Both terms refer to reducing, inhibiting, attenuating, decreasing, preventing, or stabilizing the development or progression of a disease (such as the diseases or disorders described herein), reducing the severity of the disease, or improving symptoms associated with the disease. Examples

[0037] The following examples are for illustrative purposes and are not intended to limit the scope of the invention. Example 1

[0038] There are several such pathways in NSCLC adenocarcinoma, the targets of which are typically overexpressed in females, and the disodium salt of 2,2'-dithiobis(ethyl sulfonate) modulates these targets. Thus, the disodium salt of 2,2'-dithiobis(ethyl sulfonate) targets the following key pathways: 1) kinases involved in key signaling pathways (ALK, ROS, MET, EGFR); 2) enzymes essential for DNA synthesis and repair (ERCC1, RNR1, RNR2); and 3) enzymes and proteins important for regulating cellular redox state (Trx, Prx, Grx, PDI). Mutations and overexpressions that are targeted and regulated by the disodium salt of 2,2'-dithiobis(ethyl sulfonate) are more likely to occur in females with lung adenocarcinoma, especially non-smokers.

[0039] Clinical trial results of the disodium salt of 2,2'-dithiobis(ethyl sulfonate) showed that the survival rate of female non-smokers increased from 13 months to 25 months, while the results for all groups of all genders and smoking statuses showed a slight increase in survival rate. The trial results showed that the overall survival rate of females with advanced lung adenocarcinoma receiving paclitaxel / cisplatin was 25.0 months, and the two-year survival rate was 51.4%. The above-observed results were statistically significant (p-value = 0.0477; HR = 0.579) and were observed in a retrospective analysis of a subgroup of 114 female patients. Consistent statistically significant results were observed in an earlier double-blind placebo-controlled trial of the disodium salt of 2,2'-dithiobis(ethyl sulfonate) in female adenocarcinoma patients in Japan.

[0040] The disodium salt of 2,2'-dithiobis(ethyl sulfonate) exhibits chemoprotective properties and reduces anemia, both of which disproportionately affect females. A Phase III lung trial also confirmed important safety / toxicity advantages by protecting against chemotherapy-induced nephrotoxicity and reducing anemia. These data complement earlier clinical observations regarding the ability of the disodium salt of 2,2'-dithiobis(ethyl sulfonate) to protect against neuropathy and other chemotherapy-induced toxicities. Example 2

[0041] Figure 1Shows a retrospective subgroup analysis of NSCLC adenocarcinoma patients receiving cisplatin / paclitaxel from a Phase III trial study ID DMS32212R (ClinicalTrials.gov identifier: NCT00966914), which shows significant survival benefits for females, non-smokers, and female non-smokers in the 2,2'-dithiobisethylsulfonate treatment group, as shown by the improvement in overall survival.

[0042] Figure 2 Shows that in the 2,2'-dithiobisethylsulfonate treatment group, the percentage of patients experiencing treatment failure is the lowest among non-smokers.

[0043] Figure 3 Shows that in the 2,2'-dithiobisethylsulfonate treatment group, the percentage of patients experiencing treatment failure is the lowest among female non-smokers.

[0044] While the above description relates to specific example embodiments, it will be apparent to those of ordinary skill in the art that the example embodiments of the present application can be implemented with variations in these specific details. Therefore, these example embodiments should not be construed as limited to the embodiments set forth herein.

Claims

1. A method for treating female patients suffering from non-small cell lung cancer, said method comprising: (a) selecting the patient as a non-smoker, where the patient is an individual who has never smoked, an individual who has smoked less than 100 cigarettes in her lifetime, or an individual who has not used tobacco products for at least the past year; and (b) administering to the patient in need thereof a composition of 2,2'-dithiobis(ethyl sulfonate) or a pharmaceutically acceptable salt thereof in a therapeutically effective amount sufficient to reduce treatment failure relative to patients not receiving 2,2'-dithiobis(ethyl sulfonate) treatment.

2. The method according to claim 1, wherein the non-small cell lung cancer is lung adenocarcinoma.

3. The method according to claim 1, further comprising the step of co-administering to the patient a second therapeutic agent useful for treating non-small cell lung cancer.

4. The method according to claim 3, wherein the second therapeutic agent is paclitaxel or cisplatin.

5. The method according to claim 3, wherein the second therapeutic agent is selected from camptothecin derivatives, paclitaxel, docetaxel, epothilone B, 5-FU, gemcitabine, oxaliplatin, cisplatin, carboplatin, melphalan, dacarbazine, temozolomide, doxorubicin, imatinib, erlotinib, bevacizumab, and cetuximab.

6. The method according to claim 3, wherein the non-small cell lung cancer is EGFR mutation-positive non-small cell lung cancer or EGFR deletion-positive non-small cell lung cancer.

7. The method according to claim 1, wherein about 10 grams to about 40 grams of the 2,2'-dithiobis(ethyl sulfonate) or a pharmaceutically acceptable salt thereof is administered one or more times per treatment cycle.

8. The method according to claim 1, wherein the patient is a never-smoker or has smoked at least 100 cigarettes in her lifetime.

9. A method for treating advanced and / or metastatic non-small cell lung cancer in female patients, said method comprising: (a) selecting female patients who do not smoke or have never smoked and have received at least second-line treatment for non-small cell lung cancer; and (b) administering to the patient a pharmaceutical composition comprising 2,2'-dithiobis(ethyl sulfonate) or a pharmaceutically acceptable salt thereof and a second therapeutic agent.

10. The method according to claim 9, wherein the non-small cell lung cancer is negative for activating EGFR mutations but includes MET or ALK overexpression or gene rearrangement.

11. The method according to claim 9, wherein the second therapeutic agent is paclitaxel or cisplatin.

12. A method for treating female non-smoking patients suffering from non-small cell lung cancer, said method comprising: (a) determining whether the patient is a non-smoker; and (b) administering to the non-smoker a composition comprising 2,2'-dithiobis(ethyl sulfonate) or a pharmaceutically acceptable salt thereof.

13. The method according to claim 12, further comprising detecting molecular alterations in the patient's tumor prior to said administration, said molecular alterations being selected from EGFR mutation / deletion, ALK rearrangement, ROS1 rearrangement, and MET / HGFR amplification.

14. The method according to claim 12, further comprising the step of co-administering to the patient a second therapeutic agent useful for treating non-small cell lung cancer.

15. The method according to claim 14, wherein the second therapeutic agent is paclitaxel or cisplatin.

16. The method according to claim 14, wherein the second therapeutic agent is selected from camptothecin derivatives, paclitaxel, docetaxel, epothilone B, 5-FU, gemcitabine, oxaliplatin, cisplatin, carboplatin, melphalan, dacarbazine, temozolomide, doxorubicin, imatinib, erlotinib, bevacizumab, and cetuximab.

17. The method according to claim 12, wherein the effective amount of 2,2'-dithiobis(ethanesulfonate) or a pharmaceutically acceptable salt thereof is from 0.01 grams to 10 grams per dose.

18. The method according to claim 12, further comprising determining whether the non-small cell lung cancer is ALK-, ROS1-, MET-, or EGFR-mutation positive non-small cell lung cancer.

19. The method according to claim 12, further comprising determining whether the non-small cell lung cancer comprises ALK and ROS1 gene fusions / rearrangements, EGFR gene mutations / deletions, and MET / HGFR gene amplifications.

20. A method of treating a non-smoking female patient having EGFR-mutation positive lung adenocarcinoma, the method comprising: (a) diagnosing an activating EGFR mutation in a lung adenocarcinoma tumor; and (b) co-administering to the diagnosed patient a therapeutically effective amount of (i) 2,2'-dithiobis(ethanesulfonate) or a pharmaceutically acceptable salt thereof, and (ii) a chemotherapeutic agent selected from paclitaxel or cisplatin, wherein the patient has smoked fewer than 100 cigarettes in her lifetime and exhibits advanced or metastatic symptoms.

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