Chihiro Makimura

Successful Treatment with Erlotinib after Gefitinib-Induced Severe Interstitial Lung Disease

62-year-old woman with an 18-pack-year history of smoking was found to have a solitary spiculated lesion in the right upper lung lobe and multiple pulmonary nodules on a computed tomography (CT) scan of the chest. A transcutaneous CT-guided needle biopsy specimen of the lung revealed adenocarcinoma. She received four cycles of chemotherapy with docetaxel and cisplatin, after which CT revealed marked tumor shrinkage. During follow-up for 3 months, progressive disease was diagnosed on the basis of the presence of an enhancement of cortical sulci on a CT scan of the brain. Mutation analysis of the lung cancer specimen showed the presence of an exon-19 deletion in the epidermal growth factor receptor (EGFR) gene, and gefitinib was administered orally at a dose of 250 mg once daily (Figure 1A). After 24 days of gefitinib, the patient manifested acutely deteriorating dyspnea with fever and cough. A chest CT scan revealed extensive bilateral ground-glass opacities throughout both lungs (Figure 1B). The results of sputum culture of bacteria or fungi and general blood tests, including those for fungal antigen and cytomegalovirus antigen, were negative. The patient had no prior interstitial lung disease (ILD) or preexisting collagen-vascular disease. Therefore, we concluded that the clinical course and imaging results were consistent with gefitinib-induced ILD. Gefitinib therapy was discontinued, and the treatment with high-dose methylprednisolone was initiated. Given that her symptoms and radiologic findings of gefitinib-induced ILD improved, the patient was discharged 14 days after discontinuation of gefitinib. As a result of progression of brain metastasis soon after discontinuation of gefitinib, whole-brain radiation therapy was delivered. Three months after discontinuation of gefitinib, the patient again experienced neurologic progression because of the brain metastasis, and the development of symptomatic brain metastasis was considered to be a contraindication for treatment with cytotoxic agents. After receiving full informed consent for the risk of recurrent ILD and high mortality rate after the onset of ILD, we administered erlotinib at a dose of 150 mg/d (Figure 1C). Nine weeks after the initiation of erlotinib treatment, a chest CT scan revealed no evidence of ILD and a reduction in the size of multiple pulmonary metastatic nodules (Figure 1D). After 11 weeks of erlotinib treatment, she developed meningeal carcinomatosis with progressive neurologic symptoms and discontinued erlotinib treatment. ILD has not been identified during the course of treatment with erlotinib.

Early palliative intervention for patients with advanced cancer.

BACKGROUND Early palliative intervention in advanced cancer patients with metastatic non-small-cell-lung cancer has been shown to improve survival time. Possibly, palliative intervention at the time of outpatient care further improves patient survival time. OBJECTIVE We performed a comparative study of late and early referrals of patients with advanced cancer to clarify the appropriate time for palliative intervention and the improvement in survival time. METHODS Two hundred and one cancer patients, all since deceased, who were treated in our department over a period of 4 years were divided into two groups: patients who experienced outpatient services for <7 days (late referral group, 64 patients) and those who experienced outpatient services for ≥7 days (early referral group, 137 patients). Survival time, duration of chemotherapy and post-progression survival were retrospectively analyzed through examination of medical records. RESULTS Survival time of the early referral group was longer than that of the late referral group in all the cases (19.0 vs. 6.5 months, P < 0.001). Survival time in advanced non-small-cell lung cancer was 3.5 and 14.0 months (P = 0.010) and 16.5 and 20.9 months (P = 0.039) in advanced colorectal cancer, respectively. There was no significant difference in gastric cancer (P = 0.310). Post-progression survival in each group was 0.7 and 2.7 months (P = 0.018) in non-small-cell lung cancer. CONCLUSIONS The results of this study suggested that early outpatient referral and palliative intervention leads to improvement of the outcome in patients with advanced non-small-cell lung cancer and colorectal cancer. A prospective comparative study is warranted.

Gender differences in cancer-related distress in Japan: a retrospective observation study

BackgroundCancer care is currently the most important medical issue in Japan. Total pain of cancer patients consists of a combination of four factors: physical, psychological, social distress, and spiritual pain. Previous studies showed female cancer patients ask for more psychological support and seem to suffer different types of distress compared with male patients, for example, appearance-related symptoms. However, other factors of cancer distress related to gender have not been defined comprehensively. The aim of this study is to clarify the gender differences in cancer distress types in order to elucidate the measures that should be taken in Japan to improve the quality of whole cancer care based on gender-based medicine.MethodsThe data of new patients who had visited the psycho-oncology outpatient service of Kinki University Hospital during the period of May 2013 to October 2015 were collected. Demographic factors and all assessed items were extracted from the patients’ medical charts retrospectively. Based on an inquiry of cancer patients in 2010, each item representing the four factors of “total pain” of cancer patients was chosen, i.e., physical distress (pain, changes in appearance), psychological distress (anxiety, depression), social distress (family problems, job-related problems), and spiritual pain; together with sexuality issues, and answers were analyzed. Hospital Anxiety Depression Scale (HADS) was used for the assessment of psychological distress. Chi-square test and Fisher’s exact test were performed for gender differences in the cancer distress types. Pearson’s analysis and multiple logistic regression analysis were performed for the association of gender with each item.ResultsThe data of 101 cancer patients were analyzed and there were more female patients than male patients (female: male ratio = 71:30). Female cancer patients were more likely to suffer from psycho-social issues such as changes in appearance, family problems and sexuality issues than male patients, and male patients were more likely to have spiritual pain.ConclusionsThere were gender differences in the distress types of cancer patients. In order to improve the quality of whole cancer care, more intensive intervention by medical professionals and social support is needed from the viewpoint of gender-based medicine and psycho-oncology.

Phase I study of weekly nab‐paclitaxel combined with S‐1 in patients with human epidermal growth factor receptor type 2‐negative metastatic breast cancer

We conducted a phase I study of a weekly nab‐paclitaxel and S‐1 combination therapy in patients with human epidermal growth factor receptor type 2‐negative metastatic breast cancer. The primary objective was to estimate the maximum tolerated and recommended doses. Each treatment was repeated every 21 days. Levels 1, 2a, 2b, and 3 were set depending on the S‐1 dose (65 or 80 mg/m2) and nab‐paclitaxel infusion schedule (days 1 and 8 or days 1, 8, and 15). Fifteen patients were enrolled. Dose‐limiting toxicity was observed in one patient at Level 3 (100 mg/m2 nab‐paclitaxel on days 1, 8, and 15 with 80 mg/m2 S‐1 daily for 14 days, followed by 7 days of rest). Although the maximum tolerated dose was not reached, the recommended dose was determined to be Level 3. Neutropenia was the most frequent grade 3–4 treatment‐related adverse event. For patients with measurable lesions, the response rate was 50.0% and the median time to treatment failure and median progression‐free survival was 13.2 and 21.0 months, respectively. The present results show the feasibility and potential for long‐term administration of this combination therapy.

Prospective replication study implicates the catechol-O-methyltransferase Val158Met polymorphism as a biomarker for the response to morphine in patients with cancer

Genetic differences in humans cause clinical difficulties in opioid treatment. Previous studies indicate that a single nucleotide polymorphism in the catechol-O-methyltransferase (COMT) gene (rs4680; p.Val158Met) may present as a predictive biomarker for the response to morphine treatment. In our previous pilot exploratory study, patients with a G/G genotype were demonstrated to require a higher dose of morphine, compared with patients with A/A and A/G genotypes. In the present study, the aim was to replicate the findings in an independent cohort of opioid-treatment-naïve patients exhibiting various types of cancer. This prospective study was conducted from 2011 to 2012 at the Kindai University Faculty of Medicine. A total of 50 patients with opioid-treatment naïve and histologically confirmed malignant neoplasms who were scheduled to undergo opioid treatment were evaluated in the present study. Assessments were conducted pre-treatment (day 1), post-treatment (day 1), and one week after treatment (day 8). The required dose of morphine on day 1 was significantly higher for patients with the G/G genotype of COMT, compared with those with the A/A and A/G genotypes (P=0.013). The results of the present study provide additional evidence that the COMT genotype may be a predictive biomarker for the response to morphine treatment.

Expectation of a Decrease in Pain Affects the Prognosis of Pain in Cancer Patients: a Prospective Cohort Study of Response to Morphine

PurposeCancer pain is a multidimensional experience that includes physiological, sensory, affective, cognitive, behavioral, and sociocultural dimensions. Few prospective studies have examined the relationship between a patient’s expectation of pain improvement and the pain prognosis. The aim of this prospective study was to investigate whether patients’ expectation to pain reduction was associated with pain intensity after morphine treatment in opioid treatment-naïve patients with various types of cancer.MethodsThe subjects were patients scheduled for cancer pain treatment with morphine who were taking nonsteroidal anti-inflammatory drugs daily. Morphine treatment was performed according to the standard method, including titration (NCCN Guidelines™, Adult Cancer Pain). Simple regression analysis was performed between pain intensity numerical rating scale (NRS) (day 8) as the dependent variable, expectation of pain decrease NRS (day 1), tumor types, and the following covariates as independent variables: patients’ characteristics such as age, gender, PS (day 1), genotype of catechol-O-methyltransferase, total scores of Hospital Anxiety and Depression Scale (day 1), and pain intensity NRS (day 1). Multiple regression analysis was performed using forced entry methods with pain intensity NRS (day 8) as the dependent variable, and expectation of pain decrease NRS (day 1) and the covariates as independent variables that had a p value <0.05 in the simple regression models.ResultsA total of 100 patients with baseline data were included, and 97 patients (51% female) met the inclusion criteria. Patients with a high expectation of pain decrease NRS had a significantly lower pain intensity NRS (day 8) (p = 0.001).ConclusionNon-pharmacological factors such as expectations for pain treatment could also be important factors to treat cancer pain, which might be associated with communication skills in physicians.

The physical and psychological problems of immigrants to Japan who require psychosomatic care: a retrospective observation study

BackgroundAs the number of immigrants to Japan increases, the health problems of foreign nationals also have an increasing impact on Japanese medical institutions. The aim of this study was to clarify the Japan–specific health problems related to both the physical and psychological symptoms of foreign nationals from the viewpoint of psychosomatic medicine. The second aim was to clarify the measures that should be taken in Japan and similar countries where immigration may still be considered less than common.Case PresentationThe study period was from June 2004 to May 2015. The data of non-Japanese patients who had visited the Department of Psychosomatic Medicine, Kinki University Hospital and its branches, Sakai Hospital and Nihonbashi Clinic, were collected. All patients were aged 16 years or over. Multiple factors, such as age, sex, nationality, length of stay, marital status, employment status, level of Japanese proficiency, clinical symptoms, physical and psychiatric diagnosis, psycho-social factors and therapy were retrospectively analyzed from the medical charts of 20 non-Japanese patients. Cases were divided into two groups; early onset and late onset cases. This study showed that multiple factors related to the health problems of non-Japanese patients were combined and had a mutual influence, however, they can be summarized into two important clinical observations. These are 1) cultural differences, and 2) language barriers related to both the physical and psychological symptoms of non-Japanese patients from the viewpoint of psychosomatic medicine.ConclusionsFuture efforts should focus on sensitizing health care professionals in Japan to the psychosomatic problems of non-Japanese patients as well as on facilitating medical systems with services such as medical professional interpreters and liaison-consultation models. It is essential to take measures against language barriers and to promote the field of transcultural psychiatry and psychosomatic medicine in Japan. In addition, the Japanese government should introduce a more comprehensive social support system for non-Japanese people.