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Japanese Journal of Clinical Oncology

Japanese Journal of Clinical Oncology - RSS feed of current issue

With increases in life expectancy, the focus has shifted to living a healthier, longer life. By concentrating on preventing diseases before occurrence, researchers aim to diminish the increasing gap in medical costs and health inequalities prevalent across many nations. Although we have entered an era of post-genomics, we are still in infancy in terms of personalized preventive research. Personalized preventive research has and will continue to improve with advancements in the use of biomarkers and risk assessment. More evidence based on well-designed epidemiologic studies is required to provide comprehensive preventive medical care based on genetic and non-genetic profile data. The realization of personalized preventive research requires building of evidence through appropriate methodology, verification of results through translational studies as well as development and application of prediction models.


Objective

How breast cancer subtypes should affect treatment decisions for breast cancer patients with brain metastases is unclear. We analyzed local brain metastases treatments and their outcomes according to subtype in patients with breast cancer and brain metastases.

Methods

We reviewed records and database information for women treated at the National Kyushu Cancer Center between 2001 and 2010. Patients were divided into three breast cancer subtype groups: Luminal (estrogen receptor positive and/or progesterone receptor positive, but human epidermal growth factor receptor 2 negative); human epidermal growth factor receptor 2 positive and triple negative (estrogen receptor negative, progesterone receptor negative and human epidermal growth factor receptor 2 negative).

Results

Of 524 advanced breast cancer patients, we reviewed 65 (12%) with brain metastases and records showing estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 status, as well as outcome data; there were 26 (40%) Luminal, 26 (40%) had human epidermal growth factor receptor 2 and 13 (20%) had triple negative subtypes. There was no statistical difference in the number of brain metastases among subtypes; however, rates of stereotactic radiosurgery or surgery for brain metastases differed significantly by subtype (human epidermal growth factor receptor 2: 81%, Luminal: 42% and triple negative: 47%; P = 0.03). Patients having the human epidermal growth factor receptor 2 subtype, a performance status of ≤1 and ≤4 brain metastases, who underwent systemic therapy after brain metastases and underwent stereotactic radiosurgery or surgery, were predicted to have longer overall survival after brain metastases. Multivariate analysis demonstrated that not having systemic therapy and not having the human epidermal growth factor receptor 2 subtype were independent factors associated with an increased risk of death (hazard ratio 2.4, 95% confidence interval 1.01–5.6; P = 0.05 and hazard ratio 2.9, 95% confidence interval 1.5–5.8; P = 0.003, respectively).

Conclusion

Our study showed that local brain treatments and prognosis differed by subtype in breast cancer patients with brain metastases.


Objective

We investigated the incidence and clinical features of drug-induced lung injury during cetuximab therapy in Japanese patients with colorectal cancer in a prospective multicenter registry based on a central registration system.

Methods

We investigated and followed up patients with or suspected of having drug-induced lung injury among 2006 patients with cetuximab-treated colorectal cancer. A subcommittee of medical oncologists, pulmonologists and a radiologist evaluated and discussed each case of drug-induced lung injury that occurred during cetuximab therapy.

Results

Sixty-six patients were identified and further examinations of drug-induced lung injury were conducted during the registration period. We analyzed time to onset, patient characteristics and factors associated with mortality. Cetuximab-related drug-induced lung injury occurred in 24 (1.2%) patients, and was rated as Grade 3 or worse in 15 (0.7%) patients. Fourteen patients received steroid pulse therapy. Ten patients with drug-induced lung injury died, of whom eight received steroid pulse therapy. The incidence of drug-induced lung injury was significantly higher in elderly patients, and in patients with prior interstitial lung disease. There was no particular trend in the time to onset. Patients with early onset of drug-induced lung injury (within 90 days) after starting cetuximab therapy had higher mortality than patients with later onset (over 90 days).

Conclusions

The incidence of drug-induced lung injury in cetuximab-treated patients was 1.2%. Because drug-induced lung injury is potentially serious, it is important to promptly initiate appropriate treatments. Considering that early onset drug-induced lung injury during cetuximab therapy is associated with a poor prognosis, close monitoring is mandatory for these patients.


Objective

We evaluated the feasibility of combination chemotherapy with paclitaxel, doxorubicin and cisplatin without prophylactic granulocyte colony-stimulating factor injection for intermediate-to-high-risk or recurrent endometrial cancer.

Methods

Women with histologically confirmed FIGO Stages I–II with >1/2 myometrial invasion, Stage III/IV or recurrent endometrial cancer were enrolled. Patients received intravenous doxorubicin (45 mg/m2), followed by cisplatin (50 mg/m2) on Day 1 and intravenous paclitaxel (160 mg/m2) on Day 2. Granisetron (75 µg) was administered depending on neutrophil counts on Days 3 and 8. Treatment was repeated every 21 days for six cycles or until disease progression or unacceptable toxicity. The primary endpoint was the completion rate of the scheduled chemotherapy; secondary endpoints were Grade 3/4 toxicity and response rate in patients with measurable lesions.

Results

From September 2010 to December 2012, 35 women, including 7 with FIGO Stage I, 4 with Stage II, 13 with Stage III, 10 with Stage IV and 1 with recurrent endometrial cancer, were enrolled. There were 26 endometrial carcinomas (Grade 1, 16; Grade 2, 6; Grade 3, 4), 4 carcinosarcomas, 2 serous adenocarcinomas, 1 neuroendocrine carcinoma, 1 poorly differentiated carcinoma and 1 mixed carcinoma. Twenty-five patients (71%) completed six chemotherapy cycles. Grade 3/4 hematological toxicities included neutrocytopenia (97%), thrombocytopenia (6%) and anemia (34%). Three patients (9%) experienced neutropenic fever. Grade 3/4 non-hematological toxicities were observed in 13 patients. In 15 patients with evaluable lesions, the response rate was 80%.

Conclusions

Combination chemotherapy with paclitaxel, doxorubicin and cisplatin without prophylactic granulocyte colony-stimulating factor injection is feasible.


Objective

Age is one of the important prognostic factors in thyroid cancer, and old age is generally related to higher rate of post-operative morbidity and mortality. The study analyzed the characteristics of thyroid cancer in elderly patients compared with those in younger patients.

Methods

Patients who underwent surgery between 1992 and 2011 were enrolled. The patients were divided into those ≥70 years of age (older group) and <70 years of age (younger group). Data including clinicopathological features and post-operative complications was analyzed. Molecular markers including Galectin-3, Cyclooxygenase-2, bcl-2, Cyclin D1, Epidermal growth factor receptor and BRAF mutation were reviewed. Survival analyses including recurrence-free survival and overall survival were examined.

Results

Of 1867 patients, 98 were age-classified in older group and the remaining 1769 were in younger group. Older group displayed larger tumor size, and increased extrathyroidal extension, vascular invasion and neural invasion than younger group, and all were statistically significant. Molecular marker analyses revealed no significant differences between the groups. Post-operative complication rates were not significantly different between the older and younger groups in both univariate and multivariate analyses. Elderly patients showed poor recurrence-free survival and overall survival than younger patients in univariate analyses. However, age ≥70 years was not associated with poor recurrence-free survival after adjustment of confounding factors.

Conclusion

Molecular features of elderly patients may be similar with younger patients. Even though aggravated clinicopathological features of thyroid carcinoma are more prevalent in elderly patients, thyroid surgery in elderly patients can be performed with favorable surgical and oncological outcomes.


Objective

The aims of the study were to retrospectively evaluate the imaging characteristics of cavernous sinus angioleiomyoma and explore appropriate surgical approaches.

Methods

A total of four cases admitted to our hospital for repeated episodes of headache were enrolled. The common clinical manifestations included decreased vision, diplopia, blepharoptosis and facial numbness. The first three patients were misdiagnosed with cavernous sinus hemangioma, meningioma and chordoma, respectively. The fourth case was suspected to be angioleiomyoma. Imaging examination showed an oval-shaped tumor occupying the cavernous sinus. The tumor was hypointense on T1-weighted magnetic resonance imaging and extremely hyperintense on T2-weighted scan, which was similar to the cerebrospinal fluid, and was progressively enhanced from one side after gadolinium injection, pushing the internal carotid artery toward the inner side.

Results

Surgical resection was performed via an epidural approach for these four cases. Clinical symptoms were improved after surgery and no recurrence was observed during follow-up visits (average, 47.5 months).

Conclusions

The initial symptom of cavernous sinus angioleiomyoma was repeated headache. The tumor seems extremely hyperintense on a T2-weighted image and expansive growth is pushing away the internal carotid artery rather than encasing it. It was progressively enhanced from one side after gadolinium injection. Surgical treatment based on an epidural approach had an excellent outcome in tumor resection and nerve protection.


Objective

Post-operative concurrent chemoradiotherapy significantly improves the rates of locoregional control and disease-free survival in high-risk patients but has significant adverse effects. Percutaneous endoscopic gastrostomy and opioid-based pain control increase treatment completion rates but can result in dysphagia.

Methods

The rate and duration of use of prophylactically placed percutaneous endoscopic gastrostomies were evaluated in 43 patients who underwent post-operative radiotherapy or chemoradiotherapy from April 2007 through March 2010. All patients completed treatment and received 60 Gy or more of radiotherapy.

Results

Thirty four of 43 patients (79.1%) used percutaneous endoscopic gastrostomies, which could later be removed in 25 of 34 patients. The median period of use was 108 days. Only one disease-free patient was permanently dependent on percutaneous endoscopic gastrostomy feeding. The frequency of percutaneous endoscopic gastrostomy use among patients with oral, oropharyngeal and hypopharyngeal cancer was 91.7, 100 and 54.5%, respectively.

Conclusions

Prolonged percutaneous endoscopic gastrostomy use is not required in patients receiving post-operative chemoradiotherapy and will not lead to dysphagia.


Objective

We analyzed the efficacy of treatments that included alternating chemoradiotherapy in laryngeal cancer patients.

Methods

Alternating chemoradiotherapy consisted of chemotherapy with 5-fluorouracil (600 mg/m2/day) on Days 1–6 and cisplatin (80 mg/m2) on Day 7 followed by radiotherapy with 30 Gy. Additional chemoradiotherapy was administered to responders, and laryngectomy was performed in non-responders. The contribution of alternating chemoradiotherapy to laryngeal preservation was compared with that of radiotherapy in patients with T2 disease and with that of laryngectomy in patients with T3/T4 disease.

Results

Analysis of 87 patients was conducted. The 5-year overall survival rate of T2 patients (n = 46) was 88.9% for definitive radiotherapy and 82.5% for alternating chemoradiotherapy. The laryngectomy-free rate in T2 patients was 90.5% for definitive radiotherapy and 80.0% for alternating chemoradiotherapy. In patients with T3/T4 disease (n = 41), the 5-year overall survival rate was 86.9% for alternating chemoradiotherapy and 67.4% for laryngectomy. The laryngectomy-free rate in T3/T4 patients was 91.7% for alternating chemoradiotherapy and 0.0% for laryngectomy.

Conclusions

In advanced carcinoma of the larynx, alternating chemoradiotherapy treatment might enable larynx preservation.


Objective

A large body of evidence has shown the possible relevance of polymorphisms of the genes that encode glutathione S-transferase μ, and (GSTM1, GSTP1 and GST1, respectively) to the susceptibility of acute myeloid leukemia, but the exact association still remains uncertain. Therefore, we performed a meta-analysis to derive a more precise estimation of the relationship.

Methods

A comprehensive literature search of PubMed and Web of Knowledge electronic databases was conducted to collect relevant studies until 20 February 2014. References of the retrieved articles were also screened. The extracted data were statistically analyzed, and pooled odds ratios with 95% confidence intervals were calculated to estimate the association strength using Review Manager version 5.2.

Results

Twenty-nine studies were included in the meta-analysis. The pooled analyses revealed that the GSTM1-null genotype was associated with an increased risk of acute myeloid leukemia in East Asians (P = 0.01; odds ratio = 1.22; 95% confidence interval = 1.05–1.42), and GSTT1-null genotype in Caucasians (P < 0.0001; odds ratio = 1.48; 95% confidence interval = 1.29–1.69). There was also a predilection towards the female gender for both of these polymorphisms. For GSTP1 Ile105Val polymorphism, no significant association was found under any contrast model. In addition, the presence of the double-null genotypes increased the risk of acute myeloid leukemia in both Caucasians and East Asians.

Conclusions

This meta-analysis suggested that heritable GST status could influence the risk of developing acute myeloid leukemia.


Objective

Most cancer patients become increasingly anxious toward the end of their life. The objective of this study was to identify predictors of increased opioid dosage in the last week of a terminal cancer patient's life.

Methods

We retrospectively reviewed charts of patients who died in our palliative care unit. We assigned the patients to increased group or decreased group according to changes in oral morphine equivalent dosage in their last 7 days. Logistic regression analysis was used to identify predictors of increased oral morphine equivalent dosage.

Results

We analyzed data of 158 patients (female: 43.7%, median age: 64 years). The median oral morphine equivalent dosages on Days 7 and 1 before death were 50 mg (interquartile range: 24–122) and 61 mg (28–129), respectively. Independent predictors of increased oral morphine equivalent dosage included dyspnea (odds ratio: 11.5, 95% confidence interval: 4.98–28.83, P < 0.01), age <65 years (odds ratio: 2.3, 95% confidence interval: 1.04–5.26, P = 0.04) and oral morphine equivalent dosage <50 mg on Day 7 before death (odds ratio: 3.7, 95% confidence interval: 1.68–8.89, P < 0.01). The median oral morphine equivalent dosages on Days 7 and 1 before death were 48 mg (interquartile range: 20–126) and 75 mg (36–170) in patients with dyspnea, and 50 mg (25–120) and 57 mg (25–124) in patients with pain, respectively.

Conclusions

Dyspnea, relative youth and oral morphine equivalent dosage <50 mg on Day 7 before death were predictive of increased oral morphine equivalent dosage in the last 7 days. Our findings may help oncologists to more accurately inform patients about expected opioid requirements and thus relieve their end-of-life anxiety.


Objectives

The prognosis in lung cancer patients with a prior history of extrapulmonary cancer is controversial. In the current multicenter joint research in Japan, we focused on the relationship between a history of colorectal cancer and its prognostic impact in patients with subsequent lung cancer.

Methods

Between 2000 and 2013, we designed a retrospective multicenter study at three institutes in Japan to evaluate the prognostic factors in lung cancer patients with a previous surgery for colorectal cancer.

Results

The cohorts consisted of 123/4431 lung cancer patients with/without a previous history of surgery for colorectal cancer. The median follow-up period was 6.1 years after lung cancer surgery. The 5-year overall survival in lung cancer patients with/without colorectal cancer was not significantly different, regardless of the stage of lung cancer (overall: 71.3 versus 74.7%, P = 0.1426; Stage I lung cancer: 83.3 versus 84.8%, P = 0.3779; Stage II or more lung cancer: 47.7 versus 54.4%, P = 0.1445). Based on multivariate Cox regression analysis in 4554 lung cancer patients, a past history of colorectal cancer was not a significant prognostic factor (P = 0.5335). Among the 123 lung cancer patients with colorectal cancer, age and absence of adjuvant chemotherapy for colorectal cancer were significant prognostic factors based on multivariate analysis (P = 0.0001 and 0.0236). Furthermore, there was no difference in the overall survival of lung cancer patients according to the stage of colorectal cancer (Stage I: 74.7%; Stage II/III: 66.5%, P = 0.7239).

Conclusions

A history of antecedent colorectal cancer did not contribute to the prognosis in patients with subsequent lung cancers.


Objective

To evaluate which clinical symptoms predict the survival of patients with renal cell carcinoma associated with end-stage renal disease under chronic dialysis.

Methods

We retrospectively evaluated 401 patients with renal cell carcinoma associated with end-stage renal disease who underwent radical nephrectomy at our institute up through December 2012. Patients were divided into two groups: the symptomatic group and the incidental group, by diagnosis. We compared the clinicopathologic features and patient survival of the two groups and investigated prognostic factors using Cox multivariate analysis.

Results

Of the 401 patients, 124 (30.9%) were in the symptomatic group and 277 (69.0%) in the incidental group. The symptomatic group included more advanced tumors in terms of larger tumor size, higher stage and higher grade compared with the incidental group. The 5-year cancer-specific survival and overall survival of the symptomatic and incidental groups were 76.9 vs. 95.3% (P < 0.001) and 64.2 vs. 84.9% (P < 0.001), respectively. On multivariate analysis, the presence of symptoms, higher age, higher stage, diabetic nephropathy and longer hemodialysis duration were independent prognostic factors.

Conclusions

Symptomatic detection was significantly associated with worse overall survival in patients with renal cell carcinoma associated with end-stage renal disease as well as sporadic renal cell carcinoma. The high incidence of renal cell carcinoma as well as the poor oncologic outcome in patients with longer dialysis therapy may suggest an important role for routine screening in these patients.


Objective

The aims of this study were to clarify the prognostic factors and to validate the bacillus Calmette-Guérin failure classification advocated by Nieder et al. in patients with non-muscle-invasive bladder cancer who had intravesical recurrence after bacillus Calmette-Guérin therapy.

Methods

Data from 402 patients who received intravesical bacillus Calmette-Guérin therapy between January 1990 and November 2011 were collected from 10 institutes. Among these patients, 187 with bacillus Calmette-Guérin failure were analyzed for this study.

Results

Twenty-nine patients (15.5%) were diagnosed with progression at the first recurrence after bacillus Calmette-Guérin therapy. Eighteen (62.1%) of them died of bladder cancer. A total of 158 patients were diagnosed with non-muscle-invasive bladder cancer at the first recurrence after bacillus Calmette-Guérin therapy. Of them, 23 (14.6%) underwent radical cystectomy. No patients who underwent radical cystectomy died of bladder cancer during the follow-up. On multivariate analysis of the 135 patients with bladder preservation, the independent prognostic factors for cancer-specific survival were age (≥70 [P = 0.002]), tumor size (≥3 cm [P = 0.015]) and the Nieder classification (bacillus Calmette-Guérin refractory [P < 0.001]). In a subgroup analysis, the estimated 5-year cancer-specific survival rates in the groups with no positive, one positive and two to three positive factors were 100, 93.4 and 56.8%, respectively (P < 0.001).

Conclusions

Patients with stage progression at the first recurrence after bacillus Calmette-Guérin therapy had poor prognoses. Three prognostic factors for predicting survival were identified and used to categorize patients with non-muscle-invasive bladder cancer treated with bacillus Calmette-Guérin into three risk groups based on the number of prognostic factors in each one.


Objective

To retrospectively analyze the clinical outcomes of radiation therapy with or without chemotherapy for bladder cancer in Japan.

Methods

A questionnaire-based survey of patients with pathologically proven bladder cancer treated by definitive radiation therapy between 2002 and 2006 was conducted by the Japanese Radiation Oncology Study Group, and the clinical records of 159 patients were collected from 17 institutions. Concurrent intra-arterial chemoradiotherapy and concurrent systemic chemoradiotherapy were administered in 51 and 33 patients, respectively.

Results

The 5-year overall survival and bladder preservation rates were 48 and 39%, respectively. Eighty-nine (56%) patients developed recurrence (bladder, 48; regional lymph nodes, 4; distant sites, 41). The results of multivariate analysis revealed that adoption of chemotherapy was the only significant prognostic factor for overall survival (relative risk = 0.615 [95% confidence interval: 0.439–0.862], P = 0.005). The type of chemotherapy administered did not significantly affect the local control or overall survival rates. The actuarial 5-year overall survival rates and bladder preservation in the radiation therapy combined with intra-arterial chemotherapy group were 64 and 58%, respectively, and the corresponding rates in the radiation therapy combined with systemic chemotherapy group were 67 and 42%, respectively.

Conclusions

The results of this survey revealed the current status of practice of radiation therapy for bladder cancer in Japan. A multi-institutional prospective study is needed based on the results of this study to determine the optimal radiotherapeutic approach, including the need for concurrent chemotherapy and the appropriate chemotherapy regimen for invasive bladder cancer.


Vulvar lymphatic leakage is a severe complication associated with gynecological cancer treatments. However, standard treatment strategies have not yet been determined. We encountered a rare case of a 76-year-old multiparous woman suffering from massive lymphatic fluid leakage from the entire vulva, and papules developed and were identified as lymphangiomas. A large amount of straw-colored discharge continued from all vulvar papules, which extended over the mons pubis. Nine years ago, the patient had undergone a radical hysterectomy with concurrent chemoradiation for uterine cervical cancer treatment. Her serum albumin level was 1.9 mg/dl, which was attributed to the loss of a large amount of lymph fluid due to leakage from the vulva. Her quality of life gradually decreased because of general fatigue and the need for frequent diaper exchanges every 2 h. The patient received a less-invasive treatment with cryotherapy using liquid nitrogen. She also received a multimodality treatment consisting of the intravenous administration of albumin, massage of the lower limbs and intensive rehabilitation. Cryotherapy was administered once a week for 3 months. Her discharge almost stopped and vulvar lymphangiomas decreased without any major complications. To the best of our knowledge, this is the first case report of massive lymphatic leakage complicated with vulvar lymphangiomas. Additionally, this case may represent the first successful treatment of vulva lymph leakage by cryotherapy without recurrence. Cryotherapy may have the potential to improve the quality of life as a less-invasive treatment for gynecological cancer survivors without serious complications.


Anthracycline-based regimens with cisplatin have been commonly used for inoperable and relapsed thymoma. However, little information is available regarding the usefulness of salvage chemotherapy. Here, we describe a case of invasive thymoma associated with myasthenia gravis that showed a marked response to third-line chemotherapy, with single-agent amrubicin, a synthetic anthracycline analog and potent deoxyribonucleic acid topoisomerase II inhibitor. Amrubicin appears to have significant activity against invasive thymoma.


A randomized controlled trial was started in Japan to evaluate the non-inferiority of overall survival of laparoscopic surgery to open surgery for palliative resection of primary tumor in incurable Stage IV colorectal cancer. Symptomatic, Stage IV colorectal cancer patients with non-curable metastasis are pre-operatively randomized to either open or laparoscopic colorectal resection. Surgeons in 56 specialized institutions will recruit 450 patients. The primary endpoint is overall survival. Secondary endpoints are progression-free survival, the proportion of conversion from laparoscopic surgery to open surgery, the proportion of patients who fulfill the criteria of starting chemotherapy by 6 weeks after operation, intraoperative and post-operative complications, adverse events during chemotherapy and serious adverse events.


Malignant pleural mesothelioma remains an incurable disease for which the optimal therapeutic approach remains an extremely debated issue. Though not yet clearly defined, a subset of patients may benefit from a surgery-based multimodal treatment plan, beyond what would be expected with non-surgical therapies only. Indeed, despite some disappointing results on the feasibility of a multimodality treatment (chemotherapy ± surgery and post-operative radiation therapy) based on a lung sacrificing surgery (extrapleural pleuropnemonectomy) have been recently reported, the question concerning the role of extrapleural pneumonectomy in selected mesothelioma patients is still unanswered. In the light of this, we have reviewed our mono-institutional retrospective experience in the mesothelioma management, discussing on the role of extrapleural pneumonectomy in the multimodality treatment.