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Japanese Journal of Clinical Oncology

Japanese Journal of Clinical Oncology - RSS feed of current issue

Hodgkin lymphoma is a highly curative lymphoid malignancy, but some patients relapse or experience adverse events from treatment. Therefore, prognostic markers are needed to allow a more patient-tailored approach to treatment. The positive-predictive value of interim positron emission tomography for progression-free survival was reported as 81%, and the negative-predictive value was reported as 97%. Interim positron emission tomography might identify high-risk patients who would benefit from more intensive treatment regimens as well as identify low-risk patients in whom even the standard treatment regimen might be a form of overtreatment. Indeed, major clinical study groups have conducted risk-adapted treatment protocols based on interim positron emission tomography. The Japan Clinical Oncology Group is also planning a Phase II trial of this concept for advanced Hodgkin lymphoma. These trials are now ongoing, but the data of them are expected soon. Molecular-targeted therapy is another important approach to improve outcomes for these patients. Brentuximab vedotin is an antibody–drug conjugate that targets CD30 on Hodgkin cells and has excellent efficacy when used as monotherapy. The combination of brentuximab vedotin and standard chemotherapies are being investigated in randomized Phase III trials. These approaches might lead to a paradigm shift in the treatment of Hodgkin lymphoma.


Objective

Primary breast sarcoma is a kind of extremely rare disease. Malignant phyllodes tumor represents a specific subset of breast soft tissue tumors. So till now, the classification and clinical management of primary breast sarcoma and malignant phyllodes tumor are controversial. The aim of this study is to explore the differences in clinical features, treatment, disease-free survival and overall survival between primary breast sarcoma and malignant phyllodes tumor group.

Methods

A retrospective review of 35 cases with primary breast sarcoma and 70 cases with malignant phyllodes tumor registered from 1995 to 2010 was carried out in Tianjin Medical University Cancer Institute and Hospital. Prognosis in terms of disease-free survival and overall survival was evaluated.

Results

In primary breast sarcoma group, the result of univariate analysis demonstrated that surgical type, histopathological nodal status and local recurrence were significantly correlated with disease-free survival and overall survival. While, the result of monofactorial analysis showed the tumor size was significant prognostic indicator of disease-free survival and overall survival in malignant phyllodes tumor group. The Kaplan–Meier curves for 5-year disease-free survival rates and overall survival rates demonstrated that no significant difference was found between the primary breast sarcoma and malignant phyllodes tumor group (P = 0.702 and 0.772, respectively).

Conclusions

The primary breast sarcoma patients had identical disease-free survival and overall survival compared with the malignant phyllodes tumor patients, which indicated that primary breast sarcoma and malignant phyllodes tumor patients should be treated with the same strategies. Surgical management is important for both the primary breast sarcoma and malignant phyllodes tumor patients. The role of the adjuvant radiotherapy and chemotherapy remains uncertain.


Objective

The characteristics of familial colorectal cancer type X are poorly defined. Here we aimed to clarify the differences in clinical features between suspected familial colorectal cancer type X and Lynch syndrome in Japanese patients.

Methods

We performed germline mutation analyses of mismatch repair genes in 125 patients. Patients who met the Amsterdam Criteria I but lacked mismatch repair gene mutations were diagnosed with suspected familial colorectal cancer type X.

Results

We identified 69 patients with Lynch syndrome and 25 with suspected familial colorectal cancer type X. The frequencies of gastric and extracolonic Lynch syndrome-associated cancers were lower with suspected familial colorectal cancer type X than with Lynch syndrome. The number of organs with Lynch syndrome-associated cancer was significantly lower with suspected familial colorectal cancer type X than with Lynch syndrome. The cumulative incidence of extracolonic Lynch syndrome-associated cancer was significantly lower with suspected familial colorectal cancer type X than with Lynch syndrome. We estimated that the median cancer risk in 60-year-old patients with Lynch syndrome was 89, 36 and 24% for colorectal, endometrial and gastric cancers, respectively. Analyses of family members, including probands, revealed that the median age at diagnosis of extracolonic Lynch syndrome-associated cancer was significantly older with suspected familial colorectal cancer type X than with Lynch syndrome. The frequency of extracolonic Lynch syndrome-associated cancer was significantly lower with suspected familial colorectal cancer type X than with Lynch syndrome.

Conclusion

A significant difference in extracolonic Lynch syndrome-associated cancer was evident between suspected familial colorectal cancer type X and Lynch syndrome.


Objective

The aim of this study is to evaluate the liver metastasis risk among colorectal cancer patients with liver cirrhosis.

Methods

This was a nationwide population-based cohort study of 2973 newly diagnosed colorectal cancer patients with liver cirrhosis and 11 892 age–sex matched controls enrolled in Taiwan between 2000 and 2010. The cumulative risk by Kaplan–Meier method, hazard ratio by the multivariate Cox proportional model and the incidence density were evaluated.

Results

The median time interval from the colorectal cancer diagnosis to the liver metastasis event was 7.42 months for liver cirrhosis group and 7.67 months for non-liver cirrhosis group. The incidence density of liver metastasis was higher in the liver cirrhosis group (61.92/1000 person-years) than in the non-liver cirrhosis group (47.48/1000 person-years), with a significantly adjusted hazard ratio of 1.15 (95% CI = 1.04–1.28, P = 0.007). The 10-year cumulative risk of liver metastasis for the liver cirrhosis and the non-liver cirrhosis group was 27.1 and 23.6%, respectively (P = 0.006). For early cancer stage with locoregional disease patients receiving surgery alone without adjuvant anti-cancer treatments, patients with liver cirrhosis (10-year cumulative risk 23.9 vs. 15.7%, P < 0.001) or cirrhotic symptoms (10-year cumulative risk 25.6 vs. 16.6%, P = 0.009) both still had higher liver metastasis risk compared with their counterparts. For etiologies of liver cirrhosis, the 10-year cumulative risk for hepatitis B virus and hepatitis C virus, hepatitis B virus, hepatitis C virus, other causes and non-liver cirrhosis were 29.5, 28.9, 27.5, 26.7 and 23.4%, respectively, (P = 0.03).

Conclusions

Our study found that liver metastasis risk was underestimated and even higher in colorectal cancer patients with liver cirrhosis.


Objective

Esophageal squamous cell carcinoma is increasingly treated with trimodality therapy. The objective of this Phase I/II clinical study is to assess the efficacy and safety of neoadjuvant radiochemotherapy with docetaxel and cisplatin and radiotherapy in patients with esophagectomy for locally advanced squamous cell carcinoma of the esophagus with neoadjuvant chemoradiotherapy.

Methods

Patients with esophageal squamous cell carcinoma received radiochemotherapy (50 Gy/25 fractions during Weeks 1–5) using a three-dimensional conformal radiation therapy or intensity-modulated radiation therapy technique together with weekly docetaxel (20 mg/m2 at dose levels 1 and 2, 25 mg/m2 at dose level 3 on Weeks 1–5) and cisplatin (30 mg/m2 at dose level 1, 40 mg/m2 at dose levels 2 and 3 on Weeks 1–5) from January 2009 to December 2011. The dose-limiting toxicities and maximum tolerated dose were the primary endpoints and overall response rate and progression-free survival were the secondary endpoints.

Results

Over this timeframe, a total of 49 patients completed trimodality therapy. Thirteen patients were treated at dose level 1, 21 patients at dose level 2 and 15 patients at dose level 3.The maximum tolerated dose for docetaxel was 20 mg/m2 and cisplatin 40 mg/m2. The complete response or partial response was observed in 26.5% (13/49) of patients. Thirty-four patients (69.4%) were treated with neoadjuvant radiochemotherapy followed by surgical resection. The median progression-free survival and median overall survival for all patients (n = 49) were 8 and 17.2 months, respectively. The median overall survival was 27.5 months for patients treated at dose level 2.

Conclusion

Neoadjuvant radiochemotherapy with docetaxel 20 mg/m2 and cisplatin 40 mg/m2 was effective and tolerable induction regimen in patients with esophageal tumors.


Objective

Effective biomarkers for early detection of ovarian cancer are needed. Our study previously showed that basement membrane protein, nidogen-1 plasma level was significantly increased in ovarian cancer patients. This study aimed to examine the plasma levels of nidogen-1 in a large patient population to evaluate its effectiveness in ovarian serous carcinoma and expression in tumor tissues.

Methods

The concentration of nidogen-1 in circulating plasma specimens of 265 ovarian serous cancer patients and 98 healthy individuals were assayed by enzyme linked immunosorbent assay. The medical records of 265 ovarian serous cancer cases were reviewed retrospectively. The expression status of nidogen-1 in tumor tissues of 44 ovarian serous carcinoma patients was examined by immunohistochemical analysis. For statistical analysis, we used the Mann–Whitney U test, Fisher's exact test and receiver operating characteristic.

Results

Protein levels of nidogen-1 were considerably raised in the plasma from ovarian serous cancer patients compared with those in healthy controls (P < 0.001), especially elevated in patients with advanced stage and those received neoadjuvant chemotherapy followed by interval debulking surgery. However, it was irrelevant to the grade, chemotherapy sensitivity or residual tumor of the ovarian serous carcinoma cases investigated (P > 0.05). Receiver operating characteristic curve analysis for nidogen-1 showed that it could discriminate patients with ovarian serous carcinomas from healthy controls [areas under the curve (AUC): 0. 65, 95%CI, 0.59–0.71], but CA125 was superior (AUC: 0. 98, 95%CI, 0.96–0.99). The immunohistochemical staining result showed that nidogen-1 protein was localized both in the cancer cell cytoplasm and intercellular substance, mainly expressed in extracellular matrix of ovarian serous carcinoma tissues (the positive rate was 77.3%).

Conclusions

Our study suggests that plasma nidogen-1 may be used as a diagnostic biomarker for ovarian serous carcinoma and can reflect the tumor burden.


Objective

Prophylactic percutaneous endoscopic gastrostomy may be considered before chemoradiotherapy for patients with locally advanced head and neck squamous cell carcinoma, because severe mucositis is a common complication. We evaluated the mucosal findings and necessity of prophylactic percutaneous endoscopic gastrostomy in patients with head and neck squamous cell carcinoma receiving cetuximab and radiotherapy.

Methods

Fourteen consecutive patients with locally advanced head and neck squamous cell carcinoma receiving cetuximab and radiotherapy were analyzed.

Results

Patients' backgrounds were as follows: male/female, 8/6; median age, 64.5 years (range, 35–83 years); performance status, 0/1, 9/5. Primary tumor sites included the oropharynx, hypopharynx and larynx in four, seven and three patients, respectively. Patients completed a median of eight cetuximab cycles. All patients received three-dimensional conformal radiotherapy (median dose, 70 Gy). Thirteen patients were treated with elective neck irradiation at the ipsilateral (n = 3) or bilateral (n = 10) nodes. Grade ≥3 mucositis/stomatitis (clinical examination) occurred in 85.7% patients (n = 12). The median irradiation dose was 33 Gy at the Grade 3 mucositis onset. Eight patients showed mucositis with distinctive features, a wide range of white-coated lesions with a clear border; hypopharyngeal atresia was observed in two patients. Prophylactic percutaneous endoscopic gastrostomy was performed in 11 patients, and 11 patients (78.6%) actually required nutritional support because of Grade ≥3 mucositis/stomatitis (functional/symptomatic).

Conclusions

Prophylactic percutaneous endoscopic gastrostomy is recommended because most patients receiving cetuximab and radiotherapy for locally advanced head and neck squamous cell carcinoma have Grade ≥3 mucositis with distinctive features.


Objective

A randomized, crossover, double-blinded placebo-controlled and non-blinded active drug-controlled, comparative clinical trial was conducted to evaluate the efficacy and safety of sublingual fentanyl tablet.

Methods

Subjects were patients treated with strong opioids at fixed intervals for chronic cancer pain and with oral morphine as rescue medication for breakthrough pain. Sublingual fentanyl was administered at doses that were 1/25th (high dose) and 1/50th (low dose) of the dose of rescue morphine and was compared with placebo and oral morphine. The primary endpoint was pain intensity difference at 30 min after administration. (Clinical Trials Government; NCT00684632).

Results

Fifty-one patients were enrolled in the investigation. Their mean pain intensity in visual analog scale before rescue medication prior to the investigation was 60.96 (16.44, standard deviation) mm. Compared with placebo, the low and high doses of sublingual fentanyl showed significant analgesic effects (least squares mean difference, 4.54 and 8.49 mm; P = 0.014, P < 0.001, respectively). Adverse reactions were observed in 17.6%, the most common being constipation, nausea and somnolence. The incidence of adverse reactions during the high-dose administration period was higher than that during the low-dose and active control drug administration periods.

Conclusions

Patients treated with strong opioid analgesics at fixed intervals for chronic cancer pain and with oral morphine at doses up to 20 mg as rescue medication were investigated. The doses of sublingual fentanyl to treat breakthrough pain were determined from rescue morphine doses by use of conversion ratios. In these patients, administration of sublingual fentanyl at doses determined by a conversion ratio of 1/50 was effective and safe. Further studies are needed to validate the use of this conversion method.


Objective

Japan Cancer of the Prostate Risk Assessment scores are reportedly useful for predicting progression-free survival after primary androgen deprivation therapy of prostate cancer patients. This study validated the risk assessment at a single institution.

Methods

We studied 255 prostate cancer patients given primary androgen deprivation therapy. Progression-free survival, cause-specific survival and overall survival were analyzed according to Japan Cancer of the Prostate Risk Assessment score-based risk classification. Cases with lymph node or distant metastases were subdivided by the risk classification.

Results

Ages ranged from 50 to 90 years (median: 76.5). Observation periods were 2–199 (median: 46.5) months. Primary androgen deprivation therapy includes combined androgen blockade in 150 cases (58.8%), uncombined luteinizing hormone-releasing hormone agonist in 97 (38.0%) and uncombined anti-androgenic agent in 8 (3.2%). Risk classified by Japan Cancer of the Prostate Risk Assessment scores was low in 104 cases (40.8%), intermediate in 86 (33.7%) and high in 65 (25.5%). The 5-year/10-year progression-free survival rates were 100%/80.8% in the low-risk, 82.3%/69.5% in the intermediate-risk and 34.7%/16.5% in the high-risk group. The 5-year/10-year cause-specific survival rates were 100%/100% in the low-risk, 90.7%/58.2% in the intermediate-risk and 63%/30.8% in the high-risk group. The 5-year/10-year overall survival rates were 87.5%/78.5% in the low-risk, 76.2%/43.1% in the intermediate-risk and 54.9%/25.4% in the high-risk group. For lymph node metastasis, cause-specific survival differed minimally between the intermediate- and high-risk groups (P = 0.1118). For distant metastasis, cause-specific survival differed significantly between the intermediate- and high-risk groups (P = 0.0264).

Conclusions

Japan Cancer of the Prostate Risk Assessment score-based risk classification is useful for predicting post-primary androgen deprivation therapy progression-free survival, cause-specific survival and overall survival. Subtyping patients based on Japan Cancer of the Prostate Risk Assessment scores is particularly useful for predicting cause-specific survival with distant metastasis from prostate cancer.


Objective

To investigate the prognostic value of interleukin-11 receptor α chain in patients with early-stage clear-cell renal cell carcinoma. Interleukin-11 receptor α chain, a member of the gp130-dependent receptors, exerts pleiotropic oncogenic activities by promoting proliferation, angiogenesis and metastasis in many cancers.

Methods

We retrospectively enrolled 293 patients (130 in the training cohort and 163 in the validation cohort) with early-stage (TNM Stage I + II) clear-cell renal cell carcinoma undergoing nephrectomy at a single institution. Clinicopathologic features, recurrence-free survival and overall survival were recorded. Interleukin-11 receptor α chain intensities were assessed by immunohistochemistry in tumor tissues. Kaplan–Meier method was applied to compare survival curves between groups. Cox regression models were used to analyze the impact of prognostic factors on recurrence-free survival and overall survival. The concordance index was calculated to assess predictive accuracy.

Results

In both training and validation cohorts, high interleukin-11 receptor α chain expression was associated with early recurrence (P = 0.004 and P = 0.015, respectively) and poor survival (P < 0.001 and P = 0.019, respectively) of patients with early-stage clear-cell renal cell carcinoma. Multivariate analyses confirmed that interleukin-11 receptor α chain expression was an independent prognostic factor for recurrence-free survival (P = 0.004) and overall survival (P = 0.001). The predictive accuracy of the Leibovich prognostic score was improved when interleukin-11 receptor α chain expression was incorporated. Notably, the improvement in prediction mainly took place in patients with low-risk disease defined by the Leibovich score.

Conclusion

High Interleukin-11 receptor α chain expression is an independent predictor of poor clinical outcome in patients with early-stage clear-cell renal cell carcinoma, and the prognostic value is more prominent in those with low-risk disease.


Objective

To investigate the prognostic significance of visceral obesity to predict recurrence after curative surgery for Japanese patients with localized renal cell carcinoma.

Methods

The data of 285 patients who underwent curative surgery for localized renal cell carcinoma were retrospectively reviewed. Median follow-up was 36.7 months. The association between visceral obesity and recurrence-free survival rate was evaluated using the Kaplan–Meier method and Cox regression models. Visceral fat area at the level of the umbilicus measured using pre-operative computed tomography was used as an index of visceral obesity.

Results

Twenty-nine patients (10.2%) experienced recurrence. Five-year recurrence-free survival rates were 91.3% in high visceral fat area group (≥120 cm2) and 76.9% in low visceral fat area group (<120 cm2) (P = 0.037); however, visceral fat area was not an independent predictor of recurrence-free survival in multivariate analysis. In the patients with clear cell renal cell carcinoma, 28 patients (11.6%) experienced recurrence. Five-year recurrence-free survival rates were 88.7% in high visceral fat area group and 71.0% in low visceral fat area group (P = 0.043), and visceral fat area was an independent predictor of recurrence-free survival (hazard ratio: 1.974, P = 0.042) as well as C-reactive protein, Fuhrman nuclear grade, tumor size and microvascular invasion. In patients with organ confined clear cell renal cell carcinoma in particular, visceral fat area was also a useful and independent predictor of recurrence-free survival (hazard ratio: 2.807, P = 0.038). Body mass index was not useful in either cohort.

Conclusions

High visceral fat area was a positive predictive biomarker for better recurrence-free survival after curative surgeries for localized clear cell renal cell carcinomas; however, body mass index was not a predictor.


Inguinal lymph node metastasis from adenocarcinoma arising at a colostomy site is extremely rare, and the significance of surgical resection for metastatic inguinal lymph nodes has not been established. An 82-year-old woman who had undergone abdominoperineal resection 27 years earlier was admitted to our hospital complaining of bleeding from a colostomy. Physical examination revealed that a tumor at the colostomy site directly invaded into the peristomal skin, and that a left inguinal lymph node was firm and swollen. Positron emission tomography/computed tomography scan demonstrated accumulation of 18F-fluorodeoxy glucose into both the colostomy tumor and the left swollen inguinal lymph node, while there was no evidence of metastasis to liver or lungs. She underwent open left hemicolectomy with wide local resection of the colostomy, and dissection of left inguinal lymph nodes. Histological diagnosis was a moderately differentiated adenocarcinoma that directly invaded into the surrounding skin and metastasized to the left inguinal lymph node. The patient has been followed up for >5 years without any sign of recurrence. In general, inguinal lymph node metastasis from colorectal cancers is regarded as a systemic disease with a poor prognosis, and so systemic chemotherapy and radiotherapy, but not surgical lymph node dissection, are recommended. Considering the lymphatic drainage route in the present case, inguinal lymph node metastasis does not represent a systemic disease but rather a sentinel nodal metastasis from adenocarcinoma at a colostomy site. Surgical dissection of metastatic inguinal lymph nodes should be considered to enable a favorable prognosis in the absence of distant metastasis to other organs.


A 75-year-old woman with anaplastic lymphoma kinase (ALK)-rearranged Stage IV lung adenocarcinoma was administered the selective anaplastic lymphoma kinase inhibitor, alectinib, as a third-line treatment in a Phase 1–2 study. On the 102nd day, chest computed tomography showed diffuse ground glass opacities. Laboratory data revealed high serum levels of KL-6, SP-D and lactate dehydrogenase without any clinical symptoms. There was no evidence of infection. Marked lymphocytosis was seen in bronchoalveolar lavage fluid analysis, and transbronchial lung biopsy showed mild thickening of alveolar septa and lymphocyte infiltration. Interstitial lung disease was judged to be related to alectinib based on improvements in imaging findings and serum biomarkers after discontinuation of alectinib. To our knowledge, this is the first reported case of alectinib-induced interstitial lung disease. Alectinib is a promising drug for ALK-rearranged non-small cell lung cancer. Clinical trials of this selective anaplastic lymphoma kinase inhibitor will facilitate the meticulous elucidation of its long-term safety profile.


We report a case of a 21-year-old man with alveolar rhabdomyosarcoma primarily in the right hand with lymph node, lung, bone and bone marrow metastases. Complete remission was achieved after intensive chemotherapy and radiotherapy of the primary and metastatic sites, followed by allogeneic peripheral blood stem cell transplantation with reduced-intensity conditioning from a single HLA-DR locus-mismatched mother. The patient remained relapse-free for 41 months after the diagnosis. Considering that the conventional treatment for rhabdomyosarcoma with multiple risk factors (old age, bone or bone marrow involvement, unfavorable primary sites and ≥3 metastases) is associated with a poor prognosis (5% probability of a 3-year event-free survival), the graft-versus-tumor effect may have contributed to his sustained relapse-free survival. Allogeneic hematopoietic stem cell transplantation for rhabdomyosarcoma should be done by experienced clinical oncologists on properly designed controlled trials.


A randomized Phase II dose-finding trial comparing olanzapine 10 mg with olanzapine 5 mg for patients receiving highly emetogenic chemotherapy with cisplatin was started in June 2014. The purpose of the trial is to evaluate the efficacy and safety of the two olanzapine doses and to determine which is more promising as a test arm for comparison with the current standard antiemetic care (a combination of aprepitant, a 5-HT3 receptor antagonist and dexamethasone) in a subsequent Phase III trial. Patients receiving cisplatin-containing regimens will be randomized to the olanzapine 10 or 5 mg arm. A total of 150 patients will be accumulated from nine institutions over 2 years. The primary endpoint is complete response defined as no emetic episodes and no use of rescue medications in the delayed (24–120 h) phase. This trial has been registered at the UMIN Clinical Trials Registry as UMIN000014214.