Kazushige Hayakawa

Oligometastases and oligo-recurrence: the new era of cancer therapy.

Recurrence or metastasis of cancer has been considered to occur in the last stage of the patients life. However, the new notions of oligometastases and oligo-recurrence have been proposed and the paradigm shift in the conceptualization of cancer metastasis or cancer recurrence. Oligometastases is the state in which the patient shows distant relapse in only a limited number of regions. Local therapy such as surgery, radiotherapy and radiofrequency ablation for the relapsed sites could thus improve patients survival. On the other hand, oligo-recurrence is a notion similar to oligometastases. However, the conditions of oligo-recurrence has a primary site of the cancer controlled, meaning that all gross recurrent or metastatic sites could be treated using local therapy.

Abscopal effect of radiation on lung metastases of hepatocellular carcinoma: a case report.

IntroductionThe abscopal effect is the effect of radiation therapy at a site distant to the area of irradiation. This is not a common event and has not been clearly defined, resulting in few reported cases in the literature. We discuss this phenomenon in a patient with hepatocellular carcinoma.Case presentationA 63-year-old Japanese man underwent extended right hepatic lobectomy for hepatocellular carcinoma. During his follow-up examination, a single lung metastasis and a single mediastinal lymph node metastasis were found. Trans-catheter arterial embolization was initially attempted to treat the mediastinal tumor, however this approach failed to take effect and carried risks of spinal artery embolism. External-beam irradiation, with a dose of 2.25 Gy per fraction, was performed using an antero-posterior parallel-opposed technique (total dose, 60.75 Gy). A computed tomography scan performed one month after starting radiotherapy showed a remarkable reduction of the mediastinal lymph node metastasis. In addition to this, we observed spontaneous shrinking of the lung metastasis, which was located in the right lower lobe and out of the radiation field. No chemotherapy was given during the period. There has been no recurrence of either the lung metastasis or the mediastinal lymph node metastasis during a follow-up 10 years after the radiotherapy.ConclusionWe observed a rare abscopal effect in a site distant from the area of irradiation. Irradiation of the mediastinum resulted in tumor mass regression in the untreated lung tumor.

EGFR genetic heterogeneity of nonsmall cell lung cancers contributing to acquired gefitinib resistance

Gefitinib is dramatically effective for nonsmall cell lung cancers (NSCLCs) with activating mutations of the epidermal growth factor receptor (EGFR) gene, but these tumors eventually develop drug resistance, attributable to a secondary T790M mutation or acquired MET amplification in some relapsed tumors. We analyzed EGFR mutations in matched pre‐ and post‐therapeutic tumors of 6 gefitinib‐responding lung cancers. With conventional PCR‐based sequencing, classic mutations were detected in pretreatment samples of each case. The same mutations were readily confirmed in treated lesions of 4 cases, but were absent in those of Cases 1 and 2. Subsequent mutant‐enriched peptide‐nucleic‐acid‐mediated PCR clamping and subcloning assays detected the mutation in minor cells of treated lesions of Case 1, but still failed to detect a mutation in Case 2. We thus performed microdissection‐based cell cluster mutation analysis of pretreatment tumors, and found that 3, including the first 2, concurrently contained tumor cells with either mutant or wild‐type EGFR, although the latter was only a minor fraction. These findings suggest that some NSCLCs are genetically heterogeneous with regard to EGFR mutations; gefitinib‐sensitive mutants decrease or vanish while wild clones selectively survive with gefitinib treatment. In addition, T790M was detected in a small fraction of treated lesions of 3 cases, and MET amplification was revealed in 3 treated tumors of Case 2. Thus, our results suggest that multiple mechanisms underlie acquired gefitinib resistance, and selection on a background of EGFR genetic heterogeneity also contributes to acquisition of resistance in a proportion of NSCLCs.

Bilateral crossed cerebello-cerebral diaschisis and mutism after surgery for cerebellar medulloblastoma

A 7-year-old boy developed mutism after surgery for cerebellar medulloblastoma. Postoperative magnetic resonance imaging (MRI) whowed atrophy of the cerebellar vermis and both cerebellar hemispheres, predominantly on the right side. Single photon emission computed tomography (SPECT) with technetium-99m-ethyl cysteinate dimer (Tc-99m ECD) revealed decreased cerebral blood flow (CBF) in the bilateral thalami, bilateral medial frontal lobes, and left temporal lobe in addition to the cerebellar vermis and both cerebellar hemispheres when mutism was manifest, indicating the existence of bilateral crossed cerebello-cerebral diaschisis (BCCCD). Circulatory disturbance in both cerebellar hemispheres secondary to tumor resection probably caused BCCCD in both cerebral hemispheres, predominantly in the left, via the dentatothalamocortical pathway (DTCP). With recovery of his mutism, CBF increased in the right thalamus, bilateral medial frontal lobes and left temporal lobe. Thus BCCCD was improved, with only a slight decrease in CBF still persisting in the left thalamus. The mechanism of mutism may have involved damage to the cerebellar vermis (the site of incision at operation), the left dentate nucleus (heavily infiltrated by the tumor) and the right dentate nucleus of the cerebellum (affected by circulatory disturbance secondary to acute postoperative edema). The SPECT findings suggested that mutism was associated with BCCCD-induced cerebral circulatory and metabolic hypofunction in the supplementary motor area mediated via the DTCP.

Usefulness of multidetector-row CT ( MDCT) for the diagnosis of non-occlusive mesenteric ischemia (NOMI): Assessment of morphology and diameter of the superior mesenteric artery (SMA) on multi-planar reconstructed (MPR) images

OBJECTIVE The purpose of this study was to assess the efficacy of multidetector-row CT (MDCT) for the diagnosis of non-occlusive mesenteric ischemia (NOMI) by analyzing morphology and diameter of superior mesenteric artery (SMA). We assessed whether MDCT was as useful as angiography for the diagnosis of NOMI. MATERIALS AND METHODS Four patients who were diagnosed with NOMI were retrospectively analyzed. All patients had 8-row MDCT followed by laparotomy. Two of them underwent angiography after MDCT. The morphology and diameter of SMA of these cases was analyzed on multi-planar reconstructed (MPR) images. The mean diameter of SMA of NOMI cases was compared to that of 13 control cases. RESULTS MPR images of all NOMI cases showed irregular narrowing of the SMA, spasm of the arcades of SMA, and poor demonstration of intramural vessels. MPR images of two patients who had angiography were concordant with their angiograms. The mean diameter of SMA of NOMI patients was 3.4±1.1mm, which was statistically smaller than that of 13 control patients, 6.0±1.5mm (P<0.05, Wilcoxon rank sum tests). CONCLUSION Angiography has been recognized essential for the diagnosis of NOMI. This study shows the possibility of MDCT to be an equivalently useful modality compared to angiography for the diagnosis of NOMI by interpreting morphologic appearance and diameter of SMA. Introduction of MDCT in the decision tree of NOMI treatment may bring the benefit of prompt diagnosis and subsequent early and efficient initiation of therapy, which may improve the mortality.

Single Infusion of Zoledronic Acid to Prevent Androgen Deprivation Therapy-induced Bone Loss in Men With Hormone-naive Prostate Carcinoma

Androgen‐deprivation therapy (ADT) decreases bone mineral density (BMD) and increases fracture risk in patients with prostate carcinoma. The authors investigated the effectiveness of a single infusion of zoledronic acid initiated subsequent to ADT on BMD with hormone‐naive prostate carcinoma.

A Phase II Trial of Neoadjuvant Preoperative Chemoradiotherapy With S-1 Plus Irinotecan and Radiation in Patients With Locally Advanced Rectal Cancer: Clinical Feasibility and Response Rate

PURPOSE We aimed to validate our hypothesis that a preoperative chemoradiotherapy regimen with S-1 plus irinotecan is feasible, safe, and active for the management of locally advanced rectal cancer in a single-arm Phase II setting. METHODS AND MATERIALS Eligible patients had previously untreated, locally advanced rectal adenocarcinoma. Radiotherapy was administered in fractions of 1.8 Gy/d for 25 days. S-1 was administered orally in a fixed daily dose of 80 mg/m2 on Days 1 to 5, 8 to 12, 22 to 26, and 29 to 33. Irinotecan (80 mg/m2) was infused on Days 1, 8, 22, and 29. Four or more weeks after the completion of the treatment, total mesorectal excision with lateral lymph node dissection was performed. The primary endpoint was the rate of completing treatment in terms of feasibility. The secondary endpoints were the response rate and safety. RESULTS We enrolled 43 men and 24 women in the study. The number of patients who completed treatment was 58 (86.6%). Overall, 46 patients (68.7%) responded to treatment and 24 (34.7%) had a complete histopathologic response. Three patients had Grade 3 leukopenia, and another three patients had Grade 3 neutropenia. Diarrhea was the most common type of nonhematologic toxicity: 3 patients had Grade 3 diarrhea. CONCLUSIONS A preoperative regimen of S-1, irinotecan, and radiotherapy to the rectum was feasible, and it appeared safe and effective in this nonrandomized Phase II setting. It exhibited a low incidence of adverse events, a high rate of completion of treatment, and an extremely high rate of pathologic complete response.

Prostate-specific antigen ‘bounce’ after permanent 125I-implant brachytherapy in Japanese men: a multi-institutional pooled analysis

To examine the incidence, timing, and magnitude of the prostate‐specific antigen (PSA) level ‘bounce’ after permanent prostate brachytherapy (BT) and correlate the PSA bounce with clinical and dosimetric factors in Japanese patients with prostate cancer.

Definitive Chemoradiation Therapy With Docetaxel, Cisplatin, and 5-Fluorouracil (DCF-R) in Advanced Esophageal Cancer: A Phase 2 Trial (KDOG 0501-P2)

PURPOSE A previous phase 1 study suggested that definitive chemoradiation therapy with docetaxel, cisplatin, and 5-fluorouracil (DCF-R) is tolerable and active in patients with advanced esophageal cancer (AEC). This phase 2 study was designed to confirm the efficacy and toxicity of DCF-R in AEC. METHODS AND MATERIALS Patients with previously untreated thoracic AEC who had T4 tumors or M1 lymph node metastasis (M1 LYM), or both, received intravenous infusions of docetaxel (35 mg/m(2)) and cisplatin (40 mg/m(2)) on day 1 and a continuous intravenous infusion of 5-fluorouracil (400 mg/m(2)/day) on days 1 to 5, every 2 weeks, plus concurrent radiation. The total radiation dose was initially 61.2 Gy but was lowered to multiple-field irradiation with 50.4 Gy to decrease esophagitis and late toxicity. Consequently, the number of cycles of DCF administered during radiation therapy was reduced from 4 to 3. The primary endpoint was the clinical complete response (cCR) rate. RESULTS Characteristics of the 42 subjects were: median age, 62 years; performance status, 0 in 14, 1 in 25, 2 in 3; TNM classification, T4M0 in 20, non-T4M1LYM in 12, T4M1LYM in 10; total scheduled radiation dose: 61.2 Gy in 12, 50.4 Gy in 30. The cCR rate was 52.4% (95% confidence interval [CI]: 37.3%-67.5%) overall, 33.3% in the 61.2-Gy group, and 60.0% in the 50.4-Gy group. The median progression-free survival was 11.1 months, and the median survival was 29.0 months with a survival rate of 43.9% at 3 years. Grade 3 or higher major toxicity consisted of leukopenia (71.4%), neutropenia (57.2%), anemia (16.7%), febrile neutropenia (38.1%), anorexia (31.0%), and esophagitis (28.6%). CONCLUSIONS DCF-R frequently caused myelosuppression and esophagitis but was highly active and suggested to be a promising regimen in AEC. On the basis of efficacy and safety, a radiation dose of 50.4 Gy is recommended for further studies of DCF-R.

A phase I trial of definitive chemoradiotherapy with docetaxel, cisplatin, and 5-fluorouracil (DCF-R) for advanced esophageal carcinoma: Kitasato digestive disease & oncology group trial (KDOG 0501)

BACKGROUND AND PURPOSE A dose-escalation study of docetaxel combined with cisplatin, 5-fluorouracil, and concurrent radiotherapy (DCF-R) was performed to determine the optimal dose in patients with advanced esophageal carcinoma. PATIENTS AND METHODS A total of 19 patients who had previously untreated thoracic esophageal carcinoma with T4 tumors and/or M1 lymph-node metastasis were studied. The Patients received an infusion of docetaxel (levels 1, 2, 3, 2.5: 20, 30, 40, 35 mg/m(2)) and an infusion of cisplatin (40 mg/m(2)) on days 1, 15, 29, and 43 plus a continuous infusion of 5-fluorouracil (400mg/m(2)/day) on days 1-5, 15-19, 29-33, and 43-47. And patients received 61.2 Gy/34 fractions/7 weeks of concurrent radiotherapy. RESULTS Dose-limiting toxicities (DLTs) were febrile neutropenia and grade 4 leukopenia lasting 3 days. DLT occurred in 2 of 6 patients at level 2, 3 of 4 patients at level 3, and 2 of 6 patients at level 2.5. The main toxicities were myelotoxicity and esophagitis. The overall response rate was 89.5%, including a complete response rate of 42.1%. CONCLUSIONS The maximum-tolerated dose was level 3, because 50% or more of the patients had DLTs. Therefore, level 2.5 was recommended for phase II studies. This regimen was tolerable and highly active.