Postoperative pulmonary complications after preoperative chemoradiation for esophageal carcinoma: correlation with pulmonary dose-volume histogram parameters

PURPOSE: To clarify the relationship between the percentage of lung receiving low radiation doses with concurrent chemotherapy and the occurrence of postoperative pulmonary complications in the treatment of esophageal carcinoma. METHODS: From 117 patients who underwent preoperative chemoradiation for esophageal cancer at our institution between 1998 and 2002, we selected 61 patients for whom complete pulmonary dose-volume histogram (DVH) data were available and analyzed the incidence of pneumonia and acute respiratory distress syndrome (ARDS) in this group. All patients received concurrent chemoradiation therapy, and 39 patients also received induction chemotherapy before concurrent chemoradiation. The median age was 62 years, and the median radiotherapy dose was 45 Gy. The percentage of lung volume receiving at least 10 Gy (V10), 15 Gy (V15), and 20 Gy (V20) were recorded from each pulmonary DVH. RESULTS: Eleven (18%) of the 61 patients had pulmonary complications, 2 of whom died after progression of pneumonia. Pulmonary complications were noted more often (35% vs. 8%, p = 0.014) when the pulmonary V10 was > or =40% vs. <40% and when the V15 was > or /=30% vs. < 30% (33% vs. 10%, p = 0.036). An apparent increase in pulmonary complication rate when V20 was > or =20% vs. <20% (32% vs. 10%, p = 0.079) was not significant. None of the other factors analyzed (surgical procedure, tumor location, use of induction chemotherapy, use of concurrent taxane-based chemoradiation, or smoking history) was associated with the occurrence of pulmonary complications. The median hospital stay was 17 days for patients who had pulmonary complications vs. 12 days for patients who did not (p = 0.08). CONCLUSIONS: The use of multimodality therapy may require minimization of lung volume irradiation to levels lower than previously expected. Radiotherapy techniques that decrease the volume of lung receiving low radiation doses may significantly reduce the risk of this potentially life-threatening complication.     

Clinical study of weekly paclitaxel administration for metastatic breast cancer based on time to progression (TTP) and survival

We studied 13 women aged 29-62 years for response to weekly administration of paclitaxel for metastatic breast cancer. Paclitaxel was administered by 1-hour intravenous infusion at a dose of 60-80 mg/m2 once a week. Administration was continued for 3 weeks with a 1-week rest for at least 3 cycles. This was first-line treatment in 1 patient, second-line treatment in 7, and third-line treatment in 5. The overall response rate was 68% among 13 partial responders and there were no complete responders. By recurrence site, the response rate was 71% in the liver, 75% in the lung, 18% in bone, and 67% at local sites. Pain was ameliorated in 4 of 8 patients and local recurrence of tumors decreased in 6 of 8 cases. Tumor markers decreased in 6 of 12 cases. Time to progression reached beyond 6 months in 6 of 13 cases, and was limited to within only 3 months in 6 cases. In terms of survival, 4 of 13 patients who were treated by paclitaxel as a 3rd line treatment for liver or lung metastasis died within 3 months after administration. Weekly administration of paclitaxel appears to be effective against metastatic breast cancer. However, the selection of cases based on the timing of administration is considered to be important to prolong the time to progression and improve survival.     

Role of cyclooxygenase-2 inhibitors in combination with radiation therapy in lung cancer

Cyclooxygenase-2 (COX-2) is an enzyme involved in prostaglandin production in pathologic states such as inflammatory disorders and cancer. The enzyme is often overexpressed in premalignant lesions and cancer of the lung. Overexpression of COX-2 in lung cancer is associated with more aggressive biological tumor behavior and adverse patient outcome. In preclinical studies, inhibition of this enzyme with selective COX-2 inhibitors enhances tumor response to radiation and chemotherapeutic agents. These findings have been rapidly advanced to clinical oncology. Clinical trials of the combination of selective COX-2 inhibitors with radiation therapy, chemotherapy, or both in patients with lung cancer have been initiated and some preliminary results are available. In this review, we describe the relationship between overexpression of COX-2 and lung cancer, the antitumor effect of selective COX-2 inhibitors, discuss the rationale for using selective COX-2 inhibitors combined with radiation therapy and chemotherapy, and summarize current clinical protocols and initial findings.     

Effectiveness of accelerated radiotherapy for patients with inoperable non-small cell lung cancer (NSCLC) and borderline prognostic factors without distant metastasis: a retrospective review

Purpose: The standard treatment for patients with unresectable or medically inoperable non-small cell lung cancer (NSCLC) and good prognostic factors (e.g., weight loss [WL] ≤5% and Karnofsky performance status [KPS] ≥70) is induction chemotherapy followed by definitive radiotherapy to the primary site at 1.8–2.0 Gy per fraction with a total dose of 60–63 Gy to the target volume. Patients with poor prognostic factors usually receive radiotherapy alone, but the fractionation schedule and total dose have not been standardized. To attempt to optimize irradiation doses and schedule, we compared the effectiveness of accelerated radiotherapy (ACRT) alone to 45 Gy at 3 Gy per fraction with standard radiation therapy (STRT) of 60–66 Gy at 2 Gy per fraction in regard to tumor response, local control, distant metastasis, toxicity, and survival.

Methods and Materials: Fifty-five patients treated with radiation for NSCLC at The University of Texas M. D. Anderson Cancer Center between 1990 and 1994 were identified. All 55 patients had node-positive, and no distant metastasis (N+, M0) of NSCLC. Two cohorts were identified. One cohort (26 patients) had borderline poor prognostic factors (KPS less than 70 but higher than 50, and/or WL of more than 5%) and was treated with radiotherapy alone to 45 Gy over 3 weeks at 3 Gy/fraction (ACRT). The second cohort (29 patients) had significantly better prognostic factors (KPS ≥70 and WL ≤5%) and was treated to 60–66 Gy over 6 to 6 weeks at 2 Gy per fraction (STRT) during the same period.

Results: In the first cohort treated by ACRT, the distribution of patients by AJCC stage was IIB 8%, IIIA 19%, and IIIB 73%. Sixty-two percent had KPS <70, and 76% had a WL of >5%. The maximum response rate as determined by chest X-ray was 60% among 45 of 55 patients who were evaluable for response: combined complete responses (20%) and partial responses (40%). Overall survival in these patients was 13% at 2 and 5 years, with a locoregional control rate of 42% and a freedom from distant metastasis rate of 54%. The ACRT cohort treated with 3 Gy per fraction had significantly lower KPS scores (p = 0.003) and greater WL (p = 0.063) than the cohort STRT treated with 2 Gy per fraction. However, treatment results and toxicity were not significantly different between the two cohorts in spite of significantly better prognostic factors in the STRT cohort.

Conclusions: Despite having worse prognostic factors, the cohort treated with radiotherapy alone to 45 Gy at 3 Gy per fraction over 3 weeks (ACRT) had response rates, locoregional control, and overall survival comparable to those in the cohort treated by a total dose of 60–66 Gy at 2 Gy per fraction over 6 to 6 weeks (STRT). Given that accelerated treatment schedules decrease treatment time and cost less, these may, in the current health care environment, be important factors for health care providers to consider in treating patients who have locally advanced NSCLC and borderline poor prognostic factors.     

Rutaecarpine attenuates osteoclastogenesis by impairing macrophage colony stimulating factor and receptor activator of nuclear factor κ‐B ligand‐stimulated signalling pathways

Rutaecarpine is a major alkaloid isolated from Evodia rutaecarpa. Here, we investigated the effects of rutaecarpine on osteoclast differentiation induced by macrophage colony stimulating factor (M‐CSF) and receptor activator of nuclear factor κ‐B ligand (RANKL) in bone marrow‐derived macrophages (BMMs). Treatment with rutaecarpine significantly inhibited osteoclastogenesis and prevented bone resorption of BMM‐derived osteoclasts. Mechanistically, rutaecarpine decreased the protein level of nuclear factor of activated T cells cytoplasmic‐1 (NFATc1) and the phosphorylation of other signalling pathways during the osteoclast differentiation. Thus, rutaecarpine may be useful as a therapeutic agent for the treatment of bone diseases.     

Review of neurobehavioral effects of alcohol-related neurodevelopmental disorder in an animal model]

Animal models had been investigated to clear the mechanism of neurobehavioral deficits caused by in-utero alcohol exposure. 5-HT1A agonist and antioxidants administration during pregnancy could attenuate in-utero alcohol-induced teratogenesis. Recently, activity-dependent neuroprotective peptides were reported to have the potential therapeutic effect for alcohol-related teratogenicity. Environmental and motor training for litters exposed to in-utero alcohol may have improve behavioral performance. We will review amelioration of fetal alcohol-related neurodevelopmental disorders in animal models from the prevention and treatment.     

The benefit of treatment intensification is age and histology-dependent in patients with locally advanced non-small cell lung cancer (NSCLC): a quality-adjusted survival analysis of radiation therapy oncology group (RTOG) chemoradiation studies

Purpose: Currently, chemoradiation treatment strategies in locally advanced NSCLC are essentially the same irrespective of tumor histology or patient age. The purpose of this study is to analyze the impact of age, histology, Karnofsky performance status (KPS), and specific toxicities on the median survival time (MST) and quality-adjusted survival (QTime) for each treatment strategy.

Methods and Materials: Nine hundred seventy-nine patients with Stage II–IIIB inoperable NSCLC were enrolled on 6 prospective Phase II and III studies from 1983 to 1995. Treatment regimens ranged from standard RT (SRT) to 60 Gy, hyperfractionated RT (HRT) to 69.6 Gy, induction chemotherapy (ICT) of cisplatin (CIS) and vinblastine (VBL) followed by SRT, ICT + concurrent CT (CCT) + SRT, and CCT + HRT; CCT consisted of etoposide or VBL + CIS. Toxicities assessed were skin, mucous membrane, lung, esophagus, neurologic, hematologic, and upper GI. QTime was calculated by weighting the time spent with a specific toxicity, as well as local or distant tumor progression. Each toxicity was weighted with increasing severity as the toxicity increased in grade.

Results: As expected, patients with the worst KPS (50–70) had the lowest MST (7.8 months) and QTime (6.7 months). Patients < 70 years had improved survival with more aggressive therapy (i.e., ICT + SRT or CCT + HRT), while patients > 70 years achieved the best QTime with standard RT (SRT) alone. In patients with squamous cell carcinoma, those treated with ICT + CCT + SRT had dramatically improved MST (25.7 months) and QTime (21.8 months) compared to the other treatment regimens (11.7–12.8 and 10.7–12 months, respectively). Patients with adenocarcinoma, however, generally manifested incrementally better MST and QTime as the therapies intensified. Within the concurrent chemoradiation arms, the upper GI and lung toxicities had the greatest impact on QTime.

Conclusion: This quality-adjusted survival analysis suggests that there is a critical relationship between the type of histology and its optimal treatment, age and the ability to tolerate intensive therapy, and the need to reduce lung and upper GI toxicities.     

Prognostic value of hormone receptor in breast cancer

The relationship of hormone receptor and postoperative prognosis was investigated in 166 patients with breast cancer who underwent curative operation and postoperative adjuvant chemotherapy. The endocrine therapy was performed only for the patients with recurrent disease. The content of estrogen receptor (ER) and progesterone receptor (PgR) were measured by binding assay using gel-filtration method. ER-positive cases accounted for 56% of 166 patients and PgR-positive ones for 36% of 124. The relapse free interval was not different between the ER-positive group and ER-negative one, but the survival curve after relapse was significantly different between the both groups. There was no significant difference in the relapse free interval and the survival curve after relapse between PgR-positive group and PgR-negative one. These results suggest that the ER is a good predictor as to the response to endocrine therapy given for recurrent disease, but not as to early recurrence.