Prognostic significance of serum carcinoembryonic antigen normalization on survival in rectal cancer treated with preoperative chemoradiation.

PURPOSE: The purpose of this retrospective study was to identify factors predictive of survival in rectal cancer patients who received surgery with curative intent after preoperative chemoradiotherapy (CRT). MATERIALS AND METHODS: Between July 1996 and June 2010, 104 patients underwent surgery for rectal cancer after preoperative CRT. The median dose of radiotherapy was 50.4 Gy (range, 43.2 to 54.4 Gy) for 6 weeks. Chemotherapy was a bolus injection of 5-fluorouracil and leucovorin for the first and last week of radiotherapy (n=84, 77.1%) or capecitabine administered daily during radiotherapy (n=17, 16.3%). Low anterior resection (n=86, 82.7%) or abdominoperineal resection (n=18, 17.3%) was performed at a median 47 days from the end of radiotherapy, and four cycles of adjuvant chemotherapy was administered. The serum carcinoembryonic antigen (CEA) level was checked at initial diagnosis and just before surgery. RESULTS: After a median follow-up of 48 months (range, 9 to 174 months), 5-year disease free survival (DFS) was 74.5% and 5-year overall survival (OS) was 86.4%. Down staging of T diagnoses occurred in 32 patients (30.8%) and of N diagnoses in 40 patients (38.5%). The CEA change from initial diagnosis to pre-surgery (high-high vs. high-normal vs. normal-normal) was a statistically significant prognostic factor for DFS (p=0.012), OS (p=0.002), and distant metastasis free survival (p=0.018) in a multivariate analysis. CONCLUSION: Patients who achieve normal CEA level by the time of surgery have a more favorable outcome than those who retain a high CEA level after preoperative CRT. The normalization of CEA levels can provide important information about the prognosis in rectal cancer treatment.

Retrospective analysis of treatment outcomes for extranodal NK/T-cell lymphoma (ENKL), nasal type, stage I-IIE: single institute experience of combined modality treatment for early localized nasal extranodal NK/T-cell lymphoma (ENKL).

Extranodal natural killer/T-cell lymphoma (ENKL) is a very aggressive disease frequently involving the nasal cavity and upper aerodigestive tract. We retrospectively reviewed the treatment outcomes and treatment-associated complications of the patients with stage I-II early localized ENKL. A total of 24 patients were included. All patients were treated with combined chemoradiotherapy. Three, sixteen, and five patients were initially treated with radiation therapy, chemotherapy, and surgical procedures, respectively. Nine patients underwent hematopoietic stem cell transplantation (HSCT), and four patients administered immunotherapy with pegylated-interferon alpha. The mean observation time was 71.6 months (range, 29.7-183.6 months). Twenty patients achieved complete remission; thus, the overall response rate was 83.3 %. The 5-year overall survival (OS) and relapse-free survival (RFS) rates were 70.3 % and 62.2 %, respectively. In univariate analysis, HSCT was a significant prognostic indicator for OS and RFS. By combining HSCT, the 5-year OS and RFS rates were 100.0 % vs. 52.5 % (p = 0.018) and 88.9 % vs. 45.7 % (p = 0.045), respectively. Also, absence of B symptoms was a good prognostic factor for RFS, the 5-year RFS rate, 75.0 % vs. 25.0 % (p = 0.010), and B symptoms were significant for RFS in multivariate analysis (odds ratio = 7.4, confidence interval = 1.6~34.1, p = 0.011). However, a total of four cases of grade 3 toxicities were reported. Radiation dose range (≤4,500 vs. >4,500 cGy) was significantly correlated with late complications, as more severe complications occurred more frequently with a radiation dose >4,500 cGy (p = 0.026, in multivariate analysis). For more efficient treatment of ENKL, chemotherapy, HSCT, and/or immunotherapy can be combined with radiation therapy to prolong long-term survival and achieve good local control. Also, lower radiation dose could be administered to avoid severe late complications.

Prognostic significance of the lymph node ratio regarding recurrence and survival in rectal cancer patients treated with postoperative chemoradiotherapy.

BACKGROUND/AIMS: TO EVALUATE THE PROGNOSTIC IMPACT OF THE LYMPH NODE RATIO (LNR: the ratio of positive lymph nodes to the total number of lymph nodes examined) on disease recurrence and survival among rectal cancer patients who received curative surgery and postoperative chemoradiotherapy (CRT). METHODS: Between 1995 and 2008, 124 patients with pathologic T3-4 or node-positive rectal cancer underwent curative surgery and postoperative CRT. Postoperative radiotherapy was delivered at a median dose of 50.4 Gy (range, 45 to 59.4 Gy) for 6 weeks. Chemotherapy consisted of a bolus injection of 5-fluorouracil and leucovorin in the first and last week of radiotherapy (91.9%) or daily capecitabine during radiotherapy (8.1%). Further adjuvant chemotherapy was administered after chemoradiation. RESULTS: The median follow-up was 5.1 years. In the multivariate analysis, pathologic N (pN) stage and lymphovascular invasion were significantly associated with disease-free survival and disease-specific survival (p<0.05). However, when the LNR with a cutoff value of 0.2 was included as a covariate in the model, the LNR was highly significant (p<0.001), and the pN stage lost its significance (p>0.05). CONCLUSIONS: The LNR predicts recurrence and survival more accurately than pN stage. The pN stage and the LNR should be considered together when estimating the risk of disease recurrence among rectal cancer patients.

Sequential Changes in Aberrant Crypt Foci and Lectin Expression in the Early and Late Stages of DMH-Induced Colon Carcinogenesis in Rats.

BACKGROUND/AIMS: The purpose of this study was to investigate the malignant potential of aberrant crypt foci (ACF) by measuring the multiplicity of crypts and lectin expression in the early and late stages of 1,2-dimethylhydrazine (DMH)-induced colon carcinogenesis. METHODS: Six-week-old Wistar rats were injected subcutaneously with DMH for 27 weeks. We classified ACF according to the number of crypts per ACF as a few crypts (≤3 crypts, FC ACF) or numerous crypts (≥4 crypts, NC ACF). Immunohistochemistry was used to evaluate lectin expression. RESULTS: In the early stage, FC ACF (590/1,902, 31.0%) occurred more frequently than NC ACF (35/449, 7.8%); whereas in the late stage, NC ACF (176/449, 39.2%) occurred more frequently than FC ACF (324/1,902, 17.0%). The number of ACF peaked at 15 to 20 weeks. The ratio of NC/FC ACF increased gradually during carcinogenesis. The expression of both UEA1 and PNA was higher in NC ACF than FC ACF. Lectin expression increased in the late stage compared with the early stage. CONCLUSIONS: The expression of lectin was higher in NC ACF and ACF in the late stage. Therefore, ACF with higher multiplicities in the late stage may have more malignant potential in DMH-induced colon carcinogenesis.

Radiotherapy with or without surgery for patients with idiopathic sclerosing orbital inflammation refractory or intolerant to steroid therapy.

PURPOSE: To evaluate the outcomes of patients with idiopathic sclerosing orbital inflammation (ISOI) treated with radiotherapy with or without surgery. METHODS AND MATERIALS: We retrospectively reviewed 22 patients with histopathologically confirmed ISOI who had been refractory or intolerant to steroid therapy and treated with radiation with or without surgery. The radiation dose ranged from 20 to 40 Gy (median, 20 Gy) at 2 Gy per fraction. Presenting signs and treatment outcomes were assessed. RESULTS: Proptosis was the most common sign at presentation, seen in 19 (86.3%) patients, followed by restriction of extraocular movements in 10 (45.4%) patients. Response to radiotherapy was complete in 15 (68.1%) patients, partial in 3 (13.6%) patients, and none in 4 (18.2%) patients. At the median follow-up of 34 months, 14 (63.6%) patients had progression-free state of symptoms and signs, with the progression-free duration ranging from 3 to 75 months (median, 41.5 months), whereas 8 (36.4%) patients had recurrent or persistent disease although they had received radiotherapy. Of the 14 progression-free patients, 6 underwent a bimodality treatment of debulking surgery of ocular disease and radiotherapy. They had had no recurrent disease. Cataract was the most common late complications, and 2 patients experienced a Grade 3 cataract. CONCLUSION: Our study suggests that for patients with ISOI who are refractory or intolerant to steroid therapy, 20 Gy of radiotherapy appears to be effective for the control of disease with acceptable complications, especially when it is combined with surgery.

Total lymphoid irradiation based conditioning for hematopoietic stem cell transplantation in severe aplastic anemia.

PURPOSE: To retrospectively evaluate the outcome and toxicity of total lymphoid irradiation (TLI) based conditioning regimen for allogeneic hematopoietic stem cell transplantation (HSCT) in severe aplastic anemia (SAA) patients who experienced an engraftment failure from prior HSCT or were heavily transfused. MATERIALS AND METHODS: Between 1995 and 2006, 20 SAA patients received TLI for conditioning of HSCT. All patients were multi-transfused or had long duration of disease. Fifteen (75%) patients had graft failure from prior HSCT. In 18 (90%) patients, the donors were human leukocyte antigen identical siblings. The stem cell source was the peripheral blood stem cell in 15 (75%) patients. The conditioning regimen was composed of antithymocyte globulin plus TLI with a median dose of 750 cGy in 1 fraction. The graft-versus-host disease (GVHD) prophylaxis used cyclosporine with methotrexate. RESULTS: With a median follow-up of 10.8 years, graft failures developed in 6 patients. Among them, 3 patients received their third HSCT to be engrafted finally. The Kaplan-Meier overall survival rate was 85.0% and 83.1% at 5 and 10 years, respectively. The incidence of acute and chronic GVHD was 20% and 20%, respectively. None of the patients have developed a malignancy after HSCT. CONCLUSION: In our study, TLI based conditioning in allogeneic HSCT was feasible with acceptable rates of GVHD in SAA patients who experienced graft failure from prior HSCT or was at a high risk of graft rejection. We achieved relatively better results of engraftment and survival with a long term follow-up.

The effect of metallic implants on radiation therapy in spinal tumor patients with metallic spinal implants.

The aim of this study was to evaluate the effect of metallic implants on the dose calculation for radiation therapy in patients with metallic implants and to find a way to reduce the error of dose calculation. We made a phantom in which titanium implants were inserted into positions similar to the implant positions in spinal posterior/posterolateral fusion. We compared the calculated dose of the treatment planning systems with the measured dose in the treatment equipment. We used 3 kinds of computed tomography (CT) (kilovoltage CT, extended-scaled kilovoltage CT, and megavoltage CT) and 3 kinds of treatment equipment (ARTISTE, TomoTherapy Hi-Art, and Cyberknife). For measurement of doses, we used an ionization chamber and Gafchromic external beam therapy film. The absolute doses that were measured using an ionization chamber at the isocenter in the titanium phantom were on average 1.9% lower than those in the reference phantom (p = 0.002). There was no statistically significant difference according to the kinds of CT images, the treatment equipment, and the size of the targets. As the distance from the surface of the titanium implants became closer, the measured doses tended to decrease (p < 0.001), and this showed a statistically significant difference among the kinds of CT images: the effect of metallic implants was less in the megavoltage CT than in the kilovoltage CT or the extended-scaled kilovoltage CT. The error caused by the titanium implants was beyond a clinically acceptable range. To reduce the error of dose calculation, we suggest that the megavoltage CT be used for planning. In addition, it is necessary to consider the distance between the titanium implants and the targets or the organs at risk to prescribe the dose for the target and the dose constraint for the organs at risk.

The prognostic significance of the lymph node ratio in axillary lymph node positive breast cancer.

PURPOSE: This study evaluated the prognostic impact of the lymph node ratio (LNR; i.e., the ratio of positive to dissected lymph nodes) on recurrence and survival in breast cancer patients with positive axillary lymph nodes (LNs). METHODS: The study cohort was comprised of 330 breast cancer patients with positive axillary nodes who received postoperative radiotherapy between 1987 and 2004. Ten-year Kaplan-Meier locoregional failure, distant metastasis, disease-free survival (DFS) and disease-specific survival (DSS) rates were compared using Kaplan-Meier curves. The prognostic significance of the LNR was evaluated by multivariate analysis. RESULTS: Median follow-up was 7.5 years. By minimum p-value approach, 0.25 and 0.55 were the cutoff values of LNR at which most significant difference in DFS and DSS was observed. The DFS and DSS rates correlated significantly with tumor size, pN classification, LNR, histologic grade, lymphovascular invasion, the status of estrogen receptor and progesterone receptor. The LNR based classification yielded a statistically larger separation of the DFS curves than pN classification. In multivariate analysis, histologic grade and pN classification were significant prognostic factors for DFS and DSS. However, when the LNR was included as a covariate in the model, the LNR was highly significant (p<0.0001), and pN classification was not statistically significant (p>0.05). CONCLUSION: The LNR predicts recurrence and survival more accurately than pN classification in our study. The pN classification and LNR should be considered together in risk estimates for axillary LNs positive breast cancer patients.

Stereotactic body radiotherapy for patients with unresectable primary hepatocellular carcinoma: dose-volumetric parameters predicting the hepatic complication.

PURPOSE: To identify the parameters that predict hepatic toxicity and deterioration of hepatic function. MATERIALS AND METHODS: A total of 47 patients with small unresectable primary hepatocellular carcinoma received hypofractionated stereotactic body radiotherapy (SBRT) using the CyberKnife. Of those, 36 patients received no other local treatments that could influence hepatic toxicity at least for 3 months after the completion of SBRT. The gross tumor volume (GTV) was 18.3 ± 15.9 cm(3) (range, 3.0-81.3 cm(3)), and the total dose administered was 30-39 Gy (median, 36 Gy). To assess the deterioration of hepatic function, we evaluated the presence or absence of the progression of Child-Pugh class (CP class). To identify the parameters of predicting the radiation-induced hepatic toxicity and deterioration of the hepatic function, several clinical and dose-volumetric parameters were evaluated. RESULTS: Of 36 patients, 12 (33%) developed Grade 2 or higher hepatic toxicity and 4 (11%) developed progression of CP class. The multivariate analysis showed that the only significant parameter associated with the progression of CP class was the total liver volume receiving a dose less than 18 Gy (<18 Gy). CONCLUSIONS: The progression of CP class after SBRT limits other additional local treatments and also reflects the deterioration of hepatic function. Therefore, it would be important to note that the presence or absence of the progression of CP class is a dose-limiting factor. The total liver volume receiving <18 Gy should be greater than 800 cm(3) to reduce the risk of the deterioration of hepatic function.

Image-guided robotic radiosurgery for spinal metastases.

BACKGROUND AND PURPOSE: To determine the effectiveness and safety of image-guided robotic radiosurgery for spinal metastases. MATERIALS/METHODS: From 1996 to 2005, 74 patients with 102 spinal metastases were treated using the CyberKnife at Stanford University. Sixty-two (84%) patients were symptomatic. Seventy-four percent (50/68) of previously treated patients had prior radiation. Using the CyberKnife, 16-25 Gy in 1-5 fractions was delivered. Patients were followed clinically and radiographically for at least 3 months or until death. RESULTS: With mean follow-up of 9 months (range 0-33 months), 36 patients were alive and 38 were dead at last follow-up. No death was treatment related. Eighty-four (84%) percent of symptomatic patients experienced improvement or resolution of symptoms after treatment. Three patients developed treatment-related spinal injury. Analysis of dose-volume parameters and clinical parameters failed to identify predictors of spinal cord injury. CONCLUSIONS: Robotic radiosurgery is effective and generally safe for spinal metastases even in previously irradiated patients.

CyberKnife radiosurgery for benign intradural extramedullary spinal tumors.

OBJECTIVE: Microsurgical resection of benign intradural extramedullary spinal tumors is generally safe and successful, but patients with neurofibromatosis, recurrent tumors, multiple lesions, or medical problems that place them at higher surgical risk may benefit from alternatives to surgery. In this prospective study, we analyzed our preliminary experience with image-guided radiosurgical ablation of selected benign spinal neoplasms. METHODS: Since 1999, CyberKnife (Accuray, Inc., Sunnyvale, CA) radiosurgery was used to manage 51 patients (median age, 46 yr; range, 12-86 yr) with 55 benign spinal tumors (30 schwannomas, nine neurofibromas, 16 meningiomas) at Stanford University Medical Center. Total treatment doses ranged from 1600 to 3000 cGy delivered in consecutive daily sessions (1-5) to tumor volumes that varied from 0.136 to 24.6 cm. RESULTS: Less than 1 year postradiosurgery, three of the 51 patients in this series (one meningioma, one schwannoma, and one neurofibroma) required surgical resection of their tumor because of persistent or worsening symptoms; only one of these lesions was larger radiographically. However, 28 of the 51 patients now have greater than 24 months clinical and radiographic follow-up. After a mean follow-up of 36 months, all of these later lesions were either stable (61%) or smaller (39%). Two patients died from unrelated causes. Radiation-induced myelopathy appeared 8 months postradiosurgery in one patient. CONCLUSION: Although more patients studied over an even longer follow-up period are needed to determine the long-term efficacy of spinal radiosurgery for benign extra-axial neoplasms, short-term clinical benefits were observed in this prospective analysis. The present study demonstrates that CyberKnife radiosurgical ablation of such tumors is technically feasible and associated with low morbidity.

Combined effect of heptaplatin and ionizing radiation on human squamous carcinoma cell lines.

Heptaplatin, cis-malonato [(4R,5R)-4,5-bis (amino-methyl)-2-isopropyl-1,3-dioxolane] platinum(II) (SKI-2053R, Sunpla) is a new platinum derivative with anti-tumor activity comparable to cisplatin on various cancer cell lines. Preclinical studies suggest that it is less nephrotoxic than cisplatin. This study was undertaken to examine the combined effect of heptaplatin and ionizing radiation on two established human squamous carcinoma cell lines (NCI-H520, SQ20B). The cytotoxic activity of heptaplatin was concentration-dependent in both cell lines. When low dose heptaplatin was combined with high dose ionizing radiation, there was an additive cytotoxic effect on NCI-H520 cells (P < 0.05), while a moderate dose of heptaplatin and a low dose of ionizing radiation had an additive cytotoxic effect on the growth of SQ20B cells (P < 0.05). FACS analysis and DAPI staining showed that their additive cytotoxic effects were correlated with the induction of apoptosis. Further studies are warranted using heptaplatin and ionizing radiation in squamous cell carcinoma as a substitute for cisplatin.

Clinical experience of patients with ductal carcinoma in situ of the breast treated with breast-conserving surgery plus radiotherapy: a preliminary report.

PURPOSE: Breast-conserving therapy (BCT) is a practical alternative to mastectomy for treating ductal carcinoma in situ (DCIS). We reviewed our experience for treating patients with DCIS of the breast to evaluate the outcome after performing breast-conserving surgery plus radiotherapy (BCS-RT). MATERIALS AND METHODS: Between January 1983 and December 2002, 25 patients with clinically or mammographically detected DCIS were treated by BCS-RT. One patient was diagnosed with bilateral DCIS. Thirteen cases (50%) had symptomatic lesions at presentation. All 26 cases of 25 patients underwent BCS such as lumpectomy, partial mastectomy or quadrantectomy. All of them received whole breast irradiation to a median dose of 50.4 Gy. Twenty-four cases (92.3%) received a boost to the tumor bed for a median total dose of 59.4 Gy. The median follow up period was 67 months (range: 38 to 149 months). RESULTS: Two cases (7.7%) experienced ipsilateral breast tumor recurrence (IBTR) after BCS-RT. The histology results at the time of IBTR showed invasive ductal carcinoma (IDC), and the median time to IBTR was 25.5 months. On the univariate analysis, there were no significant factors associated with IBTR in the DCIS patients. The three-year local recurrence free survival rate was 96.0% and the overall survival rate was 96.3%. CONCLUSION: After the treatment for DCIS, the IBTR rate in our study was similar to other previous studies. Considering that we included patients who had many symptomatic lesions, close or positive margins and less that complete early data, our result is comparable to the previous studies. We could not find the prognostic significant factors associated with IBTR after BCS-RT. A longer follow up period with more patients would be required to evaluate the role of any predictive factors and to confirm these short-term results.

The role of radiation therapy for the extramammary paget's disease of the vulva ; experience of 3 cases.

We have experienced three cases of extramammary Paget's disease (EMPD) of the vulva that received radiation therapy (RT). Here, we analyze the efficacy of RT and include a literature survey.Three patients with EMPD of the vulva were treated with curative RT between 1993 and 1998. One of the patients had associated underlying adenocarcinoma of the vulva. The total doses of radiation administered were 54~78 Gy/6~8 weeks. Radiation fields encompassed 2 to 3 cm outer margins free from all visible disease including or not including the inguinal area using a 9 MeV electron or a 6 MV photon beam. Follow-up durations after radiotherapy were 0.6~11 years. Complete response was obtained in all three patients. Marginal failure occurred in one patient, and another patient with underlying adenocarcinoma treated by vulvectomy with bilateral inguinal lymph node dissection followed by external RT showed no relapse. Radiation induced side effects were transient acute confluent wet desquamation in the treated area resulting in mild late atrophic skin changes.Although surgery is currently considered the preferred primary treatment for EMPD, it has a high relapse rate due to the multifocal nature of the disease. We conclude that RT is of benefit in some selected cases of EMPD.