T1-2N1M0期乳腺癌新辅助化疗后疗效分析及放疗选择的探讨

目的 评价T_1-2N₁M₀期乳腺癌新辅助化疗后辅助放疗对LC率的影响及地位。方法收集2005—2010年间收治的新辅助化疗患者资料,筛选出T_1-2N₁M₀人群,并对其辅助放疗的临床结果进行分析。共入组T_1-2N₁M₀患者144例,中位年龄45岁(23~72岁)。结果 术后30例(21%)获得乳腺原发灶和腋窝淋巴结pCR者均接受了辅助放疗,45例仅腋窝淋巴结阳性转阴性者中10例未接受辅助放疗,69例腋窝淋巴结转移仍为阳性者中6例未接受放疗,其余患者均接受了辅助放疗。全组中位随访时间88个月,46例复发转移(32%),其中pCR者5年LR率为3.0%。5年LR率新辅助化疗后腋窝淋巴结阳性转阴性者放疗组为7%、未放疗组为16%(P=0.181),腋窝淋巴结仍为阳性者放疗组为15.9%、未放疗组为33%(P=0.267)。全组pCR者DFS时间较非pCR者延长(P=0.017)。结论 新辅助化疗后获pCR者DFS期优于未获pCR者,获pCR患接受辅助放疗的LR率较低,腋窝淋巴结阳性转阴性者未能从术后辅助放疗中获益,而腋窝淋巴结转移仍为阳性者的LR率高,辅助放疗有获益趋势。     

Predictors of local recurrence after conservative surgery and whole-breast irradiation

Purpose To identify independent factors associated with increased risk of local recurrence (LR) in patients with breast cancer treated with conservative surgery and radiotherapy with or without systemic therapy.Methods and materials Between January 1997 and December 2001, 969 women were treated at the Radiation Oncology Department in Chieti. We retrospectively analyzed 802 of them who were treated with conservative surgery and whole breast irradiation with or without systemic therapy. Tangential fields delivering 50 Gy to the whole breast were used and a boost was added for a total dose of 60 Gy. χ²-test or Fisher’s exact test were used to identify independent significant factors that are predictive for LR. Kaplan–Meier method was used to calculate the 8-year rates of recurrence according to age, histologic findings, tumor size, number of positive nodes, margin status, receptor status and systemic therapy use: log-rank test was used to compare these curves. Cox proportional hazard model was used to obtain hazard ratios and 95% CI of LR for each covariate.Results Median follow-up time was 63.1 months. LR occurred in 33 (4.1%) of 802 patients. Percentage of LR was greater in <50 year-olds compared with 50–64 year-olds and ≥65 year-olds (9.8% versus 4.1 and 2.0%, respectively). LR was 18.8% in women with a tumor size >3 cm versus 3.5, 4.0, 5.5% in women with a tumor size of 0.1–1, 1.1–2, 2.1–3 cm, respectively. The 8-year LR rate calculated with Kaplan–Meier method was 6.54±1.51. Multivariate Cox regression analysis showed that independent significant factors that are predictive for LR were: age <50, tumor size >3 cm, positive margin or unknown status, and hormonal therapy alone versus chemotherapy or combined therapy.Conclusions Age and tumor size were the most important and statistically significant factors that correlated independently with higher rates of LR. Women <50 years old and with a tumor size >3 cm had a higher risk of LR. Also margin status and systemic therapy could influence LR risk.     

Results of postoperative radiotherapy in the treatment of 29 uterine sarcoma patients

AIMS AND BACKGROUND: The objective of this study was to evaluate the results of surgery combined with postoperative radiotherapy (RT) in patients with uterine sarcoma in order to describe the patterns of relapse and to define prognostic factors. METHODS: We report on 29 patients with uterine sarcoma (US) treated from 1980 to 1995; 18 patients with primary tumors were treated with surgery and adjuvant irradiation, while 11 patients with local recurrences (LR) after previous surgical resection received only radiotherapy. We evaluated the influence of stage, histology, grade, menopausal status, total radiation dose and brachytherapy on survival. Histological diagnosis was leiomyosarcoma in 13 patients (44.8%), endometrial stromal sarcoma in 10 patients (34.5%), and mixed mesodermal tumors in six patients (20.7%). Fifteen patients presented with stage I-II disease, three with stage III, and 11 with local recurrences. External pelvic RT was administered to all patients, in five patients combined with brachytherapy.The mean total dose was 54 Gy (SE 1.78). Univariate and multivariate analyses were carried out. RESULTS: Overall survival (OS) for the stage I-III group was 61.1% at two years and 33.3% at five years (median 29 months, SE 13.79). Disease-free survival (DFS) was 55.6% at two years and 33.3% at five years. Median DFS was 26 months (SE 14.85). In LR cases, median OS was only 10 months (SE 4.5). Multivariate analysis demonstrated that stage was the only prognostic factor after RT for US. CONCLUSIONS: These data suggest that postoperative and/or salvage RT has a questionable impact on disease-free and over-all survival because of the lack of homogeneity of stages in the series reported in the literature; it has, however, acceptable late side effects. Prospective multicenter trials including a statistically evaluable number of patients are necessary to further clarify the role of RT treatment programs for US.     

Impact of the mode of detection on outcome in breast cancer patients treated with breast-conserving therapy.

The impact of the mode of detection on outcome in patients with early stage breast cancer treated with breast-conserving therapy (BCT) was reviewed. Between January 1980 and December 1987, 400 cases of stage I and II breast cancer were treated with BCT. All patients underwent an excisional biopsy, external beam irradiation (RT) to the whole breast (45-50 Gy), and a boost to 60 Gy to the tumor bed. One hundred twenty-four cases (31%) were mammographically detected, whereas 276 (69%) were clinically detected. Median follow-up was 9.2 years. Patients whose cancers were detected by mammography more frequently had smaller tumors (90% T1 vs. 62%, p < 0.0001), lower overall disease stage (78% stage I vs. 47%, p < 0.0001), were older at diagnosis (78% >50 years vs. 54%, p < 0.001), less frequently received chemotherapy (8% vs. 21%, p = 0.001), and had an improved disease-free survival (DFS) (80% vs. 70%, p = 0.014), overall survival (OS) (82% vs. 70%, p = 0.005), and cause-specific survival (CSS) (88% vs. 77%, p = 0.003) at 10 years. However, controlling for tumor size, nodal status, and age, no statistically significant differences in the 5- and 10-year actuarial rates of local recurrence (LR), DFS, CSS, or OS were seen based on the mode of detection. Initial mode of detection was the strongest predictor of outcome after a LR. The 3-year DFS rate after LR was significantly better in initially mammographically detected versus clinically detected cases (100% vs. 61%, p = 0.011). Patients with mammographically detected breast cancer generally have smaller tumors and lower overall disease stage at presentation. However, the mode of detection does not independently appear to affect the success of BCT in these patients.     

放疗对改良根治术后T1～T2期伴1～3个腋窝淋巴结转移乳腺癌不同分子亚型患者预后影响

目的 探讨放疗对不同分子亚型的改良根治术后T1～T2期伴1～3个腋窝淋巴结转移乳腺癌患者的预后影响。方法 将2001-2004年本院行改良根治术的436例乳腺癌患者资料按Luminal A、Luminal B、Her2+、三阴型分子亚型分为4个组,分析各组放疗与未放疗5年局部复发(LR)率、远处转移(DM)率、无瘤生存(DFS)率和总生存(0S)率差别和影响局部复发因素。结果 随访率为86.0％;Luminal A型中放疗的5年LR率低于未放疗的(4.6％:15.8％,x2=5.74,P=0.017),DM、DFS、OS的均相似(17.2％:19.7％,x2=0.17,P=0.682;77.0％:67.1％,x2=1.99,P=0.158;87.4％:85.5％,x2=0.12,P=0.733)。Luminal B型中放疗的5年LR率低于未放疗的(3.7％:12.1％,x2 =4.13,P=0.042),DFS和OS放疗的高于未放疗的[84.0％:57.6％(x2=14.61,P=0.000)和91.4％:70.7％ (x2=11.87,P=0.001)],DM的相似(12.3％:22.2％,x2=2.97,P=0.085)。Her2+型中放疗的5年LR率低于未放疗的(5.6％:31.0％,x2 =4.31,P=0.035),DFS放疗的高于未放疗的(61.1％:13.8％,x2=11.44,P=0.001),DM和OS均相似(27.8％:41.4％,x2=0.89,P=0.345和66.7％:48.3％,x2=1.52,P=0.218)。三阴型中LR、DM、DFS、OS的均相似(8.7％:26.1％,x2=2.42,P =0.120;39.1％:47.8％,x2 =0.35,P =0.552;52.2％:26.1％,x2=3.29,P =0.070;65.2％:56.5％,x2=0.37,P=0.546)。多因素分析显示肿瘤大小和放疗为影响局部复发的独立因素(x2 =4.76,P=0.029和x2 =8.06,P=0.005)。结论 改良根治术后T1～T2期伴1～3个腋窝淋巴结转移乳腺癌患者中Luminal A、Luminal B、Her2+型均可从放疗中不同程度获益,而三阴型未显示获益。     

Radiation-induced morphological changes and radiocurability in squamous cell carcinoma of the head and neck region. A preliminary report.

Tissue samples taken from 22 patients before and during radical irradiation of squamous cell carcinomas in the head and neck region were studied by light and electron microscopy. The changes in keratinization pattern at the ultrastructural level seemed to be correlated with the outcome of the radiotherapy. The irradiation induced several cellular changes, of which nuclear atypia was the most prominent. This atypia was considered to be mainly due to cell death rather than to an aggressive nature of the tumor, because the number of mitoses decreased at the same time. The tumor invasion pattern remained unchanged. The keratinization pattern remained almost unchanged at the light microscopical level, but a slight increase of intracellular filaments and desmosomes was found in the electron microscopic study. The amount of intercellular filaments increased in three patients out of four with complete remission (CR), but in no case with tumor dissemination (n = 3) during radiotherapy. In patients with local persistent tumor or a local recurrence (LP + LR) (n = 15) the filaments either increased, decreased or remained unchanged. The number of desmosomes either increased or remained unchanged in three of four CR patients, in 13 of 15 LP + LR patients and in only one of three patients with tumor dissemination. They decreased in two patients with tumor dissemination, but only in one case with CR and in 2 cases with LP + LR. It is suggested that changes in cytoskeleton and desmosomes might be important in anchorage of tumor cells locally and might have value for prediction of the tumor response to radiotherapy. Further studies on larger materials are, however, needed before more definite conclusions can be drawn.     

Carcinoma of the vulva: clinical results of exclusive and adjuvant radiotherapy

BACKGROUND: The aim of this study was to evaluate the historical cohort of 61 patients with carcinoma of the vulva, treated with radiation therapy from 1986 to 1997. PATIENTS AND METHODS: Twenty-seven patients were submitted to radiation therapy alone and 34 received radiotherapy post limited surgery in early stages and post radical vulvectomy in advanced stages. The dose range varied from 59 to 63 Gy in post-operative patients and 65 Gy to 71 Gy in curative patients. RESULTS: Five-year Overall Survival (OS) and Disease-Free Survival (DFS) for patients treated with irradiation alone and for those treated with post-operative radiotherapy were 50.8% and 69.7%, respectively, without significant statistical difference. For OS multivariate analysis showed statistical difference for stage and age variables, and for stage variable in the case of DFS. CONCLUSION: In early stage vulvar cancer patients OS and DFS are good, with high control rate and low incidence of adverse effect. In loco-regionally-advanced patients, especially in those with stage IV or with > 2 positive lymph nodes, the outcomes are poor.     

Malignant meningioma: An indication for initial aggressive surgery and adjuvant radiotherapy

Malignant meningiomas constitute a rare subset of meningiomas and display a marked propensity for post-surgical recurrence. This retrospective study evaluates the various parameters which alter the recurrence rate. The records of all malignant meningioma patients treated from 1984 through 1992 were reviewed, and the time to recurrence or current patient status was determined, and the influence of various patient and disease parameters were analyzed. Thirty-eight patients were treated with 48 malignant meningioma resections performed (28 total and 20 subtotal), 25 at initial presentation and 23 for recurrent disease; 19 patients received postoperative radiotherapy. Subtypes included 32 anaplastic meningioma, 11 hemangiopericytoma, 2 meningiosarcoma, and 3 papillary meningioma. Followup ranged from 3 to 144 months, with five patients excluded from analysis. Actuarial disease free/progression free survival (DFS) at 5 years was 39% following total resection versus 0% after subtotal resection (p=0.001). For all totally excised lesions, the 5-yr DFS was improved from 28% for surgery alone to 57% with adjuvant radiotherapy (p=NS). Adjuvant irradiation following initial resection increased the 5-yr DFS rates from 15% to 80% (p=0.002). When administered for recurrent lesions, adjuvant radiotherapy improved the 2-yr DFS from 50% to 89% (p=0.015), but had no impact on 5-yr DFS. Multivariate analysis indicates extent of resection, adjuvant radiotherapy, and recurrence status are independent prognostic factors. Malignant meningiomas display a tendency for post surgical recurrence, with recurrence significantly increased for multicentric and recurrent disease. Complete surgical resection and the administration of adjuvant irradiation following initial resection are crucial to long-term control.     

Twelve-year clinical outcomes and patterns of failure with accelerated partial breast irradiation versus whole-breast irradiation: Results of a matched-pair analysis

Background and Purpose

To compare 12-year outcomes of accelerated partial breast irradiation (APBI) versus whole-breast irradiation (WBI) in patients treated with breast conservation.

Materials and Methods

A matched-pair analysis was performed using 199 patients receiving WBI and 199 patients receiving interstitial APBI. Match criteria included tumor size, age, nodal status, ER status, and the use of adjuvant hormonal therapy. Patterns of failure and efficacy of salvage treatments were examined.

Results

No differences were seen in the 12-year rates of local recurrence (3.8% vs. 5.0%, p = 0.40), regional recurrence (0% vs. 1.1%, p = 0.15), disease free survival (DFS) (87% vs. 91%, p = 0.30), cause-specific survival (CSS) (93% vs. 95%, p = 0.28), or overall survival (OS) (78% vs. 71%, p = 0.06) between the WBI and APBI groups, respectively. The rate of distant metastases was lower in the APBI group (10.1% vs. 4.5%, p = .05). Following LR, no difference in outcome was seen between the two groups with 5 year post-LR rates of DFS (80% vs. 86%, p = 0.55), CSS (88% vs. 75%, p = 0.77), and OS (88% vs. 75%, p = 0.77), respectively.

Conclusions

With 12-year follow-up, APBI produced outcomes equivalent to WBI. Following LR, patients treated with APBI also had similar failure patterns to those managed with WBI.     

Radiotherapy for stage 2 testicular seminoma: the prognostic influence of tumor bulk

Forty-nine consecutive patients with stage 2 testicular seminoma were treated with primary radiotherapy from 1968 to 1985. Overall diseases-free survival (DFS) for patients with 36 months minimum follow-up was 82% at 3 years. This figure did not decline further with time. Infradiaphragmatic bulk disease was found to be a significant prognostic factor for local and distant relapse as well as for ultimate survival. Patients with either stage 2A or 2B disease (infradiaphragmatic bulk less than or equal to 10 cm size) had a 3-year DFS of 89% compared with a 64% 3-year DFS rate for patients with stage 2C disease (infradiaphragmatic bulk greater than or equal to 10 cm size). The (local plus distant) relapse rate was 4.0% for patients with stage 2A disease, 16.7% for patients with stage 2B disease, and 33.3% for patients with stage 2C disease. The majority of distant relapses were multifocal and prophylactic mediastinal irradiation did not appear to influence either relapse rate nor overall survival. Of seven patients who relapsed, four died of progressive malignancy, two deaths were related to salvage chemotherapy, and only one patient is alive and well following successful chemotherapeutic salvage. On the basis of our experience, we recommend radiotherapy with the use of modern imaging techniques as initial treatment for patients with retroperitoneal masses less than 10 cm size. Aggressive cisplatin-based chemotherapy should be seriously considered for patients with retroperitoneal masses greater than or equal to 10 cm size, or for patients who relapse following radiotherapy.     

乳腺癌保乳术后放化疗５２例临床观察

目的　观察乳腺癌保乳术后放射治疗的疗效及毒副反应。方法　对可行保乳术的５２例患者行肿瘤切除或加腋窝淋巴结清扫,术后采用放疗联合辅助化疗。６ＭＶ-Ｘ线全乳腺双切线半野照射,照射剂量４５～５０Ｇｙ,局部瘤床采用１０～１５ＭｅＶβ线加量１０～２０Ｇｙ,总剂量５６～６６Ｇｙ;化疗采用ＣＡＦ或ＴＥ方案。结果　５２例患者均获随访,其１、２和３年生存率分别为９８.１％、９２.３％和９０.４％,３年局部复发率为５.７7％,乳房美容满意率达９０.４％。４０例（７６.９％）患者发生了１、２级放化疗毒副反应,主要为白细胞减少。结论　早期乳腺癌采用保乳手术加放化疗可取得满意疗效,且保留乳房的美容效果佳。     

Radiation therapy after high-dose chemotherapy with peripheral blood stem cell support for high-risk breast cancer

Multidisciplinary treatment in high-risk breast cancer improves survival and local control. The feasibility and patterns of failure after several induction and high-dose consolidation regimens of chemotherapy were evaluated in this study. Between November 1990 and January 1997, 65 patients with histologically proven breast cancer American Joint Committee on Cancer stages II-III with four or more axillary lymph nodes positive or locally advanced breast cancer underwent high-dose chemotherapy (HDC) with peripheral stem cell support after surgery and induction chemotherapy. All patients were subsequently treated with radiotherapy (up to total doses of 50-60 Gy), which included the ipsilateral axilla and supraclavicular fossa and the chest wall or breast. A minimum follow-up period of 2 years from the completion of radiotherapy was required for analysis. Local control (LC), disease-free survival (DFS), overall survival (OS), and toxicity were evaluated. With a median follow-up of 62 months (range: 32-107 months), LC was 89%, and 5-year OS and DFS were 78% and 63%, respectively. Symptomatic pneumonitis developed in six patients (9%); only one patient had her radiotherapy interrupted because of hematologic toxicity. No treatment-related mortality was observed. Radiation therapy after HDC provides excellent local control rates without excessive toxicity. Delaying the start of irradiation until recovery from HDC does not seem to increase local failure rates.     

Partial breast irradiation as second conservative treatment for local breast cancer recurrence

PURPOSE: Mastectomy is the treatment of reference for local relapse after breast cancer (BC). The aim of this study was to document the feasibility and the results of associating lumpectomy with partial breast irradiation by interstitial brachytherapy (IB) as local treatment for an isolated ipsilateral BC local recurrence (LR). METHODS AND MATERIALS: Between 1975 and 1996 at Marseille and Nice Cancer Institutes, 4026 patients received lumpectomy and radiotherapy (RT) (50-80 Gy) for a localized breast cancer of which 473 presented a LR. Among these patients, 69 (14.6%) received a second lumpectomy followed by IB, which delivered 30 Gy (Nice, n = 24) or 45-50 Gy (Marseille, n = 45) with 3 to 8 (192)Ir wires in 1 or 2 planes on the 85% isodose. RESULTS: Median age at LR was 58.2 years, median follow-up since primary BC was 10 years, and median follow-up after the second conservative treatment was 50.2 months (range, 2-139 months). Immediate tolerance was good in all cases. Grade 2 to 3 long-term complications (LTC) according to IB dose were 0%, 28%, and 32%, respectively, for 30 Gy, 45 to 46 Gy, and 50 Gy (p = 0.01). Grade 2 to 3 LTC according to total dose were 4% and 30%, respectively, for total doses (initial RT plus IB) < or = 100 Gy or >100 Gy (p = 0.008). Logistic regression showed that the only factor associated with Grade 2 to 3 complications was higher IB doses (p = 0.01). We noted 11 second LRs (LR2), 10 distant metastases (DM), and 5 specific deaths. LR2 occurred either in the tumor bed (50.8%) or close to the tumor bed (34.3%) or in another quadrant (14.9%). Kaplan-Meier 5-year freedom from (FF) LR2 (FFLR2), FFDM, and DFS were 77.4%, 86.7%, and 68.9%, respectively. Overall 5-year survival (OS) was 91.8%. Univariate analysis showed the following factors associated with a higher FFLR2: (1) number of wires used for IB (3-4 vs. 5-8 wires, p = 0.006), (2) IB doses (30-45 Gy vs. 46-60 Gy, p = 0.05), (3) number of planes (1 vs. 2, p = 0.05), (4) interval between primary breast cancer and LR (< 36 months vs. > or =36 months, p = 0.06). Multivariate analysis showed two factors associated with better local control: (1) number of wires (5-8 wires, p = 0.013) and (2) interval between primary breast cancer and LR > or =36 months (p = 0.039). The multivariate analysis showed two factors associated with better FFDM: (1) absence of initial axilla involvement (p = 0.019) and (2) relapse in a different location (p = 0.04). These two factors were also associated with a higher OS. CONCLUSION: Our experience showed that second conservative treatments for local relapse were feasible and gave results comparable to standard mastectomy. We recommend delivering IB doses of at least 46 Gy in 2 planes when initial radiotherapy delivered 50 Gy. The study gives enough information to encourage a Phase III trial that compares radical mastectomy to conservative procedures for localized breast cancer recurrences.     

Varying recurrence rates and risk factors associated with different definitions of local recurrence in patients with surgically resected,stage I nonsmall cell lung cancer

BACKGROUND:

The objective of this study was to examine the effects of different definitions of local recurrence on the reported patterns of failure and associated risk factors in patients who undergo potentially curative resection for stage I nonsmall cell lung cancer (NSCLC).

METHODS:

The study included 306 consecutive patients who were treated from 2000 to 2005 without radiotherapy. Local recurrence was defined either as “radiation” (r‐LR) (according to previously defined postoperative radiotherapy fields), including the bronchial stump, staple line, ipsilateral hilum, and ipsilateral mediastinum; or as “comprehensive” (c‐LR), including the same sites plus the ipsilateral lung and contralateral mediastinal and hilar lymph nodes. All recurrences that were not classified as “local” were considered to be distal.

RESULTS:

The median follow‐up was 33 months. The proportions of c‐LR and r‐LR at 2 years, 3 years, and 5 years were 14%, 21%, and 29%, respectively, and 7%, 12%, and 16%, respectively. Significant risk factors for c‐LR on multivariate analysis were diabetes, lymphatic vascular invasion, and tumor size; and significant factors for r‐LR were resection of less than a lobe and lymphatic vascular invasion. The proportions of distant (nonlocal) recurrence using these definitions at 2 years, 3 years, and 5 years were 10%, 12%, and 18%, respectively, and 14%, 19%, and 29%, respectively. Significant risk factors for distant failure were histology when using the c‐LR definition and tumor size when using the r‐LR definition.

CONCLUSIONS:

Local recurrence increased nearly 2‐fold when a broad definition was used instead of a narrow definition. The definition also affected which factors were associated significantly with both local and distant failure on multivariate analysis. Comparable definitions must be used when analyzing different series. Cancer 2010. © 2010 American Cancer Society.     

Stereotactic single-dose radiotherapy (radiosurgery) of early stage nonsmall-cell lung cancer (NSCLC)

BACKGROUND: The clinical results after stereotactic single-dose radiotherapy of nonsmall-cell lung cancer (NSCLC) stages I and II were evaluated. METHODS: Forty-two patients with biopsy-proven NSCLC received stereotactic radiotherapy. Patients were treated in a stereotactic body frame and breathing motion was reduced by abdominal compression. The single doses used ranged between 19 and 30 Gy/isocenter. RESULTS: After a median follow-up period of 15 months (range, 1.5-72 months) the actuarial overall survival rates and disease-free survival rates were 74.5%, 65.4%, 37.4%, and 70.2%, 49.1%, 49.1% at 12, 24, and 36 months after therapy, respectively. The actuarial local tumor control rates were 89.5%, 67.9%, and 67.9% at 12, 24, and 36 months after therapy, respectively. A significant difference (P = .032) in local tumor control was found for patients receiving 26-30 Gy (n = 32) compared with doses of less than 26 Gy (n = 10). The effect of the tumor volume on local tumor control was also evaluated. Although the difference was not statistically significant (P = .078), the subgroup of tumors with a tumor volume of less than 12 cm(3) (n = 10) experienced no tumor recurrence. Thirteen (31%) patients developed metastases during follow-up, whereas isolated regional lymph node recurrence was only encountered in 2 patients. No clinically significant treatment-associated side effects were documented. CONCLUSIONS: Stereotactic single-dose radiotherapy is a safe and effective treatment option for patients with early stage NSCLC not suitable for surgery. Especially for small tumor volumes it seems to be equally effective as hypofractionated radiotherapy, while minimizing the overall treatment time.     

Long-term outcomes after function-sparing surgery without radiotherapy for soft tissue sarcoma of the extremities and trunk.

PURPOSE: To define the rate of local recurrence (LR) and identify prognostic factors for LR for patients with soft tissue sarcoma (STS) treated with function-sparing surgery (FSS) without radiotherapy (RT). PATIENTS AND METHODS: Between 1970 and 1994, 242 patients with STS of the trunk and extremity presented with primary localized disease, 74 of whom were treated with FSS without RT (31%). The median tumor size was 4 cm (range, 0.5 to 31 cm). There were 40 patients with grade 1 tumors and 34 with grade 2 and 3 tumors. Median follow-up was 126 months. RESULTS: The 10-year actuarial local control rate was 93% +/- 4%. Resection margin status was a significant predictor for LR. Patients with closest histologic resection margins of less than 1 cm had a 10-year local control rate of 87% +/- 6% compared with 100% for patients with closest histologic resection margins of >/= 1 cm (P =.04). There was no significant association between LR and tumor grade, size, site (truncal v extremity), or depth (superficial v deep). For all patients, the 10-year actuarial survival rate was 73% +/- 6%. CONCLUSION: The 7% LR rate after treatment of STS with FSS without RT reported herein is comparable to published rates following treatment where adjuvant RT is used. These results suggest there may be a select subset of patients with STS in whom carefully performed FSS may serve as definitive therapy and in whom adjuvant RT may not be necessary. However, further study is needed to carefully define this subset of patients and to identify the optimal surgical approach and technique for patients treated without RT.     

Gene therapy for experimental brain tumors using a xenogenic cell line engineered to secrete hIL-2

Summary Local delivery of cytokines has been shown to have a potent anti-tumor activity against a wide range of malignant brain tumors. In this study, we examined the feasibility and efficacy of using a rat endothelial cell line (NTC-121) transfected with the human interleukin-2 (IL-2) gene in treating experimental murine CNS tumors. The NTC-121 cells were injected intracranially in C57BL/6 mice (N = 10/group) along with non-irradiated, non-transfected B16/F10 (wild type) melanoma cells. Sixty percent of mice treated with IL-2 (p<0.001 vs. control) were long-term survivors (LTS) of >120 days. Control animals that received only wild type cells had a median survival of 18 days (range 15–20). Histopathological examination of brains from animals sacrificed at different times showed no tumor growth in the non-irradiated NTC-121 group, moderate (1–2 mm) tumor growth in the irradiated group, and gross tumor invasion (>2 mm) and tissue necrosis in the control group. Moreover, animals treated with IL-2 showed an accumulation of CD8+ T cells around the site of the injected tumor. The use of a xenogenic cell line to deliver hIL-2 stimulates a strong immunologic cytotoxic anti-tumor response that leads to significant prolongation of survival in mice challenged with the B16/F10 intracranial melanoma tumor. Our findings demonstrate that the use of a xenogenic cell line can provide a potent vehicle for the delivery of gene therapy and may therefore represent a new approach for brain tumor therapy.     

Gene Therapy for Experimental Brain Tumors Using a Xenogenic Cell Line Engineered to Secrete hIL-2

Local delivery of cytokines has been shown to have a potent anti-tumor activity against a wide range of malignant brain tumors. In this study, we examined the feasibility and efficacy of using a rat endothelial cell line (NTC-121) transfected with the human interleukin-2 (IL-2) gene in treating experimental murine CNS tumors. The NTC-121 cells were injected intracranially in C57BL/6 mice (N = 10/group) along with non-irradiated, non-transfected B16/F10 (wild type) melanoma cells. Sixty percent of mice treated with IL-2 (p < 0.001 vs. control) were long-term survivors (LTS) of >120 days. Control animals that received only wild type cells had a median survival of 18 days (range 15–20). Histopathological examination of brains from animals sacrificed at different times showed no tumor growth in the non-irradiated NTC-121 group, moderate (1–2mm) tumor growth in the irradiated group, and gross tumor invasion (>2mm) and tissue necrosis in the control group. Moreover, animals treated with IL-2 showed an accumulation of CD8+ T cells around the site of the injected tumor. The use of a xenogenic cell line to deliver hIL-2 stimulates a strong immunologic cytotoxic anti-tumor response that leads to significant prolongation of survival in mice challenged with the B16/F10 intracranial melanoma tumor. Our findings demonstrate that the use of a xenogenic cell line can provide a potent vehicle for the delivery of gene therapy and may therefore represent a new approach for brain tumor therapy.     

The role of irradiation of the internal mammary lymph nodes in high-risk stage II to IIIA breast cancer patients after high-dose chemotherapy: a prospective sequential nonrandomized study.

PURPOSE: This phase II single-institution prospective, nonrandomized trial investigates high-dose adjuvant chemotherapy and locoregional radiotherapy in patients with breast cancer. We compared the outcome of patients in this study treated with radiotherapy fields including the internal mammary nodes (IMN) to a group of patients who did not receive IMN irradiation. PATIENTS AND METHODS: 100 patients with high-risk stage II-III breast cancer received doxorubicin-based adjuvant chemotherapy followed by high-dose chemotherapy, stem-cell support, and locoregional radiotherapy. The radiotherapy included electron-beam irradiation to the IMN. For 20 months during the study, no electron-beam facility was available and we were unable to deliver the IMN irradiation as planned to 33 patients. The remaining 67 patients (32 treated before and 35 treated after this period) received IMN irradiation. Patients with receptor-positive tumors received tamoxifen for 5 years. RESULTS: At a median follow-up of 77 months for all of the patients, disease-free survival (DFS) was significantly prolonged in patients receiving IMN radiation compared to those without IMN radiation (73% v 52%; P =.02). A trend was seen for overall survival (OS; 78% v 64%; P =.08). Cox regression multivariate analysis found IMN radiotherapy to be significant both for DFS and OS. Estrogen receptor positivity was also significant for DFS. There was no treatment related mortality. CONCLUSION: In patients with high-risk stage II to III breast cancer, the inclusion of the IMN in the radiotherapy field was associated with a statistically significant increase in DFS and a borderline increase in OS.     

Targeting toll-like receptor 9 with CpG oligodeoxynucleotides enhances tumor response to fractionated radiotherapy.

Synthetic oligodeoxynucleotides containing unmethylated CpG motifs detected by Toll-like receptor 9 of dendritic cells and B cells have potent immunomodulatory effects. CpG oligodeoxynucleotides induce cytokines, activate natural killer cells, and elicit T-cell responses leading to antitumor effects, including improved efficacy of chemotherapeutic agents and, as we reported recently, synergy between CpG oligodeoxynucleotide 1826 and single-dose radiotherapy of an immunogenic mouse fibrosarcoma. The present study extends this finding to the fractionated radiotherapy of the fibrosarcoma tumor and assesses the ability of CpG oligodeoxynucleotide 1826 to increase the radioresponse of a tumor (nonimmunogenic fibrosarcoma). The experiments used a murine immunogenic fibrosarcoma tumor, fibrosarcoma growing in the leg of mice, and response to radiotherapy was assessed by tumor growth delay and tumor cure rate (TCD50, radiation dose yielding 50% tumor cure). Multiple s.c. peritumoral or i.t. administrations of CpG oligodeoxynucleotide 1826 at a dose of 100 microg per mouse were given when established tumors were 6 mm in diameter. Local tumor irradiation was initiated when tumors grew to 8 mm in diameter; radiation was delivered in 1 to 9 Gy fractions given twice daily separated by 6 to 7 hours for 5 consecutive days to achieve a total dose of 10 to 90 Gy. CpG oligodeoxynucleotide 1826, given as a single agent, had only a small antitumor effect, but it dramatically enhanced fibrosarcoma response to radiotherapy. Although 83.1 (79.2-90.0) Gy total dose were needed to achieve tumor cures in 50% of mice treated with radiotherapy alone, only 23.0 (11.5-32.7) Gy total dose were needed in mice treated with both CpG oligodeoxynucleotide 1826 and radiotherapy. The magnitude of potentiation of tumor radioresponse at the TCD50 level was by a factor of 3.61, a much higher value than that (a factor of 1.93) that we reported for single-dose radiotherapy. Mice cured of their tumors by combined CpG oligodeoxynucleotide 1826 plus radiotherapy were highly resistant to s.c. tumor take or development of tumor nodules in the lung from i.v. injected tumor cells when rechallenged with fibrosarcoma cells 100 to 120 days after the treatment, suggesting the development of a memory response. CpG oligodeoxynucleotide 1826 also increased radioresponse of the nonimmunogenic fibrosarcoma tumor by a factor of 1.41 and 1.73 when CpG oligodeoxynucleotide 1826 was given s.c. and i.t., respectively. These findings show that CpG oligodeoxynucleotides are highly potent enhancers of tumor response to both single-dose and fractionated radiation and as such have potential to improve clinical radiotherapy.