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BACKGROUND: Stereotactic body radiotherapy (SBRT) is an alternative to surgery for clinical stage I non–small cell lung cancer (NSCLC), but comparing its effectiveness is difficult because of differences in patient selection and staging. METHODS: Two databases were combined which contained patients treated from 1999 to 2008 by lobectomy (LR, n 5132), sublobar resection (SLR, n 548), and SBRT (n 5137) after negative staging. Univariate and multivariate analysis were performed for survival (OS), total recurrence control (TRC comprises local-regional and distant control), and locoregional control (LRC) in our entire population. A matchedpair analysis was also performed that compared surgery and SBRT results. Median follow-up for the entire study population was 25.8 months. RESULTS: On univariate analysis, OS was significantly worse with SBRT and also correlated with histology, the Charlson comorbidity index, tumor size, and aspirin use; TRC correlated only with histology; and no variable significantly correlated with LRC. OS was significantly poorer for SBRT in the matched-pair analysis than for patients treated with surgery, but TRC and LRC were not significantly different between these groups. Multivariate analyses including propensity score as a covariate (controlling for all factors affecting treatment selection) found that OS correlated only with Charlson comorbidity index, and TRC correlated only with tumor grade. LRC correlated only with tumor size with or without propensity score correction. CONCLUSIONS: This retrospective study has demonstrated similar OS, LRC, and TRC with SBRT or surgery after controlling for prognostic and patient selection factors. Randomized clinical trials are needed to better compare the effectiveness of these treatments. Cancer 2013;119:2683–91. V C 2013 American Cancer Society.

BACKGROUND When found in an otherwise benign biopsy, lobular carcinoma in situ (LCIS) has been associated with an increased risk of development of a subsequent invasive breast carcinoma. However, the association between LCIS and the risk of subsequent local recurrence in patients with infiltrating carcinoma treated with conservative surgery and radiation therapy has received relatively little attention. METHODS Between 1968 and 1986, 1625 patients with clinical Stage I–II invasive breast carcinoma were treated at the Joint Center for Radiation Therapy at Harvard Medical School with breast-conserving surgery (CS) and radiation therapy (RT) to a total dose to the primary site of ≥60 grays. Analysis was limited to 1181 patients with infiltrating ductal carcinoma, infiltrating lobular carcinoma, or infiltrating carcinoma with mixed ductal and lobular features who, on review of their histologic slides, had sufficient normal tissue adjacent to the tumor to evaluate for the presence of LCIS and also had a minimum potential follow-up time of 8 years. The median follow-up time was 161 months. RESULTS One hundred thirty-seven patients (12%) had LCIS either within the tumor or in the macroscopically normal adjacent tissue. The 8-year crude risk of recurrence was not significantly increased for patients with LCIS associated with invasive ductal, invasive lobular, or mixed ductal and lobular carcinoma. Among the 119 patients with associated LCIS adjacent to the tumor, the 8-year rate of local recurrence was 13%, compared with 12% for the 1062 patients without associated LCIS. For the 70 patients with moderate or marked LCIS adjacent to the tumor, the 8-year rate of local recurrence was 13%. The extent of LCIS did not affect the risk of recurrence. The risks of contralateral disease and of distant failure were similarly not affected by the presence or extent of LCIS. CONCLUSIONS Breast-conserving therapy involving limited surgery and radiation therapy is an appropriate method of treating patients with invasive breast carcinoma with or without associated LCIS. Neither the presence nor the extent of LCIS should influence management decisions regarding patients with invasive breast carcinoma. [See editorial counterpoint and reply to counterpoint on pages 978–81 and 982–3, this issue.] Cancer 2000;88:1072–7. © 2000 American Cancer Society.

BACKGROUND The prognosis of patients with T1 breast carcinoma remains controversial. Some studies have shown a low risk of lymph node metastasis and distant failure whereas others have not, possibly due to differences in the definition of tumor size. In this study, the authors assessed the relation between macroscopic tumor size, microscopic invasive tumor size, axillary lymph node involvement, and prognosis in a group of patients with clinically lymph node negative disease. METHODS Between 1968 and 1986, 1865 women with American Joint Committee on Cancer clinical Stage I or II infiltrating carcinoma of the breast were treated at the Joint Center for Radiation Therapy with conservative surgery and radiation therapy. The study population was limited to 118 patients with clinically negative axillary lymph nodes for whom the macroscopic pathologic tumor size was identified unambiguously as being ≤ 2.0 cm, who underwent an axillary lymph node dissection with at least 6 lymph nodes sampled, and for whom the microscopic size of the invasive component could be determined. The median follow-up time for surviving patients was 134 months (range, 90-208 months). No patients with pathologically negative axillary lymph nodes received systemic therapy. RESULTS Macroscopic and microscopic tumor sizes differed by > 5 mm in 17 patients (14%), by 3-5 mm in 24 patients (20%), and by ≤ 2 mm in 77 patients (65%). The macroscopic tumor size was smaller than the microscopic size in 37 patients (31%), larger in 55 patients (47%), and equal in 26 patients (22%). Pathologic axillary lymph node involvement was present in 21% of all patients. The risk of lymph node involvement was not significantly different for those patients with tumors ≤ 1 cm compared with patients with tumors ≥ 1.1 cm, regardless of whether tumor size was measured by macroscopic or microscopic examination. The 10-year actuarial rate of freedom from distant recurrence (FFDR) was 91% for lymph node negative patients with macroscopic tumors measuring ≤ 1.0 cm compared with 77% for patients with macroscopic tumors measuring ≥ 1.1 cm (P = 0.07). When measured microscopically, the rates were 96% and 72%, respectively (P = 0.001). CONCLUSIONS There often is a discrepancy between microscopic tumor size and macroscopic tumor size. T1 tumors have a substantial risk of axillary lymph node metastasis whether measured macroscopically or microscopically. Among those patients with pathologic lymph node negative tumors who are not treated with systemic adjuvant therapy, microscopic invasive tumor size is a better predictor of 10-year FFDR than macroscopic tumor size. There is a substantial risk of distant failure for patients with tumors whose invasive component microscopically measure ≥ 1.1 cm, whereas the prognosis for patients with tumors that microscopically measured ≤ 1 cm is excellent. These results suggest that the microscopic size of the invasive component of breast carcinomas ≤2.0 cm routinely should be reported. Cancer 1998;83:2502-2508. © 1998 American Cancer Society.

BACKGROUND At 5-year follow-up, patients with Paget disease of the breast who were treated with breast-conserving surgery (BCS) and radiotherapy (RT) had excellent results. The current report provides 10- and 15-year rates of tumor control in the breast, as well as disease-free and overall survival rates following BCS and RT in a cohort of patients with Paget disease presenting without a palpable mass or mammographic density. METHODS Through a collaborative review of patients treated with BCS and RT from seven institutions, 38 cases of Paget disease of the breast presenting without a palpable mass or mammographic density were identified. All patients had pathologic confirmation of typical Paget cells at time of diagnosis. Thirty-six of 38 patients had a minimum follow-up greater than 12 months and constitute the study cohort. Ninety-four percent of patients underwent complete or partial excision of the nipple-areola complex and all patients received a median external beam irradiation dose of 50 Gy (range, 45–54 Gy) to the whole breast. Ninety-seven percent of patients also received a boost to the remaining nipple or tumor bed, a median total dose of 61.5 Gy (range, 50.4–70 Gy). RESULTS With median follow-up of 113 months (range, 18–257 months), 4 of 36 patients (11%) developed a first recurrence of disease in the treated breast only. Two of the four recurrences in the breast were ductal carcinoma in situ (DCIS) only and two were invasive with DCIS. Two additional patients had a recurrence in the breast as a component of first failure. Actuarial local control rates for the breast as the only site of first recurrence were 91% at 5 years (95% confidence interval [CI], 80–100%) and 87% (95% CI, 75–99%) at both 10 and 15 years. Actuarial local control rates for breast recurrence, as a component of first failure, were 91% (95% CI, 80–100%), 83% (95% CI, 69–97%), and 76% (95% CI, 58–94%) at 5, 10, and 15 years, respectively. No clinical factors were identified as significant predictors for breast recurrence. Five-, 10- and 15-year actuarial rates for survival without disease of 97% (95% CI, 90–100%) and 5-, 10-, and 15-year actuarial rates of overall survival of 93% (95% CI, 84–100%) at 5 years and 90% (95% CI, 78–100%) at 10 and 15 years were reported. CONCLUSIONS These data confirm excellent rates of local control, disease-free survial, and overall survival at 10 and 15 years following BCS and RT for Paget disease of the breast. This study continues to support the recommendation of local excision and definitive breast irradiation as an alternative to mastectomy in the treatment of patients with Paget disease presenting without a palpable mass or mammographic density. Cancer 2003;97:2142–9. © 2003 American Cancer Society. DOI 10.1002/cncr.11337

BACKGROUND Synchronous bilateral breast carcinoma (SBBC) is an uncommon presentation, and the management of patients with this disease is not well established. METHODS In order to evaluate whether patients with early-stage SBBC could be safely and effectively treated with bilateral breast-conserving therapy (BCT), the authors retrospectively reviewed the records of 24 patients with clinical Stage I-II SBBC treated during the period 1977-1989 with bilateral BCT. SBBC was defined as bilateral invasive carcinomas diagnosed no more than 1 month apart. The median age at diagnosis was 56 years (range, 32-85 years), and the median follow-up for surviving patients was 95 months (range, 68-157 months). Pathology slides were available for review in 19 cases. Cosmetic results and complications after BCT were scored. Outcome was compared with that of 1314 patients with unilateral Stage I or II breast carcinoma, within the same age range, treated during the same time period. RESULTS There were no significant differences between the SBBC and unilateral groups in actuarial disease free survival (70% and 74%, respectively, at 5 years), overall survival (88% and 87%, respectively, at 5 years), or crude distribution of sites of first failure. Multivariate analysis of overall survival and disease free survival also did not show bilaterality to be a significant factor. The cosmetic results for the SBBC group were not significantly different from those for the unilateral group. Physician assessment of cosmetic outcome was excellent in 57% and good in 43% of SBBC patients evaluated 25-48 months after BCT. Long term complications were rare in both groups. CONCLUSIONS Patients with early-stage SBBC can be safely treated with carefully planned, bilateral BCT, with outcome that appears to be comparable to that of patients with early-stage unilateral breast carcinoma. Cancer 1997; 79:1362-9. © 1997 American Cancer Society.

BACKGROUND There has been increasing interest in the use of sphincter-preserving therapy for patients with distal rectal carcinomas. The outcomes of conservative treatments for early stage rectal carcinoma appear to be comparable to that achieved with abdominoperineal resection. METHODS Retrospective and prospective clinical series of patients with distal rectal carcinoma treated by local excision alone, local excision with postoperative adjuvant therapy, preoperative radiation followed by local excision, or radical circumferential sphincter-sparing surgeries were reviewed. The local control rates, salvage rates, and treatment complications in patients treated by these various methods were examined. RESULTS Patients with T1 distal rectal carcinoma with favorable clinical and histopathologic characteristics treated with local excision alone had a local control rate of greater than 90% in most series. Postoperative chemoradiation improved local control for those with T1 disease with unfavorable characteristics, or those with T2 disease. Most T3 patients had failure rates of greater than 30% despite adjuvant local and systemic therapy. With high dose preoperative radiation, approximately 80% of patients with locally advanced or unresectable tumors were able to undergo sphincter-preservation treatment. CONCLUSIONS Patients with favorable T1 rectal carcinoma are likely to be adequately treated with local excision alone. Patients with T1 disease with unfavorable characteristics as well as T2 patients will benefit from postoperative chemoradiation. The use of local therapy in T3 patients needs to be carefully considered because these patients are at relatively high risk for local recurrence despite adjuvant therapy. Preoperative radiation followed by either local excision or radical circumferential sphincter-sparing resections appears promising in allowing sphincter preservation in patients with locally advanced tumors. Cancer 1997; 79:671-83. © 1997 American Cancer Society.

BACKGROUND The relationship between the microscopic margins of resection and ipsilateral breast recurrence (IBR) after breast-conserving therapy for carcinomas with or without an extensive intraductal component (EIC) has not been adequately defined. METHODS Of 1,790 women with unilateral clinical Stage I or II breast carcinoma treated with radiation therapy as part of breast-conserving therapy, 343 had invasive ductal histology evaluable for an extensive intraductal component (EIC), had inked margins that were evaluable on review of their pathology slides, and received; ce60 Gray to the tumor bed; these 343 women constitute the study population. The median follow-up was 109 months. All available slides were reviewed by one of the study pathologists. Final inked margins of excision were classified as negative > 1 mm (no invasive or in situ ductal carcinoma within 1 mm of the inked margin); negative; cc 1 mm, or close (carcinoma; cc 1 mm from the inked margin but not at the margin); or positive (carcinoma at the inked margin). A focally positive margin was defined as invasive or in situ ductal carcinoma at the margin in three or fewer low-power fields. The first site of recurrent disease was classified as either ipsilateral breast recurrence (IBR) or distant metastasis/regional lymph node failure. RESULTS Crude rates for the first site of recurrence were calculated first for all 340 patients evaluable at 5 years, then separately for the 272 patients with EIC-negative cancers and the 68 patients with EIC-positive cancers. The 5-year rate of IBR for all patients with negative margins was 2%; and for all patients with positive margins, the rate was 16%. Among patients with negative margins, the 5-year rate of IBR was 2% for all patients with close margins (negative; cc 1 mm) and 3% for those with negative > 1 mm margins. For patients with close margins, the rates were 2% and 0% for EIC-negative and EIC-positive tumors, respectively; the corresponding rates for patients with negative margins > 1 mm were 1% and 14%. The 5-year rate of IBR for patients with focally positive margins was 9% (9% for EIC-negative and 7% for EIC-positive patients). The 5-year crude rate of IBR for patients with greater than focally positive margins was 28% (19% for EIC-negative and 42% for EIC-positive patients). CONCLUSIONS Patients with negative margins of excision have a low rate of recurrence in the treated breast, whether the margin is >1 mm or; cc1 mm and whether the carcinoma is EIC-negative or EIC-positive. Among patients with positive margins, those with focally positive margins have a considerably lower risk of local recurrence than those with more than focally positive margins, and could be considered for breast-conserving therapy. Cancer 1996;78:1921-8.

BACKGROUND Although histologic grade has previously been described as a predictor of distant failure, it is uncertain whether histologic grade should be used to decide which patients should undergo axillary lymph node dissection and whether grade should be considered as a selection factor for breast-conserving therapy. METHODS The authors retrospectively analyzed data from 1081 patients with American Joint Committee on Cancer Stage I or II infiltrating ductal carcinoma treated with breast-conserving therapy at the Joint Center for Radiation Therapy between 1970 and 1986. All patients had pathology slides reviewed by one of two study pathologists. Using the Elston modification of the Bloom-Richardson grading system, patients were divided by histologic grade into 3 groups (219 with Grade I, 482 with Grade II, and 380 with Grade III). The median follow-up time for 716 survivors was 134 months. The incidence of various pathologic features was examined with respect to histologic grade. In addition, the 10-year crude rates of failure (by first site) were examined as they related to grade. A polychotomous logistic regression model was used to determine the effect of grade on local and distant failure. RESULTS High grade tumors tended to be larger, to exhibit more mononuclear cellular reaction and necrosis, and were more likely to be estrogen receptor negative. Patients with high grade tumors were also younger than those with lower grade tumors. The incidence of an extensive intraductal component and lymphatic vessel invasion did not vary significantly by histologic grade. The incidence of pathologic lymph node metastases also did not vary by grade, even when stratified by tumor size. In both univariable and multivariable analyses, the 10-year crude rate of local recurrence was not related to histologic grade (P = 0.44). Distant recurrence rates, however, were significantly higher as grade increased (P = 0.002). CONCLUSIONS Higher histologic grade predicted an increased incidence of distant recurrence, but not a greater likelihood of axillary lymph node metastases or local recurrence after breast-conserving therapy. The authors conclude that grade should not be used to make decisions regarding local management. Cancer 1996;78:1426-31.

BACKGROUND Randomized clinical trials have clearly demonstrated that the use of radiation therapy (RT) following breast-conserving surgery (CS) substantially reduces the risk of local recurrence. However, the low rate of local recurrence after CS and RT for patients without known risk factors, and the recent increase in the detection of smaller cancers due to mammographic screening have led to the speculation that a subgroup of patients who have a low risk of local recurrence without RT might be identified. In 1986, we initiated a one-arm, prospective clinical trial of CS alone for treatment of highly selected breast cancer patients without known risk factors for local recurrence. METHODS The study had a sequential design with a planned accrual of 90 patients. Criteria for entry into the trial were: a unicentric, clinical T1 infiltrating ductal, mucinous or tubular carcinoma without an extensive intraductal component or lymphatic vessel invasion; a wide excision with a pathologically-documented negative margin of at least 1 cm; and histologically negative axillary lymph nodes. No adjuvant RT or systemic therapy was administered. Seventy-six per cent of the lesions were detected by mammography alone. The median gross pathologic tumor size was 0.9 cm. The median patient age was 67 years. RESULTS Eighty-seven patients were enrolled in the trial before it closed prematurely in 1992 because the predefined stopping boundary was crossed (i.e., the sixth local recurrence was observed). At that time, the average annual local recurrence rate was 4.2%. With a median follow-up of 56 months, there are now 14 patients (16%) with local recurrence as their site of first failure (average annual local recurrence rate: 3.6%). Four patients without local recurrence developed distant metastases. Three patients have died, one of metastatic breast cancer and two of unrelated causes. CONCLUSIONS Even in a highly selected group of patients with early-stage breast cancer, there is a substantial risk of early local recurrence for those treated with wide excision alone. Cancer 1996;77:1094-100.

Background. The value of surgical staging and treatment of the axillary lymph nodes with either surgery or radiotherapy in the initial management of patients with Stage I or II invasive breast cancer is controversial. Methods. A review of retrospective and prospective clinical studies was performed to assess the risks of axillary lymph node involvement and the effectiveness and morbidity of various treatment options. Results. The risk of axillary lymph node involvement is substantial for most patients, even those with small tumors. The morbidity resulting from a careful Level I/II axillary dissection or moderate-dose axillary radiotherapy is limited. Such treatment is highly effective in preventing axillary recurrence. The symptoms resulting from axillary failure can be controlled in many, but not all, patients. The available data suggest, but do not prove, that the initial use of effective axillary treatment may result in a small improvement in long term outcome in some patient subgroups. Conclusions. Most patients should be treated with either axillary surgery or irradiation. Highly selected subgroups of patients may have such low risks of involvement that specific axillary treatment is of little value. However, such subgroups have not yet been well defined. Treatment approaches that do not involve specific axillary treatment should be considered investigational at present, and the patients should be informed as to their potential risks. Prospective clinical studies of these issues should be pursued. Cancer 1995; 76:1491–512.

Background. The relationships among the involvement of tumor at the final margins of resection, the presence of an extensive intraductal component (EIC), and the risk of local recurrence are important considerations in patients treated with conservative surgery and radiation therapy for early stage breast cancer but have not been defined adequately. Methods. Between 1982 and 1985, 885 patients were treated for clinical Stage I or II invasive breast cancer. The study population was limited to 181 patients with an infiltrating ductal carcinoma who received a radiation dose to the surgical site of 60 Gy or greater, whose final microscopic margins of resection were evaluable, and who had at least 5 years of follow-up. A positive margin was defined as tumor present at the inked margin of resection, a close margin as tumor within 1 mm of the inked margin, and a negative margin as no tumor within 1 mm of the inked margin. A focally positive margin was defined as tumor at the margin in three or fewer low-power fields. In 157 patients (87%), the tumor was evaluable for the presence or absence of an EIC. The median follow-up was 86 months. Results. In 12 of 181 patients (7%), a recurrence developed at or near the primary site (true recurrence/marginal miss [TR/MM]) within 5 years. The 5-year rate of TR/MM (with 95% confidence intervals) among patients with negative, close, focally positive, and more than focally positive margins was 0% (0-4%), 4% (0-20%), 6% (1-17%) and 21% (10-37%), respectively. Patients with positive margins also were more likely to have a distant failure within 5 years (14%, 8%, 25%, and 32% in the four groups, respectively). However, patients with positive margins more often had positive axillary lymph nodes than patients with negative or close margins (59% vs. 38%, P < 0.02). The 5-year rate of TR/MM was 20% for patients with an EIC-positive tumor and 7% for patients with an EIC-negative tumor. However, among the 127 patients with an EIC-negative tumor, the 5-year rate of TR/MM was less than 10% in all margin groups. Among the 30 patients with an EIC-positive tumor, the 5-year rate of TR/MM was 0% when margins were negative or close but 50% when margins were more than focally positive. Conclusions. These results provide support for the use of breast-conserving surgery and breast irradiation in all patients with uninvolved margins, whether the tumor is EIC-positive or EIC-negative. This study suggests that breast-conserving therapy (including a radiation boost to the primary site) also may be a reasonable option for some patients with an EIC-negative tumor and margin involvement.

BACKGROUND To evaluate the pathologic characteristics of the primary tumor relative to local control, survival, and freedom from distant metastases, an analysis was performed of 172 patients with ductal carcinoma in situ (intraductal carcinoma) of the breast treated with breast-conserving surgery and definitive breast irradiation. METHODS The clinical records and pathology slides were reviewed from 172 women with ductal carcinoma in situ treated with breast-conserving surgery and definitive breast irradiation at multiple institutions in Europe and the United States. Central pathology review was performed by one pathologist without knowledge of the clinical outcome. The clinical outcome was measured in terms of local control, overall survival, cause-specific survival, and freedom from distant metastases. The median follow-up time was 84 months (range, 17-177 months). RESULTS The pathologic parameters evaluated were histologic subtype, nuclear grade, amount of necrosis, and final pathology margin. The only pathologic parameter that correlated with the rate of local recurrence was the presence versus the absence of the combination of the histologic subtype of comedo carcinoma plus nuclear grade 3 (8-year actuarial rate of local recurrence of 20% versus 5%, respectively; P = 0.009 on univariate analysis; P = 0.017 on multivariate analysis). None of the pathologic parameters evaluated correlated with overall survival (all P > or = 0.16), cause-specific survival (all P > or = 0.13), or freedom from distant metastases (all P > or = 0.13). CONCLUSIONS These results have demonstrated that there are important differences in the rate of local recurrence based on the pathologic characteristics of the primary tumor for women with ductal carcinoma in situ treated with breast-conserving surgery and definitive irradiation. However, the differences in local recurrence have not been associated with differences in survival or freedom from distant metastases. Careful follow-up for patients at increased risk for local recurrence is warranted because of the potential ability to salvage patients with local recurrence.

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.

An analysis of 259 women with 261 treated breasts from nine institutions in Europe and the United States was performed to determine the 10-year results of the treatment of intraductal carcinoma of the breast with definitive irradiation. All patients had undergone complete gross excision of the primary intraductal carcinoma, and definitive breast irradiation was delivered in all cases. The median follow-up time was 78 months (range, 11 to 197 months). The 10-year actuarial overall survival rate was 94%, and the 10-year actuarial cause-specific survival rate (including deaths only from carcinoma of the breast) was 97%. The 10-year actuarial rate of freedom from distant metastases was 96%. There were 28 failures in the breast, and the 10-year actuarial rate of local failure was 16%. The pathologic type of local recurrences showed invasive ductal carcinoma in 14 of 28 recurrences (50%) and noninvasive ductal carcinoma in 14 of 28 recurrences (50%). The median time to local failure was 50 months (range, 17 to 129 months). Twenty-four of 28 patients with local failure were salvaged with additional treatment, generally mastectomy, and 4 of 28 patients with local failure subsequently had distant metastases. Median follow-up time after salvage treatment of breast recurrence was 29 months (range, 3 to 90 months). Two patients without local failure subsequently had distant metastases, one of which occurred after a node-positive, contralateral breast carcinoma. These results demonstrate high rates of overall survival, cause-specific survival, and freedom from distant metastases for the treatment of patients with intraductal carcinoma of the breast. The local recurrences within the treated breast were generally salvaged with additional treatment, although with limited follow-up. Because of the long natural history of intraductal carcinoma of the breast, prolonged and careful follow-up of patients after breast-conservation and definitive irradiation is required. Cancer 68:2337–2344, 1991.

To determine the frequency, pattern, and time course of tumor recurrence in the breast, the outcome of 38 women with ductal carcinoma in situ (DCIS) treated with conservative surgery and radiation therapy between 1976 and 1985 was studied. Surgery typically consisted of local excision without evaluation of the microscopic margins of resection. The median radiation dose to the tumor site was 6400 cGy. With a median follow-up time of 81 months, eight patients (21%) have experienced a recurrence in the breast. The time course to recurrence was protracted in some cases, with failures occurring at 17, 27, 43, 63, 71, 83, 92, and 104 months. The 5-year and 8-year actuarial rates of tumor recurrence in the breast were 8% and 27%, respectively. Seven patients had a recurrence at or near the primary tumor site, four with invasive carcinoma, and one had an invasive recurrence at a site elsewhere in the breast. No clinical or pathologic factor was significantly associated with an increased risk of recurrence, but the number of patients in the study population was small. The authors reached the following conclusions for patients with DCIS treated with conservative surgery and radiation therapy without careful mammographic and pathologic evaluation: (1) recurrence in the breast may be seen in at least one fifth of the patients; (2) recurrence typically occurs at or near the primary site; and (3) recurrence can occur long after treatment. Careful mammographic and pathologic assessment may be useful in reducing the local recurrence rate and should be considered essential if patients are considered for conservative surgery and radiation therapy.

In 1984, as part of a prior American Cancer Society National Conference on Breast Cancer, the authors reported on the status of conservative surgery (CS) and radiotherapy (RT) as primary local treatment for women with early stage breast cancer. Since that time, additional data have become available regarding the use of this approach and its comparability to mastectomy. In general, these data support the use of CS and RT and, as a result, this approach is now more widely employed in the United States and abroad than it was in 1984. The current focus of inquiry has shifted from whether or not CS and RT is an acceptable option for patients with early stage breast cancer to the following questions. For which patients are CS and RT suitable? What are the best techniques of surgery and RT? Are there any patients who can be treated safely with CS without RT? How should RT and systemic therapy be integrated when both are to be used? In this report, recent results on the use of CS and RT from both retrospective and prospective trials are summarized, and these current areas of inquiry are addressed.

Early adjuvant therapy studies, especially adjuvant chemotherapy studies, were performed almost exclusively on patients with histologically involved axillary lymph nodes ("node-positive" patients). These therapies were restricted to this group of patients because the toxicities of adjuvant therapy were believed too great to justify its use in patients with a very good prognosis until its benefits were fully established. However, after it was demonstrated that adjuvant therapy can significantly prolong the disease-free survival of almost all groups of node-positive patients and the overall survival of some patient subsets, adjuvant therapy trials specifically designed for patients without histologically involved lymph nodes ("node-negative" patients) were initiated. Results from some of the largest of these second generation trials were recently published, and the early results from these studies have generated new questions. For example, will the mature results from these studies be nearly identical to the results seen in node-positive patients, or will node-negative patients derive greater benefits from adjuvant therapy? Is it possible that adjuvant therapy will "cure" node-negative patients but not node-positive patients? (Cure is defined here as an effect of therapy that returns a patient to the life expectancy she might have had if she had never been diagnosed with breast cancer). Is it possible that the added years of life from adjuvant therapy or that the number of node-negative patients who benefit are so small that these benefits will be outweighed by delayed toxicities that appear in patients who might have been cured even without adjuvant therapy? At present the available data to answer these questions definitely are either contradictory or nonexistent.

Background Between 10% and 35% of women with operable breast cancer will experience an isolated locoregional recurrence following their primary treatment. There is currently no good evidence that adjuvant systemic treatment is effective in this situation and there is no standard treatment for women who have such a recurrence. Objectives To investigate whether additional systemic treatment will improve the result of local therapy in regard to relapse-free and overall survival in women with potentially curatively resected loco-regional recurrence following breast cancer, who have not had a previous or synchronous distant metastases. Search strategy Searches were done, in the first half of 2001, of the specialised register of the Cochrane Breast Cancer Collaborative Review Group, The Cochrane Library, MEDLINE and EMBASE. In addition, the records of the Early Breast Cancer Trialists' Collaborative Group were checked for any relevant trials. The citations in articles reviewing the treatment of locoregional recurrence of breast cancer were checked. Selection criteria Randomised controlled trials or trials in which women were allocated to treatment or observation by a quasi-random process (such as alternation or date of birth) were eligible. Our aim was to consider separately women with a first incidence of isolated loco-regional recurrence in the treated breast, the chest wall or the regional lymphnode areas (except clavicular nodes) which can be resected without (R0) or with (R1) microscopically demonstrable residual disease. Women with previous or synchronous distant metastases were to be excluded from this part of the review. The second part of the review was to consider women with inoperable loco-regional recurrence and / or clavicular lymphnode involvement, regardless of previous or synchronous metastases. Data collection and analysis We identified three closed studies in which there were a total of four randomised comparisons of systemic therapy versus observation for women who have received radiotherapy for loco-regional recurrence of breast cancer. One trial assessed Actinomyicin-D and randomised 32 patients in the 1960s and another randomised the same number of women to alpha-interferon versus observation in the early 1980s. The Swiss SAKK trial assessed tamoxifen for "good risk" patients and combination chemotherapy (Vincristine, Doxorubicin and Cyclophosphamide) for "poor risk" patients. It randomised 178 and 50 women respectively during 1982-1991. Where possible, data on relapse-free and overall survival were extracted for these trials and analysed using RevMan 4.1. No attempt was made to pool the results of the studies because of clinical heterogeneity and the small number of randomised patients. Three ongoing trials of chemotherapy versus observation have been identified. Main results The trial of 32 women who received either radiotherapy alone or in combination with systemic administration of Actinomycin-D found that chemotherapy improved the local control rate but had no apparent effect on overall survival. The interferon trial, which also included a total of only 32 patients, showed that the addition of alpha-Interferon to local treatment of locoregional recurrent breast cancer had no apparent effect on the further course of the disease. The Swiss SAKK trial of tamoxifen (178 women randomized) found an improvement in disease-free survival but not in overall survival and no results are available for the 50 women randomized into the concurrent trial of chemotherapy. The three ongoing trials of chemotherapy have a total target accrual of nearly 2000 patients. Reviewer's conclusions This systematic review of randomised trials provides insufficient evidence to do other than conclude that the most appropriate form of practice for women with loco-regional recurrence of breast cancer is participation in randomised trials of systemic treatment versus observation.

To determine the clinicopathologic significance of colloid carcinoma in carcinoma of the colon and rectosigmoid/rectum, a retrospective review of 462 patients who underwent potentially curative surgery at the New England Deaconess Hospital was performed. Seventy-seven patients (17%) were identified who had tumors with some component of colloid present. Colloid carcinoma occurred in 49 (11%). The remaining 28 (6%) had adenocarcinoma with colloid features. Compared to patients with pure adenocarcinoma, the 5-year actuarial survival of patients with colloid carcinoma was lower in the colon, rectosigmoid/rectum, and colorectum. Patterns of failure, expressed as the actuarial incidence of failure at 5 years, were examined by histologic condition and stage. Patients with Dukes' Stage B colloid carcinoma had a higher incidence of total failure, and patients with Dukes' Stage C colloid carcinoma had a higher incidence of local, abdominal, and total failure. None of the differences reached statistical significance. The presence of colloid carcinoma may have a real but small impact on the patterns of failure and survival in colorectal cancer.

Gross excision of the tumor followed by radiotherapy is used for treatment of early breast cancer. Local recurrence after this form of treatment is uncommon except in patients with infiltrating ductal carcinoma whose excision specimens reveal an extensive intraductal component (EIC). It is unclear whether this observation is due to a qualitative difference in the response of tumors with EIC to radiation or to a quantitative difference in the tumor burden remaining after gross excision in patients with EIC. To address this question, the authors examined pathologic material in 71 patients with infiltrating ductal carcinoma treated with gross excision of the tumor and then selected for re-excision of the tumor site prior to radiotherapy because of the presence of either EIC in the primary excision specimen or microscopic tumor at or close to margins in the initial excision. Residual carcinoma was seen in 62% of all patients but was more frequent among the 25 patients with EIC than the 46 without (88% vs. 48%, P = 0.002). The nature of the residual tumor differed for patients with and without EIC in the primary excision specimen. Residual carcinoma in patients with EIC was often widespread and composed predominantly of intraductal carcinoma. In contrast, residual tumor in patients without EIC usually consisted of only scattered microscopic foci of infiltrating and/or intraductal carcinoma. The authors conclude that patients with EIC treated with gross excision of the tumor frequently have considerable residual intraductal carcinoma near the primary site. This finding may account for the increased risk of local recurrence observed in patients with EIC treated without re-excision of the tumor site before radiation therapy.

In an effort to determine the patterns of failure and survival of rectosigmoid and rectal cancer, a retrospective review of 168 patients who underwent potentially curative surgery at the New England Deaconess Hospital was performed. The 5-year actuarial survival for the entire group was 67%. Survival rates decreased with increasing penetration of the bowel wall by tumor and the presence of lymph node metastasis, but only the latter reached statistical significance. Those patients who underwent an abdominoperineal resection also experienced a significant decrease in survival compared to a low anterior resection. Patterns of failure, expressed as the actuarial incidence of first failure at 5 years, were examined by stage. With the exception of stages B3 and C3, there was a trend towards increased abdominal, distant, and total failure with increasing bowel wall penetration by tumor. A similar trend was seen in local failure in those patients with positive nodes. Knowledge of these data may help identify those patients who may benefit most from adjuvant therapy.

The optimal local-regional treatment for patients with Stage III breast cancer has not been determined. To evaluate the effectiveness of radiation therapy as local treatment for such patients, the results of 192 patients (five with bilateral disease) treated with radiation therapy without mastectomy between July 1, 1968 and December 31, 1981 were reviewed. Excisional biopsy (gross tumor removal) was performed in only 54 of the 197 breasts. Patients typically received 4500 to 5000 cGy in 5 weeks to the breast and draining lymph nodes; a local boost to areas of gross disease was delivered to 157 patients. Multi-agent chemotherapy was given to 53 patients. The median follow-up was 65 months. The actuarial probability of survival for the entire group was 41% at 5 years and 23% at 10 years. The probability of relapse-free survival (RFS) was 30% at 5 years and 19% at 10 years. The addition of multi-agent chemotherapy was associated with a significantly improved 5-year RFS (40% versus 26%, P = 0.02). The 5-year survival rate was 51% for patients who received adjuvant multi-agent chemotherapy and 38% for patients who did not (P = 0.16). The actuarial rate of local-regional tumor control (not censored for distant failure) for all patients was 73% at 5 years and 68% at ten years, and the crude incidence of local-regional control was 78%. Local-regional tumor control was principally influenced by radiation dose. Patients who received 6000 cGy or greater to the primary site had a better 5-year rate of control in the breast than did patients who received less than 6000 cGy (83% versus 70%, P = 0.06). Significant complications were seen in 15 patients (8%); these included moderate or severe arm edema in six patients and brachial plexopathy in four patients. Cosmetic results at last evaluation were excellent or good in 56% of evaluable patients, fair in 25%, and poor in 19%. It is concluded that high-dose radiation therapy without mastectomy is an effective means of controlling local-regional tumor in patients with locally advanced breast cancer.

The combination of conservative surgery and radiation therapy has become a more widely employed treatment approach for patients with early breast cancer. Cooperation between the surgeon, radiologist, pathologist, radiation therapist and medical oncologist is critical in obtaining good results using this approach. In this article, we summarize the treatment policy at the Harvard Joint Center for Radiation Therapy with concentration on treatment techniques and their appropriate application.

Several series have examined the influence of blood vessel invasion (BVI) by tumor on survival of patients with colorectal cancer; however, little data are available regarding its influence on patterns of failure. In an effort to determine the influence of BVI on the patterns of failure and survival in rectosigmoid and rectal cancer, a retrospective review of 168 patients who underwent potentially curative surgery at the New England Deaconess Hospital was performed. In patients who had tumors with extramural BVI, there was a significant decrease in five-year actuarial survival compared with patients who had tumors with intramural BVI or were BVI-negative (BVI-). When the intramural and extramural types of BVI were combined, no significant impact was noted on the patterns of failure or survival in patients with BVI+ versus those with BVI- tumors. In contrast, the presence of lymphatic vessel invasion was found to significantly decrease survival. By using a proportional hazards analysis, it was found that BVI was not an independent prognostic variable. Therefore, the use of BVI alone is not recommended for selecting patients with rectosigmoid and rectal cancer who may benefit from adjuvant therapy.

As an alternative to radical surgery, local excision with or without adjuvant pelvic radiation therapy has been used in selected patients with rectal cancer. To determine which clinical and pathologic features can predict the presence of positive lymph nodes (LN+), a retrospective review of 168 patients who underwent potentially curative surgery for rectosigmoid and rectal cancer was performed. By univariate analysis, tumor penetration, grade, and histology were significant predictive features. This was confirmed by logistic regression analysis. The incidence of LN+ increased with increasing tumor penetration (T1, 0%; T2, 28%; T3, 36%; T4, 53%; P = 0.04), grade of adenocarcinoma (well-differentiated, 0%; moderately differentiated, 30%; poorly differentiated, 50%; P = 0.07, [borderline significance]), and the presence of any colloid histology (pure adenocarcinoma, 30%; total colloid, 52%; P = 0.04). Using 2 X 2 contingency tables, the presence of blood vessel invasion (BVI), lymphatic vessel invasion (LVI), vascular invasion (VI), total colloid histology, and high grade further increased the incidence of LN+ with increasing tumor penetration. Regardless of tumor size, grade, histology, BVI, LVI, or VI, none of the nine patients with Stage T1 tumors or the seven with well-differentiated adenocarcinomas had LN+. For this group, local excision alone is recommended. The incidence of LN+ was greater than or equal to 19% in all other categories. For this group of patients, if there is no evidence of gross tumor in the pelvis, then a local excision plus adjuvant pelvic radiation may be an alternative to radical surgery.

Craniopharyngioma, a tumor most commonly diagnosed in the young, may occur at any age. The oldest patient known to have histologic documentation of a craniopharyngioma, an 82.5-year-old woman, presented with visual field changes, panhypopituitarism, and mental status changes. This diagnosis should be considered in such patients, because craniopharyngioma is a potentially curable tumor by either surgery or radiation therapy.