It is unknown whether irradiation of the internal mammary lymph nodes improves survival in patients with early-stage breast cancer. A possible survival benefit might be offset by radiation-induced ...heart disease. We assessed the effect of internal mammary node irradiation (IMNI) in patients with early-stage node-positive breast cancer.
In this nationwide, prospective population-based cohort study, we included patients who underwent operation for unilateral early-stage node-positive breast cancer. Patients with right-sided disease were allocated to IMNI, whereas patients with left-sided disease were allocated to no IMNI because of the risk of radiation-induced heart disease. The primary end point was overall survival. Secondary end points were breast cancer mortality and distant recurrence. Analyses were by intention to treat.
A total of 3,089 patients were included. Of these, 1,492 patients were allocated to IMNI, whereas 1,597 patients were allocated to no IMNI. With a median of 8.9 years of follow-up time, the 8-year overall survival rates were 75.9% with IMNI versus 72.2% without IMNI. The adjusted hazard ratio (HR) for death was 0.82 (95% CI, 0.72 to 0.94; P = .005). Breast cancer mortality was 20.9% with IMNI versus 23.4% without IMNI (adjusted HR, 0.85; 95% CI, 0.73 to 0.98; P = .03). The risk of distant recurrence at 8 years was 27.4% with IMNI versus 29.7% without IMNI (adjusted HR, 0.89; 95% CI, 0.78 to 1.01; P = .07). The effect of IMNI was more pronounced in patients at high risk of internal mammary node metastasis. Equal numbers in each group died of ischemic heart disease.
In this naturally allocated, population-based cohort study, IMNI increased overall survival in patients with early-stage node-positive breast cancer.
To examine the importance of estrogen receptor (ER), progesterone receptor (PgR), human epidermal growth factor receptor 2 (HER-2), and constructed subtypes in a large study randomly assigning ...patients to receive or not receive postmastectomy radiotherapy (PMRT).
The present analysis included 1,000 of the 3,083 high-risk breast cancer patients randomly assigned to PMRT in the Danish Breast Cancer Cooperative Group (DBCG) protocol 82 trials b and c. Tissue microarray sections were stained for ER, PgR, and HER-2. Median follow-up time for patients alive was 17 years. End points were locoregional recurrence as isolated first event, distant metastases, and overall survival. For statistical analyses four subgroups were constructed from hormonal receptors (Rec). Rec+ was defined as ER+ and/or PgR+. Rec-as both ER-and PgR-. The four subgroups were Rec+/HER-2-, Rec+/HER-2+, Rec-/HER-2-(triple negative), and Rec-/HER-2+.
A significantly improved overall survival after PMRT was seen only among patients characterized by good prognostic markers such as hormonal receptor-positive and HER-2- patients (including the two Rec+ subtypes). No significant overall survival improvement after PMRT was found among patients with an a priori poor prognosis, the hormonal receptor-negative and HER-2+ patients, and in particular the Rec-/HER-2+ subtype. Furthermore, comparing hazard ratios and 95% CIs, significantly smaller improvements in locoregional recurrence control after PMRT were found for ER-and PgR-tumors compared with the ER+ and PgR+ tumors (P = .003 and .04, respectively), and for the triple-negative (P = .02), and the Rec-/HER-2+ subtypes (P = .003) compared with the Rec+/HER-2-subtype.
Hormonal receptor status, HER-2, and the constructed subtypes may be predictive of locoregional recurrence and survival after postmastectomy radiotherapy.
Abstract New strategies for adjuvant radiotherapy of early breast cancer are being investigated in several phase III randomised trials at the present time. Accelerated partial breast irradiation ...(APBI) is a way to offer an early breast cancer patient, who has had breast conservative surgery, an adjuvant radiotherapy of short duration aimed at the tumour bed with a certain margin. The rationale of this strategy is that most local recurrences appear close to the tumorectomy cavity and a wish to spare the patient late radiation morbidity. This review discusses the background for APBI, the different techniques, and we highlight possible pitfalls using these techniques. A systematic overview of all phase I and II studies is provided. Patient selection for this therapy is pivotal and based on evidence from previous studies on patient/tumour characteristics and pattern of local recurrences we propose inclusion criteria for patients in APBI protocols.
Postmastectomy radiotherapy (RT) in high-risk breast cancer patients can reduce locoregional recurrences (LRRs) and improve disease-free and overall survival. The aim of this analysis was to examine ...the overall disease recurrence pattern among patients randomly assigned to receive treatment with or without RT.
A long-term follow-up was performed among the 3,083 patients from the Danish Breast Cancer Cooperative Group 82 b and c trials, except in those already recorded with distant metastases (DM) or contralateral breast cancer (CBC). The end points were LRR, DM, and CBC, and the follow-up continued until DM, CBC, emigration, or death. Information was selected from medical records, general practitioners, and the National Causes of Death Registry. The median potential follow-up time was 18 years.
The 18-year probability of any first breast cancer event was 73% and 59% (P < .001) after no RT and RT, respectively (relative risk RR, 0.68; 95% CI, 0.63 to 0.75). The 18-year probability of LRR (with or without DM) was 49% and 14% (P < .001) after no RT and RT, respectively (RR, 0.23; 95% CI, 0.19 to 0.27). The 18-year probability of DM subsequent to LRR was 35% and 6% (P < .001) after no RT and RT, respectively (RR, 0.15; 95% CI, 0.11 to 0.20), whereas the probability of any DM was 64% and 53% (P < .001) after no RT versus RT, respectively (RR, 0.78; 95% CI, 0.71 to 0.86).
Postmastectomy RT changes the disease recurrence pattern in high-risk breast cancer patients; fewer patients have LRR as first site of recurrence, and overall fewer patients have DM.
Single nucleotide polymorphisms (SNPs) in genes related to the biological response to radiation injury may affect clinical normal tissue radiosensitivity. This study investigates whether seven ...selected SNPs in five candidate genes influence risk of subcutaneous fibrosis and telangiectasia after radiotherapy.
The 41 patients included in this study were given post-mastectomy radiotherapy in 1978–1982 and subsequently evaluated in detail with regard to several different normal tissue reactions. SNPs in
TGFB1 (codons 10, 25 and position −509),
SOD2 (codon 16),
XRCC3 (codon 241),
XRCC1 (codon 399) and
APEX (codon 148) were analyzed by PCR and single nucleotide primer extension. Dose–response curves were established for subcutaneous fibrosis and telangiectasia in patients with different genotypes. Differences in radiosensitivity were quantified in terms of ED
50 values and enhancement ratios.
For
TGFB1, the Pro/Pro genotype in codon 10 and the T/T genotype in position −509 correlated positively with risk of subcutaneous fibrosis. The
SOD 2 codon 16 Val/Ala genotype was associated with increased risk of subcutaneous fibrosis when compared to the Val/Val genotype. The Thr/Thr genotype in
XRCC3 codon 241 correlated with increased risk of subcutaneous fibrosis as well as telangiectasia. The Arg/Arg genotype in
XRCC1 codon 399 was associated with increased risk of radiation-induced subcutaneous fibrosis. For these polymorphisms, enhancement ratios between 1.09 and 1.25 were found. Combined analysis of multiple SNPs demonstrated that the risk of subcutaneous fibrosis correlated with the number of risk alleles in such a manner that patients with few risk alleles exhibited a remarkable degree of radioresistance.
The present study established significant correlations between five SNPs and risk of radiation-induced normal tissue reactions. These findings support the assumption that clinical normal tissue radiosensitivity should be regarded as a phenomenon dependent on the combined effect of variation in several genes and indicate that models based on multiple genetic markers may have the potential to predict normal tissue responses after radiotherapy.
Background and purpose: Hypoxic tumor cells are known to be relatively radioresistant. The aim of the study was to correlate oxygenation status and radiation response in advanced squamous cell ...carcinomas of head and neck.
Methods and patients: Pretreatment oxygenation status was measured in 34 lymph nodes and one primary tumor neck using oxygen electrodes. The primary oxygenation endpoint was the fraction of pO
2 values less than 2.5 mmHg. Patients received standardized, conventional, external radiotherapy 66–68 Gy in 33–34 fractions.
Results: Sixteen patients had loco-regional failure. Among these 16 patients the median of the fraction of pO
2 values less than 2.5 mmHg was 22% (range 0–95%) as compared to 6% (range 0–51%) among patients with loco-regional tumor control. When separating all 35 patients by the median of the fraction of pO
2 values less than 2.5 mmHg and comparing the 2 years actuarial tumor control probability using Kaplan-Meier estimates, the most hypoxic subgroup had significantly lower loco-regional tumor control (
P=0.013, Logrank test). By univariate regression analysis the fraction of pO
2 values less than 2.5 mmHg was found to be significant as continuous variable (
P=0.010). Finally, by Cox multiple regression analysis the fraction of pO
2 values less than 2.5 mmHg was found to be the strongest independent variable in predicting radiation response when using tumor control in the site of pO
2 assessment as treatment endpoint (
P=0.018).
Conclusion: These results suggest that pretreatment tumor oxygenation status is predictive of radiation response, when using the fraction of pO
2 values less than 2.5 mmHg as endpoint.
In the DBCG 82 b&c trials, 3083 patients with stages II and III breast cancer were randomised to receive post-mastectomy radiotherapy (RT) versus no RT in addition to systemic therapy. The study ...showed a decrease in loco-regional recurrences and an improved survival in patients receiving RT. The aim of the present study was to identify risk factors for loco-regional recurrence (LRR), to evaluate the treatment of LRR and to examine the prognosis after LRR.
The 18-year probabilities of LRR were calculated for different prognostic factors using the Kaplan–Meier method. The efficacy of different LRR treatments was compared. The 5-year survival and distant metastases (DM) probability after LRR was calculated with regard to initial randomization group, primary tumor and recurrence related variables.
Of the 3083 patients, 535 had a LRR alone as first site of failure. In univariate analyses, large primary tumor size, ductal carcinoma, high malignancy grade, fascia invasion, few removed nodes, many positive nodes and extracapsular invasion were all risk factors for developing LRR. Combined treatment with surgery and RT at the time of LRR increased the persistent loco-regional control. The 5-year probability of subsequent DM was 73% irrespective of initial randomization group. In multivariate analysis, large primary tumor size, many positive nodes, extracapsular invasion, supra/infraclaviculary failures, multiple LRR and a short interval less than 2 years to first LRR were poor prognostic factors for survival.
Twenty-seven percent of LRR patients had no DM 5 years after failure. Initial randomization group did not alter the prognosis after LRR. Combined treatment of the LRR with surgery and RT improved persistent loco-regional control compared with surgery or RT alone.
Purpose: A multicenter randomized and balanced double-blind trial with the objective of assessing the efficacy and tolerance of nimorazole given as a hypoxic radiosensitizer in conjunction with ...primary radiotherapy of invasive carcinoma of the supraglottic larynx and pharynx.
Patients and treatment: Between January 1986 and September 1990, 422 patients (414 eligible) with pharynx and supraglottic larynx carcinoma were double-blind randomized to receive the hypoxic cell radiosensitizer nimorazole, or placebo, in association with conventional primary radiotherapy (62–68 Gy, 2 Gy per fraction, five fractions per week). The median observation time was 112 months.
Results: Univariate analysis showed that the outcome (5-year actuarial loco-regional tumor control) was significantly related to T-classification (T1–T2 48% versus T3–T4 36%,
P=0.0008), neck-nodes (N− 53% versus N+ 33%), pre-irradiation hemoglobin (Hb) concentration (high 46% versus low 37%,
P=0.02) and sex (females 51% versus males 38%,
P=0.03). Overall the nimorazole group showed a significantly better loco-regional control rate than the placebo group (49 versus 33%,
P=0.002). A similar significant benefit of nimorazole was observed for the end-points of final loco-regional control (including surgical salvage) and cancer-related deaths (52 versus 41%,
P=0.002). This trend was also found in the overall survival but to a lesser, non-significant extent (26 versus 16%, 10-year actuarial values,
P=0.32). Cox multivariate regression analysis showed the most important prognostic parameters for loco-regional control to be positive neck nodes (relative risk 1.84 (1.38–2.45)), T3–T4 tumor (relative risk 1.65 (1.25–2.17)) and nimorazole (relative risk 0.69 (0.52–0.90)). The same parameters were also significantly related to the probability of dying from cancer. The compliance to radiotherapy was good and 98% of the patients received the planned dose. Late radiation-related morbidity was observed in 10% of the patients, irrespective of nimorazole treatment. Drug-related side-effects were minor and tolerable with transient nausea and vomiting being the most frequent complications.
Conclusion: Nimorazole significantly improves the effect of radiotherapeutic management of supraglottic and pharynx tumors and can be given without major side-effects.
Risk factors for local and distant recurrence after breast-conserving therapy and mastectomy were compared to define guidelines for the decision making between both treatments.
The data of two ...randomized clinical trials for stage I and II breast cancer patients were pooled. The total number of patients in the study was 1,772, of whom 879 underwent breast conservation, and 893, modified radical mastectomy. Representative slides of the primary tumor were available for histopathologic review in 1,610 cases (91%).
There were 79 patients with local recurrence after breast-conservation and 80 after mastectomy, the 10-year rates being 10% (95% confidence interval CI, 8% to 13%) and 9% (95% CI, 7% to 12%), respectively. Age no more than 35 years (compared with age >60: hazard ratio HR, 9.24; 95% CI, 3.74 to 22.81) and an extensive intraductal component (HR, 2.52; 95% CI, 1.26 to 5.00) were significantly associated with an increased risk of local recurrence after breast-conserving therapy. Vascular invasion was predictive of the risk of local recurrence, irrespective of the type of primary treatment (P <.01). Tumor size, nodal status, high histologic grade, and vascular invasion were all highly significant predictors of distant disease after breast-conserving therapy and mastectomy (P <.01). Age no more than 35 years and microscopic involvement of the excision margin were additional independent predictors of distant disease after breast-conserving therapy (P <.01).
Age no more than 35 years and the presence of an extensive intraductal component are associated with an increased risk of local recurrence after breast-conserving therapy. Vascular invasion causes a higher risk of local recurrence after mastectomy as well as after breast-conserving therapy and should therefore not be used for deciding between the two treatments.
