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1.  Concurrent chemoradiotherapy in adjuvant treatment of breast cancer 
Background
The optimal sequencing of chemotherapy and radiotherapy after breast surgery was largely studied but remains controversial. Concurrent chemo-radiotherapy is a valuable method for adjuvant treatment of breast cancer which is under ongoing research program in our hospital. We are evaluating the feasibility of the concomitant use of chemotherapy retrospectively.
Methods
Two hundred forty four women having breast cancer were investigated in a retrospective study. All patients were either treated by radical surgery or breast conservative surgery. The study compares two adjuvant treatments associating concomitant chemotherapy and radiotherapy. In the first group (group A) the patients were treated by chemotherapy and radiotherapy in concomitant way using anthracycline (n = 110). In the second group (group B) the patients were treated by chemotherapy and radiotherapy in concomitant way using CMF treatment (n = 134). Chemotherapy was administered in six cycles, one each 3 weeks. Radiotherapy delivered a radiation dose of 50 Gy on the whole breast (or on the external wall) and/or on the lymphatic region. The Kaplan-Meier method was used to estimate the rates of disease free survival, loco-regional recurrence-free survival and overall survival. The Pearson Khi2 test was used to analyse the homogeneity between the two groups. The log-rank test was used to evaluate the differences between the two groups A and B.
Results
After 76.4 months median follow-up (65.3 months mean follow up), only one patient relapsed to loco-regional breast cancer when the treatment was based on anthracycline. However, 8 patients relapsed to loco-regional breast cancer when the treatment was based on CMF. In the anthracycline group, the disease free survival after 5 years, was 80.4% compared to 76.4% in the CMF group (Log-rank test: p = 0.136). The overall survival after 5 years was 82.5% and 81.1% in the anthracycline and CMF groups respectively (Log-rank test: p = 0.428). The loco-regional free survival at 5 years was equal to 98.6% in group A and 94% in group B (Log-rank test: p = 0,033). The rate of grade II and grade III anaemia was 13.9% and 6.7% in anthracycline group and CMF group respectively (Khi2-test: p = 0.009). The rate of grade II and grade III skin dermatitis toxicity was 4.5% in the group A and 0% in the group B (Khi2-test: p = 0.013).
Conclusion
From the 5 years retrospective investigation we showed similar disease free survival and overall survival in the two concurrent chemo-radiotherapy treatments based on anthracycline and CMF. However in the loco-regional breast cancer the treatment based on anthracycline was significantly better than that of the treatment based on CMF. There was more haematological and skin dermatitis toxicity in the anthracycline group.
doi:10.1186/1748-717X-4-12
PMCID: PMC2679760  PMID: 19351405
2.  Sequencing chemotherapy and radiotherapy in locoregional advanced breast cancer patients after mastectomy – a retrospective analysis 
BMC Cancer  2008;8:114.
Background
Combined chemo- and radiotherapy are established in breast cancer treatment. Chemotherapy is recommended prior to radiotherapy but decisive data on the optimal sequence are rare. This retrospective analysis aimed to assess the role of sequencing in patients after mastectomy because of advanced locoregional disease.
Methods
A total of 212 eligible patients had a stage III breast cancer and had adjuvant chemotherapy and radiotherapy after mastectomy and axillary dissection between 1996 and 2004. According to concerted multi-modality treatment strategies 86 patients were treated sequentially (chemotherapy followed by radiotherapy) (SEQgroup), 70 patients had a sandwich treatment (SW-group) and 56 patients had simultaneous chemoradiation (SIM-group) during that time period. Radiotherapy comprised the thoracic wall and/or regional lymph nodes. The total dose was 45–50.4 Gray. As simultaneous chemoradiation CMF was given in 95.4% of patients while in sequential or sandwich application in 86% and 87.1% of patients an anthracycline-based chemotherapy was given.
Results
Concerning the parameters nodal involvement, lymphovascular invasion, extracapsular spread and extension of the irradiated region the three treatment groups were significantly imbalanced. The other parameters, e.g. age, pathological tumor stage, grading and receptor status were homogeneously distributed. Looking on those two groups with an equally effective chemotherapy (EC, FEC), the SEQ- and SW-group, the sole imbalance was the extension of LVI (57.1 vs. 25.6%, p < 0.0001).
5-year overall- and disease free survival were 53.2%/56%, 38.1%/32% and 64.2%/50%, for the sequential, sandwich and simultaneous regime, respectively, which differed significantly in the univariate analysis (p = 0.04 and p = 0.03, log-rank test). Also the 5-year locoregional or distant recurrence free survival showed no significant differences according to the sequence of chemo- and radiotherapy. In the multivariate analyses the sequence had no independent impact on overall survival (p = 0.2) or disease free survival (p = 0.4). The toxicity, whether acute nor late, showed no significant differences in the three groups. The grade III/IV acute side effects were 3.6%, 0% and 3.5% for the SIM-, SW- and SEQ-group. By tendency the SIM regime had more late side effects.
Conclusion
No clear advantage can be stated for any radio- and chemotherapy sequence in breast cancer therapy so far. This could be confirmed in our retrospective analysis in high-risk patients after mastectomy. The sequential approach is recommended according to current guidelines considering a lower toxicity.
doi:10.1186/1471-2407-8-114
PMCID: PMC2377278  PMID: 18433485
3.  Hypofractionated radiotherapy and adjuvant chemotherapy do not increase radiation-induced dermatitis in breast cancer patients 
Current Oncology  2010;17(5):22-27.
Purpose
Radiation-induced dermatitis is a common side effect of breast irradiation, with hypofractionation being a well-known risk factor. In the context of the widespread adoption of hypofractionated breast radiotherapy, we evaluated the effect of hypofractionated radiotherapy on the incidence of skin toxicity in patients receiving adjuvant chemotherapy.
Patients and Methods
We retrospectively reviewed the records of patients with breast cancer treated from 2004 to 2006 at a single institution. Patients undergoing lumpectomy with or without adjuvant chemotherapy followed by hypofractionated radiotherapy consisting of 42.4 Gy in 16 fractions were included in the study. Using cosmetic and skin toxicity scales, all patients were evaluated weekly during treatment and at scheduled follow-up visits with the radiation oncologist.
Results
During the study period, 162 patients underwent radiotherapy, and 30% of those (n = 48) received chemotherapy. Radiotherapy boost to the tumour bed was more common in the chemotherapy group [n = 20 (42%)] than in the radiotherapy-alone group [n = 30 (26%)]. We observed no statistically significant difference between the groups with regard to acute skin toxicity of grade 3 or higher (2.1% in the chemotherapy group vs. 4.4% in the radiation-alone group, p = 0.67) or of grades 1–2 toxicity (62.5% vs. 51.7% respectively, p = 0.23). There was also no significant difference in late grade 3 or higher skin toxicity between the groups (2.1% vs. 0% respectively, p = 0.30) or in grades 1–2 toxicity (20.8% vs. 25.5% respectively, p = 0.69). Similarly, excellent or good cosmetic result scores were similar in both groups (p = 0.80)
Conclusions
In our single-institution review, we observed no adverse effects of chemotherapy in combination with hypofractionated whole-breast irradiation. Further investigations are necessary to better elucidate the effects of chemotherapy on skin toxicity in the context of hypofractionated irradiation.
PMCID: PMC2949365  PMID: 20975875
Breast cancer; hypofractionated radiotherapy; chemotherapy; skin toxicity
4.  Clinical practice guidelines for the care and treatment of breast cancer: 15. Treatment for women with stage III or locally advanced breast cancer 
Objective
To define the optimal treatment for women with stage III or locally advanced breast cancer (LABC).
Evidence
Systematic review of English-language literature retrieved from MEDLINE (1984 to June 2002) and CANCERLIT (1983 to June 2002). A nonsystematic review of the literature was continued through December 2003.
Recommendations
· The management of LABC requires a combined modality treatment approach involving surgery, radiotherapy and systemic therapy.
Systemic therapy: chemotherapy
Operable tumours
· Patients with operable stage IIIA disease should be offered chemotherapy. They should receive adjuvant chemotherapy following surgery, or primary chemotherapy followed by locoregional management.
· Chemotherapy should contain an anthracycline. Acceptable regimens are 6 cycles of FAC, CAF, CEF or FEC. Taxanes are under intense investigation.
Inoperable tumours
· Patients with stage IIIB or IIIC disease, including those with inflammatory breast cancer and those with isolated ipsilateral internal mammary or supraclavicular lymph-node involvement, should be treated with primary anthracycline-based chemotherapy.
· Acceptable chemotherapy regimens are FAC, CAF, CEF or FEC. Taxanes are under intense investigation.
· Patients with stage IIIB or IIIC disease who respond to primary chemotherapy should be treated until the response plateaus or to a maximum of 6 cycles (minimum 4 cycles). Patients with stage IIIB disease should then undergo definitive surgery and irradiation. The locoregional management of patients with stage IIIC disease who respond to chemotherapy should be individualized. In patients with stage IIIB or IIIC disease who achieve maximum response with fewer than 6 cycles, further adjuvant chemotherapy can be given following surgery and irradiation. Patients whose tumours do not respond to primary chemotherapy can be treated with taxane chemotherapy or can proceed directly to irradiation followed by modified radical mastectomy, if feasible.
Systemic therapy: hormonal therapy
Operable and inoperable tumours
· Tamoxifen for 5 years should be recommended to pre- and postmenopausal women whose tumours are hormone responsive.
Locoregional management
Operable tumours
· Patients with stage IIIA disease should receive both modified radical mastectomy (MRM) and locoregional radiotherapy if feasible. They may be managed with MRM followed by chemotherapy and locoregional radiotherapy, or chemotherapy first followed by MRM and locoregional radiotherapy. Breast-conserving surgery is currently not a standard approach.
· Locoregional radiotherapy should be delivered to the chest wall and to the supraclavicular and axillary nodes. The role of internal mammary irradiation is unclear.
Inoperable tumours
· Patients with stage IIIB disease who respond to chemotherapy should receive surgery plus locoregional radiotherapy.
· The locoregional management of patients with stage IIIC disease who respond to chemotherapy is unclear and should be individualized.
· Patients whose disease remains inoperable following chemotherapy should receive locoregional radiotherapy with subsequent surgery, if feasible.
Validation
The authors' original text was revised by members of the Steering Committee on Clinical Practice Guidelines for the Care and Treatment of Breast Cancer. Subsequently, feedback was provided by 9 oncologists from across Canada. The final document was approved by the steering committee.
Sponsor
The Steering Committee on Clinical Practice Guidelines for the Care and Treatment of Breast Cancer was convened by Health Canada.
Completion date
December 2003.
doi:10.1503/cmaj.1030944
PMCID: PMC359433  PMID: 15023926
5.  High-dose accelerated hypofractionated three-dimensional conformal radiotherapy (at 3 Gy/fraction) with concurrent vinorelbine and carboplatin chemotherapy in locally advanced non-small-cell lung cancer: a feasibility study 
Background
Increasing the radiotherapy dose can result in improved local control for non-small-cell lung cancer (NSCLC) and can thereby improve survival. Accelerated hypofractionated radiotherapy can expose tumors to a high dose of radiation in a short period of time, but the optimal treatment regimen remains unclear. The purpose of this study was to evaluate the feasibility of utilizing high-dose accelerated hypofractionated three-dimensional conformal radiotherapy (at 3 Gy/fraction) with concurrent vinorelbine (NVB) and carboplatin (CBP) chemotherapy for the treatment of local advanced NSCLC.
Methods
Untreated patients with unresectable stage IIIA/IIIB NSCLC or patients with a recurrence of NSCLC received accelerated hypofractionated three-dimensional conformal radiotherapy. The total dose was greater than or equal to 60 Gy. The accelerated hypofractionated radiotherapy was conducted once daily at 3 Gy/fraction with 5 fractions per week, and the radiotherapy was completed in 5 weeks. In addition to radiotherapy, the patients also received at least 1 cycle of a concurrent two-drug chemotherapy regimen of NVB and CBP.
Results
A total of 26 patients (19 previously untreated cases and 7 cases of recurrent disease) received 60Gy-75Gy radiotherapy with concurrent chemotherapy. All of the patients underwent evaluations for toxicity and preliminary therapeutic efficacy. There were no treatment-related deaths within the entire patient group. The major acute adverse reactions were radiation esophagitis (88.5%) and radiation pneumonitis (42.3%). The percentages of grade III acute radiation esophagitis and grade III radiation pneumonitis were 15.4% and 7.7%, respectively. Hematological toxicities were common and did not significantly affect the implementation of chemoradiotherapy after supportive treatment. Two patients received high dose of 75 Gy had grade III late esophageal toxicity, and none had grade IV and above. Grade III and above late lung toxicity did not occur.
Conclusion
High-dose accelerated hypofractionated three-dimensional conformal radiotherapy with a dose of 60 Gy or greater with concurrent NVB and CBP chemotherapy might be feasible. However esophagus toxicity needs special attention. A phase I trial is recommended to obtain the maximum tolerated radiation dose of accelerated hypofractionated radiotherapy with concurrent chemotherapy.
doi:10.1186/1748-717X-8-198
PMCID: PMC3751137  PMID: 23937855
Non-small-cell lung cancer; Accelerated hypofractionated radiotherapy; Concurrent chemoradiotherapy; Three-dimensional conformal radiotherapy; Vinorelbine; Carboplatin
6.  The combination of radiotherapy, adjuvant chemotherapy (cyclophosphamide-doxorubicin-ftorafur) and tamoxifen in stage II breast cancer. Long-term follow-up results of a randomised trial. 
British Journal of Cancer  1992;66(6):1171-1176.
Two hundred patients with node positive stage II breast cancer were randomised to four groups after radical mastectomy and axillary evacuation: (1) Postoperative radiotherapy, (2) Adjuvant chemotherapy with eight courses of CAFt (cyclophosphamide 500 mg m-2 + doxorubicin 40 mg/m-2 + ftorafur 20 mg kg-1 orally day 1-14) every fourth week, (3) Postoperative radiotherapy and adjuvant chemotherapy and (4) postoperative radiation, adjuvant chemotherapy and tamoxifen 40 mg daily for 2 years. Thirty-two per cent of the patients discontinued treatment due to GI-toxicity, while 26% required dose reductions due to leukopenia. Radiation pneumonitis was more frequent after the combination of postoperative radiotherapy with chemotherapy. There was a better relapse-free survival in the groups receiving chemotherapy compared to radiotherapy alone (P = 0.05), which was highly significant in a multivariate Cox analysis (P = 0.004). No significant survival differences were seen. Tamoxifen had no clear overall effect but there were better relapse-free (P = 0.04) and overall (P = 0.004) survival with tamoxifen in estrogen receptor positive patients, while estrogen receptor negative patients had a somewhat poorer survival (P = 0.07) after tamoxifen. Local control was better (NS) after the combination (93%) radiotherapy and chemotherapy compared to either treatment alone (76% with radiotherapy and 74% with chemotherapy at 5 years).
PMCID: PMC1978025  PMID: 1457360
7.  Breast cancer (non-metastatic) 
Clinical Evidence  2011;2011:0102.
Introduction
Breast cancer affects at least 1 in 10 women in the UK, but most present with primary operable disease, which has an 80% 5-year survival rate overall.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of interventions after breast-conserving surgery for ductal carcinoma in situ? What are the effects of treatments for primary operable breast cancer? What are the effects of interventions in locally advanced breast cancer (stage 3B)? We searched: Medline, Embase, The Cochrane Library, and other important databases up to April 2009 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 83 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: adding chemotherapy (cyclophosphamide/methotrexate/fluorouracil and/or anthracycline and/or taxane-based regimens), or hormonal treatment to radiotherapy; adjuvant treatments (aromatase inhibitors, adjuvant anthracycline regimens, tamoxifen); axillary clearance; axillary dissection plus sentinel node dissection; axillary radiotherapy; axillary sampling; combined chemotherapy plus tamoxifen; chemotherapy plus monoclonal antibody (trastuzumab); extensive surgery; high-dose chemotherapy; hormonal treatment; less extensive mastectomy; less than whole-breast radiotherapy plus breast-conserving surgery; multimodal treatment; ovarian ablation; primary chemotherapy; prolonged adjuvant combination chemotherapy; radiotherapy (after breast-conserving surgery, after mastectomy, plus tamoxifen after breast-conserving surgery, to the internal mammary chain, and to the ipsilateral supraclavicular fossa, and total nodal radiotherapy); sentinel node biopsy; and standard chemotherapy regimens.
Key Points
Breast cancer affects at least 1 in 10 women in the UK, but most present with primary operable disease, which has an 80% 5-year survival rate overall.
In women with ductal carcinoma in situ (DCIS), radiotherapy reduces local recurrence and invasive carcinoma after breast-conserving surgery. The role of tamoxifen added to radiotherapy for DCIS remains unclear because of conflicting results.
In women with primary operable breast cancer, survival may be increased by full surgical excision, tamoxifen, chemotherapy, radiotherapy, ovarian ablation, or trastuzumab (in women who over-express HER2/neu oncogene). Incomplete excision may increase the risk of local recurrence, but less-extensive mastectomy that excises all local disease is as effective as radical mastectomy at prolonging survival, with better cosmetic results. Axillary clearance (removal of all axillary lymph nodes) achieves local disease control, but has not been shown to increase survival, and can cause arm lymphoedema. Sentinel lymph node biopsy or 4-node sampling may adequately stage the axilla with less morbidity compared with axillary clearance. Adjuvant tamoxifen reduces the risk of recurrence and death in women with oestrogen-positive tumours. Primary chemotherapy may facilitate successful breast-conserving surgery instead of mastectomy. Adjuvant combination chemotherapy improves survival compared with no chemotherapy, with greatest benefit likely with anthracycline-based regimens at standard doses for 4 to 6 months.Radiotherapy decreases recurrence and mortality after breast-conserving surgery. Post-mastectomy radiotherapy for women who are node-positive or at high risk of recurrence decreases recurrence and mortality. Adjuvant aromatase inhibitors improve disease-free survival compared with tamoxifen, but their effect on overall survival is unclear. Adjuvant taxane-based regimens may improve disease-free survival over standard anthracycline-based therapy.
In women with locally advanced breast cancer, radiotherapy may be as effective as surgery or tamoxifen at increasing survival and local disease control. Adding tamoxifen or ovarian ablation to radiotherapy increases survival compared with radiotherapy alone, but adding chemotherapy may not reduce recurrence or mortality compared with radiotherapy alone.We don't know if chemotherapy alone improves survival in women with locally advanced breast cancer as we found few trials.
PMCID: PMC3217212  PMID: 21718560
8.  Breast cancer (non-metastatic) 
Clinical Evidence  2007;2007:0102.
Introduction
Breast cancer affects at least 1 in 10 women in the UK, but most present with primary operable disease, which has an 80% 5-year survival rate overall.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of interventions after breast-conserving surgery for ductal carcinoma in situ? What are the effects of treatments for primary operable breast cancer? What are the effects of interventions in locally advanced breast cancer (stage IIIB)? We searched: Medline, Embase, The Cochrane Library and other important databases up to February 2006 (BMJ Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 79 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: adding chemotherapy (cyclophosphamide/methotrexate/ fluorouracil and/or anthracycline and/or taxane-based regimens), or hormonal treatment to radiotherapy; adjuvant treatments (aromatase inhibitors, adjuvant anthracycline regimens, tamoxifen); axillary clearance; axillary dissection plus sentinel node dissection; axillary radiotherapy; axillary sampling; combined chemotherapy plus tamoxifen; chemotherapy plus monoclonal antibody (trastuzumab); extensive surgery; high-dose chemotherapy; hormonal treatment; less extensive mastectomy; less than whole breast radiotherapy plus breast conserving surgery; multimodal treatment; ovarian ablation; primary chemotherapy; prolonged adjuvant combination chemotherapy; radiotherapy (after breast-conserving surgery, after mastectomy, plus tamoxifen after breast-conserving surgery, to the internal mammary chain, and to the ipsilateral supraclavicular fossa, and total nodal radiotherapy); sentinel node biopsy; and standard chemotherapy regimens.
Key Points
Breast cancer affects at least 1 in 10 women in the UK, but most present with primary operable disease, which has an 80% 5-year survival rate overall.
In women with ductal carcinoma in situ, radiotherapy reduces local recurrence and invasive carcinoma after breast-conserving surgery, but may not improve survival.
In women with primary operable breast cancer, survival may be increased by full surgical excision, tamoxifen, chemotherapy, radiotherapy, ovarian ablation or trastuzumab (in women who overexpress HER2/neu oncogene). Incomplete excision may increase the risk of local recurrence, but less-extensive mastectomy that excises all local disease is as effective as radical mastectomy at prolonging survival, with better cosmetic results. Axillary clearance (removal of all axillary lymph nodes) achieves local disease control, but has not been shown to increase survival, and can cause arm lymphoedema. Sentinel lymph node biopsy or 4-node sampling may adequately stage the axilla with less morbidity compared with axillary clearance. Adjuvant tamoxifen reduces the risk of recurrence and death in women with oestrogen-positive tumours, but adverse effects begin to outweigh benefit after 5 years of treatment. Primary chemotherapy may facilitate successful breast-conserving surgery instead of mastectomy. Adjuvant combination chemotherapy improves survival compared with no chemotherapy, with greatest benefit likely with anthracycline-based regimens at standard doses for 4-6 months.Radiotherapy decreases recurrence and mortality after breast-conserving surgery. Post-mastectomy radiotherapy for women who are node-positive or at high risk of recurrence decreases recurrence and mortality, but may increase mortality in node-negative women. Adjuvant aromatase inhibitors improve disease-free survival compared with tamoxifen, but their effect on overall survival is unclear.Adjuvant taxoid regimens may improve disease-free survival over standard anthracycline-based therapy.
In women with locally advanced breast cancer, radiotherapy may be as effective as surgery or tamoxifen at increasing survival and local disease control. Adding tamoxifen or ovarian ablation to radiotherapy increases survival compared with radiotherapy alone, but adding chemotherapy may not reduce recurrence or mortality compared with radiotherapy alone.Chemotherapy alone, while widely used, does not improve survival in women with locally advanced breast cancer.
PMCID: PMC2943780  PMID: 19450345
9.  Neoadjuvant-intensified treatment for rectal cancer: Time to change? 
AIM: To investigate whether neoadjuvant-intensified radiochemotherapy improved overall and disease-free survival in patients with locally advanced rectal cancer.
METHODS: Between January 2007 and December 2011, 80 patients with histologically confirmed rectal adenocarcinoma were enrolled. Tumors were clinically classified as either T3 or T4 and by the N stage based on the presence or absence of positive regional lymph nodes. Patients received intensified combined modality treatment, consisting of neoadjuvant radiation therapy (50.4-54.0 Gy) and infusional chemotherapy (oxaliplatin 50 mg/m2) on the first day of each week, plus five daily continuous infusions of fluorouracil (200 mg/m2 per die) from the first day of radiation therapy until radiotherapy completion. Patients received five or six cycles of oxaliplatin based on performance status, clinical lymph node involvement, and potential risk of a non-sphincter-conserving surgical procedure. Surgery was planned 7 to 9 wk after the end of radiochemotherapy treatment; adjuvant chemotherapy treatment was left to the oncologist’s discretion and was recommended in patients with positive lymph nodes. After treatment, all patients were monitored every three months for the first year and every six months for the subsequent years.
RESULTS: Of the 80 patients enrolled, 75 patients completed the programmed neoadjuvant radiochemotherapy treatment. All patients received the radiotherapy prescribed total dose; five patients suspended chemotherapy indefinitely because of chemotherapy-related toxicity. At least five cycles of oxaliplatin were administered to 73 patients. Treatment was well tolerated with high compliance and a good level of toxicity. Most of the acute toxic effects observed were classified as grades 1-2. Proctitis grade 2 was the most common symptom (63.75%) and the earliest manifestation of acute toxicity. Acute toxicity grades 3-4 was reported in 30% of patients and grade 3 or 4 diarrhoea reported in just three patients (3.75%). Seventy-seven patients underwent surgery; low anterior resection was performed in 52 patients, Miles’ surgery in 11 patients and total mesorectal excision in nine patients. Fifty patients showed tumor downsizing ≥ 50% pathological downstaging in 88.00% of tumors. Out of 75 patients surviving surgery, 67 patients (89.33%) had some form of downstaging after preoperative treatment. A pathological complete response was achieved in 23.75% of patients and a nearly pathologic complete response (stage ypT1ypN0) in six patients. An involvement of the radial margin was never present. During surgery, intra-abdominal metastases were found in only one patient (1.25%). Initially, 45 patients required an abdominoperineal resection due to a tumor distal margin ≤ 5 cm from the anal verge. Of these patients, only seven of them underwent Miles’ surgery and sphincter preservation was guaranteed in 84.50% of patients in this subgroup. Fourteen patients received postoperative chemotherapy. In the full analysis of enrolled cohort, eight of the 80 patients died, with seven deaths related to rectal cancer and one to unrelated causes. Local recurrences were observed in seven patients (8.75%) and distant metastases in 17 cases (21.25%). The five-year rate of overall survival rate was 90.91%. Using a median follow-up time of 28.5 mo, the cumulative incidence of local recurrences was 8.75%, and the overall survival and disease-free survival rates were 90.00% and 70.00%, respectively.
CONCLUSION: The results of this study suggest oxaliplatin chemotherapy has a beneficial effect on overall survival, likely due to an increase in local tumor control.
doi:10.3748/wjg.v19.i20.3052
PMCID: PMC3662944  PMID: 23716984
Rectal cancer; Neoadjuvant treatment; Intensified radiochemotherapy; Oxaliplatin; Fluorouracil
10.  Thermal boost combined with interstitial brachytherapy in breast conserving therapy – Assessment of early toxicity 
Background
Hyperthermia (HT) causes a direct damage to cancerous cells and/or sensitize them to radiotherapy with usually minimal injury to normal tissues. Adjuvant HT is probably one of the most effective radiation sensitizers known and works best when delivered simultaneously with radiation. In breast conserving therapy, irradiation has to minimize the risk of local relapse within the treated breast, especially in an area of a tumor bed. Brachytherapy boost reduces 5-year local recurrence rate to mean 5,5%, so there still some place for further improvement. The investigated therapeutic option is an adjuvant single session of local HT (thermal boost) preceding standard CT-based multicatheter interstitial HDR brachytherapy boost in order to increase the probability of local cure.
Aim
To report the short-term results in regard to early toxicity of high-dose-rate (HDR) brachytherapy (BT) boost with or without interstitial microwave hyperthermia (MV HT) for early breast cancer patients treated with breast conserving therapy (BCT).
Materials and methods
Between February 2006 and December 2007, 57 stage IA–IIIA breast cancer patients received a 10 Gy HDR BT boost after conservative surgery and 42.5–50 Gy whole breast irradiation (WBI) ± adjuvant chemotherapy. 32 patients (56.1%) were treated with additional pre-BT single session of interstitial MW HT to a tumor bed (multi-catheter technique). Reference temperature was 43 °C and therapeutic time (TT) was 1 h. Incidence, severity and duration of radiodermatitis, skin oedema and skin erythema in groups with (I) or without HT (II) were assessed, significant p-value ≤ 0.05.
Results
Median follow-up was 40 months. Local control was 100% and distant metastasis free survival was 91.1%. HT sessions (median): reference temperature 42.2 °C, therapeutic time (TT) 61.4 min, total thermal dose 42 min and a gap between HT and BT 30 min. Radiodermatitis grades I and II occurred in 24 and 6 patients, respectively, differences between groups I and II were not significant. Skin oedema and erythema occurred in 48 (85.7%) and 36 (64.3%) cases, respectively, and were equally distributed between the groups. The incidence and duration of skin oedema differed between the subgroups treated with different fractionation protocols of WBI, p = 0.006. Skin oedema was present up to 12 months. No difference in pattern of oedema regression between groups I and II was observed, p = 0.933.
Conclusion
Additional thermal boost preceding standard HDR BT boost has a potential of further improvement in breast cancer local control in BCT. Pre-BT hyperthermia did not increase early toxicity in patients treated with BCT and was well tolerated. All side effects of combined treatment were transient and were present for up to 12 months. The increase in incidence of skin oedema was related to hypofractionated protocols of WBI. The study has to be randomized and continued on a larger group of breast cancer patients to verify the potential of local control improvement and to assess the profile of late toxicity.
doi:10.1016/j.rpor.2011.02.004
PMCID: PMC3863141  PMID: 24376963
Hyperthermia; Brachytherapy boost; Breast cancer
11.  Sequential chemotherapy and radiotherapy as sandwich therapy for the treatment of high risk endometrial cancer 
Objective
The purpose of this retrospective study was to assess the tolerability and efficacy of sequential chemotherapy and radiotherapy for the treatment of high risk endometrial cancer.
Methods
We conducted a retrospective study of previously untreated high risk endometrial cancer patients who received sequential chemotherapy and radiotherapy in accordance with the sandwich approach from June 2008 until June 2011. High risk endometrial cancer patients underwent complete surgical staging followed by adjuvant therapy encompassing sequential chemotherapy, radiation therapy and consolidation chemotherapy.
Results
The study analysis comprised 32 endometrial cancer patients. All subjects were treated with carboplatin and paclitaxel chemotherapy; currently, 186 cycles have been administered and 94% of patients have completed the planned number of cycles. Grade 3 neutropenia developed in 1 (3.1%) patient; there was no incidence of grade 4 neutropenia. Moreover, we observed grade 3 anemia in four (12.5%) patients and grade 4 anemia in one (3.1%) patient. One (3.1%) patient developed grade 3 thrombocytopenia; grade 4 thrombocytopenia was not observed. Five patients exhibited progressive disease, three of whom have since expired; mean progression free survival and follow-up were 17.4 months and 18.9 months, respectively.
Conclusion
The preliminary results from our study suggest that the sandwich approach to treating high risk endometrial cancer patients is feasible. Hematologic toxicity was well tolerated and non-hematologic toxicity was mild and easily managed. Further study of this novel regimen in a larger patient population with extended follow-up is necessary.
doi:10.3802/jgo.2012.23.1.22
PMCID: PMC3280062  PMID: 22355463
Chemotherapy; Endometrial cancer; Gynecologic oncology; Radiotherapy
12.  Socioeconomic Inequalities in Lung Cancer Treatment: Systematic Review and Meta-Analysis 
PLoS Medicine  2013;10(2):e1001376.
In a systematic review and meta-analysis, Lynne Forrest and colleagues find that patients with lung cancer who are more socioeconomically deprived are less likely to receive surgical treatment, chemotherapy, or any type of treatment combined, compared with patients who are more socioeconomically well off, regardless of cancer stage or type of health care system.
Background
Intervention-generated inequalities are unintended variations in outcome that result from the organisation and delivery of health interventions. Socioeconomic inequalities in treatment may occur for some common cancers. Although the incidence and outcome of lung cancer varies with socioeconomic position (SEP), it is not known whether socioeconomic inequalities in treatment occur and how these might affect mortality. We conducted a systematic review and meta-analysis of existing research on socioeconomic inequalities in receipt of treatment for lung cancer.
Methods and Findings
MEDLINE, EMBASE, and Scopus were searched up to September 2012 for cohort studies of participants with a primary diagnosis of lung cancer (ICD10 C33 or C34), where the outcome was receipt of treatment (rates or odds of receiving treatment) and where the outcome was reported by a measure of SEP. Forty-six papers met the inclusion criteria, and 23 of these papers were included in meta-analysis. Socioeconomic inequalities in receipt of lung cancer treatment were observed. Lower SEP was associated with a reduced likelihood of receiving any treatment (odds ratio [OR] = 0.79 [95% CI 0.73 to 0.86], p<0.001), surgery (OR = 0.68 [CI 0.63 to 0.75], p<0.001) and chemotherapy (OR = 0.82 [95% CI 0.72 to 0.93], p = 0.003), but not radiotherapy (OR = 0.99 [95% CI 0.86 to 1.14], p = 0.89), for lung cancer. The association remained when stage was taken into account for receipt of surgery, and was found in both universal and non-universal health care systems.
Conclusions
Patients with lung cancer living in more socioeconomically deprived circumstances are less likely to receive any type of treatment, surgery, and chemotherapy. These inequalities cannot be accounted for by socioeconomic differences in stage at presentation or by differences in health care system. Further investigation is required to determine the patient, tumour, clinician, and system factors that may contribute to socioeconomic inequalities in receipt of lung cancer treatment.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Lung cancer is the most commonly occurring cancer worldwide and the commonest cause of cancer-related death. Like all cancers, lung cancer occurs when cells begin to grow uncontrollably because of changes in their genes. The most common trigger for these changes in lung cancer is exposure to cigarette smoke. Most cases of lung cancer are non-small cell lung cancer, the treatment for which depends on the “stage” of the disease when it is detected. Stage I tumors, which are confined to the lung, can be removed surgically. Stage II tumors, which have spread to nearby lymph nodes, are usually treated with surgery plus chemotherapy or radiotherapy. For more advanced tumors, which have spread throughout the chest (stage III) or throughout the body (stage IV), surgery generally does not help to slow tumor growth and the cancer is treated with chemotherapy and radiotherapy. Small cell lung cancer, the other main type of lung cancer, is nearly always treated with chemotherapy and radiotherapy but sometimes with surgery as well. Overall, because most lung cancers are not detected until they are quite advanced, less than 10% of people diagnosed with lung cancer survive for 5 years.
Why Was This Study Done?
As with many other cancers, socioeconomic inequalities have been reported for both the incidence of and the survival from lung cancer in several countries. It is thought that the incidence of lung cancer is higher among people of lower socioeconomic position than among wealthier people, in part because smoking rates are higher in poorer populations. Similarly, it has been suggested that survival is worse among poorer people because they tend to present with more advanced disease, which has a worse prognosis (predicted outcome) than early disease. But do socioeconomic inequalities in treatment exist for lung cancer and, if they do, could these inequalities contribute to the poor survival rates among populations of lower socioeconomic position? In this systematic review and meta-analysis, the researchers investigate the first of these questions. A systematic review uses predefined criteria to identify all the research on a given topic; a meta-analysis is a statistical approach that combines the results of several studies.
What Did the Researchers Do and Find?
The researchers identified 46 published papers that studied people with lung cancer in whom receipt of treatment was reported in terms of an indicator of socioeconomic position, such as a measure of income or deprivation. Twenty-three of these papers were suitable for inclusion in a meta-analysis. Lower socioeconomic position was associated with a reduced likelihood of receiving any treatment. Specifically, the odds ratio (chance) of people in the lowest socioeconomic group receiving any treatment was 0.79 compared to people in the highest socioeconomic group. Lower socioeconomic position was also associated with a reduced chance of receiving surgery (OR = 0.68) and chemotherapy (OR = 0.82), but not radiotherapy. The association between socioeconomic position and surgery remained after taking cancer stage into account. That is, when receipt of surgery was examined in early-stage patients only, low socioeconomic position remained associated with reduced likelihood of surgery. Notably, the association between socioeconomic position and receipt of treatment was similar in studies undertaken in countries where health care is free at the point of service for everyone (for example, the UK) and in countries with primarily private insurance health care systems (for example, the US).
What Do These Findings Mean?
These findings suggest that patients in more socioeconomically deprived circumstances are less likely to receive any type of treatment, surgery, and chemotherapy (but not radiotherapy) for lung cancer than people who are less socioeconomically deprived. Importantly, these inequalities cannot be explained by socioeconomic differences in stage at presentation or by differences in health care system. The accuracy of these findings may be affected by several factors. For example, it is possible that only studies that found an association between socioeconomic position and receipt of treatment have been published (publication bias). Moreover, the studies identified did not include information regarding patient preferences, which could help explain at least some of the differences. Nevertheless, these results do suggest that socioeconomic inequalities in receipt of treatment may exacerbate socioeconomic inequalities in the incidence of lung cancer and may contribute to the observed poorer outcomes in lower socioeconomic position groups. Further research is needed to determine the system and patient factors that contribute to socioeconomic inequalities in lung cancer treatment before clear recommendations for changes to policy and practice can be made.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001376.
The US National Cancer Institute provides information about all aspects of lung cancer for patients and health care professionals (in English and Spanish); a monograph entitled Area Socioeconomic Variations in U. S. Cancer Incidence, Mortality, Stage, Treatment, and Survival, 19751999 is available
Cancer Research UK also provides detailed information about lung cancer and links to other resources, such as a policy statement on socioeconomic inequalities in cancer and a monograph detailing cancer and health inequalities in the UK
The UK National Health Service Choices website has a page on lung cancer that includes personal stories about diagnosis and treatment
MedlinePlus provides links to other US sources of information about lung cancer (in English and Spanish)
doi:10.1371/journal.pmed.1001376
PMCID: PMC3564770  PMID: 23393428
13.  Gemcitabine-based or capecitabine-based chemoradiotherapy for locally advanced pancreatic cancer (SCALOP): a multicentre, randomised, phase 2 trial 
The Lancet Oncology  2013;14(4):317-326.
Summary
Background
In the UK, chemotherapy is the standard treatment for inoperable, locally advanced, non-metastatic pancreatic cancer. Chemoradiotherapy is also an acceptable treatment option, for which gemcitabine, fluorouracil, or capecitabine can be used as concurrent chemotherapy agents. We aimed to assess the activity, safety, and feasibility of both gemcitabine-based and capecitabine-based chemoradiotherapy after induction chemotherapy for patients with locally advanced pancreatic cancer.
Methods
In this open-label, randomised, two-arm, phase 2 trial, patients aged 18 years or older with histologically proven, locally advanced pancreatic cancer (with a tumour diameter of 7 cm or less) were recruited from 28 UK centres between Dec 24, 2009 and Oct 25, 2011. After 12 weeks of induction gemcitabine and capecitabine chemotherapy (three cycles of gemcitabine [1000 mg/m2 on days 1, 8, 15 of a 28-day cycle] and capecitabine [830 mg/m2 twice daily on days 1–21 of a 28-day cycle]), patients with stable or responding disease, tumour diameter of 6 cm or less, and WHO performance status 0–1 were randomly assigned to receive a further cycle of gemcitabine and capecitabine chemotherapy followed by either gemcitabine (300 mg/m2 once per week) or capecitabine (830 mg/m2 twice daily, Monday to Friday only), both in combination with radiation (50·4 Gy in 28 fractions). Randomisation (1:1) was done via a central computerised system and used stratified minimisation. The primary endpoint was 9-month progression-free survival, analysed by intention to treat including only those patients with valid CT assessments. This trial is registered with ISRCTN, number 96169987.
Findings
114 patients were registered and 74 were randomly allocated (38 to the gemcitabine group and 36 to the capecitabine group). After 9 months, 22 of 35 assessable patients (62·9%, 80% CI 50·6–73·9) in the capecitabine group and 18 of 35 assessable patients (51·4%, 39·4–63·4) in the gemcitabine group had not progressed. Median overall survival was 15·2 months (95% CI 13·9–19·2) in the capecitabine group and 13·4 months (95% CI 11·0–15·7) in the gemcitabine group (adjusted hazard ratio [HR] 0·39, 95% CI 0·18–0·81; p=0·012). 12-month overall survival was 79·2% (95% CI 61·1–89·5) in the capecitabine group and 64·2 (95% CI 46·4–77·5) in the gemcitabine group. Median progression-free survival was 12·0 months (95% CI 10·2–14·6) in the capecitabine group and 10·4 months (95% CI 8·9–12·5) in the gemcitabine group (adjusted HR 0·60, 95% CI 0·32–1·12; p=0·11). Eight patients in the capecitabine group had an objective response at 26 weeks, as did seven in the gemcitabine group. More patients in the gemcitabine group than in the capecitabine group had grade 3–4 haematological toxic effects (seven [18%] vs none, p=0·008) and non-haematological toxic effects (ten [26%] vs four [12%], p=0·12) during chemoradiation treatment; the most frequent events were leucopenia, neutropenia, and fatigue. Two patients in the capecitabine group progressed during the fourth cycle of induction chemotherapy. Of the 34 patients in the capecitabine group who received chemoradiotherapy, 25 (74%) received the full protocol dose of radiotherapy, compared with 26 (68%) of 38 patients in the gemcitabine group. Quality-of-life scores were not significantly different between the treatment groups.
Interpretation
Our results suggest that a capecitabine-based regimen might be preferable to a gemcitabine-based regimen in the context of consolidation chemoradiotherapy after a course of induction chemotherapy for locally advanced pancreatic cancer. However, these findings should be interpreted with caution because the difference in the primary endpoint was non-significant and the number of patients in the trial was small.
Funding
Cancer Research UK.
doi:10.1016/S1470-2045(13)70021-4
PMCID: PMC3620899  PMID: 23474363
14.  Adjuvant Chemotherapy, a Valuable Alternative Option in Selected Patients with Cervical Cancer 
PLoS ONE  2013;8(9):e73837.
Radiotherapy is the standard treatment for cervical cancer, but causes radiotherapy-induced complications. Recently, chemotherapy has been more extensively utilized. Here, we perform a large-scale comparison of chemotherapy and radiotherapy. From 2002 to 2008, 2,268 patients were grouped according to adjuvant radiotherapy or chemotherapy before and/or after surgery, and we compared the 5-year overall survival (OS) and disease-free survival (DFS) rates, recurrence rates, side effects, quality of life (QoL), and sexual activity. There were no significant differences between the treatment groups for the 5-year OS and DFS rates (OS: p = 0.053, DFS: p = 0.095), although marginally improved outcomes were observed in the chemotherapy group (OS: 86.5% vs. 82.8%; DFS: 84.5% vs. 81.4%). However, patients with early-stage disease, clinical response, and younger age had increased 5-year OS and DFS rates following chemotherapy compared to radiotherapy (p<0.05). The chemotherapy group exhibited significantly lower 5-year recurrence and distant failure rates compared to the radiotherapy group (p<0.001 and p = 0.007, respectively). Nausea and vomiting were the most frequent short-term complications of chemotherapy, whereas bowel and urinary complications were more frequent in the radiotherapy group. Compared to the chemotherapy group, patients who received radiotherapy reported a lower QoL, less frequent sexual activity, and more severe menopausal symptoms (p<0.05). Cervical cancer patients treated with chemotherapy, especially those with early-stage disease, clinical responses, and younger ages, have more positive outcomes, fewer complications, better QoL and sexual activity, suggesting that chemotherapy may be a valuable alternative option for selected patients.
doi:10.1371/journal.pone.0073837
PMCID: PMC3772826  PMID: 24058496
15.  Radical radiotherapy with concurrent weekly cisplatin in loco-regionally advanced squamous cell carcinoma of the head and neck: a single-institution experience 
Head & Neck Oncology  2009;1:17.
Background
The dominant pattern of failure for squamous cell carcinoma of head and neck remains loco-regional, although distant metastases are now being increasingly documented. Radical radiotherapy with concurrent chemotherapy is contemporary standard of care in the non-surgical management of these loco-regionally advanced cancers, based on large randomized controlled trials utilizing high-dose cisplatin (80–100 mg/m2) cycled every three-weekly during definitive radiotherapy. Although efficacious, this is associated with high acute morbidity necessitating intensive supportive care with attendant resource implications. The aim of this retrospective study was to assess the efficacy and acute toxicity of an alternative schedule i.e. concurrent weekly cisplatin-based radical radiotherapy and it's potential to be an optimal regimen in advanced head and neck cancers.
Methods
Outcome data of patients with Stage III & IV head and neck squamous cell carcinoma, excluding nasopharynx, planned for radical radiotherapy (66–70 Gy) with concurrent weekly cisplatin (30 mg/m2) treated in a single unit between 1996–2004 was extracted.
Results
The dataset consisted of 264 patients with a median age of 54 years. The median radiotherapy dose was 70 Gy (range 7.2–72 Gy) and median number of chemotherapy cycles was 6 (range 1–7). Two-thirds (65%) of patients received ≥85% of planned cisplatin dose. With a mean follow-up of 19 months, the 5-year local control; loco-regional control; and disease free survival was 57%; 46%; and 43% respectively. Acute grade 3 or worse mucositis and dermatitis was seen in 77 (29%) and 92 (35%) patients respectively, essentially in patients receiving doses ≥66 Gy and 6 or more cycles of chemotherapy. Other toxicities (hematologic, nausea and vomiting) were mild and self-limiting. Overall, the acute toxicity of this concurrent weekly chemo-radiation regimen though mildly increased did not mandate intensive supportive care. Stage grouping, primary site, and intensity of treatment were significant predictors of loco-regional control and disease free survival.
Conclusion
Radical radiotherapy with concurrent weekly cisplatin has moderate efficacy and acceptable acute toxicity with potential to be an optimal regimen in loco-regionally advanced squamous cell carcinoma of the head and neck, particularly in limited-resource settings. Stage grouping, primary site, and treatment intensity are important determinants of outcome.
doi:10.1186/1758-3284-1-17
PMCID: PMC2702367  PMID: 19527507
16.  Concurrent Docetaxel-Based Chemoradiotherapy in Squamous Cell Esophageal Cancer 
Background:
The incidence of esophageal cancer has risen worldwide in recent decades. In Romania, the incidence is 5.3/100,000 population in males and 0.7/100,000 in females, with mortality rates of 4.8/100,000 and 0.5/100,000 in males and females, respectively. Esophageal cancer is a treatable but rarely curable cancer, as many patients have advanced-stage disease at diagnosis. We evaluated a multimodality approach of preoperative radiochemotherapy for patients with squamous cell esophageal carcinoma in terms of safety, tumor response, and resectability rate.
Methods:
From January 2004 to May 2007, 87 patients were included in the study. Inclusion criteria were histologically confirmed squamous esophageal cancer not amenable to curative surgery, no distant metastases, ECOG performance status ≤ 2, and no previous anticancer therapy. The preoperative treatment schedule was conformal radiotherapy (40 Gy) with concomitant weekly docetaxel (25 mg/m2) and carboplatin (AUC=2). Patients were evaluated at baseline, after having received 40 Gy radiotherapy, and 3 months after treatment ended. Endoscopy, barium swallow X-ray, and CT scan of the chest and upper abdomen were used to evaluate patients. Patients whose tumors were resectable underwent surgery; those with unresectable tumors continued radiotherapy to a total dose of 60 Gy and received four cycles of docetaxel (75 mg/m2) and carboplatin (AUC=6) (q3wk regimen). The resected patients received adjuvant chemotherapy with four cycles of the same docetaxel/carboplatin q3wk regimen.
Results:
The median patient age was 53.6 years (range, 32–70 years); 78 of the patients were males and 9 were females. Median follow-up time was 35 months. Survival rate at 1 year was 57.5% and at 2 years, 44.8%. After patients had received 40 Gy radiotherapy, 39 were determined to have resectable disease and 30 underwent surgery (6 patients refused surgery and 3 had contraindications for surgery); 48 patients had tumor regression with clinical benefit but were not operable. No patient progressed. Six of the 30 patients undergoing surgery had complete remissions. The treatment schedule was well tolerated, with no treatment-related deaths or additional hospitalizations. All except 5 of the patients were able to receive the intended chemoradiotherapy regimen. These 5 patients stopped chemoradiotherapy because of hematologic toxicity; radiotherapy was continued (after an approximate 1-week delay) following hematologic recovery. The operated patients had no additional perioperative complications. Radiation therapy was delivered as intended with no toxicity-related interruptions, except in the 5 patients mentioned above. Chemotherapy was delayed in 15 additional cases due to grade 3–4 hematologic effects; a 25% dose reduction was necessary in 9 cases.
Conclusions:
Multimodality treatment of locally advanced esophageal cancer (concurrent radiochemotherapy ± surgery) can be considered superior to each method as single-agent therapy. Radiotherapy and chemotherapy may convert some tumors considered initially unresectable to resectable status. The weekly docetaxel/carboplatin regimen was well tolerated when administered concurrently with radiation therapy. This regimen resulted in a 44.8% resectability rate in patients considered initially unresectable, and 15.4% of patients undergoing surgery had complete remissions. Further investigation of this regimen is warranted.
PMCID: PMC3056309
17.  Optimal Sequence of Implied Modalities in the Adjuvant Setting of Breast Cancer Treatment: An Update on Issues To Consider 
The Oncologist  2010;15(11):1169-1178.
Breast surgery, radiotherapy, chemotherapy, hormonotherapy, and targeted agents are all being used together concomitantly or sequentially with the aim to achieve local and distant control and improve survival in breast cancer patients. With this goal being reached more and more often nowadays, quality of life emerges as another issue of pivotal importance. Existing data on the maximum acceptable delay of radiotherapy when given as sole adjuvant treatment after surgery and the optimal sequence of all these modalities with respect to each other are reviewed.
The adjuvant setting of early breast cancer treatment is an evolving field where different modalities must be combined to improve outcomes; moreover, quality of life of breast cancer survivors emerges as a new important parameter to consider, thus implying a better understanding of toxicities of these modalities. We have conducted a review focusing on the latest literature of the past 3 years, trying to evaluate the existing data on the maximum acceptable delay of radiotherapy when given as sole adjuvant treatment after surgery and the optimal sequence of all these modalities with respect to each other. It becomes evident radiotherapy should be given as soon as possible and within a time frame of 6–20 weeks. Chemotherapy is given before radiotherapy and hormone therapy. However, radiotherapy should be started within 7 months after surgery in these cases. Hormone therapy with tamoxifen might be given safely concomitantly or sequentially with radiotherapy although solid data are still lacking. The concurrent administration of letrozole and radiotherapy seems to be safe, whereas data on trastuzumab can imply only that it is safe to use concurrently with radiotherapy. Randomized comparisons of hormone therapy and trastuzumab administration with radiotherapy need to be performed.
doi:10.1634/theoncologist.2010-0187
PMCID: PMC3227907  PMID: 21041378
Radiotherapy; Chemotherapy; Hormone therapy; Trastuzumab; Sequence; Delay; Breast cancer; AROME
18.  Exquisite Sensitivity of TP53 Mutant and Basal Breast Cancers to a Dose-Dense Epirubicin−Cyclophosphamide Regimen 
PLoS Medicine  2007;4(3):e90.
Background
In breast cancers, only a minority of patients fully benefit from the different chemotherapy regimens currently in use. Identification of markers that could predict the response to a particular regimen would thus be critically important for patient care. In cell lines or animal models, tumor protein p53 (TP53) plays a critical role in modulating the response to genotoxic drugs. TP53 is activated in response to DNA damage and triggers either apoptosis or cell-cycle arrest, which have opposite effects on cell fate. Yet, studies linking TP53 status and chemotherapy response have so far failed to unambiguously establish this paradigm in patients. Breast cancers with a TP53 mutation were repeatedly shown to have a poor outcome, but whether this reflects poor response to treatment or greater intrinsic aggressiveness of the tumor is unknown.
Methods and Findings
In this study we analyzed 80 noninflammatory breast cancers treated by frontline (neoadjuvant) chemotherapy. Tumor diagnoses were performed on pretreatment biopsies, and the patients then received six cycles of a dose-dense regimen of 75 mg/m2 epirubicin and 1,200 mg/m2 cyclophosphamide, given every 14 days. After completion of chemotherapy, all patients underwent mastectomies, thus allowing for a reliable assessment of chemotherapy response. The pretreatment biopsy samples were used to determine the TP53 status through a highly efficient yeast functional assay and to perform RNA profiling. All 15 complete responses occurred among the 28 TP53-mutant tumors. Furthermore, among the TP53-mutant tumors, nine out of ten of the highly aggressive basal subtypes (defined by basal cytokeratin [KRT] immunohistochemical staining) experienced complete pathological responses, and only TP53 status and basal subtype were independent predictors of a complete response. Expression analysis identified many mutant TP53-associated genes, including CDC20, TTK, CDKN2A, and the stem cell gene PROM1, but failed to identify a transcriptional profile associated with complete responses among TP53 mutant tumors. In patients with unresponsive tumors, mutant TP53 status predicted significantly shorter overall survival. The 15 patients with responsive TP53-mutant tumors, however, had a favorable outcome, suggesting that this chemotherapy regimen can overcome the poor prognosis generally associated with mutant TP53 status.
Conclusions
This study demonstrates that, in noninflammatory breast cancers, TP53 status is a key predictive factor for response to this dose-dense epirubicin–cyclophosphamide regimen and further suggests that the basal subtype is exquisitely sensitive to this association. Given the well-established predictive value of complete responses for long-term survival and the poor prognosis of basal and TP53-mutant tumors treated with other regimens, this chemotherapy could be particularly suited for breast cancer patients with a mutant TP53, particularly those with basal features.
Hugues de The and colleagues report thatTP53 status is a predictive factor for responsiveness in breast cancers to a dose-dense epirubicin-cyclophosphamide chemotherapy regimen, and suggests that this regimen might be well suited for patientsTP53 mutant tumors.
Editors' Summary
Background.
One woman in eight will develop breast cancer during her life. As with other cancers, breast cancer arises when cells accumulate genetic changes (mutations) that allow them to grow uncontrollably and to move around the body. These altered cells are called malignant cells. The normal human breast contains several types of cell, any of which can become malignant. In addition, there is more than one route to malignancy—different sets of genes can be mutated. As a result, breast cancer is a heterogeneous disease that cannot be cured with a single type of treatment. Ideally, oncologists would like to know before they start treating a patient which therapeutic approach is going to be successful for that individual. Recently, researchers have begun to identify molecular changes that might eventually allow oncologists to make such rational treatment decisions. For example, laboratory studies in cell lines or animals indicate that the status of a gene called TP53 determines the chemotherapy agents (drugs that preferentially kill rapidly dividing cancer cells) to which cells respond. p53, the protein encoded by TP53, is a tumor suppressor. That is, in normal cells it prevents unregulated growth by controlling the expression of proteins involved in cell division and cell death. Consequently, p53 is often inactivated during cancer development.
Why Was This Study Done?
Although laboratory studies have linked TP53 status to chemotherapy responses, little is known about this relationship in human breast cancers. The clinical studies that have investigated whether TP53 status affects chemotherapy responses have generally found that patients whose tumors contain mutant TP53 have a poorer response to therapy and/or a shorter survival time than those whose tumors contain normal TP53. In this study, the researchers have asked whether TP53 status affects tumor responses to a dose-intense chemotherapy regimen (frequent, high doses of drugs) given to women with advanced noninflammatory breast cancer before surgery. This type of treatment is called neoadjuvant chemotherapy and is used to shrink tumors before surgery.
What Did the Researchers Do and Find?
The researchers collected breast tumor samples from 80 women before starting six fortnightly cycles of chemotherapy with epirubicin and cyclophosphamide. After this, each woman had her affected breast removed and examined to see whether the chemotherapy had killed the tumor cells. The researchers determined which original tumor samples contained mutated TP53 and used a technique called microarray expression profiling to document gene expression patterns in them. Overall, 28 tumors contained mutated TP53. Strikingly, all 15 tumors that responded completely to neoadjuvant chemotherapy (no tumor cells detectable in the breast tissue after chemotherapy) contained mutated TP53. Nine of these responsive tumors were basal-cell–like breast tumors, a particularly aggressive type of breast cancer; only one basal-cell–like, TP53-mutated tumor did not respond to chemotherapy. Patients whose tumors were unresponsive to the neoadjuvant chemotherapy but contained mutated TP53 tended to die sooner than those whose tumors contained normal TP53 or those with chemotherapy-responsive TP53-mutated tumors. Finally, expression profiling identified changes in the expression of many p53-regulated genes, but did not identify an expression profile in the TP53-mutated tumors unique to those that responded to chemotherapy.
What Do These Findings Mean?
These findings indicate that noninflammatory breast tumors containing mutant TP53—in particular, basal-cell–like tumors—are very sensitive to dose-dense epirubicin and cyclophosphamide chemotherapy. Intensive regimens of this type have rarely been used in previous studies, which might explain the apparent contradiction between these results and the generally poor response to chemotherapy of TP53-mutated breast tumors. More tumors now need to be examined to confirm the association between complete response, TP53 status and basal-cell–like tumors. In addition, although complete tumor responses generally predict good overall survival, longer survival studies than those reported here are needed to show that the tumor response to this particular neoadjuvant chemotherapy regimen translates into improved overall survival. If the present results can be confirmed and extended, dose-dense neoadjuvant chemotherapy with epirubicin and cyclophosphamide could considerably improve the outlook for patients with aggressive TP53-mutant, basal-cell–like breast tumors.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040090.
The US National Cancer Institute provides patient and physician information on breast cancer and general information on understanding cancer
Cancer Research UK offers patient information on cancer and breast cancer
The MedlinePlus encyclopedia has pages on breast cancer
Emory University's CancerQuest discusses the biology of cancer, including the role of tumor suppressor proteins
Wikipedia has pages on p53 (note that Wikipedia is a free online encyclopedia that anyone can edit)
doi:10.1371/journal.pmed.0040090
PMCID: PMC1831731  PMID: 17388661
19.  Neoadjuvant or adjuvant therapy for resectable gastric cancer? A practice guideline 
Canadian Journal of Surgery  2002;45(6):438-446.
Objective
To make recommendations on the use of neoadjuvant or adjuvant therapy in addition to surgery in patients with resectable gastric cancer (T1–4, N1–2, M0).
Options
Neoadjuvant or adjuvant treatments compared with “curative” surgery alone.
Outcomes
Overall survival, disease-free survival, and adverse effects.
Evidence
The MEDLINE, CANCERLIT and Cochrane Library databases and relevant conference proceedings were searched to identify randomized trials.
Values
Evidence was selected and reviewed by one member of the Cancer Care Ontario Practice Guidelines Initiative (CCOPGI) Gastrointestinal Cancer Disease Site Group and methodologists. A systematic review of the published literature was combined with a consensus process around the interpretation of the evidence in the context of conventional practice, to develop an evidence-based practice guideline. This report has been reviewed and approved by the Gastrointestinal Cancer Disease Site Group, comprising medical oncologists, radiation oncologists, surgeons, a pathologist and 2 community representatives.
Benefits, harms and costs
When compared with surgery alone, at 3 years adjuvant chemoradiotherapy has been shown to increase overall survival by 9% (50% v. 41%, p = 0.005) and to improve relapse-free survival from 31% to 48% (p = 0.001). At 5 years, it has been shown to increase overall survival by 11.6% (40% v. 28.4%) and to improve relapse-free survival from 25% to 38% (p < 0.001). Treatment has been associated with toxic deaths in 1% of patients. The most frequent adverse effects (> grade 3 [Southwest Oncology Group toxicity scale] are hematologic (54%), gastrointestinal (33%), influenza-like (9%), infectious (6%) and neurologic (4%). The radiation fields used can possibly damage the left kidney, resulting in hypertension and other renal problems. Furthermore, this therapy could increase the demand on radiation resources. Physicians and patients should understand the tradeoffs between survival benefit and toxicity and cost before making treatment decisions.
Recommendations
After surgical resection, patients whose tumours have penetrated the muscularis propria or involve regional lymph nodes should be considered for adjuvant combined chemoradiotherapy. The current standard protocol consists of 1 cycle of 5-fluorouracil (5-FU) (425 mg/m2 daily) and leucovorin (20 mg/m2 daily) administered daily for 5 days, followed 1 month later by 45 Gy (1.8 Gy/d) of radiation given with 5-FU (400 mg/m2 daily) and leucovorin (20 mg/m2 daily) on days 1 through 4 and the last 3 days of radiation. One month after completion of radiation, 2 cycles of 5-FU (425 mg/m2 daily) and leucovorin (20 mg/m2 daily) in a daily regimen for 5 days are given at monthly intervals. There is no evidence on which to make a recommendation for patients with node-negative tumours that have not penetrated the muscularis propria. For patients unable to undergo radiation, adjuvant chemotherapy alone may be of benefit, particularly for those with lymph-node metastases. The optimal regimen remains to be defined. There is insufficient evidence from randomized trials to recommend neoadjuvant chemotherapy, or neoadjuvant or adjuvant radiotherapy or immunotherapy, either alone or in combination, outside a clinical trial.
Validation
A draft version of this document was circulated to 166 clinicians using a 21-item feedback questionnaire. Ninety-nine (63%) returned the questionnaire, and 74 of these indicated that the guideline was relevant to their clinical practice and completed the survey. Of the 74 clinicians, 52 (70%) agreed that the document should be approved as a practice guideline.
Sponsors
The CCOPGI is supported by Cancer Care Ontario and the Ontario Ministry of Health and Long-Term Care.
PMCID: PMC3684659  PMID: 12500920
20.  Anthracycline and concurrent radiotherapy as adjuvant treatment of operable breast cancer: a retrospective cohort study in a single institution 
BMC Research Notes  2010;3:247.
Background
Concurrent chemoradiotherapy (CCRT) after breast surgery was investigated by few authors and remains controversial, because of concerns of toxicity with taxanes/anthracyclines and radiation. This treatment is not standard and is more commonly used for locally advanced breast cancer. The aim of our study was to evaluate the efficacy and safety of the concomitant use of anthracycline with radiotherapy (RT).
Findings
Four hundred women having operable breast cancer, treated by adjuvant chemotherapy (CT) and RT in concomitant way between January 2001 and December 2003, were included in this retrospective cohort study. The study compares 2 adjuvant treatments using CCRT, the first with anthracycline (group A) and the second with CMF (group B). The CT treatment was repeated every 21 days for 6 courses and the total delivered dose of RT was 50 Gy, divided as 2 Gy daily fractions. Locoregional recurrence free (LRFS), event free (EFS), and overall survivals (OS) were estimated by the Kaplan-Meier method. The log-rank test was used to compare survival events. Multivariate Cox-regression was used to evaluate the relationship between patient characteristics, treatment and survival.
In the 2 groups (A+B) (n = 400; 249 in group A and 151 in group B), the median follow-up period was 74.5 months. At 5 years, the isolated LRFS was significantly higher in group A compared to group B (98.7% vs 95.3%; hazard ratio [HR] = 0.258; 95% CI, 0.067 to 0.997; log-rank P = .034). In addition, the use of anthracycline regimens was associated with a higher rate of 5 years EFS (80.4% vs 75.1%; HR = 0.665; 95% CI, 0.455 to 1.016; log-rank P = .057). The 5 years OS was 83.2% and 79.2% in the anthracycline and CMF groups, respectively (HR = 0.708; 95% CI, 0.455 to 1.128; log-rank P = .143). Multivariate analysis confirmed the positive effect of anthracycline regimens on LRFS (HR = 0.347; 95% CI, 0.114 to 1.053; log-rank P = .062), EFS (HR = 0.539; 95% CI, 0.344 to 0.846; P = 0.012), and OS (HR = 0.63; 95% CI, 0.401 to 0.991; P = .046). LRFS, EFS and OS were significantly higher in the anthracycline group where the patients (n = 288) received more than 1 cycle of concurrent CT (P = .038, P = .026 and P = .038, respectively). LRFS and EFS were significantly higher in the anthracycline group within the BCT subgroup (P = .049 and P = .04, respectively). There were more hematologic, and more grade 2/3/4 skin toxicity in the anthracycline group.
Conclusions
After mastectomy or BCT, the adjuvant treatment based on anthracycline and concurrent RT reduced breast cancer relapse rate, and significantly improved LRFS, EFS and OS in the patients receiving more than 1 cycle of concurrent CT. There were more hematologic and non hematologic toxicities in the anthracycline group.
doi:10.1186/1756-0500-3-247
PMCID: PMC2958885  PMID: 20920323
21.  Preoperative/Neoadjuvant Therapy in Pancreatic Cancer: A Systematic Review and Meta-analysis of Response and Resection Percentages 
PLoS Medicine  2010;7(4):e1000267.
Jörg Kleef and colleagues systematically reviewed studies on neoadjuvant therapy and tumor response, toxicity, resection, and survival percentages in pancreatic cancer and suggest that patients with locally nonresectable tumors should be included in neoadjuvant protocols.
Background
Pancreatic cancer has an extremely poor prognosis and prolonged survival is achieved only by resection with macroscopic tumor clearance. There is a strong rationale for a neoadjuvant approach, since a relevant percentage of pancreatic cancer patients present with non-metastatic but locally advanced disease and microscopic incomplete resections are common. The objective of the present analysis was to systematically review studies concerning the effects of neoadjuvant therapy on tumor response, toxicity, resection, and survival percentages in pancreatic cancer.
Methods and Findings
Trials were identified by searching MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials from 1966 to December 2009 as well as through reference lists of articles and proceedings of major meetings. Retrospective and prospective studies analyzing neoadjuvant radiochemotherapy, radiotherapy, or chemotherapy of pancreatic cancer patients, followed by re-staging, and surgical exploration/resection were included. Two reviewers independently extracted data and assessed study quality. Pooled relative risks and 95% confidence intervals were calculated using random-effects models. Primary outcome measures were proportions of tumor response categories and percentages of exploration and resection. A total of 111 studies (n = 4,394) including 56 phase I–II trials were analyzed. A median of 31 (interquartile range [IQR] 19–46) patients per study were included. Studies were subdivided into surveys considering initially resectable tumors (group 1) and initially non-resectable (borderline resectable/unresectable) tumors (group 2). Neoadjuvant chemotherapy was given in 96.4% of the studies with the main agents gemcitabine, 5-FU (and oral analogues), mitomycin C, and platinum compounds. Neoadjuvant radiotherapy was applied in 93.7% of the studies with doses ranging from 24 to 63 Gy. Averaged complete/partial response probabilities were 3.6% (95% CI 2%–5.5%)/30.6% (95% CI 20.7%–41.4%) and 4.8% (95% CI 3.5%–6.4%)/30.2% (95% CI 24.5%–36.3%) for groups 1 and 2, respectively; whereas progressive disease fraction was estimated to 20.9% (95% CI 16.9%–25.3%) and 20.8% (95% CI 14.5%–27.8%). In group 1, resectability was estimated to 73.6% (95% CI 65.9%–80.6%) compared to 33.2% (95% CI 25.8%–41.1%) in group 2. Higher resection-associated morbidity and mortality rates were observed in group 2 versus group 1 (26.7%, 95% CI 20.7%–33.3% versus 39.1%, 95% CI 29.5%–49.1%; and 3.9%, 95% CI 2.2%–6% versus 7.1%, 95% CI 5.1%–9.5%). Combination chemotherapies resulted in higher estimated response and resection probabilities for patients with initially non-resectable tumors (“non-resectable tumor patients”) compared to monotherapy. Estimated median survival following resection was 23.3 (range 12–54) mo for group 1 and 20.5 (range 9–62) mo for group 2 patients.
Conclusions
In patients with initially resectable tumors (“resectable tumor patients”), resection frequencies and survival after neoadjuvant therapy are similar to those of patients with primarily resected tumors and adjuvant therapy. Approximately one-third of initially staged non-resectable tumor patients would be expected to have resectable tumors following neoadjuvant therapy, with comparable survival as initially resectable tumor patients. Thus, patients with locally non-resectable tumors should be included in neoadjuvant protocols and subsequently re-evaluated for resection.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Pancreatic cancer is the fourth leading cause of cancer-related deaths worldwide. It begins when a cell in the pancreas (an organ lying behind the stomach that produces digestive enzymes and hormones such as insulin that controls blood sugar levels) acquires genetic changes that allow it to grow uncontrollably and, sometimes, to spread around the body (metastasize). Because pancreatic cancer rarely causes any symptoms early in its development, it is locally advanced in more than a third of patients and has already metastasized in another half of patients by the time it is diagnosed. Consequently, on average, people die within 5–8 months of a diagnosis of pancreatic cancer. At present, the only chance for cure is surgical removal (resection) of the tumor, part of the pancreas, and other nearby digestive organs. This procedure—the Whipple procedure—is only possible in the fifth of patients whose tumor is found when it is small enough to be resectable, and even in these patients, the cure rate associated with surgery is less than 25%, although radiotherapy or chemotherapy after surgery (adjuvant therapy) can be beneficial.
Why Was This Study Done?
For patients whose tumor has metastasized, palliative chemotherapy to slow down tumor growth and to minimize pain is the only treatment option. But, for the many patients whose disease is locally advanced and unresectable at diagnosis, experts think that “neoadjuvant” therapy might be helpful. Neoadjuvant therapy—chemotherapy and/or radiotherapy given before surgery—aims to convert unresectable tumors into resectable tumors by shrinking the visible tumor and removing cancer cells that cannot be seen with the naked eye. Randomized phase III trials—studies in which groups of patients are randomly assigned to different interventions and specific outcomes measured—are the best way to determine whether an intervention has any clinical benefits, but no randomized phase III trials of neoadjuvant therapy for unresectable pancreatic cancer have been undertaken. Therefore, in this systematic review (a study that uses predefined criteria to identify all the research on a given topic) and meta-analysis (a statistical method for combining the results of several studies), the researchers analyze data from other types of studies to investigate whether neoadjuvant therapy for pancreatic cancer provides any clinical benefits.
What Did the Researchers Do and Find?
In their systematic review, the researchers identified 111 studies involving 4,394 patients in which the effects of neoadjuvant chemotherapy and/or radiotherapy on tumor response, tumor resectability, and patient survival had been investigated. They subdivided the studies into two groups: group 1 studies included patients whose tumors were considered resectable on preoperative examination, and group 2 studies included patients whose tumors were borderline resectable or unresectable. In their meta-analysis, the researchers found that similar percentages of the tumors in both groups responded to neoadjuvant therapy by shrinking or regressing and that about a fifth of the tumors in each group grew larger or metastasized during neoadjuvant therapy. In the group 1 studies, three-quarters of the tumors were resectable after neoadjuvant therapy (a decrease in the proportion of tumors that could be treated surgically) whereas in the group 2 studies, a third of the tumors were resectable after neoadjuvant therapy (an increase in the proportion of tumors that could be treated surgically). After resection, the average survival time for group 1 patients was 23.3 months, a similar survival time to that seen in patients treated with surgery and adjuvant therapy. The average survival time for group 2 patients after resection was 20.5 months.
What Do These Findings Mean?
The finding that the average survival time after neoadjuvant therapy and surgery in patients whose tumor was judged resectable before neoadjuvant therapy was similar to that of patients treated with chemotherapy and/or radiotherapy after surgery suggests that for patients with resectable tumors, neoadjuvant therapy will not provide any clinical benefit. By contrast, the finding that a third of patients initially judged unresectable were able to undergo resection after neoadjuvant therapy and then had a similar survival rate to patients judged resectable before neoadjuvant treatment strongly suggests that patients presenting with locally advanced/unresectable tumors should be offered neoadjuvant therapy and then re-evaluated for resection. Randomized trials are now needed to confirm this finding and to determine the optimum neoadjuvant therapy for this group of patients.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000267.
The US National Cancer Institute provides information for patients and health professionals about all aspects of pancreatic cancer (in English and Spanish), including a booklet for patients
The American Cancer Society also provides detailed information about pancreatic cancer
The UK National Health Service and Cancer Research UK include information for patients on pancreatic cancer on their Web sites
MedlinePlus provides links to further resources on pancreatic cancer (in English and Spanish)
Pancreatica.org, PancreaticDuct.org, and the Pancreatic Cancer Action Network give more information to pancreatic cancer patients, their families, and caregivers
doi:10.1371/journal.pmed.1000267
PMCID: PMC2857873  PMID: 20422030
22.  Intensified Adjuvant IFADIC Chemotherapy for Adult Soft Tissue Sarcoma: A Prospective Randomized Feasibility Trial 
Sarcoma  2000;4(4):151-160.
Purpose. The present prospective randomized adjuvant trial was carried out to compare the toxicity, feasibility and efficacy of augmented chemotherapy added to hyperfractionated accelerated radiotherapy after wide or marginal resection of grade 2 and grade 3 soft tissue sarcoma (STS).
Patients and methods. Fifty-nine patients underwent primary surgery by wide or marginal excision and were subsequently randomized to receive radiotherapy alone or under the addition of six courses of ifosfamide (1500 mg/m2 , days 1–4), dacarbazine (DTIC) (200 mg/m2 , days 1–4) and doxorubicin (25 mg/m2 , days 1–2) administered in 14-day-intervals supported by granulocyte-colony stimulating factor (30 × 106 IU/day, s.c.) on days 5–13. According to the randomization protocol, 28 patients received radiotherapy only, whereas 31 patients were treated with additional chemotherapy.
Results. The relative ifosfamide–doxorubicin–DTIC (IFADIC) dose intensity achieved was 93%. After a mean observation period of 41±19.7 months (range, 8.1–84 months), 16 patients (57%) in the control group versus 24 patients (77%) in the chemotherapy group were free of disease (p>0.05).Within the control group, tumor relapses occurred in 12 patients (43%;six patients with distant metastases, two with local relapse, four with both) versus seven patients (23%; five patients with distant metastases, one with local recurrence, one with both) from the chemotherapy group. Relapse-free survival (RFS) (p=0.1), time to local failure (TLF) (p=0.09), time to distant failure (TDF) (p=0.17) as well as overall survival (OS) (p=0.4) did not differ significantly between the two treatment groups. Treatment-related toxicity was generally mild in both treatment arms.
Conclusion. We conclude that the safety profile of intensified IFADIC added to radiotherapy was manageable and tolerable in the current setting. Inclusion of intensified IFADIC was not translated into a significant benefit concerning OS, RFS, TLF andTDF as compared with radiotherapy only, although a potential benefit of chemotherapy for grade 3 STS patients needs to be validated in prospective randomized trials including larger patient numbers.
doi:10.1080/13577140020025869
PMCID: PMC2395444  PMID: 18521295
23.  The value of radiotherapy in breast cancer patients with isolated ipsilateral supraclavicular lymph node metastasis without distant metastases at diagnosis: a retrospective analysis of Chinese patients 
OncoTargets and therapy  2014;7:281-288.
Background
The purpose of this study was to investigate the prognosis of ipsilateral supraclavicular lymph node metastasis (ISLM) without evidence of distant metastases at diagnosis in Chinese women with breast cancer and to elucidate the clinical value of adjuvant radiotherapy.
Methods
We performed a retrospective analysis of clinical data for 39 patients with ISLM from breast cancer without distant metastasis at diagnosis. Combined modality therapy, consisting of neoadjuvant chemotherapy, surgery, and adjuvant chemotherapy with or without adjuvant radiotherapy, was offered to the patients.
Results
The patients in this study accounted for 1% of all breast cancer patients treated during the same time period. The median follow-up was 35 months. The 5-year locoregional recurrence-free survival, distant metastasis-free survival, disease-free survival (DFS), and overall survival (OS) were 57.3%, 42.3%, 34.4%, and 46.2%, respectively. Twenty-three patients received postoperative adjuvant radiotherapy. However, there was no significant difference in the 3- and 5-year locoregional recurrence-free survival (P=0.693), ISLM-free recurrence (P=0.964), distant metastasis-free survival (P=0.964), DFS (P=0.234), and OS (P=0.329) rates between the groups of patients who received or did not receive adjuvant radiotherapy (P=0.840). No significant difference in the 3-year locoregional control rate (P=0.900) was found between patients who were treated with adjuvant radiotherapy at ≤50 Gy and >50 Gy. Univariate analysis showed that clinical tumor size stage and age were prognostic factors that impacted DFS and OS.
Conclusion
Combined modality treatment may achieve satisfactory efficacy in Chinese women with ISLM from breast cancer without distant metastasis at the time of diagnosis, suggesting that ISLM might be considered a curable locoregional disease. Adjuvant radiotherapy did not, however, improve the results of these patients.
doi:10.2147/OTT.S56596
PMCID: PMC3931660  PMID: 24627640
prognosis; breast cancer; supraclavicular lymph node-metastasis; radiotherapy
24.  Chemoradiotherapy for locally advanced head and neck cancer: 10-year follow-up of the UK Head and Neck (UKHAN1) trial 
The Lancet Oncology  2009;10(9):872-876.
Summary
Background
Between 1990 and 2000, we examined the effect of timing of non-platinum chemotherapy when combined with radiotherapy. We aimed to determine whether giving chemotherapy concurrently with radiotherapy or as maintenance therapy, or both, affected clinical outcome. Here we report survival and recurrence after 10 years of follow-up.
Methods
Between Jan 15, 1990, and June 20, 2000, 966 patients were recruited from 34 centres in the UK and two centres from Malta and Turkey. Patients with locally advanced head and neck cancer, and who had not previously undergone surgery, were randomly assigned to one of four groups in a 3:2:2:2 ratio, stratified by centre and chemotherapy regimen: radical radiotherapy alone (n=233); radiotherapy with two courses of chemotherapy given simultaneously on days 1 and 14 of radiotherapy (SIM alone; n=166); or 14 and 28 days after completing radiotherapy (SUB alone, n=160); or both (SIM+SUB; n=154). Chemotherapy was either methotrexate alone, or vincristine, bleomycin, methotrexate, and fluorouracil. Patients who had previously undergone radical surgery to remove their tumour were only randomised to radiotherapy alone (n=135) or SIM alone (n=118), in a 3:2 ratio. The primary endpoints were overall survival (from randomisation), and event-free survival (EFS; recurrence, new tumour, or death; whichever occurred first) among patients who were disease-free 6 months after randomisation. Analyses were by intention to treat. This trial is registered at www.Clinicaltrials.gov, number NCT00002476.
Findings
All 966 patients were included in the analyses. Among patients who did not undergo surgery, the median overall survival was 2·6 years (99% CI 1·9–4·2) in the radiotherapy alone group, 4·7 (2·6–7·8) years in the SIM alone group, 2·3 (1·6–3·5) years in the SUB alone group, and 2·7 (1·6–4·7) years in the SIM+SUB group (p=0·10). The corresponding median EFS were 1·0 (0·7–1·4), 2·2 (1·1–6·0), 1·0 (0·6–1·5), and 1·0 (0·6–2·0) years (p=0·005), respectively. For every 100 patients given SIM alone, there are 11 fewer EFS events (99% CI 1–21), compared with 100 given radiotherapy, 10 years after treatment. Among the patients who had previously undergone surgery, median overall survival was 5·0 (99% CI 1·8–8·0) and 4·6 (2·2–7·6) years in the radiotherapy alone and SIM alone groups (p=0·70), respectively, with corresponding median EFS of 3·7 (99% CI 1·1–5·9) and 3·0 (1·2–5·6) years (p=0·85), respectively. The percentage of patients who had a significant toxicity during treatment were: 11% (radiotherapy alone, n=25), 28% (SIM alone, n=47), 12% (SUB alone, n=19), and 36% (SIM+SUB, n=55) among patients without previous surgery; and 9% (radiotherapy alone, n=12) and 20% (SIM alone, n=24) among those who had undergone previous surgery. The most common toxicity during treatment was mucositis. The percentage of patients who had a significant toxicity at least 6 months after randomisation were: 6% (radiotherapy alone, n=13), 6% (SIM alone, n=10), 4% (SUB alone, n=7), and 6% (SIM+SUB, n=9) among patients who had no previous surgery; and 7% (radiotherapy alone, n=10) and 11% (SIM alone, n=13) among those who had undergone previous surgery. The most common toxicity 6 months after treatment was xerostomia, but this occurred in 3% or less of patients in each group.
Interpretation
Concurrent non-platinum chemoradiotherapy reduces recurrences, new tumours, and deaths in patients who have not undergone previous surgery, even 10 years after starting treatment. Chemotherapy given after radiotherapy (with or without concurrent chemotherapy) is ineffective. Patients who have undergone previous surgery for head and neck cancer do not benefit from non-platinum chemotherapy.
Funding
Cancer Research UK, with support from University College London and University College London Hospital Comprehensive Biomedical Research Centre.
doi:10.1016/S1470-2045(09)70306-7
PMCID: PMC2806549  PMID: 19875337
25.  Locoregional Interaction of Ixabepilone (Ixempra) After Breast Cancer Radiation 
The Oncologist  2013;18(3):265-270.
Chemotherapy-radiotherapy interactions are uncommon but potentially serious adverse events. The authors identified 3 of 19 patients with clinically significant interactions when ixebepilone was given shortly after radiotherapy.
Learning Objectives
Describe the significant locoregional clinical interaction that may result from ixabepilone chemotherapy following radiation.Explain the importance of awareness, detection, and management of radiation recall by both the medical and the radiation oncologist.Describe the spectrum of toxicity represented by radiation recall that can range from erythema to chest wall necrosis requiring reconstructive surgery.
Background.
Radiation recall is an acute inflammatory reaction within a previously irradiated field triggered by chemotherapy administration. We observed a series of patients with unexpectedly severe reactions that included radiation recall and delayed healing when patients received the microtubule stabilizer ixabepilone (Ixempra; Bristol-Myers Squibb, Princeton, NJ) after radiation. We therefore decided to evaluate our experience in patients receiving ixabepilone following radiotherapy.
Methods.
We performed a retrospective chart review of all patients treated with curative intent in the Department of Radiation Oncology at the MD Anderson Cancer Center from 2008–2011 who received any ixabepilone after completion of external-beam radiation therapy. These patients received adjuvant ixabepilone on one of two protocols, either for locally advanced breast cancer or for metastatic breast cancer. In total, 19 patients were identified and their charts were subsequently reviewed for evidence of ixabepilone-related toxicity.
Results.
Of the 19 patients identified who received ixabepilone following radiation therapy, three (15.8%) had unexpectedly serious reactions in the months following radiation therapy. Complications included delayed wound closure and drain placement into the seroma, intense erythema, and delayed wound closure and grade 4 chest wall necrosis requiring latissimus flap and skin grafting. The average number of days between the end of radiation therapy and documentation of reaction was 99.
Conclusions.
Ixabepilone chemotherapy may induce radiation recall and delayed wound healing when used shortly after the completion of external-beam radiotherapy. Significant clinical interactions have not been previously reported and merit further evaluation.
doi:10.1634/theoncologist.2012-0348
PMCID: PMC3607521  PMID: 23404814
Ixabepilone; Radiation recall; Breast cancer; Microtubule stabilizer

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