Rationale: to eradicate micro metastases after surgical removal of all gross disease.
The affect of adjuvant chemotherapy on survival is based on the eradication of microscopic metastatic deposits in a proportion of patients who would otherwise be destined in to have cancer recurrence.
Many patients receive unnecessary therapies because they will never have a recurrence or will have disease relapse because of tumor resistance to treatment.
Clinical assumption is that chemotherapy should commence as soon as practical, and that little or no benefit is derived if treatment begins beyond a 3 month adjuvant chemotherapy delay-but no evidence supports either of these assumptions.
Preclinical tumor growth and kinematic models support the hypothesis that chemotherapy is most effective when initiated when tumor burden is low.
A delay in time to adjuvant chemotherapy beyond three months for colorectal and breast cancers was associated with a significant decreased cancer specific survival and overall survival based on SEER-Medicare data (Hershman D et al).
Randomized studies have shown survival benefit for colorectal, gastric, lung and breast cancers.
Adjuvant chemo therapy for patients with stage III colon cancer demonstrated noninferiority of three months versus six months of therapy.
Ovarian dysfunction rate in premenopausal women aged greater than 50 years is at 90%, and remains higher for women age greater than 40 years compared to those less than 40 years of age when receiving adjuvant chemotherapy (Bines J).
BREAST CANCER
Breast cancer-patients with poor prognostic features benefit the most from adjuvant therapy for breast cancer.
Breast cancer-60% of patients undergoing adjuvant chemotherapy for breast cancer will experience ovarian failure within one year of beginning treatment (Pfeilschifter J).
Breast cancer-trials demonstrating benefit of adding chemotherapy require chemotherapy to be administered within 7 to 8 weeks of definitive surgery.
Breast cancer-adjuvant chemotherapy for breast cancer studies on retrospective analysis suggests that benefits are restricted to a subset of patients with either poor are negative estrogen receptors, or patients with HER-2 positive breast cancers (Hayesb DF et al).
Breast cancer-The Danish Breast Cancer Consortium Group did not observe improved survival among patients with early initiation of adjuvant chemotherapy among women who began treatment at any point within 90 days of surgery (Baum M).
Breast cancer-Adjuvant chemotherapy trials have found that the benefit adjuvant chemotherapy is most clearly shown in a subset of patients with tumors are measured to have a high recurrence score in the Oncotype DX analysis.
Breast cancer-in a study of women whose adjuvant chemotherapy was initiated more than 90 days after surgery a lower survival was noted to the present (Lohrisch C et al).
Breast cancer-in a meta-analysis of adjuvant chemotherapy for breast cancer including >20,000 patients with follow-up of 5 years demonstrated a benefit of disease free survival and overall survival when docetaxel was added to the chemotherapy regimen: clear benefits for node positive patients (Laporte S et al).
Breast cancer-the above meta-analysis showed benefits for older, younger, ER+,ER- HER2+,HER2-groups all benefited from the addition of a taxane, except for node negative patients (Laporte S et al).
Breast cancer-Analyses of HER2 status among 5200 patients participating in a large randomized adjuvant trials comparing anthracycline with non-anthracycline chemotherapy regimens showed that only women with HER2 positive breast cancer derived an incremental benefit from anthracycline use.
Breast cancer-the initiation of adjuvant chemotherapy in elderly women showed a worse overall and cause specific survival among patients whose therapy was initiated more than 90 days after surgery (Hershman DL et al).
Breast cancer-adjuvant chemotherapy for breast cancer recommended for patients with lymph node involvement, for patients with hormonal receptor negative lesions greater than 1 cm, for hormone receptor negative patients with HER-2 positive disease and tumor greater than 1cm, and suggested for patients with tumors .6-1.0 cm regardless of hormone receptors and for patients with hormone positivity HER 2 negative process with tumor size greater than 1cm. (NCCN)
Breast cancer-St. Galen recommendations for adjuvant chemotherapy for breast cancer treatment include patients with hormone receptor positive disease, high risk disease or hormone receptor negative disease with intermediate or high risk disease. (High risk disease defined as 4 or more positive nodes with any HER 2 status, or 1-3 nodes involved and HER 2 positivity, and low risk disease defined as ?35 years of age, tumor size ?2 cm, grade 1, no lymphovascular invasion and HER 2 negative status.)
Breast cancer-Docetaxel/cyclophosphamide (TC) vs doxorubicin/cyclophosphamide (AC) in adjuvant therapy for breast cancer resulted in longer disease free survival and overall survival with the use of TC (Jones).
Breast cancer-tANGo trial revealed no benefit of the addition of gemcitabine to paclitaxel as a component of the adjuvant regimen of epirubicin plus cyclophosphamide.
Adjuvant Chemotherapy is associated with nearly twice the reduction in the rate of death from breast cancer among women younger than 50 years of age as compared with older women: attributed to direct cytotoxic effect in eradicating micrometastatic disease and an anti-estrogen effect from chemotherapy induced ovarian failure and premature menopause.
Breast cancer-epirubicin is at least as effective as doxorubicin in the adjuvant setting.
Breast cancer-NSABP B-15 and B-23 demonstrated that 4 cycles of AC (Adriamycin/Cyclophosphamide) is as efficacious as 6 cycles of CMF in both node positive and negative women.
Breast cancer-In the NSABP 15 no additional benefit noted by administration of 3 cycles of CMF after completion of 4 cycles of AC in the node positive population.
Breast cancer-overall impact of combination chemotherapy in early stage breast cancer results in a 15.2% relative reduction in mortality.
Breast cancer-there is a greater reduction in younger women with a 27% relative reduction in mortality for women <50 years of age and an 8% reduction even in women 60-69 years treated with adjuvant chemotherapy for breast cancer.
Breast cancer-the absolute improvement in survival is smaller in node-negative than in node-positive patients.
Breast cancer-the absolute reduction in mortality in women younger than 50 years is 5.7% in node-negative patients and 12.4% in node-positive patients.
Breast cancer-the absolute reduction in mortality in older women 50-69 years is 6.4% for node-negative and 2.3% for node-positive patients.
Breast cancer-Early Breast Cancer Trialists’ Collaborative Group in 1998 compared CMF with anthracycline containing chemotherapy and showed that the anthracycline based treatment was associated with significant reductions in the rates of recurrence and death.
Breast cancer-anthracycline regimens compared to no chemotherapy at all reduces the odds of recurrence by 33% and the odds of death by 26% (Early Breast Cancer Trials Collaborative Group).
Breast cancer-compared to chemotherapy regimens without anthracyclines, anthracycline regimens reduced the odds of recurrence by an additional 11%, and the odds of death by an additional 16% over what can be achieved with CMF combination therapy.
Breast cancer- the addition of a taxane to a anthracycline combination reduces the hazard of recurrence by an additional 15%.
Breast cancer-Early Breast Cancer Trialists’ Collaborative Group (EBCTCG)evaluated 145,000 women participating in 194 trials of adjuvant chemotherapy compared polychemotherapy versus no chemotherapy, the former conferred greater benefits for recurrence rate and mortality rate.
Breast cancer-French Adjuvant Study Group (FASOG) randomized weekly epirubicin compared to no postoperative chemotherapy foe ER+, node positive patients over the age of 65 years, all of whom received adjuvant tamoxifen: modest but statistically improved disease free survival, but no improvement in overall survival for the epirubicin treated patients.
Breast cancer-in individual trials CMF and doxorubicin plus cyclophosphamide were equivalent in terms of relapse free and overall survival, but cyclophosphamide, epirubicin and fluorouracil containing regimens were superior to CMF.
Breast cancer-The addition of adjuvant trastuzumab significantly improved disease free and overall survival among women with HER2 positive breast cancer in a study of 3222 women with early stage BC comparing doxorubicin and cyclophosphamide followed by docetaxel, the same treatment plus trastuzumab, or docetaxel plus carboplatin plus trastuzumab: Estimated disease free survival at 5 years 75%,84%, and 81%, respectively and overall survival 87%,92%, and 91%, respectively (Slamon D et al).
Breast cancer-docetaxel, doxirubicin and cyclophosphamide compared to 5FU, doxirubicin and cyclophosphamide results in a 30% relative reduction in risk of death and a 28% relative reduction in the risk of disease recurrence at a median follow-up of 55 months.
Breast cancer-women with ER-positive disease have a smaller benefit from the use of adjuvant chemotherapy in breast cancer than in women with ER-negative disease.
Breast cancer-with the use of tamoxifen provides additional benefits in reducing breast cancer recurrence.
Breast cancer-CMF adjuvant chemotherapy 20 year analysis revealed significant improvement in relapse free survival and overall survival.
Breast cancer-for early stage breast cancer adjuvant chemotherapy with doxorubicin (60mg/m2)and cyclophosphamide (600mg/m2) (AC) for four cycles compared to docetaxel (75mg/m2) plus cyclophosphamide (600mg/m2) (TC) for four cycles resulted in a disease free survival at 60 months of 86% for the TC group and 80% for the AC group, an overall survival was also greater for the TC group was greater than the AC group although not yet statistically significant 90% vs. 87%.
Breast cancer-decision to use chemotherapy in addition to hormonal treatment in axillary node negative and estrogen receptor positive disease is based on prognostic information and prediction of the degree of benefit from chemotherapy.
Breast cancer-phase III Southwest Oncology Group 8814/The Breast Cancer Intergroup of North America (TBCI) 01000 trial randomized 1,477 postmenopausal women with ER+, node positive disease to tamoxifen alone, tamoxifen and concurrent cyclophosphamide, doxorubicin and 5 FU (CAF) or tamoxifen after 6 cycles of CAF: 10 year survival and overall survival superior in tamoxifen after chemotherapy group.
Breast cancer-Cancer and Leukemia Group B (CALGB/CTSU protocol 49,907 compared CMF (Cyclophosphamide, Methotrexate,5FU) or AC (Adriamycin, Cyclophosphamide) or 6 cycles of capecitabine for patients 65 years of age or older: with a median follow-up at 2.4 years relapse occurred significantly more frequently in the capecitabine group, recurrences more frequent with larger tumors those with positive lymph nodes and ER negative tumors, relapse free survival for patients treated with capecitabine was significantly shorter than with standard chemotherapy, more patients in the capecitabine are died of breast cancer, for patients with ER positive disease there was little difference between CMF, AC or capecitabine for relapse free or overall survival while with ER negative tumors CMF and AC superior to capecitabine for relapse free survival and overall survival.
Breast cancer-phase III study for high-risk node negative patients comparing TAC (docetaxel, doxorubicin, cyclophosphamide or FAC (fluorouracil, doxorubicin, cyclophosphamide every three weeks for 6 cycles: with a median follow-up of 6 years the disease free survival for TAC was 91% vs.86% for FAC, with a overall survival of 97% for TAC and 95% for FAC (Iluch).
Breast cancer-docetaxel does not have significantly different effects on the risk of recurrence or death in ER positive or ER negative patients in adjuvant breast cancer chemotherapy trials.
Breast cancer-randomized chemotherapy trials with adjuvant chemotherapy for breast cancer suggest that patients with ER positive disease derive less benefit from anthracycline and paclitaxel regimens than do ER negative patients.
Breast cancer-Cancer and Leukemia Group B 9344 trial evaluated doxorubicin/cyclophosphamide with or without paclitaxel revealed that the reduction in the risk of death with paclitaxel was 24% in the ER negative group compared with 11% in the ER positive patients.
Breast cancer-In a random assignment of 4162 women older than age 18 to 600 mg/M2 of 5-FU, 60 mg/M2 of epirubicin, and 600 mg/M2 cyclophosphamide at 3-week intervals for four cycles followed by 100 mg/M2 of Docetaxel at 3-week intervals for four cycles compared to a control group which was similar drugs of 5-FU/epirubicin/cyclophosphamide for eight cycles or epirubicin for four cycles followed by cyclophosphamide/methotrexate/5-FU for four cycles. There were 2073 patients in the treatment group, and the median follow-up was 62 months. At five years, 75.6% of the treatment group and 74.3% in this control group were disease-free and alive suggesting that the addition of Docetaxel to anthracycline chemotherapy showed no additional benefit. (Ellis, P)
TailoRx trial demonstrated about 70% of patients with hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative, axillary node-negative early-stage breast cancer, who received intermediate score on the Oncotype Dx test, could be
spared chemotherapy.
The trial found no difference in the disease-free survival whether these women were treated with endocrine therapy alone or with the combination of endocrine therapy with chemotherapy.
The trial found about half of all breast cancers are hormone receptor positive, HER2 negative, and axillary node negative but up to 30% of patients have recurrences by 10 years,
This population can be spared an estimated 70% of patients and limit chemotherapy to the 30% who may benefit from it.
Adjuvant chemotherapy in the above patients reduced the risk for relapse, but the absolute benefit was only 3% to 5%,suggesting many women are being overtreated, because endocrine therapy would be adequate,
Breast cancer-Adjuvant chemotherapy is not necessary for a large proportion of women with early-stage breast cancer.
Application of the Oncotype Dx to clinical practice in this population will spare an estimated 70% of patients and limit chemotherapy to the 30% who may benefit from it.
About 70% of patients with hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative, axillary node-negative early-stage breast cancer, who received a midrange score on the Oncotype Dx test, could be spared chemotherapy.
The trial found no difference in the disease-free survival whether these women were treated with endocrine therapy alone or with the combination of endocrine therapy with chemotherapy.
About half of all breast cancers are hormone receptor positive, HER2 negative, and axillary node negative, but up to 30% of patients have incurable recurrences by 10 years.
Adjuvant chemotherapy is typically recommended to reduce this risk for relapse, but the absolute benefit is small (3% to 5%), resulting in many women being overtreated, because endocrine therapy would be adequate.
Oncotype DX-Patients who obtain a high score are considered to be at high risk for relapse and so are considered to benefit from chemotherapy.
Patients who obtain a low score (0 to 10) are considered to have a very low rate of distant recurrence (2% at 10 years), and that recurrence is not likely to be affected with use of adjuvant chemotherapy.
For the patients who score in the midrange between these two extremes,about two thirds who undergo testing, whether chemotherapy would reduce the risk for recurrence has been unclear.
10,273 women with hormone receptor-positive, HER2-negative, axillary node-negative breast cancer were enrolled, and of this group, 6711 had a midrange recurrence score of 11 to 25.
They were randomly assigned to receive endocrine therapy alone or endocrine therapy and chemotherapy.
At a median follow-up of 90 months, there were 836 events of invasive disease recurrence, second primary cancer, or death.
This included 338 (40.4%) recurrences of breast cancer as the first event, of which 199 (23.8% of the total events) were distant recurrences.
Overall, endocrine therapy was noninferior to chemotherapy plus endocrine therapy, with a hazard ratio (HR) for invasive disease recurrence, second primary cancer, or death of 1.08.
9-year rates were similar between both groups for disease-free survival (83.3% vs 84.3%), distant recurrence (94.5% vs 95.0%), and overall survival (93.9% vs 93.8%).
Chemotherapy did appear to have some benefit in patients who were age 50 years or younger with a recurrence score of 16 to 25.
There were 2% fewer distant recurrences for recurrence scores 16 to 20, and 7% fewer for recurrence scores of 21 to 25.
Breast cancer-Incorporation of bevacizumab into sequential anthracycline- and taxane-containing adjuvant therapy does not improve DFS or overall survival in patients with high-risk human epidermal growth factor receptor 2-negative breast cancer (Miller KD).
High-dose chemotherapy in the adjuvant setting offers a long-term survival advantage for women with very-high-risk stage III breast cancer, but does not improve survival odds for women with lower-risk cancers, an analysis of 20 years of follow-up data shows.
Among 885 women younger than 56 years at the time of treatment who had 4 or more involved axilliary lymph nodes, there was no overall survival difference over 2 decades between the total population of women randomized to receive adjuvant high-dose chemotherapy (HDCT) and those assigned to receive conventional-dose chemotherapy (CDCT).
However, women with 10 or more involved axilliary nodes and those with triple-negative breast cancer had an approximately 15% absolute improvement in 20-year overall survival with high-dose chemotherapy, although the difference for triple-negative disease fell just short of statistical significance.
(Netherlands Cancer Institute).
HDCT has no significant overall survival benefit compared with CDCT for unselected patients with stage III breast cancer.
However, we found a 14.6%improvement in 20-year OS estimates with HDCT in the predefined subgroup of patients with 10 or more lymph nodes involved.
After a median follow-up of 20.4 years, the 20-year overall survival (OS) rates were 45.3% for patients who had received high-dose chemotherapy and 41.5% for those who had received the conventional dose: nonsignificant hazard ratio of 0.89.
For patients with 10 or more involved axillary nodes, the 20-year OS rates were 44.5% with HDCT and 29.9% with CDCT, translating into an absolute OS advantage for high-dose chemotherapy of 14.6% and an HR of 0.72.
COLN CANCER
Colon cancer-Adjuvant chemotherapy is generally recommended in certain cases of stage II and in all cases stage III colorectal cancers.
Colon cancer-Stage II colon cancer are at increased risk for recurrence if the tumor has penetrated the wall of the colon.
Colon cancer-Adjuvant therapy decreases the risk for recurrence by approximately 1/3
Colon cancer-5FU plus levamisole 5 year survival 70% compared to a control group of 58%.
Colon cancer-Oxaliplatin/5FU/leucovorin adjuvant therapy results in 78.2% 3-year disease free survival.
Colon cancer-oxaliplatin adds approximately five percentage points to the three-year disease-free survival rate.
Colon-cancer-ACCENT data suggested limited benefit from addition of oxiplatin to fluorouracil in elderly patients.
Colon cancer 5FU+LV(leucovorin) vs. capecitabine (Xeloda) revealed 3 year disease free survival of 60.6% and 64.2%, respectively, an insignificant difference, and an overall survival of 77.6% and 81.3%
Colon cancer-Mosaic Trial-2246 randomized patients with stage II/III colorectal cancer received 6 months of 5FU/LV-bolus and infusional 5FU/LV or FOLFOX4 (5FU/LV/oxaliplatin) with a 24% decrease in risk recurrence at 5 years with the FOLFOX4 regimen.
Colon cancer-MOSIAC trial-the Multicenter Internaional Study of Oxaliplatin/5 Fluoracil/Leucovorin on the Adjuvant Treatment of Colon Cancer included 2,246 patients showed the addition of oxaliplatin to fluoracil/leucovorin regimen improved 5 year disease free survival from 67.4% to 73.3% and improved 6 year overall survival rates from 76%to 78.5%.
Colon cancer-In the MOSAIC trial, all patients with stage III who received FOLFOX4 showed significant gains of 7.5% in DFS at 5 years and 4.2% in overall survival at 6 years.
Colon cancer-NSABP C-07 Trial-2407 patients compared adjuvant oxaliplatin, fluoracil, and leucovorin against fluoracil and leucovorin:triple therapy improved 3 year disease free survival from 71.8% to 76.11% and an improvement in 4 year disease free survival from 67% to 73.2%.
Colon cancer-Mosaic Trial-disease free survival only significant for stage III disease and not stage II disease.
Colon cancer-in the Mosaic Trial ( The Multi-center International Study of Oxaliplatin/5-fluorouracil/Leukovorin in the Adjutant Treatment of Colon Cancer): the six-year overall survival results was not maintained in patients over 65 years (Andre T et al).
Colon cancer-meta-analysis revealed that the relative overall survival decreased by 14% for every 4 week interval delay in the initiation of adjuvant therapy (Biagi JJ et al).
Colon cancer-Evidence suggest delays in adjuvant chemotherpay for colorectal cancer longer than 8 weeks leads to a worse overall survival with hazard ratios ranging from 1.4-1.7.
Adjuvant chemo therapy for patients with stage III colon cancer demonstrated noninferiority of three months versus six months of therapy.
Rectal cancer-For stage II and III locally advanced rectal cancer treated with preoperative chemotherapy and radiation followed by surgery, four months of adjuvant chemo therapy improves overall survival.
ENDOMETRIAL CANCER
Regimens combining taxane and platinum are feasible alternatives to doxorubicin plus cisplatin in adjuvant chemotherapy for patients with endometrial cancer.
The efficacy of taxane plus platinum regimens has been demonstrated for advanced or recurrent endometrial cancer.
A total of 788 patients with endometrial cancer at high-risk stage I or II or stage III or IV that did not extend beyond the abdominal cavity and had ?2 cm residual tumor.
After a median of 7 years follow-up there was reported no statistical difference of in PFS (doxorubicin plus cisplatin, docetaxel plus cisplatin, paclitaxel plus carboplatin,or OS between the 3 study arms.
At 5 years, the PFS rates were 73.3% for the doxorubicin plus cisplatin arm, 79.0% for the docetaxel plus cisplatin arm, and 73.9% for the paclitaxel plus carboplatin arm; 5-year OS rates were 82.7%, 88.1%, and 86.1%, respectively.
There is no significant difference of survival among patients receiving doxorubicin plus cisplatin, docetaxel plus cisplatin, or paclitaxel plus carboplatin as postoperative adjuvant chemotherapy for endometrial cancer.
Regimens combining taxane and platinum are feasible alternatives to doxorubicin plus cisplatin in adjuvant chemotherapy for patients with endometrial cancer.
The efficacy of taxane plus platinum regimens has been demonstrated for advanced or recurrent endometrial cancer.
A total of 788 patients with endometrial cancer at high-risk stage I or II or stage III or IV that did not extend beyond the abdominal cavity and had ?2 cm residual tumor.
After a median of 7 years follow-up there was reported no statistical difference of in PFS (doxorubicin plus cisplatin, docetaxel plus cisplatin, paclitaxel plus carboplatin,or OS between the 3 study arms.
At 5 years, the PFS rates were 73.3% for the doxorubicin plus cisplatin arm, 79.0% for the docetaxel plus cisplatin arm, and 73.9% for the paclitaxel plus carboplatin arm; 5-year OS rates were 82.7%, 88.1%, and 86.1%, respectively.
There is no significant difference of survival among patients receiving doxorubicin plus cisplatin, docetaxel plus cisplatin, or paclitaxel plus carboplatin as postoperative adjuvant chemotherapy for endometrial cancer.
PANCREATIC CANCER
Pancreatic cancer-ESPAC-1 (European Study Group for Pancreatic Cancer) studies four groups of 70 patients with surgery alone, chemotherapy alone, chemo radiation alone and chemo radiation followed by chemotherapy: median survival 20.1 months for those receiving chemotherapy and 15.5 months for those who did not receive chemotherapy and 2 and 5 year survival estimates were 40% and 21%, respectively among patients who received chemotherapy, compared to 30% and 8%, respectively, among patients who received no chemotherapy.
Pancreatic cancer-ESPAC-1 (European Study Group for Pancreatic Cancer) concluded 5FU based chemotherapy has a survival advantage while chemo radiation offered no such benefit and in fact may be detrimental in adjuvant management of pancreatic cancer.
NON-SMALL CELL CARCINOMA OF THE LUNG
Non-Small Cell Carcinoma of the Lung (NSCLC)-Adjuvant chemotherapy for non-small cell lung cancer administered postoperatively to eradicate micro metastases and attempting to improve long-term disease free survival and overall survival.
Non-small cell lung cancer- and Non-Small Cell Lung Cancer Collaborative Group analyzed 14 trials of adjuvant lung cancer therapy for non-small cell and found 85% reduction in the absolute risk of death at five years with cisplatin-based chemotherapy.
Non-small cell lung cancer- Eastern Cooperative Oncology Group 3590 randomized 488 patients with stage II or stage IIIA non-small cell lung cancer to postoperative radiation alone or combined with 4 cycles of cisplatinum and etoposide: there was no survival benefit with a median survival of 38 months in the combination arm versus 39 months in the radiation only group (Keller SM et al).
Non-small cell lung cancer-Big Lung Trial randomized patients with stage I-III NSCLC to receive three cycles of chemotherapy or no chemotherapy in conjunction with primary treatment of surgery, radiotherapy, or best supportive care: four cisplatin-based chemotherapy regimens were utilized- Overall survival was not improved with adjuvant chemotherapy for non-small cell lung cancer, and the majority of the patients in the study had stage I disease a setting in which adjuvant chemotherapy is least beneficial (Waller D et al A).
Non-small cell lung cancer adjuvant chemotherapy after resection of stage II-IIIA disease improves survival and is recommended therapy.
Non-small cell lung cancer Stage I adjuvant therapy limited to patients with a resected tumor 4 cm or larger.
Non-small cell lung cancer-Adjuvant chemotherapy remains efficacious when started 7-18 weeks after non-small cell lung cancer resection (National Cancer Database).