Dose Adjuvant Chemotherapy Research Articles

Present status and potential role of high-dose adjuvant chemotherapy in breast cancer with poor prognosis.

Adjuvant systemic treatments have undoubtedly altered the natural course of re­ sectable breast cancer in patients at high risk of relapse and death. Adjuvant chem­ otherapy has been demonstrated to produce moderate but consistent improvements in long-term disease-free and overall survival, mainly in premenopausal patients. These achievements have been obtained with regimens which are not curative in metastatic disease. The most extensively used regimens are based on cyclophos­ phamide, methotrexate and 5-fluorouracil (CMF). However, women with more than three histologically positive axillary lymph nodes still have a poor prognosis. In fact, after adjuvant standard CMF for 12 months more than half of these patients relapsed within 44 months and died within 82 months of surgery (in the Milan trial). Review of the data from International Breast Cancer Study Group adjuvant breast cancer trials shows that women with breast cancer four or more involving axillary lymph nodes have a 70% risk of relapse at 5 years and approximately 60% risk of death from their disease at 9 years after primary treatment with standard­ dose adjuvant chemotherapy, regardless of menopausal and restrogen status. The outcome of adjuvant systemic therapy might be dependent on the dose intensity of the regimens used. Dose reduction of chemotherapy, if given with curative intent, may lead to poor results. Dose escalation for CMF treatment proved not to be fea­ sible because of subjective and objective toxicity. Introduction of anthracycline­ containing regimens and development of new means such as haematological growth factors and autologous stern cell support allowed dose escalation of regimens us­ ing alkylating agents and anthracyclines, commonly accepted as the most active therapeutic agents available for the treatment of breast cancer. Among the most active agents - the anthracyclines - epirubicin can be escalated considerably. In the 1980s single alky lating agents were studied at high doses requiring autologous stern cell support in patients with advanced breast cancer which had become re­ fractory to conventional chemotherapy. An overall response rate of about 30% was observed. High-dose combination of alkylating agents in these patients produced a response rate of 75%, with compIete response in 15% of the patients. However, the median response duration was short. Extramedullary dose-limiting toxicities produced by these regimens were considerable. The mortality rates associated with these programmes were in the range of 15-20%. Further development of these reg­ imens and more experience in the use of supportive care lowered the treatment-as­ sociated morbidity and mortality considerably. These improvements facilitated

Adjuvant Therapy of Breast Cancer

This article examines questions about adjuvant systemic therapy, especially in premenopausal and postmenopausal women. The impact of adjuvant therapy on quality of life is addressed, as is the role of doxorubicin in adjuvant chemotherapy. The value of high dose adjuvant chemotherapy and late effects of adjuvant therapy are also examined.

Impact of irradiation of residual breast on adjuvant chemotherapy dose intensity.

The chemotherapy dose intensity for breast cancer has been recently considered to be an important factor in determining clinical outcome. Many trials have shown routine postoperative irradiation to have a detrimental effect on the delivered dose of adjuvant chemotherapy. In this paper the impact of radiotherapy on the dose intensity of adjuvant chemo- or hormonotherapy was evaluated in 237 breast cancer patients. 177 patients had radical mastectomy and 60 quadrantectomy followed by radiotherapy. Chemotherapy comprised 6 cycles of FEC (5-fluorouracil, epidoxorubicin, cyclophosphamide) alternated to 6 cycles of CMF (cyclophosphamide, methotrexate, 5-fluorouracil)+tamoxifen for 5 years. There were no significant differences in the adjuvant chemotherapy dose intensity in the mastectomy group compared to the radiotherapy group.

LOCALLY ADVANCED BREAST-CARCINOMA - RESULTS OF A MULTIMODAL THERAPY INCLUDING ALTERNATING NEOADJUVANT CHEMOTHERAPY, SURGERY AND RADIOTHERAPY

Thirty women with locally advanced breast cancer (LABC), but no evidence of distant metastases, were prospectively treated with four fixed cycles of neoadjuvant chemotherapy (CT). This regimen consisted of epidoxorubicin (Epi) alternated every 21 days with cyclophosphamide, methotrexate and 5-fluorouracil (CMF). After this induction CT, subsequent therapy was planned according to the response obtained as follows: (a) modified mastectomy with axillary dissection was performed in patients who had major objective response (complete or partial), followed by four doses of adjuvant CT and radiotherapy (RT); (b) debulking rescue surgery followed by RT and 2nd line CT with mitomycin C were given in patients with stable disease or minor response. The response rate to induction CT was 63% (19 of 30 patients) (95% confidence limits 46-80%). Overall, 43% of patients had no persistance of tumor at the end of the planned therapy. After a median follow-up time of 36 months, disease-free survival (DFS) and overall survival (OS) were 35% and 47%, respectively. The median duration of DFS was 16 + months (4-52+ months). A significantly better OS was observed in complete responders compared to the others (77% versus 23.5%; p=0.01). Compliance to treatment was high, gastrointestinal and hematological toxicities were the most common side-effects. Thus, this multimodal approach is effective in reducing primary tumor size with acceptable morbidity. Five of the 11 (45%) patients non responsive to induction CT obtained a transient local control of disease after debulking surgery, RT and mitomycin C. To assess the role of alternating non cross resistant regimens as induction therapy in LABC vs conventional schedules, phase III comparative studies are warrented.

Association of disease-free survival and percent of ideal dose in adjuvant breast chemotherapy

The relationship between percent of ideal dose and disease-free survival was examined in 256 Stage II and III patients who participated in a 2-year breast adjuvant chemotherapy trial consisting of cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) given postoperatively. When analyzed analogously to previous work, the results confirmed a dose-response relationship: that is, there appeared to be an improved disease-free survival for patients receiving higher doses of adjuvant chemotherapy. The major criticism of such an analysis is its bias. This bias was addressed by considering only patients who were still receiving therapy at 6, 12, and 24 months; then, the dose-response relationship was no longer seen. Although causality cannot be inferred, the apparent differences in disease-free survival among the dose groups can be attributed to recurrences in the first 2 years among patients receiving lower doses of chemotherapy.

Adjuvant chemotherapy after resection of adenocarcinoma of the periampullary region and the head of the pancreas

From 1980 till 1984 16 patients were entered into a non-randomized pilot study, to investigate the feasibility of five courses of adjuvant 5-fluorouracil, Adriamycin and mitomycin C (FAM) after a curative resection of pancreatic or periampullary cancer. The survival of this group of patients was compared with that of 36 patients who underwent a curative resection alone between 1977 and 1984. Four patients received less than 20%, 4 patients 50%-60% and 7 patients greater than or equal to 80% of the calculated dose of adjuvant chemotherapy. The chemotherapy was badly tolerated. Only 1 patient resumed some of his normal activity during chemotherapy. The 3-year actuarial survival after curative resection with and without FAM was similar, i.e. 24% and 28% respectively. These data suggest that adjuvant FAM after a Whipple's operation or total pancreatectomy is not feasible because of additive postoperative and chemotherapy-induced morbidity.

Adjuvant chemotherapy after conservative surgery plus irradiation versus modified radical mastectomy: Analysis of drug dosing and toxicity

In a cohort of 764 evaluable patients with primary breast cancer, we have compared the ability to deliver full doses of adjuvant chemotherapy in two patient groups: one undergoing conservative breast surgery plus irradiation and the other having modified radical mastectomy as primary treatment for the cancer. We have also analyzed the toxicities of the concurrent radiation and chemotherapy. The group having irradiation had significantly more moderate leucopenia, which caused a short delay (median, three weeks) in the overall time necessary to complete the planned chemotherapy. However, among those patients who completed the planned chemotherapy cycles, the fraction who received more than 85 percent average drug doses was 96 percent or higher in all but one small subgroup. Interaction between the irradiation and chemotherapy caused mild breast skin reactions in 42 percent of patients so analyzed and worse reactions in 12 percent. When follow-up tracings were performed, mild electrocardiogram abnormalities occurred in 19 percent of patients, apparently because of the irradiation. We conclude that intravenous adjuvant chemotherapy, as administered in this study, can be delivered as intensely with conservative primary treatment as after mastectomy and that toxicity is mild, rarely requiring intervention or treatment discontinuation.

Adjuvant chemotherapy (CMF) for breast carcinoma

Seventy-five patients accepted postmastectomy adjuvant CMF chemotherapy for Stage II and III carcinoma of the breast. All patients, irrespective of age, were started on the same drug dosages. About 77% of the patients stayed on the treatment for at least 6 months, and 50%, for 12 or more months (compliance rate unrelated to age). Among the 58 patients who received 6 or more cycles of CMF, 12 (21%) actually received more than 85% of the planned mean total dose (MTD). Adjuvant CMF doses had to be reduced for toxicity related to drug (52% of patients) and reasons not related to drug (27%). Premenopausal patients are more likely to skip cycle due to personal reasons and to have leukopenia, while postmenopausal patients are more likely to have gastrointestinal toxicity and flu-like syndromes. Theoretically, excluding nondrug-related side effects, only 30-40% of the patients can receive over 85% of the planned dose of CMF adjuvant chemotherapy.

The effect of postoperative radiotherapy on the feasibility of optimal dose adjuvant CMF chemotherapy in stage II breast carcinoma

The impact of a number of variables upon the effectiveness of adjuvant chemotherapy given to 87 patients with Stage II breast carcinoma was retrospectively analyzed. Adjuvant chemotherapy consisted of cyclophosphamide, methotrexate and 5-fluorouracil (CMF). Drugs were given in optimal doses (85% or more of the planned dose) to 17% of the patients; in intermediate doses (66 to 84% of the planned dose) to 50% of the patients; and in low doses (65% or less of the planned dose) to 33% of the patients. Myelosuppression was the main reason for giving intermediate or low doses. At a median follow-up of three years, 84% of all patients remain alive. Radiation therapy preceding chemotherapy was given to 70 % of the patients, concomitant irradiation and chemotherapy to 15 %, and 13 patients (15%) received chemotherapy only. Of the 14 patients who received optimal doses of CMF, 12 (86%) also received radiation therapy. Disease-free survival at three years is similar for irradiated and nonirradiated patients, but the latter have a higher incidence of local recurrence (5 % vs. 15 %), although the difference is not statistically significant. Delay in the initiation of chemotherapy, mostly because of the administration of postoperative irradiation, adversely affected the probability and duration of disease-free survival, particularly in premenopausal women in whom chemotherapy was started within more than 90 days of mastectomy. The administration of optimal doses of adjuvant chemotherapy should follow the primary treatment to the breast tumor as closely as possible. If radiation therapy is indicated as well, it should be delivered concomitantly with chemotherapy, given the feasibility of administering both modalities simultaneously, as demonstrated in this study.

Current status and indications for adjuvant therapy in breast cancer.

1. Modified radical mastectomy is the standard surgical procedure today in most countries. 'Lesser surgery' associated with radiotherapy emerges as an alternative for patients with T1N0 lesions. 2. The potential risk of occult micrometastases is best predicted by careful axillary staging and possibly by the ER status of the primary tumor. 3. Additional risk factors such as tumor size, patients age, menopausal status, and intramammary lymphatic or vascular invasion are less well established and need clarification. 4. Previous studies showed no significant long-term benefit of adjuvant radiotherapy and at best a marginal increase of lifespan by adjuvant castration in patients subjected to radical surgery. 5. Various types of adequately intensive adjuvant chemotherapy resulted in a significant increase of relapse-free survival and probably also overall survival 5-6 years after mastectomy in pre- and possibly also postmenopausal N+ patients. 6. Treatment intensity (full doses) of adjuvant chemotherapy seems to be more critical than treatment duration (CMF X 6 is as good as CMF X 12). 7. Adjuvant chemotherapy with drug combinations is generally more effective than single drugs. No combination so far (if adequate doses are given) is clearly superior. 8. Whether early peri-operative onset of adjuvant chemotherapy or combinations with endocrine measures or cyclic, alternating drug regimens increase effectiveness remains to be shown. 9. Adjuvant chemotherapy in N- patients, though still experimental, appears rewarding. 10. The pattern of first relapse has not been significantly altered by the use of adjuvant chemotherapy. Response rate and duration with secondary treatments are consistent with common experience in metastatic disease. 11. Up to 5-6 years median observation time there is no proof that the risk of second neoplasms is increased by currently used adjuvant chemotherapy regimens. 12. More and highly critical prospective trials are needed to assess not only effectiveness, but also patient tolerance (cost-benefit ratio) of adjuvant therapies in breast cancer.

Ewing sarcoma: treatment with high dose radiation and adjuvant chemotherapy.

Twenty-one patients with pathologically proven Ewing sarcoma without overt metastases at diagnosis were treated with a protocol designed by the Royal Marsden/St. Bartholomew's Hospitals Children's Solid Tumour Group (CSTG). They received megavoltage radiotherapy to the involved bone and adjuvant chemotherapy with a combination of four cytotoxic drugs. Seven patients have so far relapsed, four at the original site and three in other bones. The other 14 are clinically free of disease a median of 36 months from diagnosis. Comparison with a historical control group of 19 patients treated with surgery or radiotherapy, but without initial chemotherapy, shows a significant improvement in survival for the study group (P = 0.03). Seventeen of the controls have died. The treatment regime was moderately toxic, but there were no treatment-related deaths. These results confirm that an improved survival time and hopefully cure rate can be expected from treating Ewing tumour with high doses of megavoltage radiation and combination chemotherapy. Future goals must be the better control of large primary lesions and the eradication of micrometastases in other bones. The place of surgery should be re-evaluated in the treatment of the primary tumour, and better adjuvant chemotherapy regimes are needed.

The effect of cancer chemotherapeutic agents on fibrin formation and stabilization in vitro.

Extract: Functional and morphologic studies of fibrin formation in the presence of a variety of cancer chemotherapeutic agents in vitro showed that some of these drugs cause fibrinolysis, inactivation of fibrin-stabilizing factor (FSF), or a combination of both. The drugs with most potent activity are 5-[3,3-bis(2-chloroethyl)-1-triazeno]imidazole-4-carboxamide (TIC mustard), 5-fluorouracil, nitrogen mustard, adriamycin, and daunomycin. These changes were dose related.Speculation: Interference with fibrin formation by anticoagulation has been associated with reduced implantability of tumor emboli in experimental systems. This study presents evidence that some cancer chemotherapeutic agents have chemical properties of an anticoagulant nature. In addition to any influence on cell multiplication, high pulse doses of adjuvant chemotherapy at the time of tumor manipulation such as surgery may interfere with fibrin formation around tumor emboli and discourage metastatic implantation.