Dose Adjuvant Chemotherapy Research Articles

Dose variation and regimen modification of adjuvant chemotherapy in daily practice affect survival of stage I–II and operable stage III Taiwanese breast cancer patients

To assess the effect of a non-standard dose and regimen of adjuvant chemotherapy on the clinical outcome in stage I–II and operable stage III Taiwanese breast cancer patients. Variables studied included treatment variation (regimen and dose of adjuvant therapy), lymph node status, tumor size, histologic grade, and hormone receptor status. Cox's multivariate regression analyses were used to select prognostic factors significant for disease-free survival (DFS) and overall survival (OS). In the multivariate analysis, lymph node-positive, a tumor size greater than 5 cm, grade III, hormone receptor-negative status, and non-standard adjuvant chemotherapy were independent prognostic factors for DFS and/or OS. Node-positive patients treated with standard adjuvant chemotherapy had a significantly better DFS (HR = 0.6; P = 0.032) and OS (HR = 0.54; P = 0.025) than those treated with non-standard adjuvant chemotherapy. Breast cancer patients receiving standard adjuvant chemotherapy have a better DFS and OS than those receiving non-standard adjuvant chemotherapy.

Influence of activation state of ErbB-2 (HER-2) on response to adjuvant cyclophosphamide, doxorubicin, and fluorouracil for stage II, node-positive breast cancer: study 8541 from the Cancer and Leukemia Group B.

ErbB-2 (human epidermal growth factor receptor 2) overexpression may be predictive of relative resistance and/or sensitivity to specific chemotherapeutic agents. Results from a previous study from the Cancer and Leukemia Group B (CALGB 8541) demonstrated an interaction between ErbB-2 and increasing dose of adjuvant cyclophosphamide, doxorubicin, and fluorouracil (CAF) chemotherapy. Other studies have suggested that evaluation of the phosphorylated/activated form of ErbB-2 might be more precise in defining the impact of ErbB-2 in breast cancer. We have evaluated tumor tissue sections from CALGB 8541 patients to determine whether the interaction of ErbB-2 with CAF dose is dependent on ErbB-2 activation state, and whether phosphorylated ErbB-2 is an adverse prognostic factor in patients treated with CAF. Patients were randomly assigned to one of three dosing regimens of CAF. Paraffin samples from 992 of 1,572 patients who participated in CALGB 8541 were available. Of the 570 tumors with any staining for ErbB-2, 488 had tissue available for assay for phosphorylated ErbB-2, which was performed by immunohistochemistry. Of 910 total assessable cases, 112 of 488 ErbB-2-positive cases (23%) stained positively for phosphorylated ErbB-2. The previously described interaction of dosing regimen of CAF with ErbB-2 was not dependent on phosphorylation status of ErbB-2. Monitoring phosphorylation of ErbB-2 with an antiphospho-ErbB-2 antibody did not add further precision to identifying those patients most likely to benefit from increased dose of anthracycline-based adjuvant chemotherapy. Favorable outcomes are observed in ErbB-2-overexpressing patients treated with high-dose CAF regardless of ErbB-2 phosphorylation state.

Gemcitabine and concurrent radiation as a salvage treatment of chest wall recurrence in breast cancer

11027 Background: Chest wall recurrences are seen despite postoperative chemotherapy and radiotherapy. For patients with unresectable lesions who have previously received radiotherapy no standard treatment is available. We devised a protocol of low dose gemcitabine as radiosensitizer concurrent with low dose of radiation and conducted this study with the objectives to document the efficacy and toxicity of this protocol. Methods: From January 2003 to August 2005, 48 patients were included in this study. A histopthological or cytological evidence of chest wall recurrence was required. Females between 18–70 years, with previous modified radical mastectomy, post operative radiation and adjuvant chemotherapy were included. Patients with metastatic disease were excluded. Written informed consent was obtained. A dose of 150 mg / m2 of gemcitabine in 200 ml of normal saline was infused in 2 hour on day 1, 8, 15 and 22 of radiation. Radiation was delivered 2 hours after the completion of infusion. Conventional fractionation was used to deliver a total dose of 36 Gy given in 3.5 weeks. RECIST and RTOG criteria were used. Results: Twenty recurrences were related to the scar, 10 to the involved internal mammary lymph node region invading sternum and ribs and 18 were associated with the soft tissue masses outside the scar area. All patients were evaluable for response and toxicity. Complete response was seen in 6 (12.5 %) patients, (95 % CI, 13.87_37.16), partial response was seen in 30 (62.5 %) (95 % CI, 44.92 -71.40) with an over all response rate of 75 % (95 % CI, 70.57—91.40) Stable disease was seen in 9 (18.8 %) patients and disease progression in 3 (6.3 %) patients. Grade I skin reaction was seen in 15 (31.2 % ) patients grade II in 11 ( 22.9 % ) and grade III in 3 ( 6.3 % ) patients. No systemic toxicity was seen. Conclusions: Low dose gemcitabine and concurrent radiotherapy is a reasonable salvage treatment in chest wall recurrence in breast cancer patients who have previously received adjuvant chemotherapy and full dose of radiotherapy. This approach has acceptable toxicity. No significant financial relationships to disclose.

Older Female Cancer Patients: Importance, Causes, and Consequences of Undertreatment

Despite increased interest in treatment of senior cancer patients, older patients are much too often undertreated. This review aims to present data on treatment practices of older women with breast and gynecologic cancers and on the consequences of undertreatment on patient outcome. We also discuss the reasons and validity of suboptimal care in older patients. Numerous studies have reported suboptimal treatment in older breast and gynecologic cancer patients. Undertreatment displays multiple aspects: from lowered doses of adjuvant chemotherapy to total therapeutic abstention. Undertreatment also concerns palliative care, treatment of pain, and reconstruction. Only few studies have evaluated the consequences of nonstandard approaches on cancer-specific mortality, taking into account other prognostic factors and comorbidities. These studies clearly showed that undertreatment increased disease-specific mortality for breast and ovarian cancers. For other gynecological cancers, data were insufficient to draw conclusions. Objective reasons at the origin of undertreatment were, notably, higher prevalence of comorbidity, lowered life expectancy, absence of data on treatment efficacy in clinical trials, and increased adverse effects of treatment. More subjective reasons were putative lowered benefits of treatment, less aggressive cancers, social marginalization, and physician's beliefs. Undertreatment in older cancer patients is a well-documented phenomenon responsible for preventable cancer deaths. Treatments are still influenced by unclear standards and have to be adapted to the older patient's general health status, but should also offer the best chance of cure.

Primary and Central Hypothyroidism After Radiotherapy for Head-and-Neck Tumors

To investigate the incidence of radiotherapy (RT)-induced central and primary hypothyroidism regarding total dose, fractionation, and adjuvant chemotherapy. We retrospectively reviewed the data from 312 patients treated with RT for extracranial head-and-neck tumors between 1964 and 2000. The cervical lymph nodes were irradiated in 197 patients. The radiation doses to the thyroid gland and hypothalamic-pituitary axis were estimated by reconstructing the treatment plans. Clinical central hypothyroidism (CH) was observed in 17 patients (5.4%); the median clinical latency was 4.8 years. Clinical primary hypothyroidism (PH) was observed in 40 patients (20.3%); the median clinical latency was 3.1 years. Multivariate analysis of clinical CH revealed that fractionation, adjuvant chemotherapy, and total dose to the pituitary were not significant. Multivariate analysis of clinical PH revealed that the total dose to the thyroid (p = 0.043) was significant, but adjuvant chemotherapy, age, and gender were not. Of the patients tested for hypopituitarism, 14 (20.3%) of 69 demonstrated subclinical CH and 17 (27.4%) of 62 demonstrated subclinical PH. The 5-year and 10-year rates of freedom from clinical CH and PH were 97% and 87% and 68% and 67%, respectively. Of the patients tested, the 5-year and 10-year rates of freedom from subclinical CH and PH were 91% and 78% and 71% and 71%, respectively. Clinical and subclinical manifestations of late radiation toxicity were observed in the thyroid and hypothalamic-pituitary axis. Although CH did not indicate a dependence on fractionation, adjuvant chemotherapy, or total dose to the pituitary, PH showed a dependence on the total dose to the thyroid gland.

Impact of hemoglobin levels on outcomes of adjuvant chemotherapy in resected non-small cell lung cancer: The JBR.10 trial experience

Cisplatin-induced anemia may correlate with adverse events, poor quality of life (QoL), decreased adjuvant chemotherapy (ACT) dose intensity, shorter relapse-free survival (RFS) or overall survival (OS). The JBR.10 trial demonstrated significantly longer survival with adjuvant cisplatin and vinorelbine (n=242) compared to observation (n=240) in patients with resected NSCLC [Winton T, Livingston R, Johnson D, Rigas J, Johnston M, Butts C, et al. Vinorelbine plus cisplatin vs. observation in resected non-small-cell lung cancer. N Engl J Med 2005;352(25):2640-2]. This exploratory analysis evaluates the predictive value of baseline (in all patients) and during-treatment (in ACT arm only) hemoglobin (Hb) levels on OS and RFS when adjusted for prognostic factors. Baseline (in all patients) and during treatment (in ACT arm only) Hb levels were also correlated with adverse events, QoL, morbidity and ACT dose intensity. Baseline Hb did not predict RFS or OS. However, there was a trend to shorter OS (p=0.1) when baseline Hb was <120g/L. Lower baseline Hb predicted increased hospitalization (p=0.04) and worse QoL (SOB item, p=0.03) but had no impact on adverse events or dose intensity. There was a trend to longer RFS (p=0.08) in patients with lower nadir during-treatment Hb and to longer OS (p=0.06) and RFS (p=0.08) in patients with maximum during-treatment Hb drop >30% that was not maintained when ACT dose intensity was included in the model. Maximum during-treatment Hb drop >30% correlated with increased lethargy (p=0.003) and worse QoL (fatigue item, p=0.07). Lower baseline and during-treatment Hb levels seem associated with poorer QoL, fatigue and increased hospitalization. There is a trend for shorter OS in patients with lower baseline Hb levels.

Non-clinical factors associated with intentionally reduced breast cancer chemotherapy doses

6020 Background: Breast cancer survival and case-fatality rates are lower in women of lower socioeconomic status (SES) compared to those of higher SES. Disparities in the quality of chemotherapy may contribute to poorer outcomes among women of lower SES. The purpose of this study was to investigate the relation between SES (as measured by both individual and area-level characteristics) and the use of intentionally reduced breast cancer adjuvant chemotherapy doses. Methods: The cohort consisted of 764 breast cancer patients treated with a standard adjuvant chemotherapy regimen for stages I, II, or III enrolled in an IRB approved prospective registry. Information was collected on patient, disease, and treatment characteristics, including chemotherapy doses. Zip code level data on median household income (MHI), and proportions of residents with a high school (HS) or college degree were obtained from the US 2000 Census. Doses for cycle 1 of chemotherapy &lt; 85% of standard were considered to be reduced. Multivariate logistic regression analysis was performed to identify factors associated with the use of reduced first cycle doses. Results: In bivariate analysis, body mass index (BMI) (P=.003), education (P=.002), and region (P &lt; .001) were associated with the use of reduced doses. Race was borderline significant (P=.056). Reduced doses were more commonly administered to patients who lived in zip codes with lower MHI (P &lt; .001), lower education (P=.006), and higher levels of poverty (P &lt; .001). Age, stage, comorbidity, hormone receptor status, insurance, occupation, employment and marital status were not associated with use of reduced doses. In multivariate analysis without practice effects, high BMI (P &lt; .001), education less than HS (P=.009), and geographic region (P &lt; .001) were independently associated with reduced doses. The effect of BMI (P &lt; .001) stayed significant after adjustment for practice site, but education (P=.082) and geographic region (P=.127) became less so. Conclusions: Non-clinical factors, such as educational attainment and area level income, are associated with intentionally reduced doses of adjuvant chemotherapy. Interventions directed at improving quality of chemotherapy may improve breast cancer outcomes in patients of lower SES. No significant financial relationships to disclose.

Ethnic Disparities in Adjuvant Chemotherapy for Breast Cancer Are Not Caused by Excess Toxicity in Black Patients

Background Black patients with breast cancer may be at greater risk for chemotherapy-related hematologic toxicity than white patients because of lower baseline blood cell counts. We hypothesize that these baseline differences could lead to excess hematologic toxicity and greater modification of chemotherapy dosing in black patients and that this may contribute to the poorer survival observed in black patients with breast cancer compared with white patients with breast cancer. Patients and Methods We performed a retrospective cohort study of black and white patients with breast cancer treated with adjuvant chemotherapy at an academic medical center over an 18-month period. Clinical chart review and pharmacy records were used to collect data on the following: modification of chemotherapy dose or administration; hematologic toxicity; blood cell counts before, during, and after therapy; occurrence of febrile neutropenia; use of prophylactic antibiotics; and use of granulocyte colony-stimulating factor in order to determine whether ethnicity was an independent predictor of these outcomes. Results Among 23 black patients and 98 white patients with breast cancer treated with adjuvant chemotherapy, modification of chemotherapy administration occurred in 56 patients (46%). Modification was more common among black patients (65.2% vs. 41.8%; relative risk [RR], 1.56; P = 0.04). Black patients were more likely to receive reduced cumulative doses of adjuvant chemotherapy (RR, 2.49; P = 0.03). Conclusion Our findings suggest that hematologic tolerability of adjuvant chemotherapy is similar in black and white patients. Strategies aimed at improving psychosocial barriers to adjuvant therapy and at reducing surgical complications in black patients may improve overall breast cancer outcomes in this group.

Obesity and Outcomes in Premenopausal and Postmenopausal Breast Cancer

Obesity is associated with adverse outcomes in postmenopausal women with breast cancer. In premenopausal women, the association is less clear. A population-based sample of 1,360 Australian women with breast cancer before the age of 60 years, 47% diagnosed before age 40, and 74% premenopausal, was studied prospectively for a median of 5 years (range, 0.2-10.8 years). Obesity was defined as a body mass index of > or =30 kg/m2. The hazard ratio (HR) for adverse clinical outcome associated with obesity was estimated using Cox proportional hazard survival models. Obesity increased with age (P < 0.001) and was associated with increased breast cancer recurrence (P = 0.02) and death (P = 0.06), larger tumors (P = 0.002), and more involved axillary nodes (P = 0.003) but not with hormone receptor status (P > or = 0.6) or with first cycle adjuvant chemotherapy dose reductions (P = 0.1). Adjusting for number of axillary nodes, age at diagnosis, tumor size, grade, and hormone receptor status, obese women of all ages were more likely than nonobese women to have disease recurrence [HR, 1.57; 95% confidence interval (95% CI), 1.11-2.22; P = 0.02] and to die from any cause during follow-up (HR, 1.56; 95% CI, 1.01-2.40; P = 0.05). In premenopausal women, the adjusted HRs were 1.50 (95% CI, 1.00-2.26; P = 0.06) and 1.71 (95% CI, 1.05-2.77; P = 0.04), respectively. Obesity is independently associated with poorer outcomes in premenopausal women, as it is in postmenopausal women, and this is not entirely explained by differences in tumor size or nodal status. Given the high and increasing prevalence of obesity in western countries, more research on improving the treatment of obese breast cancer patients is warranted.

Undertreatment of Obese Women Receiving Breast Cancer Chemotherapy

Systematic undertreatment of breast cancer in overweight and obese women may contribute to the poorer prognosis in these women. The objective of this study was to investigate treatment patterns in overweight and obese women undergoing breast cancer adjuvant chemotherapy. We performed a retrospective cohort study of 9672 women treated with doxorubicin hydrochloride and cyclophosphamide between 1990 and 2001. The main outcome measure was the quality of chemotherapy as measured by the use of reduced doses for the first treatment (compared with standard doses), the overall dose proportion (actual-expected dose ratio), and relative dose intensity. First-cycle dose reductions (defined as a dose proportion of <0.9 compared with standard published doses) were administered to 9% of the healthy weight, 11% of the overweight, 20% of the obese, and 37% of the severely obese women (P<.001). First-cycle reduction was independently associated with being overweight (P = .03), obese (P<.001), severely obese (P<.001), older than 60 years (P<.001), and having a serious comorbid condition (P = .03). Practices varied greatly in the use of dose reductions in overweight and obese patients. Severe obesity was independently associated with a lower likelihood of admission for febrile neutropenia, even among those subjects given full weight-based doses (odds ratio, 0.61; 95% confidence interval, 0.38-0.97). Overweight and obese women with breast cancer often receive intentionally reduced doses of adjuvant chemotherapy. Administration of initial and overall full weight-based doses of adjuvant chemotherapy in overweight and obese women is likely to improve outcomes in this group of patients.

A randomized trial of self-hypnosis to contol nausea in women receiving moderately emetogenic chemotherapy

8182 Background: Control of nausea is an important component of cancer chemotherapy and typically involves the use of costly anti-emetic drugs. Self-hypnosis, used as an adjunct to anti-emetic drug therapy, may improve nausea control and reduce the use of costly anti-emetic drugs. Methods: Twenty-five women with breast, lung or ovarian cancer receiving moderately emetogenic cancer chemotherapy in a staff-model HMO outpatient cancer clinic were invited to participate. Patients were randomly assigned to a control group or to an intervention group. Those in the intervention group received two 1-hour sessions with a health psychology clinician to learn self-relaxation/self-hypnosis techniques prior to a first dose of adjuvant chemotherapy. All patients received standard pre-medication with dexamethasone 20mg IV and granisetron 1mg PO prior to chemotherapy. Patients received a supply of prochlorperazine and ondansetron for use as post-therapy anti-emetics. Primary endpoints, severity of nausea and vomiting and amount of medication used, were assessed as follows: episodes of vomiting were counted numerically whereas patients rated the degree of nausea using an analog scale at 2 and 7 days after chemotherapy and prior to the second cycle. Pill bottles were counted to assess anti-emetic drug usage. The intervention and control groups were compared using the non-parametric Wilcoxon rank sum test and chi square tests. Results: There were no significant differences between the control group (n=12) and intervention group (n=13) in terms of age, diagnosis or chemotherapy regimen (cyclophosphamide/doxorubicin vs. carboplatin/paclitaxel) received. Patients practicing self-relaxation/self-hypnosis experienced significantly less nausea (p=0.042) than patients in the control group. There was a trend toward decreased ondansetron usage in the intervention group that did not reach statistical significance (p= 0.18). Vomiting was equally well controlled in both groups. Conclusion: Interventional health psychology methods such as self-hypnosis can effectively be used in an out-patient managed care setting to improve nausea control in women with cancer and may reduce anti-emetic drug usage. No significant financial relationships to disclose.

Place des thérapeutiques médicales dans la prise en charge des tumeurs desmoïdes de l'enfant

Aggressive fibromatoses (desmoids tumors) are a rare nonmetastasizing fibrous tumor characterized by a local invasive capacity, a high recurrence rate after excision. Surgery remains the standard treatment. Wide excision with negative margins seems to decrease the chance of recurrence but must be not mutilating. Adjuvant high dose radiotherapy may have a good result but must be employed in selected patients. Drug therapy, essentially with continuous low dose adjuvant chemotherapy using methotrexate and vinblastine may be a reasonable choice, with low toxicity. Non-cytotoxic drug therapy represented by antiestrogens and non-steroidal anti-inflammatory drugs may have a beneficial effect. Antiproliferative effects of interferon and other drugs such as retinoïc acid have shown an encouraging response rates. The exactly role of this therapies remains controversial. Cellular, molecular and genetic investigations may be helpful to understand the mechanism of desmoid tumor proliferation. The aim of this study is to discuss the place of different medical therapies in the treatment of desmoid tumors, with review of literature.

584 poster The effect of biological dose escalation and adjuvant chemotherapy on the survival of glioblastoma patients

584 poster The effect of biological dose escalation and adjuvant chemotherapy on the survival of glioblastoma patients

Dose and dose intensity effect of adjuvant anthracycline-based chemotherapy in early breast cancer: a retrospective analysis.

The purpose of this study was to determine the importance of the dose of adjuvant chemotherapy in patients with breast cancer, and to determine which variables had influence on the dose of chemotherapy received. We reviewed the records of 196 patients with node-positive breast carcinoma that were treated with anthracycline-based adjuvant chemotherapy. We analyzed the influence on treatment efficacy of the dose of anthracyclines (total dose and dose intensity), and a multivariate analysis was performed to identify independent prognostic factors of chemotherapy total dose. There were no differences in disease-free survival or overall survival between patients who received doses below or above the median total dose and median dose intensity of anthracyclines. A positive correlation was observed between the total dose of anthracycline received and the number of axillary lymph nodes. The clinical outcome of patients with node-positive breast cancer receiving adjuvant anthracycline-based chemotherapy is not affected by the amount of chemotherapy delivered. There exists a clinical practice of administering more chemotherapy in patients with poorer prognosis, which does not result in better therapeutic outcomes.

High-dose chemotherapy in breast cancer: Dutch randomized studies

The role of high-dose chemotherapy in the adjuvant treatment of breast cancer will eventually be defined by a range of randomized trials that still require years for maturation. Two underpowered single-institution studies (from the MD Anderson Cancer Center and from the Netherlands Cancer Institute) failed to show an advantage for high-dose therapy. A randomized Scandinavian study compared prolonged and intensive chemotherapy without stem-cell support with brief chemotherapy followed by the STAMP-V regimen. The intensive conventional treatment arm was shown to be superior in terms of relapse-free survival. Two large studies comparing conventional dose adjuvant chemotherapy with high-dose chemotherapy have been reported in abstract form: the American Intergroup study (ASCO 1999) and the Dutch National Study (ASCO 2000). The American study shows fewer relapses in the high-dose arm. The Dutch study suggests a modest disease-free survival advantage for the high-dose arm, but further follow up is required to ascertain statistical significance (P = 0.057, two-sided, at the early analysis). In 2002, a 24% reduction in hazard rate will be detectable with 80% power. Both the efficacy and toxicity of high-dose therapy may depend on the drugs, dosage and schedules selected. In the Dutch study, a regimen was employed that is similar to the frequently used CTCb (STAMP-V) regimen. The carboplatin dose is, however, twice as high, and the agents are administered as short-term infusions rather than as continuous 96-h infusions. This may have an impact on the activation of the prodrug cyclophosphamide; the activation route is strongly inhibited by the presence of even low concentrations of thiotepa.

Randomized trials of high dose chemotherapy for breast cancer

‘Now is not the end. It is not even the beginning of the end. But it is, perhaps, the end of the beginning’ Winston Churchill in a speech to the Canadian Senate and House of Commons, December 30, 1941 In laboratory models of cancer, dose of cytotoxic chemotherapy correlates with curative therapy, while cumulative dose is associated with longer survival for those who are not cured [1]. These observations suggests a strategy of using high doses when cure is the objective but smaller doses over a prolonged period when palliation and survival are the goal. A strategy combining repetitive cycles of higher doses of cytotoxic therapy, followed by the optimal combination of hormonal and biological agents based on the tumor’s receptors might contribute to both the highest possible cure rate and the longest survival. The development of bone marrow transplant (BMT) for leukemias, and its subsequent modification for support after high dose therapy for other malignancies, has a long, complex and emotional history in medicine. At least partly because of firmly held opinions and the way large randomized trials are funded in the United States, few American randomized trials of BMT or high dose therapy strategies have been completed. The vast majority of published randomized BMT and high dose studies are European. Interestingly, in contrast, two large American randomized trials of high dose chemotherapy for breast cancer had actually completed accrual. Accrual on a third was on target until the presentation of five very small or very early randomized trials at the American Society of Clinical Oncology meeting in May of 1999. Results from some of these trials, which were analyzed after a relatively brief follow-up, are too premature to allow definitive conclusions. Nevertheless, these data have been over and misinterpreted within the scientific and lay communities. The remaining studies included a limited number of patients, thus restricting the statistical power of the observations. The desire for quick answers impeded dispassionate analysis of the available data. The opportunity for collegial review of the data further deteriorated with another round of press coverage when the data from the South African adjuvant study were found to be unreliable. Rather than increasing commitment to accrual on randomized and appropriate pilot trials, accrual to the only large American study in existence at that time tricked to a halt. In response to press coverage, Susan Edmonds from the Fred Hutchinson Cancer Research Center observed that ‘the NYT article tends to cast shadows generally on the therapy and those providing the therapy rather than pointing out early in the article (where the public will readily see it) that there are a number of very credible research institutions conducting research directed at breast cancer, some looking at high dose chemotherapy and stem cell transplantation.’ Dr. Rodenhuis, presenting the large positive Dutch Randomized study (funded by the Dutch insurance industry) at ASCO in 2000, commented on the ‘unreasonably high expectations until 1999’ and ‘unreasonably negative [opinion-ed] since 1999’ for high dose adjuvant chemotherapy for breast cancer.

Dose Escalation of Carboplatin and Cyclophosphamide Supported by GM-CSF in the Treatment of Patients with Advanced Ovarian Cancer (FIGO III and IV) – a Phase I Study

Background: Up to 75% of ovarian cancers are diagnosed in advanced, incurable stage. Only one fifth of these patients survives 5 years despite radical surgery and adjuvant chemotherapy. The study evaluates dose escalation of carboplatin (CBDCA) and cyclophosphamide (CTX) in combination with myelosupportive therapy with granulocyte-macrophage-stimulating factor (GM-CSF) in the treatment of advanced ovarian cancer. Patients and Methods: 25 patients with ovarian cancer (FIGO stages III and IV) were registered and treated with escalating doses of adjuvant chemotherapy. Starting dose of CBDCA was 350 mg/m² and of CTX was 800 mg/m² body surface area, supported by granulocyte-macrophage-stimulating factor (GM-CSF) 5 mg/kg body weight subcutaneously, days 4–14 of chemotherapy. Intra-patient dose escalation of chemotherapy was modified according to the degree of myelosuppression. Tumor restaging was performed after four chemotherapy cycles clinically and with radiological evaluation and/or laboratory testings. Results: 104 chemotherapy cycles in 23 evaluable patients could be analyzed. 91 chemotherapy cycles were administered with GM-CSF. The planned therapy interval of 21 days could be met in only 28% of the cycles. In 61% of treatments a delay of therapy was caused by persistent myelosuppression. 50% of the patients had grade-III leukopenia, and grade-IV leukopenia was seen in 20% of the patients. One third of the patients developed grade-IV thrombopenia. Hematologic nadirs were observed between days 12 and 21 of the treatment cycles. Dose escalation of CBDCA was possible in 21% of the patients with a maximum tolerated dose of 460 mg/m² and of CTX in 39% with a maximum tolerated dose of 1,184 mg/m². Dose intensity (mg/m² body surface area/week) ranged significantly below the expected dose intensity due to therapy delays (p = 0.0004 and p = 0.002 for CBDCA and CTX, respectively). The overall response rate was 65%, with a complete remission rate of 48%. In 6 out of 23 patients tumor progression (as best response) was observed. Median time to progression was 373 days. 12 of 23 patients died in the follow-up period of 3.6 years. Conclusions: A positive effect of GM-CSF was observed regarding low- to intermediate-type leukopenias. Severe myelosuppression allowed only a minor dose escalation and caused marked therapy delays. Therefore, no escalation of dose intensity was possible and the applied dose intensity ranged clearly below the intended range.

Autologous stem-cell transplant after conventional dose adjuvant chemotherapy for high-risk breast cancer: Impact on the delivery of local-regional radiation therapy

High-dose chemotherapy with autologous stem-cell transplantation is used increasingly in the treatment of poor-prognosis primary breast cancer. Because these patients may be cured with standard multimodality therapy, it is important to address both the efficacy of transplantation, and its effect on the delivery of standard treatments including local radiation therapy. Patients with high risk primary breast cancer were treated with high-dose cyclophosphamide and thiotepa and stem-cell transplant following surgery and conventional-dose adjuvant chemotherapy. Outcome, including sites of failure and delivery of local radiation therapy, was assessed for 103 patients. Overall and disease-free survival rates at 18 months were 83% (+/- 4%) and 77% (+/- 4%) respectively. Twenty patients (19.4%) received radiation therapy prior to transplant. Of the remaining 83, 77 received radiation therapy after transplant. Overall, 5 (19.2%) of 26 first sites of recurrence were local alone. For patients receiving radiation prior to transplant, 3 of 7 (43%, 95% CI: 6%-80%) sites of first recurrence were local, while 2 of 19 (10.5%, 95% CI: 0%-24.5%) sites of first recurrence were local alone in patients receiving post-transplant radiation or no radiation. Transplantation does not appear to significantly compromise the delivery or outcome of local radiation therapy for primary breast cancer.

HOW SHOULD WE INTRODUCE HIGH‐DOSE CHEMOTHERAPEUTIC STRATEGIES INTO THE ADJUVANT MANAGEMENT OF HIGH‐RISK BREAST CANCER IN AUSTRALASIA?

Development of bone marrow support techniques has altered the standard chemotherapeutic management of haematological malignancies, and these techniques are now being increasingly utilized in solid tumours. In breast cancer, survival benefits have resulted from conventional dose adjuvant chemotherapy, but outcomes remain poor in many women with high-risk disease. Improved response rates with high-dose chemotherapy (HDC) in metastatic disease have led to the investigation of these techniques in adjuvant therapy of high-risk localized disease. In some high-risk patient subgroups survival is extremely poor, with 5-year rates below 30%. Improved adjuvant strategies for patients in these subgroups are therefore urgently required. In Australasia, oncology departments are currently considering accrual of women with high-risk disease into the International Breast Cancer Study Group (IBCSG) 15-95 Trial investigating HDC/stem cell transplantation. The present paper reviews the available data on the efficacies and toxicities of currently available high-dose chemotherapeutic strategies; discussing methodological considerations relevant to their introduction and safe use in the adjuvant setting in Australia and New Zealand. Although response rates with HDC in metastatic disease are encouraging, the clinical effectiveness of current HDC regimens in adjuvant management has not been established and is limited by significant toxicity. The introduction of HDC strategies for high-risk breast cancer in Australia encounters difficulties both in trial design and potential clinical practice.

THE NUMBER OF METASTATIC NODES AS A PROGNOSTIC FACTOR IN ADVANCED BREAST CANCER

To determine the adjustment to high dose adjuvant chemotherapy with autologous hematopoietic stem cell transplantation for advanced breast cancer, we examined the prognosis of breast cancer patients based on the number of metastatic nodes. The examination was made on 182 patients with breast cancer operated on in the hospital from 1973 to 1992 who had four or more metastatic axillary nodes with or without metastatic internal mammary nodes, excluding stage IV cancer patients. These patients were classified into two groups according to the number of metastatic nodes. A cut off number of metastatic nodes was set up, and used to divide the patients into two groups. The first group had the same or more number of metastatic nodes than the set up value, and the second group had less. The 10-year disease free survival rate of the two groups were statistically analysed and an univaliant analysis was used between the groups classified by each number of metastatic nodes. The most significant P-value was found between the groups classified by 11 metastatic nodes. The 10-year disease free survival rate of 11 or more metastatic nodes group (28.8%) was significantly poorer than that of the group under 11 (56.2%) (p<0.0001). The same analysis was made on 126 patients with metastatic nodes limited in the axillary region. The results were almost the same. The 10-year disease free survival rate of schirrous carcinoma patients with 7 to 10 metastatic nodes (32.3%) was as poor as that of the 11 or more metastatic nodes group. It suggests that high dose adjuvant chemotherapy is needed to gain better prognosis not only for the patients who have 11 or more metastatic nodes but also for schirrous carcinoma patients with 7 to 10 metastatic nodes, both patient's groups with a high recurrence rate of about 70%.