Dominant Site Of Disease Research Articles

Primary extranodal lymphoma: a report of six cases in a private cancer centre in Nigeria

Primary extra-nodal lymphoma (PENL) refers to lymphomas which present with disease in any organ or tissue other than lymph nodes or spleen. Symptoms at initial presentation are mainly from extra nodal involvement and after routine staging procedures, the extra nodal involvement remains the clinically dominant site of disease with little or no nodal disease [1, 2]. About 25–40% of lymphomas arise at extra nodal sites and with clinical presentation similar to solid tumors [3, 4] creating ambiguity in diagnosis and delays in treatment especially in resource poor settings. We report six cases of PENL seen at a private cancer centre in Lagos, Nigeria between 2021 and 2022. The age range was 32–95 years with five females and one male. Two patients were HIV positive. Five patients had initial symptoms of vague abdominal pain with one patient investigated multiple times for peptic ulcer disease. One patient presented with pathological fracture of left femur. Another patient had previously been diagnosed with an inoperable cholangiocarcinoma. All patients had non-Hodgkin’s lymphoma, DLBCL being most common (83.37%). Four patients started chemotherapy. All treated patients showed good outcomes with complete or good partial response highlighting the importance of accurate diagnosis. Initial histological diagnosis in most of the cases did not suggest lymphoma until immunohistochemistry (IHC) results were received. Cancer care in Nigeria is fraught with difficulties obtaining accurate diagnosis due in part to the limited availability of IHC and molecular testing facilities required to characterize the malignant cells leading to delays in treatment and poorer prognosis [6–8].

General Selection Criteria of Patients for Radioembolization of Liver Tumors

A combined treatment approach that incorporates surgical resection, ablation, chemotherapy, targeted agents, and radiotherapy has augmented the management of liver tumors (both primary and metastatic). The challenge that remains is how to reduce the burden of liver disease and thus enable greater patient eligibility for resection as well as lengthened survival for those who remain unsuitable for surgery. Radioembolization can deliver high doses of radiation preferentially to liver tumors and is a valuable treatment option that should be considered as part of a multimodal treatment approach for the management of patients in whom the liver is the sole or dominant site of disease. Essential in this consideration is a careful assessment by a multidisciplinary team of the individuals most likely to benefit from this treatment modality. Along with the clinical benefits, integration of radioembolization into the treatment paradigm can provide added options of using systemic chemotherapy synergistically as a radiosensitizer and to control extrahepatic metastases, permitting a reduction in hepatic disease and conserving remaining liver function. If successful, the possibility of improved patient survival and quality of life is increased.

Candidate Selection for Prostate Cancer Focal Therapy

Focal therapy has emerged as a potential treatment paradigm for men with localized prostate cancer, because it serves as a medium between the ambiguity of surveillance and the potential reduction of quality of life observed with radical treatment. Candidate selection remains the major challenge of implementing focal therapy in clinical practice. While focal therapy is potentially widely applicable, there is general consensus that initial efforts to initiate focal therapy protocols in practice should be limited to men with disease features that are low to low-intermediate risk, thereby limiting the likelihood of early systemic failure. Selection of candidates is first dependent on the intent of focal therapy. Curative intent focal therapy is limited to a small number of men with isolated, low-risk, unifocal, or unilateral disease. In men for whom local control-and potential prolongation of the natural history of disease-is desired, mapping strategies would focus on identification of the dominant site of disease and ruling out high-risk features. Tools such as conventional transrectal biopsy, transperineal saturation biopsy, and prostate MRI all have relative merits and shortcomings. While ultimately limitation of biopsy is desirable through combinations of transrectal biopsy and imaging, for now, limitations of conventional imaging modalities make it likely that most men will need transperineal saturation biopsy before inclusion in focal therapy protocols.

SUCON Trial (SUnitinib CONsolidation Therapy in Metastatic Breast Cancer): A Belgian Multicenter Phase II Randomized Trial in Her2 Negative Metastatic Breast Cancer Evaluating Consolidation Antiangiogenic Therapy with Sunitinib after Objective Response to Taxane Chemotherapy.

Abstract Under the auspices of the Belgian Society of Medical Oncology (BSMO).Background: New drugs are generally tested in patients with metastatic disease where bulky tumor mass is present. However, antiangiogenic compounds are probably more beneficial in the prevention of regrowth from tumors with small tumor load than in bulky tumors. This study wants to test the hypothesis that antiangiogenic compounds such as sunitinib are able to delay tumor progression after tumor mass reduction by taxanes, i.e. an objective response (PR or CR).Materials and methods: This is a dual-arm open-label randomized multicenter phase II clinical trial with 2:1 randomization evaluating the efficacy of sunitinib (study arm) versus no therapy (control arm, only for descriptive purposes) in patients with metastatic breast cancer after objective response to taxane chemotherapy. Eligible patients had metastatic HER2 negative breast cancer, had received 10 to 20 weeks of first- or second line taxane containing chemotherapy resulting in an objective response (RECIST). Patients received sunitinib (arm A) 50 mg/d po 4w/6 (amended to 37.5 mg continuously in 1-2008) or no therapy (arm B). Patients were stratified for disease free interval and dominant site of disease. Patients randomized to arm B were offered the opportunity to receive open-label sunitinib treatment upon development of disease progression. Treatment was pursued until disease progression or major intolerance or patients refusal. All patients who received at least day 1 of study treatment were evaluated for efficacy, toxicity and safety. The duration of response after taxane treatment in previous studies with metastatic breast cancer is around 7 months. Based on this, the median time interval between the end of chemotherapy and tumor progression was expected to be about 5 months in our study population. The primary endpoint was to determine the proportion of patients alive and without disease progression (PFS) at 5 months after study entry in arm A. If ≤ 18/36 patients are progression-free and alive at 5 months, sunitinib will be declared insufficiently active (beta 0.05); if ≥ 22 patients are progression-free and alive at 5 months, sunitinib will be declared active (alpha 0.05) and it will be recommended to continue the trial as a phase III design.Results: 10/36 patients (28%) reached 5 months PFS in arm A and 4/19 in arm B (21%). Median PFS was 3.4 months in Arm A and 3.1 months in Arm B. Toxicity and overall survival data will be reported at the meeting.Discussion: This study does not confirm the hypothesis that sunitinib can lead to a significant proportion of patients with PFS of ≥ 5 months after objective response to taxanes. This proof-of-principle study suggests that also the role of consolidation therapy with other (already approved) antiangiogenic treatments should be evaluated carefully in prospective clinical trials (high economic cost). Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 203.

Gemcitabine-oxaliplatin combination (SEGEMOX) in anthracycline (A) and taxanes (T) pretreated metastatic breast cancer (MBC): Results from the GERCOR-SEGEMOX phase II trial

1108 Objectives: To evaluate efficacy and safety of SEGEMOX regimen for previously A and T pre-treated MBC patients. Methods: Forty-five women with MBC not eligible for A and/or T chemotherapy were enrolled on SEGEMOX study. SEGEMOX was delivered as follows: Gemcitabine was given at 1000 mg/m2/100min on day 1, followed by oxaliplatin at 100 mg/m2/120min iv on day 2 every 2 weeks. Efficacy results were analyzed and are presented in an intention to treat analysis and toxicity according to the total number of cycles regimen. Results: Forty-four of the 45 patients received at least 1 cycle of SEGEMOX. Fifty-eight perccent of the patients have received previous adjuvant chemo, 36% 1st line and 42% 2nd line for MBC before the protocol inclusion. Visceral metastases were dominant site of disease (44% liver; 36% lung; 44% bone). Median age of the population was 55.8 years (36–73). After a median of 7.7 cycles (3.5 months of treatment); the overall response rate (ORR) is 38% [95%CI; 23%-51%] [1 CR (2.2%) and 16 PR (35.6%)]; 33% of stable disease [95%CI; 17%-43%], 24.4% progressive disease with a clinical benefit (CB) of 71% [95%CI; 57%-85%]. The median progression free survival (PFS) is 7.1 months for responders and 4.8 months for patients with stable disease. The all population median overall survival (OS) is 21.4 months with 22.7 months MOS for responders. Concerning toxicity analysis: 339 cycles of gemcitabine and 312 of oxaliplatinum were delivered. Respectively, grade 3–4 neutropenia occurred in 43% of patients (febrile neutropenia in 7%), grade 3–4 thrombocytopenia in 41%, and anemia in 2.3%. The most frequent non hematologic toxicities were represented by grade 3 peripheral neuropathy (Levi Scale) in 11.4% of the patients and grade 2 alopecia in 11.4%. For the subgroup of hormone receptor negative MBC (n = 12) the ORR is 33% [95%CI; 2%-64%], CB 50% [95%CI; 16%-73%], PFS of 2.8 months and MOS of 12 months. Conclusions: The SEGEMOX combination has relevant activity in A and T not eligible MBC patients, with a manageable toxicity profile. In the limited number of patients with HRN MBC even if the response rate is close to the overall population the prognosis seems still worse. No significant financial relationships to disclose.

Initial Anatomic Geographic Presentation of Glottal Dysplasia

Glottal dysplasia is likely the most common laryngeal disease with a discernible lesion; however, investigations describing its initial anatomic geographic presentation are rare. To examine this, we identified 52 patients who did not have significant prior treatment or glottal cancer. Thirty-one patients had bilateral disease, so there were 83 vocal folds with precancerous dysplasia. The phonatory mucosa was the dominant disease site in all; the epicenter was on the superior surface in 65 of the 83 folds and on the medial surface in 18 of the 83 folds. The arytenoid mucosa was involved in 8 of the 83 folds. Nineteen of the 52 patients had direct anterior-commissure involvement, and none had interarytenoid mucosal disease. The investigation established the commonly held principle that glottal dysplasia occurs primarily on phonatory mucosa. Given the frequent occurrence and recurrence of glottal dysplasia, treatment goals should focus on disease control to prevent malignant degeneration while preserving the subepithelial superficial lamina propria, necessary for phonatory mucosal pliability, vocal fold vibration, and optimal vocal function.

Risk factors for brain relapse in HER2-positive metastatic breast cancer patients

Brain relapse is a common occurrence in HER2-positive breast cancer patients. However, the factors determining the risk of brain metastasis in these patients remain to be established. The aim of this study was to assess the impact of particular clinical and pathological factors on the risk of brain relapse in HER2-positive advanced breast cancer patients. The study group included 264 consecutive HER-2 positive metastatic breast cancer patients, most of whom (210; 80%) were administered trastuzumab, usually in combination with chemotherapy. Time from the diagnosis to distant relapse ranged from 0 to 142 months (median 16 months). The most common dominant site of metastatic disease was viscera (80%), followed by soft tissue (11%) and bones (10%). After a median follow-up of 3.1 years, the symptomatic brain relapse occurred in 103 patients (39%). Median time from treatment dissemination to brain relapse was 15 months (range, 0-81 months), and the cumulative 1-year, 3-year and 5-year risk of brain relapse was 17, 42 and 55%, respectively. The average annual risk of brain relapse for surviving patients during consecutive 7 years of follow-up was 10.0% (95% CI, 6.6-13.5%). In the univariate analysis the only variable significantly related to the increased risk of brain relapse was time from initial diagnosis to distant relapse shorter than 2 years (HR = 1.55, 95% CI, 1.03-2.33, P = 0.034). Patients with dominant site of disease in soft tissue or bones tended to have lower risk of relapse (HR = 0.54 and 0.62; P = 0.098 and 0.203, respectively) compared to patients with visceral metastases. Treatment with trastuzumab was not associated with reduced risk of brain relapse (HR = 0.91, 95% CI, 0.47-1.77, P = 0.78). In the multivariate analysis, time from initial diagnosis to distant relapse shorter than 2 years remained the only significant variable related to increased risk of brain relapse (adjusted HR = 1.62, 95% CI, 1.07-2.44; P = 0.022). HER2-positive breast cancer patients remain at high and continuous risk of brain relapse for a prolonged period of time after diagnosis of disease dissemination. Short time from initial diagnosis to distant relapse is related to increased risk of brain relapse. Molecular predictors are sorely needed to better characterize patients with high probability of early brain relapse.

Liposomal-encapsulated doxorubicin plus cyclophosphamide as first-line therapy in metastatic breast cancer: a phase II multicentric study

BackgroundThe objective of this study is to evaluate the efficacy and toxicity of the liposome-encapsulated doxorubicin (TLC D-99) plus cyclophosphamide (CTX) as first-line treatment of metastatic breast cancer in light of the potential cardioprotective effect of TLC D-99 as compared with conventional doxorubicin. Materials and methodsSixty-seven patients as defined according Simon's two-stage phase II design were enrolled. They received TLC D-99 at the dosage of 60 mg/m2 plus CTX 600 mg/m2, with cycles repeated every 3 weeks. Cardiac function was assessed by ultrasonography at baseline and every two cycles. ResultsThe principal characteristics of the 67 enrolled patients were as follows: median age 60 years (range 33–75), median World Health Organization performance status of 1 (range 0–2) and dominant disease site (viscera/bone/soft tissue): 47/15/15 There were nine complete responses and 32 partial responses for an overall response rate of 64%; a further 14 patients had stable disease and the remaining nine patients progressed. Median number of administered cycles was six. Median duration of response was 10 and 9 months, respectively, for complete responders and partial responders. Median duration of survival was 17+ months (range 3 to 33+). Hematological toxicity consisted in leucopenia (G1–G2) in 21 patients and anemia (G1–G2) in 20 patients; G1 thrombocytopenia was observed only in 2 patients. Non-hematological toxicity was generally mild with G1–G2 nausea/vomiting in 23 patients and G1–G2 mucositis in 10. Hair loss was registered in 30 patients and it was G2 in 14 patients. As to concern cardiac toxicity, one patient developed an asymptomatic 20% decline of left ventricular ejection fraction from the baseline value. ConclusionsThe results of our study show that the combination of TLC D-99 plus CTX is active and well tolerated, with no unexpected toxicity.

Gemcitabine and Oxaliplatin in Patients With Metastatic Breast Cancer Resistant to or Pretreated With Both Anthracyclines and Taxanes

To evaluate the efficacy, the toxicity and the pharmacokinetics of a gemcitabine (GEM) and oxaliplatin (OXA) combination in metastatic breast cancer patients (MBC), previously treated with anthracycline and taxanes. A total of 40 women were enrolled; 37 patients had visceral metastases as dominant site of disease, including 20 patients with liver metastases and 14 with multiple visceral metastases. Three patients received neo-adjuvant chemotherapy, 13 patients adjuvant chemotherapy alone, 24 patients chemotherapy for MBC alone. Gemcitabine was given at 1000 mg/m2 on days 1, 8 followed by oxaliplatin at 100 mg/m2 iv on day 2 every 2 weeks (GEM-OXA sequence). Possible pharmacokinetic interactions were studied in 10 patients, by administering on cycle 1 gemcitabine d1/oxaliplatin d2 (GEM-OXA) and on cycle 2 oxaliplatin d1/gemcitabine d2 (OXA-GEM). After a median of 8 cycles, 10 partial response (PR) (25%), 16 stable disease (SD) (40%), and 14 progressive disease (PD) (35%) were obtained. The median duration of response was 6 months (3-9) for responding patients and 4.9 months (2-7.5) for patients with stable disease. For PR, SD and PD patients, median survival was 18 (10-23+), 13 (8-18), and 6 months (4-13), respectively. G3-4 neutropenia occurred in 20% of patients (febrile G3 neutropenia in 2.5%), G3-4 thrombocytopenia and anemia in 15% and 7.5%. The most frequent G3-4 nonhematologic toxicity was represented by peripheral neuropathy (20%), always reversible. The GEM-OXA and OXA-GEM schedules showed a similar pharmacokinetic behavior, with no sequence-dependent interaction. The combination gemcitabine plus oxaliplatin has moderate activity in anthracycline and taxanes resistant/relapsed heavily treated patients, mild toxicity and no administration sequence-dependent pharmacokinetic interactions.

Trans-arterial hepatic radioembolisation of yttrium-90 microspheres

The liver represents a frequent site for metastatic disease, in addition to being a site for primary cancer. Hepatic metastases from certain neoplasms, such as colon, neuroendocrine, melanoma and gastrointestinal stromal tumour have a distinct predilection to metastasize the liver, which in many cases may represent the only or the dominant site of disease. In these circumstances, cytoreduction via surgery or in situ ablative techniques aims to influence the natural history of the disease progression and improve clinical outcomes.Liver directed therapy utilising yttrium-90 microspheres represents a recently introduced in situ multidisciplinary cancer therapy that has caught the attention of many physicians faced with the challenges of treating these complex patients. Although similar to other forms of trans-arterial liver directed therapy, there are discrete differences and potentially fatal treatment consequences unique to this therapy. This objective of this review article is to provide the reader a basis for understanding the therapeutic principles, patient exclusion criteria, pre and post therapy investigations and salient clinical results in the two most commonly treated disease types; metastatic colorectal cancer and hepatocellular cancer.

A pilot study of weekly versus 3-week docetaxel in combination with capecitabine in patients with anthracycline-pretreated metastatic breast cancer

10771 Background: Capecitabine in combination with docetaxel given every 3 weeks has shown a high degree of activity in anthracycline-pretreated metastatic breast cancer (MBC), but with high toxicities. To improve the therapeutic index, we performed a clinical pilot trial to evaluate the efficacy and safety of weekly or 3-week docetaxel in combination with capecitabine given for 14 days every 21 days. Methods: Patients with at least one measurable lesion were randomized to receive the treatment arms: docetaxel 75mg/m2 on days 1, oral capecitabine 950 mg/m2 twice daily on days 1–14 (Arm A); docetaxel 37.5mg/m2 on days 1 and 8, oral capecitabine 950 mg/m2 twice daily on days 1–14 (arm B). Each cycle was repeated every 3 weeks. Patients remained on study for a maximum 6 cycles or until tumor progression or unacceptable toxicity occurred, response assessments were scheduled every two cycles. Results: 64 pts were enrolled, 62 eligible for safety and tumor assessment. Key baseline variables were well balanced. Dominant site of disease was visceral in 66.1%; 24.2% had ≥3 organ sites of disease; all patients had previously received anthracyclines, 24.2% for MBC. 43. 6% were ER negative and 46.8% were HER-2 overexpress. The overall clinical response rate of all groups was 59.7% (37/62). There was no progressive disease (PD) after two cycles. Efficacy outcomes were similar in the two arms. The response rate of group A and B were 60% (18/30) and 59.4% (19/32) respectively. There were no drug-related deaths observed. Neutropenia was the most common toxicity. In all, the frequence of Grade 3/4 neutropenia were similar in two arm, but Grade 4 neutropenia of Group A 66.7% (20/30) was higher than Group B 34.4% (11/32), P = 0.021. Conclusions: The study confirmed the superior activity of docetaxe-capecitabine combination therapy in anthracycline resistant MBC, and comparing with 3-week schedule, weekly docetaxel plus capecitabine has same high efficacy with a favourable safety profile. No significant financial relationships to disclose.

Liposome-encapsulated doxorubicin plus cyclophosphamide as first-line therapy in metastatic breast cancer: A phase II study

10646 Background: The objective of this study is to evaluate the efficacy and toxicity of the liposome- encapsulated doxorubicin (TLC D-99) plus cyclophosphamide (CTX) as first-line treatment of metastatic breast cancer in light of the potential cardioprotective effect of TLC D-99 as compared to conventional doxorubicin. Furthermore the study is aimed also to understand the role of troponin I as a sensitive marker of left ventricular dysfunction. Methods: Sixty-three patients as defined in a phase II group sequential design will be enrolled. Since september 2004, fifty-four patients with untreated metastatic breast cancer were enrolled. They received TLC D-99 at the dosage of 60 mg/m2 plus CTX 600 mg/m2, with cycles repeated every three weeks. Cardiac function was assessed by ultrasonography at baseline and every three weeks, as well as troponin I dosage. Results: The principal characteristics of the 54 actually enrolled patients were as follows: median age 60 years (range 33–75), median WHO performance status 1 (range 0–2) and dominant disease site (viscera/bone/soft tissue) 36/10/8. To date 39 pts are evaluable: 8 complete responses and 18 partial responses were observed for an overall response rate of 67%; a further 9 pts had stable disease and the remaining 4 pts progressed. Median number of administered cycles was 6. Median duration of response was 10 months (range 3–15+) and median duration of survival was 12+ months (range 2+-15+). Hematological toxicity consisted in leucopenia (G1-G2) in 11 patients ed anemia (G1-G2) in 10 pts; G1 thrombocytopenia was observed only in 2 pts. Non-hematological toxicity was generally mild with G1-G2 nausea/vomiting in 14 pts e G2 mucositis in one patient. Hair-loss was registered in 12 pts and it was G2 in 6 pts. As to concer cardiac toxicity, one patient developed an asymptomatic 20% decline of left ventricular ejection fraction from the baseline value. Conclusions: The preliminary data show that the combination of TLC D-99 plus CTX is active and well tolerated, with no unexpected toxicity. The relationship between cardiac function and troponin I is underway. No significant financial relationships to disclose.

Predictors of brain relapse in HER-2 positive metastatic breast cancer (MBC) patients (pts)

10508 Background: Brain relapse is a common occurrence in HER2-positive breast cancer pts. We assessed factors determining the risk of this event in a large unselected series of HER2-positive MBC pts. Methods: Study group included 233 consecutive HER2-positive (IH 3+ or FISH+) MBC pts (median age 53 years); 49% premenopausal, 49% postmenopausal and 2% with unknown menopausal status. Dominant site of disease included viscera (78%), soft tissue (11%) and bones (10%). Of the 206 pts (88%) with known steroid receptor status, ER+/PgR+, ER+/PgR-, ER-/PgR+, ER-/PgR- phenotypes included 58%, 15%, 5% and 21% of pts, respectively. Prior (neo)adjuvant chemotherapy, endocrine therapy or a combination thereof was administered in 40%, 6% and 35% of pts, respectively. Disease-free interval to the development of MBC ranged between 0 and 142 months (median 16 months). 184 pts (79%) received trastuzumab for MBC, usually in combination with chemotherapy. Statistical analysis included contingency tables, chi-square test, Kaplan-Meier survival analysis and Cox proportional hazard model. Results: Median follow-up from the development of MBC was 25 months (range 0.5–130 months). 54 pts (23%) developed brain metastases after a median of 13 months (range, 0 to 81 months). Cumulative risk of brain relapse was 11% (95% CI: 7–16%) and 24% (95% CI: 17–32%) at one and two years, respectively. Trastuzumab treatment was associated with insignificantly reduced risk of brain metastases (HR 0.63, 95% CI 0.29–1.39, p = 0.25). In the univariate analysis, premenopausal status was the only significant factor associated with increased risk of brain relapse (HR 2.56, 95% CI 1.28–5.00, p = 0.008). Conclusion: HER-2 positive MBC pts carry high risk of brain relapse, in particular prior to menopause. Protective role of trastuzumab warrants further research. [Table: see text]

Randomized phase II trial of three gemcitabine (GEM)-taxane combinations in metastatic breast cancer (MBC

710 Background: Two-drug combinations of GEM and paclitaxel (P) or docetaxel (D) have shown promising efficacy in MBC. This study evaluated efficacy and safety of GEM plus single or split dose taxanes. Methods: Major eligibility criteria: tissue diagnosis of breast carcinoma; stage IV; prior anthracycline therapy; KPS ≥70; age ≥18; adequate bone marrow, liver and kidney function; written informed consent. Patients (pts) were randomized to receive: GEM 1250 mg/m2 D1+8 and P 175 mg/m2 as 3-hr infusion D1 (GP1); GEM 1000 mg/m2 D1+8 and P 100 mg/m2 as 1-hr infusion D1+8 (GP2); GEM 1000 mg/m2 D1+8 and D 40 mg/m2 as 1-hr infusion D1+8 (GD) in a 3-week cycle (8 cycles max). Primary endpoint was response rate; secondary endpoints were time to progression (TTP), time to treatment failure (TTTF), response duration and toxicity. Results: 210 pts were enrolled, 208 qualified for safety and time-to-event efficacy analysis, 204 for response assessment. Baseline variables were balanced across arms. Dominant site of disease was visceral in 70%; >50% had ≥3 organ sites of disease; all but 1 pt had previously received anthracyclines, 46% for MBC. Efficacy outcomes were similar in the 3 arms. Neutropenia was the main toxicity in each arm. Grade 4 neutropenia, Grade 3+4 anemia, febrile neutropenia, infection and diarrhea were higher for GD as were use of G-CSF, IV antibiotics and blood transfusions. There were 6 drug-related deaths (2.9%; 2 pts on GP1, 3 on GP2, 1 on GD), mostly from myelotoxicity complications. Conclusions: The three GEM-taxane regimens appear to have high efficacy and manageable toxicity in MBC after prior anthracycline therapy. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Eli Lilly Asian Operations Eli Lilly & Co. Eli Lilly & Co. Eli Lilly Singapore Pty Ltd. Eli Lilly and Company

Randomized phase II trial of three gemcitabine (GEM)-taxane combinations in metastatic breast cancer (MBC

710 Background: Two-drug combinations of GEM and paclitaxel (P) or docetaxel (D) have shown promising efficacy in MBC. This study evaluated efficacy and safety of GEM plus single or split dose taxanes. Methods: Major eligibility criteria: tissue diagnosis of breast carcinoma; stage IV; prior anthracycline therapy; KPS ≥70; age ≥18; adequate bone marrow, liver and kidney function; written informed consent. Patients (pts) were randomized to receive: GEM 1250 mg/m2 D1+8 and P 175 mg/m2 as 3-hr infusion D1 (GP1); GEM 1000 mg/m2 D1+8 and P 100 mg/m2 as 1-hr infusion D1+8 (GP2); GEM 1000 mg/m2 D1+8 and D 40 mg/m2 as 1-hr infusion D1+8 (GD) in a 3-week cycle (8 cycles max). Primary endpoint was response rate; secondary endpoints were time to progression (TTP), time to treatment failure (TTTF), response duration and toxicity. Results: 210 pts were enrolled, 208 qualified for safety and time-to-event efficacy analysis, 204 for response assessment. Baseline variables were balanced across arms. Dominant site of disease was visceral in 70%; >50% had ≥3 organ sites of disease; all but 1 pt had previously received anthracyclines, 46% for MBC. Efficacy outcomes were similar in the 3 arms. Neutropenia was the main toxicity in each arm. Grade 4 neutropenia, Grade 3+4 anemia, febrile neutropenia, infection and diarrhea were higher for GD as were use of G-CSF, IV antibiotics and blood transfusions. There were 6 drug-related deaths (2.9%; 2 pts on GP1, 3 on GP2, 1 on GD), mostly from myelotoxicity complications. Conclusions: The three GEM-taxane regimens appear to have high efficacy and manageable toxicity in MBC after prior anthracycline therapy. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Eli Lilly Asian Operations Eli Lilly & Co. Eli Lilly & Co. Eli Lilly Singapore Pty Ltd. Eli Lilly and Company

Clinical Data and Pharmacokinetics of a Docetaxel-vinorelbine Combination in Anthracycline Resistant/Relapsed Metastatic Breast Cancer

The aim of this study was to evaluate the pharmacokinetic parameters, efficacy and toxicity of a docetaxel and vinorelbine combination in metastatic breast cancer patients previously treated with anthracycline. A population of 40 patients was analyzed; 30 patients (75%) had visceral metastases as the dominant site of disease, including 20 patients (50%) with liver metastases. Three or more organs were involved in 43% of patients. All patients had received prior anthracycline therapy. Five patients (12%) had primary resistant disease, 10 patients (25%) secondary resistant disease and 25 patients (63%) had progressive metastatic breast cancer after first-line chemotherapy. Docetaxel and vinorelbine were given at 80 mg/m2 and 20 mg/m2 i.v., respectively, on day 1 every 3 weeks. After a median of 5 cycles, it was found that 5 patients had a complete remission (13%), 19 a partial remission (48%), 9 had stable disease (22%) and 7 had progressive disease (17%). Response rates in patients with visceral and liver metastases were 57% and 50%, respectively. After a median follow-up of 24 months (13-36), median time to progression was 8.5 months and median overall survival 17 months. Grade 4 neutropenia was observed in 78% of courses (febrile neutropenia in 9%). Possible pharmacokinetic interactions were studied in 23 patients by administering docetaxel immediately followed by vinorelbine (protocol A) or vinorelbine followed by docetaxel (protocol B). Patients in protocol B had significantly higher vinorelbine plasma levels and more pronounced neutropenia. Docetaxel plus vinorelbine is an effective combination in anthracycline resistant/relapsed metastatic breast cancer. The administration sequence docetaxel→vinorelbine is safer than the reverse order.

Lack of activity of stealth liposomal doxorubicin in the treatment of patients with anthracycline-resistant breast cancer.

We conducted a single-institution phase II clinical trial to determine the objective response rate, duration of response, time to progression, and overall survival in patients with anthracycline-resistant breast cancer treated with Doxil. Patients with metastatic breast cancer were eligible if they had disease progression while receiving an anthracycline-containing regimen or developed evidence of metastatic disease during or within 6 months after the last cycle of an anthracycline-containing adjuvant regimen. Prior treatment with liposomal doxorubicin was not allowed. Patients received a dose of 50 mg/m(2) infused every 4 weeks via a peripheral vein or central line. Doxil was administered for a total of six cycles or until disease progression. We treated 11 patients with stage IV breast cancer of whom two had never received chemotherapy for their metastatic disease. Most had a performance status of 1 and had visceral involvement as their dominant site of disease. All patients had received prior therapy with doxorubicin. No clinical evidence of congestive heart failure or cardiac toxicity was observed. The most common toxicities were nonhematologic and were mostly grade 1/2. These included fatigue, nausea, vomiting, and stomatitis. Significant myelosuppression was only observed in one patient. No complete or partial response was observed. There were two patients who had a minimal response and two other patients who had evidence of stable disease. Doxil was well tolerated with minimal toxicity. However, the lack of antitumor activity in anthracycline-resistant breast cancer patients indicates that further evaluation in this patient population is not warranted.

Clinical and pharmacokinetic data of a docetaxel-epirubicin combination in metastatic breast cancer.

In order to explore activity and pharmacokinetic data of a docetaxel-epirubicin combination we analyzed a population of 60 metastatic breast cancer patients. All the patients had an ECOG performance status < 3; 41 patients (68%) had visceral metastases as dominant site of disease, including 33% with liver metastases. Three or more involved organs were present in 43% of patients; 35% had received prior hormonotherapy; 10% for metastatic disease. Twenty-five patients (42%) had received prior adjuvant chemotherapy; 15% a CAF regimen. Twenty per cent of patients had less than 12 months disease-free interval. Docetaxel and epirubicin were both given at a dose of 75 mg/m2 i.v. d. 1 every 3 weeks. After a median of six cycles we had 5 CR (8.3%), 40 PR (66.6%), 7 NC (11.6%), and 8 PD (13.3%). Response rates in patients with visceral and liver metastases were 78% and 55% respectively. Premenopausal status, < 1 year disease free survival and > 3 metastatic sites were associated with a lower response rate. After a median follow-up of 19 months (12-36), median disease-free survival is 11 months and median overall survival has not been reached. Grade 4 neutropenia was observed in 75% of courses but with febrile neutropenia in 6.2% of courses only. Non-hematologic toxicity wasn't clinically important. A NYHA class III reversible cardiac failure was observed in one patient (1.6%). The pharmacokinetic evaluation in 16 patients has shown that docetaxel transiently interfered with epirubicin plasma level when docetaxel was administered 1 h after epirubicin.

Identification and interpretation of clinical and quality of life prognostic factors for survival and response to treatment in first-line chemotherapy in advanced breast cancer

The aim of the project was to identify clinical and quality of life (QL) factors that together predict survival and response to chemotherapy in advanced breast cancer. Potential prognostic factors were studied in 187 women with baseline QL data from a trial of paclitaxel versus doxorubicin as first-line chemotherapy. Demographic and clinical factors studied were age, performance status, dominant site of disease and preceding disease-free interval (DFI). Factors from the EORTC QLQ-C30 were all function scales, fatigue, nausea/vomiting, pain, dyspnoea, insomnia, loss of appetite and global QL. The proportional hazards regression model with stratification for treatment, and the logistic regression model adjusting for treatment arm were used for univariate and multivariate analyses of survival and response to treatment, respectively. For survival, multiple sites of visceral disease, pain, global QL and fatigue were significant prognostic factors in the univariate analysis. The final multivariate model predicted poor survival with multiple sites of visceral disease ( P=0.003), DFI ⩽2 years ( P=0.026) and pain ( P=0.003). For response, age, dyspnoea, fatigue and global QL were significant predictive factors in the univariate analysis. The final multivariate model for response selected DFI ( P=0.009), multiple sites of visceral disease ( P=0.037) and dyspnoea ( P=<0.001) using forward selection, but model instability was indicated by the inclusion of fatigue and emotional function in the final model when backward selection was used. In addition to known clinical factors, patient-assessed QL variables appear to be prognostic for survival and response to chemotherapy in women with advanced breast cancer. However, identification of prognostic factors from responses to questionnaires may be unstable, and their reliability and clinical utility should be tested prospectively.

Mitoxantrone, L-leucovorin and 5-fluorouracil: an effective and well tolerated first-line treatment for advanced breast cancer.

The combination of mitoxantrone plus leucovorin/fluorouracil in heavily pretreated patients with advanced breast cancer has shown significant activity and extremely good tolerability. The aim of this study was to evaluate the activity of this combination in patients not previously submitted to chemotherapy. From May 1993 to December 1995 we treated 80 patients with advanced breast cancer with a combination of mitoxantrone, l-leucovorin and 5-fluorouracil. All patients had histologically or cytologically proven breast cancer, WHO performance status 0-3, normal hematological parameters and normal serum bilirubin. Prior chemotherapy for metastatic disease was not allowed, whereas adjuvant CMF (cyclophosphamide, methotrexate and 5-fluorouracil) or adjuvant anthracycline (doxorubicin or epirubicin) therapy was allowed; a single prior hormone treatment was permitted. Chemotherapy consisted of mitoxantrone 12 mg/m2 i.v. day 1, l-leucovorin 150 mg/m2 i.v. days 1, 2 and 3 and 5-fluorouracil 350 mg/m2 i.v. days 1, 2 and 3. The courses were repeated every 3 weeks. Objective response (CR + PR) was observed in 46/80 (57%) patients (95% CI, 46%-68%). Complete response (CR) was observed in 21/80 cases (26%). Response was observed in 14/24 (58%) patients with soft tissues as the dominant site of disease, in 22/34 (65%) patients with visceral involvement and in 10/22 (45%) of those with bone as the dominant site of disease. The median duration of response and survival was 9 months (range, 3-16) and 22 months (range, 2-48+), respectively. Toxicity was very manageable, with grade 4 leukopenia and thrombocytopenia in 6/80 (7.5%) and 1/80 (1.25%) patients, respectively, and negligible non-hematological toxicity. The combination of mitoxantrone, 5-fluorouracil and high-dose l-leucovorin is a safe and effective regimen for first-line treatment of advanced breast cancer.