Phase I/II trial of intravenous Doxil and whole abdomen hyperthermia in patients with refractory ovarian cancer.

OBJECTIVE: A phase I/II study of Doxil combined with whole abdomen hyperthermia was conducted in patients with refractory ovarian cancer. Liposomal doxorubicin combined with hyperthermia has been shown to increase both liposomal delivery and drug extravasation into tumour xenografts resulting in enhanced cytotoxic effects. PATIENTS AND METHODS: Thirty patients with either recurrent or persistent epithelial ovarian cancer were enrolled. All patients had either measurable or assessable disease. Patients received intravenous (IV) Doxil at a dose of 40 mg m-2 as a 1-h infusion followed by whole abdomen hyperthermia. The phase I portion of the study was performed to determine the maximal tolerated dose (MTD) of hyperthermia. Quality of life (QoL) was performed at baseline, prior to each cycle and every 3 months. Plasma pharmacokinetic studies were performed with the first cycle. RESULTS: Ten patients participated in the phase I portion of the study which demonstrated that the MTD of hyperthermia was 60 min after either average vaginal and rectal temperatures of 40 degrees C had been achieved or after 30 min of power application, whichever was shorter. All 30 patients were either paclitaxel and/or platinum resistant initially or developed resistant disease. The median number of prior chemotherapeutic regimens was three (range 2-8) and six patients had been previously treated with Doxil. There were three partial responses for a response rate of 10% (95% CI: [2%, 27%]) and eight patients (27%; 95% CI: [12%, 46%]) had disease stabilization. The median time to progression or death was 3.4 months (95% CI: [2.6, 5.2]) and the median survival was 10.8 months (95% CI: [8.8, 17.4]). Twelve patients (40%) experienced palmar-plantar erythrodysesthesia (PPE), but only four (13%) experienced grade 3-4 PPE toxicity. Doxil systemic exposure was higher in those with grade 3-4 PPE compared to those with no PPE. None of the patients had grade 3-4 thermal toxicity due to hyperthermia. QoL was not decreased in patients responding to therapy. CONCLUSIONS: Therapy with intravenous Doxil and whole abdomen hyperthermia for patients with platinum/paclitaxel resistant ovarian cancer is feasible and does not negatively impact quality of life.

Prospective assessment of quality of life in ovarian cancer patients receiving whole abdomen hyperthermia and liposomal doxorubicin.

PURPOSE: Prospective assessment of quality of life (QoL) in patients with refractory, residual or recurrent ovarian cancer receiving whole abdomen hyperthermia and intravenous liposomal doxorubicin chemotherapy. METHODS: Treatment consisted of six cycles of intravenous liposomal doxorubicin at 40 mg m2 followed by whole abdomen hyperthermia with each cycle delivered every 4 weeks. QoL assessment was performed at baseline, prior to each cycle of chemotherapy and every 3 months during follow-up using self-administered questionnaires. Global QoL was rated on a seven-point scale and specific domains of QoL, disease related symptoms and treatment related toxicity were rated on a four-point scale. RESULTS: Thirty-two patients were enrolled on the study and 129 QoL questionnaires were completed. Average age was 57.9 (range 45-76); nine patients had persistent and 23 recurrent disease. Ten patients completed six cycles of therapy. Three patients returned follow-up surveys. Subjects rated their overall QoL and health at baseline as above average with mean scores 5.10 (95% CI=4.62-5.58) and 4.66 (95% CI=4.23-5.08), respectively. No significant change in overall QoL was found between baseline and cycles 4-6 of therapy. Mean ratings of overall health and subject reported differences in QoL between cycles were not significantly changed during therapy. Limited follow-up data were available, but scores suggest possible improvement in QoL for patients completing all therapy. Subjects rated the greatest negative impact on QoL in areas of role functioning and social functioning, where the mean (SD) over all cycles was 2.00 (0.67) and 1.98 (0.70), respectively. For physical symptoms, fatigue and sleep disturbance had the most negative impact on QoL with means (SD) of 2.26 (0.62) and 1.91 (0.70). The moderate treatment related toxicity seen in this study did not significantly impact patients reported QoL. CONCLUSIONS: Patients with unfavourable ovarian cancer responding to intravenous liposomal doxorubicin and whole abdomen hyperthermia maintained above average QoL during therapy. Limited data on patients completing protocol therapy demonstrated possible improvement in QoL.

Ultrasound guided pO2 measurement of breast cancer reoxygenation after neoadjuvant chemotherapy and hyperthermia treatment.

The objective of this study was to determine whether neoadjuvant chemotherapy in combination with hyperthermia (HT) would improve oxygenation in locally advanced breast tumours. The study describes a new optimized ultrasound guided technique of pO2 measurement using Eppendorf polarographic oxygen probes in 18 stage IIB-III breast cancer patients. Prior to treatment, tumour hypoxia (median pO2<10 mmHg) was present in 11/18 patients (average median pO2=3.2 mmHg). Seven patients had well oxygenated tumours (median pO2 of 48.3 mmHg). Eight patients with hypoxic tumours prior to treatment had a significant improvement (p=0.0008) in tumour pO2 after treatment (pO2 increased to 19.2 mmHg). In three patients, tumours remained hypoxic (average median pO2=4.5 mmHg). The advantages of the ultrasound guided pO2 probe are in the accuracy of the Eppendorf electrode placement in tumour tissue, the ability to monitor electrode movement through the tumour tissue during the measurement and the ability to avoid electrode placement near or in large blood vessels by using colour Doppler imaging. The results of this preliminary study suggest that the combination of neoadjuvant chemotherapy and hyperthermia improves oxygenation in locally advanced breast tumours that are initially hypoxic.

Counterpoint: test the value of hyperthermia in patients with carcinoma of the cervix being treated with concurrent chemotherapy and radiation.

Major advances in the treatment of locally advanced cervical carcinoma were reported in 1999-2000 in five studies from the Gynecologic Oncology Group, Radiation Therapy Oncology Group and Southwestern Oncology Group. Collectively these trials reported a decrease in the risk of recurrence or death from cervical cancer ranging from 30-50% with the use of concurrent chemoradiation, as compared with radiation alone. On the basis of these trials the National Cancer Institute in 1999 issued a clinical alert concluding 'Strong consideration should be given to the incorporation of concurrent cisplatin-based chemotherapy with radiation therapy in women who require radiation therapy for treatment of cervical cancer.' Concurrently with these publications there appeared the publication in the Lancet in 2000 of the Dutch Deep Hyperthermia Group trial of radiotherapy alone versus combined radiation and hyperthermia for locally advanced pelvic tumors including carcinoma of the cervix. This multi-center phase III trial demonstrated an approximate doubling of the three year survival from 27 to 51% for the addition of hyperthermia to radiotherapy in patients with locally advanced cervical carcinoma. Additional trials to test the value of hyperthermia in patients with cervical carcinoma treated with concurrent chemotherapy and radiation are imperative and take precedence over a trial to investigate the value of chemotherapy in patients treated with hyperthermia and radiation.

A phase II trial testing the thermal dose parameter CEM43 degrees T90 as a predictor of response in soft tissue sarcomas treated with pre-operative thermoradiotherapy.

We prospectively evaluated whether delivering a thermal dose of > 10 cumulative equivalent minutes at 43 degrees C to >90% of the tumour sites monitored (CEM43 degrees T90) would produce a pathologic complete response (pCR) in > 75% of high-grade soft tissue sarcomas treated pre-operatively with thermoradiotherapy. The impact of thermal dose on local failure (LF), distant metastasis (DM), and toxicity was also assessed. Thirty-five patients > or = 18 years old with grade 2 or 3 soft tissue sarcomas accessible for invasive thermometry were enrolled on the protocol. All patients received megavoltage external beam radiotherapy (RT) in daily fractions of 1.8-2.0 Gy, five times a week, to a median total dose of 50 Gy and an initial hyperthermia treatment (HT) of I h duration utilizing the BSD 2000 with Sigma 60 or MAPA applicators at frequencies of 60-140 MHz. Further HT was given for patients with CEM43 degrees T90 > 0.5 after initial HT ('heatable' patients), twice a week to a maximum of 10 HT or CEM43 degrees T90 > 100. Of the 35 patients entered, 30 had heatable tumours, one of which was inevaluable for pCR or LF as the patient died of DM prior to surgery, leaving 29 evaluable patients. Of these 29 patients, 15 (52%) had a pCR (95% CI: 37-73%), significantly less than the projected rate of > or = 75% (p = 0.02). Of the 25 heatable tumours that achieved CEM43 degrees T90 > or = 10, 14 (56%) had a pCR (95% CI: 39-78%) significantly less than the projected rate (p = 0.06). Three of the 29 patients (10%) with heatable tumours had a LF, versus 1/5 unheatable tumours (p = 0.48). Fourteen of the 30 patients (47%) with heatable tumours developed DM, versus 2/5 unheatable tumours (p = 1.00). Ten of the 30 patients (33%) with heatable tumours developed treatment-induced toxicity. Thus, no correlation of thermal dose with histologic response was observed. Prospective control of CEM43 degrees T90 failed to achieve the projected pCR rate following pre-operative thermoradiotherapy for high-grade soft tissue sarcomas, despite excellent local control. Possible explanations for this outcome are discussed.

A pilot study of preoperative continuous infusion 5-fluorouracil, external microwave hyperthermia, and external beam radiotherapy for treatment of locally advanced, unresectable, or recurrent rectal cancer.

PURPOSE: To determine the feasibility of combining external beam radiotherapy, continuous infusion 5-fluorouracil (5-FU), and external microwave hyperthermia in patients with locally advanced, unresectable, or recurrent adenocarcinoma of the rectum. METHODS AND MATERIALS: From 7/95 through 2/99, 15 patients were enrolled in the study. The treatment regimen consisted of continuous infusion 5-FU 250 mg/m(2)/d 7 days/week beginning on day 1, external beam radiotherapy to the pelvis, 4500 cGy, 180 cGy/d 5 days/week using a 3 or 4-field technique, and external microwave hyperthermia on days 3, 8, 15, 22, and 29. Chemotherapy was stopped on the last day of radiotherapy. Surgical resection, if feasible, was scheduled 3-6 weeks after completing thermochemoradiotherapy. For this regimen to be considered feasible, no more than 2 of the 15 patients should fail to complete therapy due to life-threatening toxicity. Toxicity was scored using National Cancer Institute Criteria. RESULTS: All patients completed the chemoradiotherapy portion of the protocol. Eleven of the 15 patients completed all 5 hyperthermia treatments. Of the 4 patients who did not receive the full course of hyperthermia, only 1 patient had treatment stopped due to life-threatening toxicity. The other 3 patients did not complete hyperthermia due to scheduling errors (n = 2) or patient request (n = 1). Five of 15 patients required a treatment interruption due to toxicity > or = Grade 3. Seven patients experienced lesser degrees of toxicity which did not require treatment interruption. Three patients experienced no side effects. The most common toxicities were dermatitis and diarrhea. Of the 14 patients in whom surgery was planned, 11 (79%) were resectable. There was one pathologic complete response. CONCLUSIONS: It is feasible to deliver thermochemoradiotherapy, as prescribed in this study, to patients with locally advanced, unresectable, or recurrent rectal cancer. The therapy is moderately toxic, with one-third of patients requiring temporary treatment interruptions. The regimen appears active against rectal cancer, and appears to warrant further consideration as a treatment option for this patient population.

The treatment of high-grade soft tissue sarcomas with preoperative thermoradiotherapy.

PURPOSE: To explore the use of a novel program of preoperative radiation and hyperthermia in the management of high-grade soft tissue sarcomas (STS). METHODS AND MATERIALS: Eligible patients were adults over 18 with Grade 2 or 3 STS, surgically resectable without a local excision prior to referral to Duke University Medical Center and without distant metastases. Patients were staged generally with CT and/or MR imaging. The diagnosis was established with fine needle aspiration or incisional biopsy. Patients were then treated with 5000 to 5040 cGy, 180-200 cGy per fraction. Chemotherapy was usually not employed. Generally two hyperthermia treatments per week were given with a planned thermal dose of 10-100 CEM 43 degrees T90. Invasive thermometry and thermal mapping were done in all patients. Surgical resection was planned 4-6 weeks after the completion of radiation and hyperthermia. RESULTS: Ninety-seven patients were treated on study between 1984 and 1996. Follow-up ranged from 12 to 155 months (median 32). All tumors were high-grade in nature, 44 greater than 10 cm in size (maximum tumor diameter), 43 5-10 cm in size, 10 less than 5 cm. Seventy-eight of the 97 tumors were located in an extremity. Of the 97 patients, 48 remain alive and continually free of disease following initial therapy. Of the remaining 49 patients, 44 have relapsed (34 dead, 10 living with disease), 3 have died secondary to complications of therapy, and 2 have died of unrelated causes. Ten-year actuarial overall survival, cause-specific survival, and relapse-free survival are 50, 47, and 47% respectively. The predominant pattern of failure has been distant metastases with only 2 patients developing local failure alone. Ten-year actuarial local control for extremity tumors is 94%, 63% for the 19 patients with tumors at sites other than the extremity. Of the 78 patients with extremity lesions, 63 have had limb preservation and remain locally controlled. Overall 38 patients experienced 57 major complications. There were 3 deaths, one due to adriamycin cardiomyopathy and two secondary to wound infections. Four patients required amputation secondary to postoperative wound healing problems. Complications directly attributable to hyperthermia occurred in 15 patients with 11 instances of second- or third-degree burns and two instances of subcutaneous fat necrosis. The hyperthermia complications were generally not severe and either healed readily or were excised at the time of surgical resection of the primary tumor. CONCLUSIONS: For these aggressive high-grade soft tissue sarcomas, this treatment program of preoperative thermoradiotherapy provided excellent local regional control for extremity lesions (95%) and satisfactory local regional control (63%) of nonextremity sarcomas, but did not appear to influence the rate of distant metastases or survival. Complications were frequent but apart from the direct thermal burns, not too different from those reported for preoperative radiotherapy alone. More effective adjuvant systemic therapy is necessary to impact favorably on survival.

Combined external beam irradiation and external regional hyperthermia for locally advanced adenocarcinoma of the prostate.

PURPOSE: To determine the safety and efficacy of combined external beam irradiation and external regional hyperthermia in the treatment of adenocarcinoma of the prostate. METHODS AND MATERIALS: From 1987 to 1994, 30 patients received combined external beam irradiation and external regional hyperthermia for locally advanced prostate cancer. The results of the 21 patients with newly diagnosed (n = 18) or locally recurrent (n = 3) adenocarcinoma are reported herein. No patient had evidence of distant metastases. Total radiotherapy doses of 65-70 Gy to the prostate were planned using a four-field box technique. Hyperthermia treatments were delivered using an annular phased array microwave device. The treatment goal was to achieve temperatures > or = 42 degrees C in all measured points within the prostate. RESULTS: Of the newly diagnosed patients, 16 out of 18 (89%) had T3 or T4 tumors, 11 out of 18 (61%) had Gleason scores of 7-9, and the mean pretreatment Prostate Specific Antigen (PSA) was 69 ng/ml. The median follow-up of all 21 patients was 36 months. None of the patients achieved the treatment goal of all intratumoral temperatures > or = 42 degrees C. The mean CEM 43 T90 was 2.34 min. The disease-free survival at 36 months is 25%; 12 out of 18 (67%) of the patients have relapsed. The only significant predictor of relapse was pretreatment PSA. There were no complications > Grade 3. CONCLUSIONS: In spite of the inability to achieve high tumor temperatures, the relapse-free survival rate in this population of patients with very advanced localized prostate cancer treated with radiation therapy plus hyperthermia compares favorably with most series using radiation therapy alone. Further studies aimed at improving the ability to deliver hyperthermia to the prostate are warranted.

Hyperthermic treatment of malignant diseases: current status and a view toward the future.

New studies in hyperthermia at the basic science, engineering, and clinical level have stimulated renewed enthusiasm for re-investigating its potential as an anticancer therapy. This article reviews the salient features of these recent results and points out areas for additional investigation. Highlighting these new results is the publication of several positive phase III trials for thermoradiotherapy compared to radiotherapy alone. Important highlights are the encouraging results using magnetic resonance imaging for noninvasive thermometry. If this technology is successfully implemented with real time power control it will revolutionize the clinical application of hyperthermia.

Radiation therapy and hyperthermia improve the oxygenation of human soft tissue sarcomas.

The adverse prognostic impact of tumor hypoxia has been demonstrated in human malignancy. We report the effects of radiotherapy and hyperthermia (HT) on soft tissue sarcoma oxygenation and the relationship between treatment-induced changes in oxygenation and clinical treatment outcome. Patients receiving preoperative radiotherapy and HT underwent tumor oxygenation measurement pretreatment after the start of radiation/pre-HT and one day after the first HT treatment. The magnitude of improvement in tumor oxygenation after the first HT fraction relative to pretreatment baseline was positively correlated with the amount of necrosis seen in the resection specimen. Patients with <90% resection specimen necrosis experienced longer disease-free survival than those with > or = 90% necrosis. Increasing levels of tumor hypoxia were also correlated with diminished metabolic status as measured by P-31 magnetic resonance spectroscopy.

The effects of hyperthermia in bone marrow purging of breast cancer.

The number of autologous bone marrow transplants done for solid tumours, particularly breast cancer, has risen steadily over the last ten years. The role of bone marrow or peripheral blood progenitor cell purging in transplantation is incompletely understood. Theoretically, the reinfusion of untreated bone marrow containing tumour cells might result in relapse in some patients treated with high-dose chemotherapy and hematopoietic support. Therefore, safe and effective purging techniques may increase long-term, disease-free survivorship. In this study, hyperthermia was evaluated for its ability to purge CAMA-1 breast cancer cells from normal human bone marrow. Between two and nine trials of a range of temperatures (42-45 degrees C) and durations of treatment (1-4 h) were performed. The effect of hyperthermia on normal bone marrow alone and in mixes with breast cancer cells was also evaluated. Hyperthermia (45 degrees C, 4 h) produced > 5 logs of CAMA-1 cell kill. Exposures of 45 degrees C for 2 h and 44 degrees C for 4 h resulted in approximately three logs of cell kill, corresponding to < 1% survival of clonogenic cells. Normal bone marrow was considerably more vulnerable to heat treatments, however, with approximately 1% of progenitors remaining clonogenic after exposure of 43 degrees C for 2 h and 44 degrees C for 1 h. Therefore, although hyperthermia is able to achieve adequate CAMA-1 breast cancer cell kill, it remains more toxic to normal bone marrow as a purging method. To make hyperthermia useful in purging systems, mechanisms to selectively alter thermal sensitivity must be pursued.

Cumulative minutes with T90 greater than Tempindex is predictive of response of superficial malignancies to hyperthermia and radiation.

PURPOSE: To better define thermal parameters related to tumor response in superficial malignancies treated with combined hyperthermia and radiation therapy. METHODS AND MATERIALS: Patients were randomized to receive one or two hyperthermia treatments per week with hyperthermia given during each week of irradiation. Hyperthermia was given for 60 min with treatments begun within 1 hr following irradiation. Power was increased to patient tolerance or normal tissue temperature of 43.0 degrees C. Irradiation was generally given 5 times per week with doses prescribed to normal tissue tolerance (generally 24-70 Gy at 1.8-2.5 Gy per fraction). Multipoint thermometry was used with temperatures obtained every 5 min. RESULTS: One hundred eleven individual treatment fields containing 1 or more tumor nodules were completely evaluable. The complete and overall response rates were 46% and 80%, respectively. Forty-one percent of all treatment fields (51% of responding lesions) remained controlled at 2 years. Multivariate analysis revealed that the cumulative minutes that the temperature achieved by 90% of the measured tumor sites (T90) was > or = 40.0 degrees C, tumor histology, tumor volume, and radiation dose were significantly associated with complete tumor response. The complete response rate was not significantly affected by the number of hyperthermia treatments given per week. The incidence of clinically significant complications was low. CONCLUSIONS: These results support the usefulness of the cumulative minute system in describing time-temperature relationships. The significance of thermal variables with regard to tumor response strongly supports the contention that hyperthermia can be a useful adjunct to irradiation for the local control of cancer.

Relationships among tumor temperature, treatment time, and histopathological outcome using preoperative hyperthermia with radiation in soft tissue sarcomas.

The lack of an unambiguous thermal dosimetry continues to impede progress in clinical hyperthermia. In an attempt to define better this dosimetry, a model based on the cumulative minutes during which arbitrary percentages of measured tumor temperature points exceeded an index temperature was tested in patients with soft tissue sarcomas treated with preoperative hyperthermia and conventional radiation therapy. Patients received 5000-5040 cGy at 180-200 cGy per fraction. Hyperthermia was delivered 30-60 minutes after radiation therapy and given for 60 minutes. Patients were randomized between one and two hyperthermia treatments per week for a total of five or 10 treatments, respectively. Lesions were excised 4-6 weeks after completion of hyperthermia/radiation therapy. Successful treatment outcome was considered to be the finding of greater than 80% necrosis of the sarcoma upon histopathologic examination of the resected specimen. Forty-five patients were eligible with thermometry data available in 44 patients. An average of 19 interstitial sites were monitored each treatment per tumor. Sixty percent of tumors had a successful histopathologic outcome. Univariate analysis demonstrated that several descriptors of the temperature distribution were strongly related to treatment outcome; more strongly than nonthermometric factors, such as the number of treatments per week, tumor volume and patient age and more strongly than the commonly used temperature descriptors Tmin and Tmax. Descriptors that incorporated both temperature and time were also superior to the more commonly used descriptors Tmin and Tmax. Multivariate stepwise logistic regression analysis revealed that a descriptor of both the hyperthermia treatment time and the frequency distribution of intratumoral temperatures was the strongest predictor of histopathologic outcome and that the best predictive model combined this time/temperature descriptor and one versus two treatment per week grouping. The more conventional temperature descriptor, minimum measured tumor temperature, did not significantly enhance the predictive power of treatment group. Based on these results, we recommend that descriptors based on both the frequency distribution of intratumoral temperatures and hyperthermia treatment time be tested for relationships with treatment outcome in other clinical data bases. Furthermore, we recommend that temperature descriptors that are less sensitive to catheter placement and tumor boundary identification than Tmin and Tmax (such as T90, T50, and T10) be tested prospectively along with other important thermal variables in Phase II trials in further efforts to define a thermal dosimetry for spatially nonuniform temperature distributions.

Post-mastectomy radiotherapy following adjuvant chemotherapy and autologous bone marrow transplantation for breast cancer patients with greater than or equal to 10 positive axillary lymph nodes. Cancer and Leukemia Group B.

Between 2/87 and 2/91, 49 women with operable breast cancer involving greater than or equal to 10 axillary nodes were treated following mastectomy, with four cycles of Cyclophosphamide, Adriamycin, 5FU, followed by high doses of Cyclophosphamide, Cisplatin, Carmustine (HDCT) with autologous bone marrow transplant support. Forty patients received local-regional radiotherapy (generally to the chest wall, internal mammary, supraclavicular, +/- axillary nodal areas; minimum 44-50 Gy, 1.8-2 Gy/fraction, +/- 10-15 Gy scar boost; standard radiation techniques). The first nine patients did not receive local-regional radiotherapy. Three developed a local-regional failure (6-12 months after HDCT); six are without evidence of disease. Local-regional radiotherapy (LR XRT) was delivered to the subsequent 40 patients following HDCT+autologous bone marrow transplant. Six received less than 44 Gy of the planned local-regional radiotherapy due to significant toxicity and one of these failed locally. Only one local failure was observed among the 34 patients who received greater than or equal to 44 Gy. Two additional patients developed distant metastases. None of these 40 patients have failed in the axilla despite the fact that the axilla was irradiated in only 18 cases. Overall, 36/40 (90%) of these patients are without evidence of disease 4-30 months following HDCT (approximately 10-36 months after mastectomy, median 22 months). Radiotherapy was interrupted or discontinued because of progressive dyspnea, thrombocytopenia, or neutropenia in nine patients. Further studies to determine the roles of local-regional radiotherapy and HDCT in the development of these toxicities are underway. These encouraging results suggest that HDCT + autologous bone marrow transplant+local-regional radiotherapy may improve the survival rate in these high risk patients. A national randomized study to test the efficacy of this HDCT regimen is currently underway (Cancer and Leukemia Group B#9082 and Southwest Oncology Group #9114).

Inflammatory breast carcinoma. Effective multimodal approach.

Twenty-two patients with inflammatory breast carcinoma received preoperative chemotherapy consisting of weekly administration of cyclophosphamide, doxorubicin hydrochloride, fluorouracil, and vincristine sulfate for six weeks. Postoperative therapy consisted of 22 weeks of biweekly administration of these drugs. Regional radiotherapeutic consolidation followed chemotherapy. Nineteen patients completed therapy. Twelve of these patients remain disease free (median, 15 months; range, four to 32 months). Median disease-free survival for all 22 patients is 13 months or more (range, zero to 32 months). Median overall survival is 18 months or more (range, one to 33 months). This regimen compares favorably with prolonged adjuvant and maintenance chemotherapy for inflammatory breast carcinoma.