Phase I-II trial of high-dose epirubicin in patients with lymphoma.

High-dose doxorubicin has shown considerable activity in both previously treated and previously untreated patients with lymphoma. Because of the toxicities of doxorubicin at high dose, we elected to study a new anthracycline at doses comparable to doxorubicin at high dose, to assess response and toxicity. Epirubicin was administered at doses of 120 mg/m2, 150 mg/m2, and 180 mg/m2 every 3 weeks (maximum four doses) to groups of six patients with previously treated intermediate- and high-grade lymphoma. Sixteen of the patients had received significant prior therapy with an anthracycline and/or anthracenedione. At all dose levels, myelosuppression was severe, with median granulocyte nadirs less than 504/mm3. Hematological recovery occurred by day 21 at the 120 mg/m2 and 150 mg/m2 dose levels, allowing for the next cycle of therapy. However, at the 180 mg/m2 dose level, the majority of patients failed to have hematological recovery by the day of the next scheduled therapy. Forty-two % of patients (eight patients) had fever/neutropenia, and required antibiotics. One treatment-related septic death occurred (at 150 mg/m2). Alopecia (68%), fever immediately following treatment (63%), mild/moderate stomatitis (58%), and nausea/vomiting (53%) were the most common nonhematological toxicities. These toxicities were independent of the dose levels and were not dose limiting. A significant change (greater than or equal to 0.10) in the radionuclide ejection (EF) was seen in seven patients. The median of the entire group of patients fell from 0.63 to 0.56. No patient developed clinical or radiological evidence of congestive heart failure. A response rate of 58% (two complete responses, nine partial responses) was achieved with a median duration of 5 months (range, 1-15+). High-dose epirubicin can be successfully utilized in patients with previously treated lymphoma. The only dose-limiting toxicity observed at these dose levels was the lack of hematological recovery by day 21 with 180 mg/m2. Since epirubicin at high dose will be incorporated into high-dose anthracycline regimens in previously untreated patients utilizing a 3-week treatment cycle, 150-180 mg/m2 may be the maximally tolerated dose for such studies.

Phase I-II study of epirubicin in multiple myeloma.

Forty patients with relapsed (26) or refractory (14) myeloma were treated with epirubicin of doses of 75, 90, 105, and 120 mg/m2 in groups of 6 or more patients to test for response, maximum tolerated dose, and toxicity. Thirteen patients had received prior doxorubicin and were included in the dose findings part of the study only. Staging was I (1), II (5), and III (34). Partial responses were seen in 5 patients (18.5%) (duration 1.5, 2, 2.5, 10, and 18 months) not previously treated with doxorubicin. No responses were seen in patients treated with prior anthracycline. Responses were not dependent upon dose level of epirubicin. Median nadir white blood cell count at the four-dose levels were 2,300, 1,000, 1,600, and 1,700/mm3 with median nadir granulocyte counts of 897, 720, 688, and 192/mm3. Fever/neutropenia was infrequently observed at the three lower dose levels but occurred in 6 of 10 patients at 120 mg/m2. Platelet nadirs were 110,000, 83,000, 169,000, and 42,000/mm3. Nonhematological toxicity was not dose dependent and included alopecia (100%), nausea/vomiting (40%), and stomatitis (25%). Six patients had greater than or equal to 0.10 changes in the resting ejection fraction with one patient developing congestive heart failure that responded to medical management. This patient had received prior doxorubicin and had a history of myocardial infarction. Epirubicin can produce remissions in patients with previously treated myeloma who have not received prior doxorubicin. Since the response rate was not enhanced at 120/m2 and since fever/neutropenia was seen regularly at this dose level, the recommended dose for further study is 105 mg/m2.

Phase II study of oral idarubicin in favorable histology non-Hodgkin's lymphoma.

Idarubicin, a new analogue of daunorubicin, was administered p.o. for 3 consecutive days every 3 weeks at a dose of 45 mg/m2 in 46 patients (45 eligible and evaluable) with previously treated, favorable histology, non-Hodgkin's lymphoma. Median clinical characteristics included an age of 66 years, a performance status of 1, and one prior chemotherapeutic regimen. Forty-one patients were relapsing from prior therapy, and 37 had stage IV disease. Patients with prior anthracycline therapy were excluded. Responses were observed in 58% of patients (10 complete and 16 partial), with a median duration of 6+ months (2-41+ months). Idarubicin was well tolerated. Nonhematological toxicities (nausea/vomiting, mucositis/diarrhea, alopecia, and anorexia) were observed in less than or equal to 50% of patients. Median hematological values during the first cycle include a WBC of 4100/mm3 and a platelet count of 147,000/mm3. With dose escalation, hematological toxicity was the dose-limiting toxicity. Symptomatic cardiac toxicity was not observed. Median values for the resting left ventricular ejection fraction during the course of therapy were 0.65 (initial) and 0.63 (final). Idarubicin in oral form is an active drug in previously treated patients with favorable histology non-Hodgkin's lymphoma.

Phenotypic heterogeneity in cultured human head and neck squamous cell carcinoma lines with low-level methotrexate resistance.

Low-level methotrexate (MTX) resistance (less than 20-fold) was induced by gradual selection pressure in four human head and neck squamous cell carcinoma lines established in culture from biopsies of patients not previously treated with MTX. Each parental and resistant line was characterized with respect to MTX uptake and polyglutamylation, dihydrofolate reductase (DHFR) content, and growth rate. Relative DHFR gene copy numbers and amounts of DHFR-related cytoplasmic messenger RNA were analyzed by plasmid complementary DNA hybridization in a dot blot assay and were correlated with the amount of gene product. The resistant lines were not cloned in order to simulate in vitro the conditions which might exist in an in vivo setting, where multiple resistant subpopulations of cells may be present in a tumor. The study was restricted to cells with low-level resistance since these are likely to be the clinically most relevant type. Of the four resistant lines characterized, one showed a severe defect in MTX uptake and polyglutamylation, another was a DHFR overproducer with only small changes in uptake and polyglutamylation, a third was likewise a DHFR overproducer but also showed lower MTX uptake, and the fourth was minimally altered except for growth rate. The diversity in resistance phenotype among these cells in vitro suggests that in vivo resistance in patients with head and neck carcinoma who are treated with MTX may similarly involve multiple mechanisms and that further therapeutic intervention using MTX or other antifolates should take this into account.

Primary lymphomas of the central nervous system: patterns of failure and factors that influence survival.

Primary lymphomas of the CNS are rare tumors accounting for less than 2% of all extranodal non-Hodgkin's lymphomas. The treatment for this disease has been disappointing. Radiation therapy and surgery have produced consistently poor control of this disease, with a median survival of 15 months. We have reviewed ten cases of primary lymphoma of the CNS treated at the Joint Center for Radiation Therapy or Dana-Farber Cancer Institute (Boston) from 1968 to 1981. All patients had biopsy-proven CNS lymphomas without systemic disease at presentation. In our series, control of CNS lymphoma was seen only in patients receiving craniospinal radiation or CNS-penetrating chemotherapy.

An analysis of induction and adjuvant chemotherapy in the multidisciplinary treatment of squamous-cell carcinoma of the head and neck.

This study examines the role of combination chemotherapy with surgery and/or radiotherapy in the initial treatment of patients with advanced stage III and IV squamous-cell carcinoma of the head and neck (SCCHN). Two courses of initial (induction) cisplatin, bleomycin, and methotrexate with oral calcium leucovorin (PBM) were used with the principal intent of increasing the effectiveness of subsequent surgery and/or radiotherapy. Following induction chemotherapy and local treatment, disease-free patients who had responded to initial chemotherapy were entered into a randomized trial of adjuvant PBM. The response rates to induction PBM chemotherapy were a complete response (CR) rate of 26% and a partial response (PR) rate of 52%, for an overall response rate of 78%. A response to induction PBM was highly correlated with failure-free survival (P less than .0001). A Cox multistep regression analysis of potential prognostic factors was performed. After adjusting for the significant prognostic factors of performance status, initial tumor size, and primary tumor site, a response to induction chemotherapy remained independently associated with improved survival (P = .0002). The randomized trial of adjuvant chemotherapy demonstrated that such treatment significantly improved failure-free survival by decreasing local-regional failures. The benefit of adjuvant chemotherapy was particularly evident in patients who had a PR to induction chemotherapy (P = .01). The toxicity of this multidisciplinary approach was predictable and acceptable. Surgery and radiotherapy were not compromised by induction or adjuvant chemotherapy. Definitive evidence that chemotherapy can favorably influence survival awaits confirmation of these results by a randomized trial using a control arm of patients treated with conventional surgery and/or radiotherapy alone.

Multidisciplinary treatment of advanced squamous carcinoma of the head and neck.

Advanced squamous carcinoma of the upper aerodigestive tract continues to be a therapeutic challenge. With recent advances in chemotherapy, systemic treatment has been used in an attempt to improve treatment results produced by radiation therapy and/or surgery. Such multidisciplinary experimental approaches have given new hope for cure in stage III and stage IV disease, but have reopened old questions as to the natural history and underlying biology of this disease. Multidisciplinary treatment, whether synchronous or sequential, appears to improve survival for stage III and stage IV patients achieving a complete response to chemotherapy plus irradiation. The role of surgery or radiotherapy for control of primary or nodal disease remains unchanged and is an essential component of all curative treatment plans.

Chemotherapeutic strategies in the multidisciplinary treatment of head and neck cancer.

A role for chemotherapy in the multidisciplinary treatment of patients with advanced squamous cell carcinoma of the head and neck (SCCHN) is yet to be defined. Results of uncontrolled studies indicate high response rates to induction chemotherapy and an association between a response to chemotherapy and either local-regional control or survival. Unfortunately, results of randomized, controlled trials have not confirmed an overall survival advantage with such treatment. From 1979 to the present, the Dana-Farber Cancer Institute has registered more than 224 patients on two trials of induction and adjuvant chemotherapy for patients with stage III to IV SCCHN. Protocol 80-016 (1979 to 1983) evaluated two cycles of induction cisplatin, bleomycin, and methotrexate/leucovorin (PBM) before local regional treatment in 114 patients. Eighty-nine (78%) patients responded to PBM, with 30 (28%) patients achieving a complete response (CR). After surgery and/or radiotherapy (RT), 46 responders to induction PBM entered a trial of the randomly assigned additional adjuvant PBM. Protocol 83-084 (1983 to present) randomly assigned patients to receive up to four cycles of either induction PBM or cisplatin and infusion 5-fluorouracil before local treatment. Adjuvant chemotherapy was not used in the latter study. Updated results from both trials will be presented, with their implications for future phase II and III multidisciplinary studies. Optimal approaches to the treatment of patients with advanced SCCHN can include planned reductions in the extent of surgery or RT offered to selected patients with a good response to induction chemotherapy but may require adjuvant chemotherapy for patients at high risk for recurrent disease. Until the rate of CR to induction chemotherapy is reproducibly over 50%, documentation of an improved overall survival with multidisciplinary treatment may be difficult.

Toxicity of aggressive multimodality therapy including cisplatinum, bleomycin and methotrexate with radiation and/or surgery for advanced head and neck cancer.

A combined modality regimen employing induction chemotherapy with cisplatinum, bleomycin and methotrexate followed by surgery and/or radiation therapy was initiated in patients with advanced squamous cell carcinoma of the head and neck. In the first 23 patients treated with this program there was a 90% response rate to induction chemotherapy (9% CR and 81% PR). Toxicity associated with radiotherapy, but not surgery, was increased with 11 of 23 patients (48%) who experienced some toxicity during or immediately after radiotherapy. Mucositis was worse than expected and severe delayed mucositis was seen in 2 patients, one or whom required hospitalization. Late complications, possibly related to therapy included one myocardial infarction and one episode of hypoglycemia, both of which were fatal. One other patient voluntarily failed to take prescribed oral leucovorin, dying of unrescued methotrexate toxicity during adjuvant therapy, a questionable suicide. Further follow-up and analysis of failure will be necessary to determine if the value of a combined modality regimen in producing an increased cure rate and long term survival will out weight increased toxicity.

The influence of beam energy on the outcome of postoperative radiotherapy in head and neck cancer patients: secondary analysis of RTOG 85-03.

PURPOSE: To determine whether any difference in toxicity or efficacy occurs when head and neck cancer patients are treated postoperatively with (60)C0, 4 MV, or 6 MV photon beam. METHODS AND MATERIALS: This is a secondary analysis of the Intergroup Study 0034. Three hundred ninety-two patients were evaluable for comparison between treatment with (60)C0, 4 MV, or 6 MV photon beam. All patients had advanced but operable squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx. Patients were randomized following surgical resection to receive treatment with either postoperative irradiation alone, or postoperative irradiation plus three cycles of cisplatin and 5-fluorouracil. Patients were categorized as having either "low risk" or "high risk" treatment volumes based on whether the surgical margin was 5 mm or less, presence of extra capsular nodal extension, and/or carcinoma in situ at the surgical margins. Low-risk volumes received 50-54 Gy, and high-risk volumes were given 60 Gy. Patients were compared in regards to acute and late radiotherapy toxicities as well as overall survival and loco-regional control according to the beam energy used. RESULTS: One-hundred fifty-seven, 140, and 95 patients were treated by (60)C0, 4 MV, and 6 MV, respectively. No differences were seen in acute or late toxicity among treatment groups. Locoregional control was achieved in 75%, 79%, and 80% of patients treated with (60)C0, 4 MV, or 6 MV (p = 0.61). Patients treated with 6 MV had a higher incidence of ipsilateral neck failure as first event (13%) than patients treated by (60)C0 and 4 MV (9%). This difference was not statistically significant. CONCLUSION: No differences in outcome, acute, or late toxicity were discernible in patients with advanced head and neck cancer treated with (60)C0, 4 MV, or 6 MV. This result should be interpreted with caution as increased incidence, albeit nonsignificant, of ipsilateral neck recurrence was observed in patients treated with 6 MV and the power of the study to detect a statistically significant difference is small.

Adjuvant chemotherapy for resectable squamous cell carcinomas of the head and neck: report on Intergroup Study 0034.

To test the efficacy of sequential chemotherapy as an adjuvant to surgery and postoperative radiotherapy for patients with locally-advanced but operable squamous cell cancers of the head and neck region, a randomized clinical trial was conducted under the auspices of the Head and Neck Intergroup (Radiation Therapy Oncology Group, Southwest Oncology Group, Eastern Oncology Group, Cancer and Leukemia Group B, Northern California Oncology Group, and Southeast Group). Eligible patients had completely resected tumors of the oral cavity, oropharynx, hypopharynx, or larynx. They were then randomized to receive either three cycles of cis-platinum and 5-FU chemotherapy followed by postoperative radiotherapy (CT/RT) or postoperative radiotherapy alone (RT). Patients were categorized as having either "low-risk" or "high-risk" treatment volumes depending on whether the surgical margin was greater than or equal to 5 mm, there was extracapsular nodal extension, and/or there was carcinoma-in-situ at the surgical margins. Radiation doses of 50-54 Gy were given to "low-risk" volumes and 60 Gy were given to "high-risk" volumes. A total of 442 analyzable patients were entered into this study with the mean-time-at-risk being 45.7 months at the time of the present analysis. The 4-year actuarial survival rate was 44% on the RT arm and 48% on the CT/RT arm (p = n.s.). Disease-free survival at 4 years was 38% on the RT arm compared to 46% on the CT/RT arm (p = n.s.). At 4 years the local/regional failure rate was 29% vs. 26% for the RT and CT/RT arms, respectively (p = n.s.). The incidence of first failure in the neck nodes was 10% on the RT arm compared to 5% on the CT/RT arm (p = 0.03 without adjusting for multiple testing) and the overall incidence of distant metastases was 23% on the RT arm compared to 15% on the CT/RT arm (p = 0.03). Treatment related toxicity is discussed in detail, but, in general, the chemotherapy was satisfactorily tolerated and did not affect the ability to deliver the subsequent radiotherapy. Implications for future clinical trials are discussed.

Is a surgical resection leaving positive margins of benefit to the patient with locally advanced squamous cell carcinoma of the head and neck: a comparative study using the intergroup study 0034 and the Radiation Therapy Oncology Group head and neck database.

PURPOSE: The purpose of this study was to determine whether or not for patients with squamous cell carcinomas of the head and neck, a surgical resection leaving positive margins followed by postoperative adjuvant therapy improves the outcome compared to a matched group of patients treated with definitive radiotherapy alone. METHODS AND MATERIALS: From January 1985 through January 1990 a consortium of national cooperative groups (Radiation Therapy Oncology Group, Cancer and Leukemia Group B, Eastern Cooperative Oncology Group, Northern California Oncology Group, Southeast Group, and Southwest Oncology Group) conducted a phase III clinical trial testing the efficacy of adjuvant chemotherapy for patients with resectable, squamous cell carcinomas of the head and neck. One hundred and nine patients were excluded from this study due to positive surgical margins. These patients have been followed prospectively with regards to local/regional tumor control, development of distant metastases, and survival. The postoperative treatment of these patients was not specified by the protocol but the majority of patients received postoperative radiotherapy +/- chemotherapy. These patients were compared with a matched group of patients from the Radiation Therapy Oncology Group head and neck database of patients treated with definitive radiotherapy alone using a standard fractionation schema. Matching parameters included primary tumor site, T-stage, N-stage, Karnofsky performance status, and age. RESULTS: Actuarial curves are presented for local/regional control and survival. At 4 years the local/regional control rate is 44% for the positive margin patients compared to 24% for the patients from the data base (p = 0.007). However, there is no significant difference between the survival curves (p = 0.76) with respective median survivals being 18.1 months vs. 17.9 months and 4-year survivals being 29% vs. 25%. CONCLUSION: While an incomplete excision followed by postoperative therapy does not seem to improve survival compared to treatment with radiotherapy alone, it appears to yield significantly better local/regional control. This would argue for its applicability in selected palliative settings. A follow-up, Phase III trial for patients with advanced tumors may be warranted to test traditional resectability criteria.

Treatment complications after sequential combination chemotherapy and radiotherapy with or without surgery in previously untreated squamous cell carcinoma of the head and neck.

One hundred consecutive patients with previously untreated advanced squamous cell carcinoma of the head and neck were treated with induction combination chemotherapy followed by definitive surgery and/or radiotherapy, and were evaluated for radiotherapy related toxicity. The induction regimen consisted of cisplatin, bleomycin and methotrexate/leucovorin. Acute toxicity consisted predominantly of mucositis and weight loss, and was mild or moderate by degree in 94% of patients. Six percent of patients experienced severe or life threatening acute toxicities. Two acute toxic deaths were noted in this series, one from a combination of mucositis, weight loss and infection and one from hypoglycemia of unknown origin. Thirty-five percent of patients had radiation treatment interrupted briefly because of acute toxicity. Toxicity was greatest in patients who were nonresponders to induction chemotherapy and such may have been related to the continued presence of advanced tumor. Radiotherapy dose, surgical intervention and age did not have an impact on the presence or degree of acute toxicity. Late toxicities included: hypothyroidism in 32% of patients tested: osteoradionecrosis in 5% of patients, associated primarily with a composite resection (4 of 5 cases); and soft tissue ulcerations in 3%. Taken together, these data indicate that induction combination chemotherapy did not significantly increase the toxicity of subsequent radiotherapy with or without surgery.

A phase I trial of combination therapy with continuous-infusion PALA and continuous-infusion 5-FU.

Thirty-four patients were treated with N-(phosphonacetyl)-L-aspartate (PALA) at a dose of 850 mg/m2/day x 5 by continuous intravenous infusion (days 1-5) and 5-fluorouracil (5-FU) on an escalating dose schedule of 300-630 mg/m2/day x 5 by continuous intravenous infusion (days 2-6). Dose-limiting oral mucositis occurred at a 5-FU dose of 560 mg/m2/day; other toxicities included nausea, vomiting, diarrhea, skin rash, and superficial venous phlebitis. Myelosuppression was rare. One partial response was observed in a patient with metastatic colorectal carcinoma. Plasma PALA levels were monitored in seven patients. Steady-state levels were achieved by the 2nd day of drug infusion and ranged between 10 and 20 micrograms/ml.

Improved survival for patients with advanced carcinoma of the head and neck treated with methotrexate-leucovorin prior to definitive radiotherapy or surgery.

Patients presenting with Stage III-IV squamous carcinoma of the head and neck often relapse following aggressive surgery and/or radiotherapy. In an attempt to increase survival in this high risk group of patients, HD-MTX, 3 gm./m2/dose, given weekly, was administered to 21 inoperable patients with Stage III/IV squamous carcinoma of head and neck prior to, and for 1 month after, definitive surgery and/or radiotherapy. Six of 11 patients (55%) who showed a significant response (greater than 50% reduction in tumor volume) to HD-MTX are alive and free of tumor greater than 38 months following treatment (p = 0.6) (Fisher Exact Test). Responder median survival is greater than 38 months while non-responder median survival is 15 months (p = .02) (Log Rank Test). For the entire treatment group, at a mean duration of 44.2 months following initiation of therapy, 7 patients (33%) remain alive and free of tumor. Patients responding to induction MTX-LCV more often become eligible for combined modality approach than did the non-responder group. This "downstaging" of the tumor prior to aggressive surgery or radiotherapy may be responsible for the increased survival rate seen in those patients who responded to MTX-LCV.

Small cell carcinomas of the larynx: results of combined modality treatments.

Four cases of primary small cell carcinoma of the larynx are described. Two patients presented with extensive metastatic disease and two with tumor limited to the larynx. All four cases responded (3PR, 1CR) to systemic combination chemotherapy. Long-term remission was achieved in one patient with limited disease who underwent chemotherapy with a complete response followed by definitive radiotherapy. Treatment results are compared with previously reported cases. The importance of early diagnosis through staging, and combined treatment in small cell carcinoma of the larynx is discussed.

Pathology of surgery after induction chemotherapy: an analysis of resectability and locoregional control.

At the Dana-Farber Cancer Institute Head and Neck Cancer Clinic, 114 previously untreated patients with advanced squamous cell carcinoma of the head and neck (17% stage III; 83% stage IV) were managed with induction chemotherapy using cis-platinum, bleomycin, and methotrexate, followed by definitive extirpative surgery and/or radiation therapy. The present report evaluates this group from a surgical and surgical pathology standpoint. The following aspects are evaluated: predictability of, and conversion to, resectability during induction chemotherapy; ease of surgical technique and intraoperative assessment; patterns of pre-op and post-op risks and complications; gross and histopathologic observations of the extent and character of residual primary and nodal disease, particularly after a response to chemotherapy; patterns of locoregional control or failure related to treatment variables. The issues subsequently addressed include: how does chemotherapy affect the operative candidacy and resectability of proposed surgical patients? Could, or should surgery be eliminated in the management of some patients treated with induction chemotherapy? Can less radical surgery be contemplated in patients significantly "downstaged" by prior chemotherapy treatment? Is increased locoregional or distant metastatic control observed in these patients? What is the role of surgery in the responder to chemotherapy?

Incidence of hypothyroidism following multimodality treatment for advanced squamous cell cancer of the head and neck.

The incidence of chemical hypothyroidism, as manifested by elevated thyroid stimulating hormone (TSH) levels, has been estimated to be as high as 25% after radiation therapy and 45% after radiation therapy and surgery to the neck for treatment of nodal metastases from squamous carcinoma of the head and neck. We prospectively evaluated 43 previously untreated patients seen in the Dana Farber Cancer Institute Interdisciplinary Head and Neck Service who were treated with aggressive combination chemotherapy in addition to standard surgery and/or radiotherapy. All patients were serially monitored for serum TSH, serum T4, and clinical evidence of hypothyroidism. Following cis-platinum, bleomycin, and methotrexate chemotherapy and subsequent surgery and/or radiotherapy, decreased thyroid reserve appeared in 37% of patients at a median follow-up of 9 months. Thirty percent of patients receiving radiotherapy alone and 43% of patients receiving surgery and radiotherapy developed elevated TSH levels. Only one patient developed clinical symptoms. Other patients were asymptomatic despite persistently elevated TSH levels. Abnormalities appeared within the first 4 months after completion of all therapy and were slowly progressive. The addition of combination chemotherapy does not appear to increase the incidence or severity of thyroid dysfunction following radiation therapy and surgery to the neck. In view of the extended survival seen in patients treated with interdisciplinary regimens, we recommend that all patients receiving irradiation to the neck--particularly those patients having neck dissections or total laryngectomies--have routine thyroid function studies performed following the cessation of treatment.

Phase II study of aclarubicin in acute myeloblastic leukemia.

Aclarubicin is a new anthracycline antibiotic that produces substantially less cardiotoxicity in animals that does doxorubicin. Based upon prior Phase I and II trials in leukemia, a Phase II study in acute myeloblastic leukemia was developed to assess the response rate and toxicity in previously treated patients. Forty patients received aclarubicin 100 mg/m2 per day X 3 with repeated course on days 14-16 if marrow hypoplasia was not produced. Complete responses were achieved in 27.5% (11/40) with durations of 1.5, 2, 2, 2, 3, 3+, 4, 5+, 32+, 33+, and 34+ months. Toxic effects of this therapy included severe neutropenia and thrombocytopenia, nausea/vomiting, mucositis, and diarrhea. No patient developed significant changes in the left ventricular ejection fraction, as measured by radionuclide angiography, or any clinical cardiac symptoms. Alopecia was minimal. Aclarubicin can produce a significant response rate in previously treated patients with acute myeloblastic leukemia and should be considered for study in initial therapy.

Chemical modulation of the hypoxic fraction in the treatment of head and neck cancer.

Treatment of large squamous carcinomas of the head and neck often requires intensive of multidisciplinary treatment. Despite such aggressive measures, local recurrence is common. Possible reasons for such local failure are numerous. Hypoxic but viable tumor cells may be one means of resistance to radiotherapy and chemotherapy. If surgical removal cannot eliminate these cells, tumor regrowth may occur. Modulation of the hypoxic fraction is one means of potentially altering resistance to radiotherapy. Misonidazole, a radiosensitizer, has been thought to increase free radical formation in hypoxic cells in vitro thus increasing the radiosensitivity. This observation is discussed with reference to advanced head and neck cancer.