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Over 500 clinical trials are investigating combination radiotherapy and immune checkpoint blockade (ICB) as cancer treatments; however, the majority of trials have found no positive interaction. Here we perform a comprehensive molecular analysis of a randomized phase I clinical trial of patients with non-small cell lung cancer (NSCLC) treated with concurrent or sequential ablative radiotherapy and ICB. We show that concurrent treatment is superior to sequential treatment in augmenting local and distant tumor responses and in improving overall survival in a subset of patients with immunologically cold, highly aneuploid tumors, but not in those with less aneuploid tumors. In addition, radiotherapy alone decreases intratumoral cytotoxic T cell and adaptive immune signatures, whereas radiotherapy and ICB upregulates key immune pathways. Our findings challenge the prevailing paradigm that local ablative radiotherapy beneficially stimulates the immune response. We propose the use of tumor aneuploidy as a biomarker and therapeutic target in personalizing treatment approaches for patients with NSCLC treated with radiotherapy and ICB.

Background Human papillomavirus (HPV)-associated oropharyngeal cancer (OPC) has a favorable prognosis which has led to efforts to de-intensify treatment. Response-adaptive de-escalated treatment is promising, however improved biomarkers are needed. Quantitative cell-free HPV-DNA (cfHPV-DNA) in plasma represents an attractive non-invasive biomarker for grading treatment response and post-treatment surveillance. This prospective study evaluates dynamic changes in cfHPV-DNA during induction therapy, definitive (chemo)radiotherapy, and post-treatment surveillance in the context of risk and response-adaptive treatment for HPV + OPC. Methods Patients with locoregional HPV + OPC are stratified into two cohorts: High risk (HR) (T4, N3, $$\ge$$ ≥ 20 pack-year smoking history (PYH), or non-HPV16 subtype); Low risk (LR) (all other patients). All patients receive induction chemotherapy with three cycles of carboplatin and paclitaxel. LR with ≥ 50% response receive treatment on the single-modality arm (minimally-invasive surgery or radiation alone to 50 Gy). HR with ≥ 50% response or LR with ≥ 30% and Discussion A de-escalation treatment paradigm that reduces toxicity without compromising survival outcomes is urgently needed for HPV + OPC. Response to induction chemotherapy is predictive and prognostic and can select candidates for de-escalated definitive therapy. Assessment of quantitative cfHPV-DNA in the context of response-adaptive treatment of represents a promising reliable and convenient biomarker-driven strategy to guide personalized treatment in HPV + OPC. Trial registration This trial is registered with ClinicalTrials.gov on October 1st, 2020 with Identifier: NCT04572100.

Background Sorafenib, an inhibitor of B-raf, VEGFR2, and PDGFR-β, has activity against pancreatic cancer in preclinical models. In a phase I trial of gemcitabine plus sorafenib, 57% of pancreatic cancer patients achieved stable disease. Patients and methods We conducted a multi-center phase II trial of sorafenib plus gemcitabine in chemo-naive patients with histologically-confirmed, advanced pancreatic cancer. Patients received sorafenib 400 mg twice daily and gemcitabine 1,000 mg/m2 on days 1, 8 and 15 of a 28 day cycle. Results Seventeen patients enrolled at 4 centers; 13 were evaluable for response. There were no objective responses; 18% had stable disease. Median overall survival was 4.0 months (95% CI: 3.4, 5.9); median progression-free survival was 3.2 months (95% CI: 1.6, 3.6). Grade 3/4 toxicities included thrombosis in 18% of patients, dehydration or hand-foot syndrome in 12%, and hypertension or gastrointestinal bleeding in 6%. Conclusion Gemcitabine plus sorafenib is inactive in advanced pancreatic cancer.

We performed a phase II trial to evaluate a docetaxel-based regimen in locoregionally advanced esophageal cancer. Untreated stage II-IVa esophageal cancer patients with performance status 0-2 were included. Tumor resectability was determined prior to initiation of study. Induction docetaxel (75 mg/m(2)) and cisplatin (75 mg/m(2)) day 1 with prophylactic filgrastim was delivered every 21 days for 3 cycles. Subsequent concomitant chemoradiotherapy (CRT) utilized weekly docetaxel (20 mg/m(2)) and concurrent radiotherapy (2 Gy/day) in resectable/resected patients (50 Gy) and in unresectable patients (66 Gy). A total of 78 patients (15 squamous cell carcinoma, 60 adenocarcinoma, 3 mixed/undifferentiated; 68 men, 10 women; median age 61 years) were accrued. The regimen was administered to 59 (76%) potentially resectable patients and 13 (17%) unresectable patients; 6 patients (8%) received the regimen post-operatively. Response rate in 66 evaluable patients following induction chemotherapy was 30%. Sixty-nine patients underwent CRT. Ten patients had disease progression during CRT. Forty-five out of 59 potentially resectable patients underwent esophagectomy after CRT, and 42 patients had complete tumor resection with negative margins. Eighteen out of 59 patients who were potentially resectable patients had pathologic complete response (pCR-31%). Grade 3/4 toxicity during induction chemotherapy included leucopenia, neutropenia, vomiting, and neuropathy. Esophagitis was the predominant toxicity during CRT. Median overall survival was 11.4 months for unresectable patients, 14.3 months for resectable patients and 10.4 months for patients who received the regimen post-operatively (log-rank P = 0.2492). Docetaxel-based CRT regimen is active and tolerable in esophageal cancer. The observed pCR in the potentially resectable group indicates good local control.

Purpose Hepatobiliary cancers respond poorly to cytotoxic chemotherapy. We evaluated the activity and safety of ixabepilone, an epothilone B analogue which stabilizes microtubules, in a phase II trial in patients with advanced cancers of the gallbladder, bile duct, and liver. Methods Eligible patients had previously-untreated, histologically-proven unresectable hepatobiliary cancer. Ixabepilone, 40 mg/m2, was administered intravenously over 3 h every 21 days. Results Between January 2002 and April 2005, 54 patients (19 hepatocelluar carcinoma, 13 cholangiocarcinomas, 22 gallbladder carcinomas) were enrolled; 47 patients were evaluable for efficacy. The objective response rate was 8.5%; 51% had stable disease. Median overall survival was 7.0 months (95% CI, 5.0 to 10.8 months) and median progression-free survival was 2.6 months (95% CI, 1.4 to 4.1 months). Grade 3/4 toxicities included neutropenia (39%), fatigue (9%), allergic/hypersensitivity reaction (4%) and sensory neuropathy (4%). Conclusion Single agent ixabepilone has limited activity in advanced hepatobiliary cancers.

Angiogenesis inhibition is now a proven therapeutic strategy in treatment of several solid tumors. Vatalanib is a potent inhibitor of all known vascular endothelial growth factor receptor (VEGFR) tyrosine kinases. In view of the effectiveness of angiogenesis inhibitor therapy when combined with chemotherapy and the established role of capecitabine in treatment of colorectal and breast cancer, we undertook a phase I clinical trial of the combination of capecitabine and vatalanib with the goal of developing a combination oral regimen. The study objectives were to determine the maximally tolerated dose of vatalanib that could be safely administered daily with capecitabine given orally for 14 out of 21 days to patients with advanced cancer; to characterize the safety, tolerability, and pharmacokinetic profile of vatalanib given in combination with capecitabine; and to describe any pharmacokinetic interactions between the drugs. The study had an initial dose escalation phase followed by a dose expansion phase. During the dose escalation phase, cohorts of at least three patients each were treated with capecitabine and escalating doses of vatalanib until the maximally tolerated dose of vatalanib was determined. Vatalanib given continuously at a dose of 1,250 mg/day could be safely combined with capecitabine at a dose of 2,000 mg/m2/day given for 14 of 21 days. Dose-limiting toxicities of the combination included fatigue, hypertension, dizziness, and proteinuria. Vatalanib did not alter the pharmacokinetics of 5-FU, the active metabolite of capecitabine. Vatalanib and capecitabine can be safely combined without unexpected toxicities or significant pharmacokinetic interactions.

During the past 20 years, the advent of neoadjuvant, primary, and adjuvant concurrent chemoradiotherapy has improved cancer care dramatically. Significant contributions have been made by technological improvements in radiotherapy, as well as by the introduction of novel chemotherapy agents and dosing schedules. This article will review the rationale for the use of concurrent chemoradiotherapy for treating malignancies. The molecular basis and mechanisms of action of combining classic cytotoxic agents (e.g. platinum-containing drugs, taxanes, etc.) and novel agents (e.g. tirapazamine, EGFR inhibitors and other targeted agents) with radiotherapy will be examined. This article is part one of two articles. In the subsequent article, the general principles outlined here will be applied to head and neck cancer, in which the impact of concurrent chemoradiotherapy is particularly evident.

Purpose: Tumor resistance to alkylating agents such as carmustine (BCNU) has been found to be associated with intracellular expression of O 6 -methylguanine-DNA methyltransferase (MGMT). Administration of O 6-benzylguanine (O 6-BG), a substrate that inactivates MGMT, may help overcome chemotherapy resistance. We performed a phase II study to explore the activity of O 6-BG in combination with BCNU in patients with advanced soft tissue sarcoma. Experimental design: Informed consent was obtained from patients with metastatic soft tissue sarcoma naive to systemic chemotherapy (adjuvant chemotherapy allowed). Patients received O 6 -BG 120 mg/m2 I.V. followed by BCNU 40 mg/m2 I.V. Treatment was repeated every 6 weeks until disease progression or development of unacceptable toxicity. Results: No objective responses were observed in 12 enrolled patients. Four patients exhibited stable disease lasting 11–25+ weeks. The median overall survival was 16.9 months (95% CI, 2.9–NR). The most common grade 3–4 toxicities were neutropenia, thrombocytopenia, and anemia. Depletion of MGMT activity was demonstrated in peripheral blood mononuclear cells. Immunohistochemical estimation of MGMT expression from archival tissue ranged from 20 to 99% positive staining cells. Conclusions: Observed toxicities were consistent with previous studies of O 6-BG plus BCNU. The degree of MGMT expression was variable in this small sample of heterogeneous sarcomas. Further development of this regimen and dose for the treatment of soft tissue sarcoma is not warranted due to the lack of objective responses.

Introduction: Despite the extensive clinical experience with irinotecan, significant concerns remain regarding its toxicity. In a phase I trial, we modulated irinotecan pharmacokinetics by inhibiting biliary excretion of SN-38, the active metabolite of irinotecan, using cyclosporine. The modulation appeared to decrease the gastrointestinal toxicity of irinotecan and suggested that irinotecan activity might also be retained. Hence, we conducted this phase II trial in patients with colorectal cancer (CRC) to further evaluate the toxicity and activity of irinotecan modulated with cyclosporine. Patients and Methods: Sixteen patients with 5-fluorouracil refractory CRC were treated. Cyclosporine (5 mg/kg) was administered as a 6-h infusion and irinotecan (60 mg/m2/day, 90-min infusion) was started 3 h after initiation of the Cyclosporine. Both agents were given weekly for 4 weeks, every 6 weeks. Responses were assessed every 12 weeks, and toxicity was monitored weekly. Results: Sixteen patients were evaluable for toxicity and 11 for response. There was 1 partial response (6%). Five patients had SD lasting a median of 12 weeks. Grade 3/4 diarrhea was observed in only 13% of the patients. Conclusion: Pharmacokinetic modulation of irinotecan using parenteral cyclosporine appears to decrease the incidence of diarrhea in CRC patients. Given the modest activity of irinotecan monotherapy, a larger study would be required to assess if the modulation improves the toxicity without compromising this activity. The available clinical data suggest that pharmacokinetic modulation of irinotecan should be evaluated further to define its optimal clinical utility.

9-Aminocamptothecin (9-AC) is a water-insoluble camptothecin derivative that demonstrated broad activity in pre-clinical studies. In vitro, greater anti-tumor efficacy can be achieved with prolonged administration. A minor response was observed in gastric cancer in a phase I study. We conducted a phase II study of 9-AC in 15 patients with previously untreated metastatic gastric cancer and adenocarcinoma of the gastroesophageal junction. 9-AC was administered at a dose of 25 microg/m(2)/h over 120 hours (3000 microg/m(2) over 5 days) on two consecutive weeks every 21 days. Fourteen patients were evaluable for response. There were no objective responses. Three patients had stable disease lasting a median of 3.4 months (range 1.6-4.3 months). Median time to progression was 1.4 months; median survival was 5.2 months. Grade 3 neutropenia developed in 20% of patients, and anemia in 7%. Grade 3 nausea and fatigue each developed in 7% of patients. We conclude that 9-AC given by 120-hour continuous infusion demonstrates no clinical activity in patients with metastatic gastric cancer.

Outcomes for patients with oropharyngeal cancer are determined by their tumor characteristics and associated demographics. The role of human papilloma virus-related disease for prognosis and outcomes with chemoradiotherapy is being more clearly defined. EGFR inhibitors are used in conjunction with radiotherapy, and the importance of optimizing radiation quality and minimizing toxicity is the focus of ongoing studies.

In a previous phase II trial of the synthetic topoisomerase I inhibitor, 9-aminocamptothecin (9-AC), given as a 72-h infusion, we identified modest single agent activity of 9% in patients with previously untreated advanced non-small cell lung cancer (NSCLC). Preclinical studies suggested that a more prolonged continuous infusion of the drug might lead to greater antitumor activity. A phase I study recommended a phase II dose of 25 microg/m2/hr for 120 h (3000 microg/m2 over 5 days), administered for 2 consecutive weeks of a 3-week cycle. We utilized this schedule and enrolled 13 chemotherapy-naïve patients with Stage IIIB and IV NSCLC in this trial: median age 67 (range 57-74); 46% male; 92% stage IV; and median performance status 1. Twelve patients are available for response and toxicity evaluation after 2 cycles of therapy. One patient achieved a partial response. Four patients had stable disease while seven patients had progressive disease. Patients with stable or progressive disease after two cycles received no additional 9-AC, and were offered conventional chemotherapy. The median survival time was 10.2 months and the one-year survival rate 28% (95% confidence interval, 5-58%). Significant toxicities included myelosuppression, fatigue, and anorexia. One patient had grade 4 neutropenia following the first week of cycle 2, and did not receive additional therapy. There were no neutropenia-related infections. These data suggest that this prolonged schedule is unlikely to increase 9-AC's very modest activity in NSCLC above that seen with the simpler 72-h administration schedule. Further evaluation of 9-AC in NSCLC is not recommended.

JM216 is an orally administered platinum analogue. We undertook this study to determine the maximally tolerated dose (MTD) of JM216 when administered with concomitant radiotherapy to the chest (200 cGy daily, 5 x/week) in patients with locoregionally advanced non-small cell lung (NSCLC) or esophageal cancer. Patients were excluded for inadequate bone marrow reserve, prior radiotherapy to the primary tumor or previous treatment with platinum drugs. A dose-limiting toxicity (DLT) was defined using the National Cancer Institute (NCI) Common Toxicity Criteria (CTC) and consisted of gradeor = 2 renal, hepatic, cardiac, or pulmonary toxicity or gradeor = 3 hematologic, neurological, or gastrointestinal toxicity. A total of 23 patients were registered; two never received treatment and are excluded from analyses. Six patients were treated at a dose of 30 mg/m2/day for 5 days with two grade 2 DLT's: cough (1 pt) and elevated trans-aminases (1 pt). Seven evaluable patients were treated at 60 mg/m2/day and seven experienced grade 3 or 4 toxicity, five related to myelosuppression. The dose was then reduced to 45 mg/m2/d. Eight patients were evaluable for toxicity, of which 5 experienced DLT: myelosuppression (3 pts), esophagitis (2 pts), dyspnea (1 pt), and elevated creatinine (1 pt). Fourteen patients were evaluable for efficacy, of which 6 had an objective response, including one complete response. The recommended phase II dose of JM216 with concurrent radiation therapy is 30 mg/m2/d for 5 days. The major DLT is myelosuppression with only limited increased toxicity within the field of radiation. This conceivably may limit the use of JM216 as a radiation sensitizer.

The simultaneous administration of chemotherapy and radiation has produced a significant impact on the treatment of advanced squamous cell carcinomas of the head and neck. Although no single regimen has emerged as the “standard” approach, recent trials have consistently demonstrated the superiority of combined treatment programs over radiotherapy alone for local tumor control and overall survival. More-over, multimodal treatment has emerged with important ancillary goals of organ preservation, improved cosmesis, and enhancement of quality of life. With improving survival in all stages of disease, much attention can be given to identifying effective measures to reduce the risk of metachronous primary cancers in this high-risk group.

The IAEA-ACC study compared accelerated radiotherapy with standard radiotherapy in a multicenter trial conducted in developing countries. Advantages were most notable in patients with early-stage disease, which may limit the utility of this therapy. In countries where resources are limited, however, this strategy may be a cost-effective approach to improving outcomes in patients with head and neck cancer.

Purpose: To determine the feasibility, maximal tolerated doses, and response rates for a combined regimen of the platinum and 5-fluorouracil oral analogues bis-acetato-ammine-dichloro-cyclohexyl-amine platinum(IV) (JM-216) and uracil/ftorafur (UFT) coadministered as a 14 consecutive-day every 28-day schedule. Methods: Of 20 patients enrolled in this investigation, 17 on the following dose escalation scheme were evaluable for toxicity and/or response: I UFT 300 mg/day, JM-216 5 mg/day (three patients), II UFT 300 mg/day, JM-216 10 mg/day (four patients), III UFT 300 mg/day, JM-216 20 mg/day (ten patients). Results: All 17 evaluable patients were evaluable for toxicity. At dose level III, dose-limiting nausea and emesis were observed in one patient despite maximal antiemetic support. Importantly, neurotoxicity and nephrotoxicity were not observed at the JM-216 dose levels examined in this study. This observation is consistent with results seen with single agent JM-216. Conclusion: For JM-216 and UFT administered at 20 mg/day and 300 mg/day over 14 days, nausea and emesis were observed as the principal dose-limiting toxicities. These doses are considerably below the maximally tolerated doses of single agent JM-216 and UFT. Shorter administration schedules should be explored in an attempt to increase the dose intensity and minimize the toxicity of this combination oral regimen.

A combination of oral 13-cis-retinoic acid (cis-RA) and subcutaneous interferon alfa-2a (IFN) has been reported to yield high response rates in patients with squamous cell carcinomas (SCCAs) of the cervix and skin. Cisplatin and 5-fluorouracil with leucovorin (5-FU/LV) are chemotherapeutic agents commonly used for SCCAs. Purpose: To determine the maximum tolerated doses (MTDs) of cisplatin and 5-FU/LV when combined with IFN and cis-RA, and to define a recommended phase II regimen for testing in cervical cancer and other appropriate tumor types. Methods: Phase I cohort design. Cisplatin was administered every 3 weeks. 5-FU and LV were administered together as a weekly 24-h infusion. Cis-RA was given orally twice daily. IFN was initially given subcutaneously at a dose of 3 million units (MU) daily. Results: A total of 31 patients were treated. The IFN dose was reduced to 3 MU three times weekly because of patient intolerance. Cytopenias prevented the administration of weekly 5-FU/LV. Single-agent cisplatin with three times weekly IFN and twice daily cis-RA was tolerable. Four partial responses were observed, in patients with adrenal cancer, bladder cancer, gastric cancer, and adenocarcinoma of unknown primary. Conclusions: The recommended phase II regimen is cisplatin 100 mg/m2 every 3 weeks, IFN 3 MU three times weekly, and cis-RA 1 mg/kg daily. This appears to be more toxic than single-agent cisplatin, but the preliminary activity observed warrants further testing.

Purpose To construct an efficient pilot study design to determine whether interferon alfa-2b modifies the pharmacokinetics and pharmacodynamics of continuous-infusion etoposide. Patients and methods A two-stage randomized 2 × 2 factorial design was used to evaluate interferon alfa-2b at two doses (2 or 10 MU/m2/day SQ for 3 days) and two schedules (interferon alfa-2b administered before or concurrent with 72-hour continuous-infusion etoposide). Etoposide was administered at 75, 100, or 125 mg/m2/day. In lieu of comparing the experimental arms to an etoposide-alone control arm to determine effect of interferon alfa-2b dose and schedule, a novel analytic approach was used. The effect of interferon alfa-2b on etoposide-induced leukopenia was assessed indirectly by comparison of the observed white blood cell (WBC) nadir to the nadir predicted from an established pharmacodynamic model for single agent etoposide. Results Based on 29 patients, dose-normalized 24-hour total and estimated free etoposide concentrations did not differ with interferon alfa-2b dose or schedule. Patients treated with interferon alfa-2b before etoposide had, on average a WBC nadir 545 ± 225 cells/μl lower than that predicted by a pharmacodynamic model for etoposide alone. An optimal nonlinear model for leukopenia was defined by interferon alfa-2b schedule in addition to 24-hour etoposide concentration. Conclusion A novel study design and statistical analysis provided an efficient preliminary evaluation of the combination of interferon alfa-2b with etoposide in a modest number of patients. Exploitation of a previously validated pharmacodynamic model allowed evaluation of interferon alfa-2b effect and eliminated the need for an etoposide-alone control arm. The pharmacokinetics of continuous-infusion etoposide at doses from 75 to 125 mg/m2/day appear to be unchanged by interferon alfa-2b at the doses and schedules tested and the combination appears to be feasible. We hypothesize that leukopenia may be enhanced when interferon alfa-2b is administered before etoposide, especially at a higher dose of interferon alfa-2b. Clinical Pharmacology & Therapeutics (1996) 59, 349–359; doi

Amonafide (nafidimide), a synthetic organic compound with an inhibitory effect on cellular replication, was used in a phase II study conducted by the Illinois Cancer Center in order to assess its efficacy and toxicity in advanced or recurrent squamous cell cancer of the head and neck. Eligible patients had received no more than one prior adjuvant or neoadjuvant chemotherapy, had normal bone marrow, renal and hepatic function, ECOG performance status of 0–2, and bidimensionally measurable disease. Eligible patients were administered amonafide at a starting dose of 300 mg/m2 for five consecutive days every 3 weeks with dose escalation or de-escalation according to established hematologic criteria in the absence of disease progression. Nineteen of 22 entered patients were evaluable for response and all patients were evaluable for toxicity. Eleven of 19 patients achieved stable disease. Median time to progression after start of treatment was 57 days, for the 18 patients for whom the date of progression is known. There were no partial or complete responses. Hematologic toxicity was dose limiting with grade 3–4 neutropenia in 50 percent of patients and 4 deaths associated with neutropenic sepsis. Non-hematologic toxicity was mild to moderate with nausea and vomiting predominating. In this study, amonafide was a myelotoxic, inactive treatment in advanced/ recurrent head and neck cancer. Further use in head and neck cancer appears unwarranted.

Concomitant chemoradiotherapy with cisplatin and combination chemotherapy in the neoadjuvant setting have both shown promising results.Purpose: To identify a locally and systemically active concomitant chemoradiotherapy regimen incorporating high-dose cisplatin, interferon alfa-2a (IFN), fluorouracil (5-FU), hydroxyurea (HU) and radiotherapy.Methods: Phase I cohort design establishing the maximal tolerated dose (MTD) of cisplatin with and without granulocyte colony stimulating factor (GCSF). For the first six dose levels, a 4-week cycle consisted of escalating doses of cisplatin during weeks 1 and 2, IFN (week 1), and 5-FU and HU (week 2) with single daily radiation fractions of 200 cGy during days 1–5 of weeks 1–3 and no treatment in week 4. When dose-limiting neutropenia was encountered, GCSF was added during weeks 1, 3, and 4. Finally, to decrease esophagitis, the radiotherapy schedule was altered to 150 cGy twice daily during weeks 1 and 2, followed by a 2-week break (level 7).Results: Forty-nine patients with refractory chest malignancies were treated. The MTD of this regimen without GCSF was cisplatin 50 mg/m2 in weeks 1 and 2, IFN 5 million Units (MU)/m2 per day on days 1–5 in week 1, 5-FU 800 mg/m2 per day for 5 days by continuous infusion, and HU 500 mg every 12 h for 11 doses during week 2. The addition of GCSF during weeks 1, 3, and 4 allowed for escalation of cisplatin to 100 mg/m2 during weeks 1 and 2, with a decreased dose of IFN at 2.5 MU/m2 per day to avoid renal toxicity. Dose-limiting toxicity (DLT) included severe neutropenia, thrombocytopenia, and esophagitis in 5 of 13 patients. Increased thrombocytopenia in patients receiving GCSF was not observed. During hyperfractionated radiotherapy (level 7) chemotherapy doses were as above except for a reduction of 5-FU to 600 mg/m2 per day. While severe esophagitis was reduced, grade 4 thrombocytopenia became more prevalent and was seen in 6 of 7 patients. In-field tumor responses were observed in 17 of 28 evaluated patients with non-small-cell lung cancer. The median times to progression and survival were 4 and 6 months, respectively. When only patients with all known disease confined to the radiotherapy field were considered the corresponding times were 6 and 15 months, respectively. Most treatment failures occurred outside of the irradiated field.Conclusions: (1) This intensive multimodality regimen can be given with aggressive supportive care incorporating GCSF. The recommended phase II doses for a 4-week cycle are cisplatin 50 mg/m2 week 1, and 100 mg/m2 week 2, IFN 2.5 MU, HU 500 mg every 12 h×11 and 5-FU 800 mg/m2 per day with single fraction radiotherapy during weeks 1–3 and GCSF during weeks 1, 3, and 4. (2) GCSF can be safely administered and provides effective support of neutrophils when administered simultaneously with IFN, cisplatin, and chest radiotherapy. (3) There is synergistic renal toxicity when high doses of IFN and cisplatin are given together. (4) Hyperfractionated radiotherapy decreases the severity of esophagitis but increases thrombocytopenia. (5) Although highly toxic, response rates, time to progression and survival figures with this regimen are encouraging and support its investigation in the phase II setting.

Background: We designed a trial of intensive multimodality therapy for carcinoma of the esophagus and gastroesophageal junction to assess tumor response and operability after neoadjuvant chemotherapy and to determine the impact of trimodality therapy on long-term survival. Methods: Thirty-two patients with resectable (clinical stage IIa, n=17; IIb, n=1; III, n=14) squamous cell cancer (n=15) or adenocarcinoma (n=17) were treated with neoadjuvant chemotherapy (cisplatin, 5-fluorouracil, leukovorin), resection, and postoperative chemoradiotherapy (hydroxyurea, 5-fluorouracil; 50–66 Gy). Results: Use of neoadjuvant chemotherapy yielded the following results: a measurable clinical response in 22 patients, stable disease in eight patients, disease progression in one patient, and death in one patient. Thirty-one patients underwent resection, with the following results: two operative deaths (6.5%) and nonfatal morbidity in 17 (59%); the median hospital stay was 13 days. Pathologic staging was stage 0, n=1; I, n=2; IIa, n=11; IIb, n=5; III, n=7; and IV, n=5. Postoperative chemoradiotherapy was completed in 23 patients with one death, for an overall treatment-related mortality rate of 12.5% (four of 32). At a mean follow-up of 22.5 months, median survival is 19.7 months and 14 patients are alive and disease free. Conclusions: Neoadjuvant therapy for cancer of the esophagus and cardia results in good tumor response. Esophagectomy in this setting can be accomplished with acceptable morbidity and mortality. Results of an interim analysis of survival are encouraging and suggest that further investigation of this regimen is warranted.

The use of cytokines in head and neck cancer is increasingly under investigation. Clinical trials have tested the interferons, interleukin-2 and other cytokines as single agents and in various combinations. The addition of interferon to the cisplatin and 5-fluorouracil (5-FU) regimens (with and without leucovorin) has been explored. A randomized international trial comparing cisplatin and 5-FU with cisplatin, 5-FU and interferon-alpha 2b is in progress.

In this phase I study, we added escalating doses of interferon-alpha 2A (IFN) to cisplatin and twice-daily radiotherapy based on the following rationale. Radiation enhancement has been shown for both interferon and cisplatin; in addition, potentiation of the cytotoxic activity of cisplatin by interferon has been demonstrated. A total of 48 patients with advanced solid tumors were treated with radiotherapy in 2 daily fractions of 125 cGy plus cisplatin at 8-10 mg/m2 per day delivered on 3 different schedules (continuous infusion, daily short-term infusion, and single short-term infusion of 50 mg/m2). IFN was injected s.c. 2 h preceding the first daily fraction of radiation. IFN doses ranged from 0 to 5.0 x 10(6) U/m2 per day. All therapy was given over 5 days of every other week until completion of the radiotherapy. Treatment at all dose levels was well tolerated during cycles 1 and 2, with no instance of acute grade 3 or 4 toxicity being noted. However, cumulative myelosuppression in patients receiving more than two treatment cycles was seen at all dose levels and was attributed to the repeated administration of cisplatin. Alteration of the cisplatin schedule did not allow for further dose escalation of cisplatin. Our recommended doses are cisplatin given at 8 mg/m2 per day as a continuous infusion with IFN at 5.0 x 10(6) U/m2 per day. Among 24 patients with non-small-cell lung cancer, 2 had a complete response, 9 had a partial response, and 7 had stable disease. We conclude that this concomitant cisplatin-IFN-radiotherapy regimen is feasible. Activity was seen in non-small-cell lung cancer, and further studies of this regimen in that disease appear indicated.

Cisplatin (CDDP), 5-fluorouracil (5-FU), and hydroxyurea (HU) have individually demonstrated activity against several solid tumors, act synergistically with each other in vitro, and may act as radiation sensitizers. Therefore, we designed a phase I study to determine the maximally tolerated dose of cisplatin as given in addition to our previously described combination of 5-FU, HU, and concomitant radiotherapy (XRT). Patients exhibiting advanced solid tumors requiring palliative XRT were eligible. The regimen consisted of 1 g HU given p.o.b.i.d. on days 1–5,600 mg/m2 5-FU given i.v. daily by continuous infusion (c.i.) on days 1–5, escalating doses of cisplatin starting at 10 mg/m2 daily given by c.i. on days 1–5, and involved-field XRT carried out on days 1–5. The cycle was repeated every 14 days until the target XRT dose had been reached. In all, 19 patients were entered at the first dose level, and cumulative grade 3–4 myelosuppression was seen in 16 subjects. As no dose escalation was feasible, the chemotherapy was subsequently altered by using the above regimen for cycles 1, 3, 5, and 7 and substituting the less myelosuppressive regimen of 1 g HU given p.o.b.i.d. on days 1–5, 400 mg/m2 5-FU given i.v. daily by c.i., and 100 mg leucovorin given p.o. 4 h on days 1–5 for cycles 2, 4, and 6. On this alternating program, 28 patients were treated with escalating doses of CDDP. The dose-limiting toxicity was again myelosuppression, which was prohibitive at a CDDP dose of 20 mg/m2 daily. In the final phase of the protocol, 30 subjects were treated with the above alternating-cycle regimen at a CDDP dose of 20 mg/m2 daily and a decreased HU dose of 500 mg p.o.b.i.d. in an attempt to circumvent the myelosuppression associated with this dose of CDDP. Although severe acute toxicity (cycles 1 and 2) was observed less frequently, cumulative toxicity (all cycles) remained pronounced. The other major toxicity encountered was mucositis, which was particularly pronounced in patients receiving radiation to the head and neck and following leucovorin-containing cycles. Plasma concentrations of free platinum did not correlate with the CDDP dose, possibly due to the narrow range of doses given. Pharmacodynamic modeling demonstrated that the CDDP dose and the HU dose were associated with leukopenia. Antitumor activity was demonstrated in a number of solid tumors, particularly non-small-cell lung cancer and head and neck cancer. Due to the high incidence of severe cumulative toxicity, we recommend further use of this regimen only as part of a curative treatment strategy for patients presenting with locoregionally advanced solid tumors.

Fourteen patients with squamous cell carcinoma of the head and neck received 9-AC/DMA infusions of 850 mg/M2/day over 72 hours. Eligibility criteria included good performance status, advanced disease incurable by conventional means, no prior treatment of metastatic disease, and measurable lesions for objective response assessment. The infusions were repeated at 21 day intervals until progression or prohibitive toxicity occurred. A median of 3 cycles (range 1-7) was given. No objective responses were observed. Median survival of the group was 6 months. Toxicity was hematologic which was modest and promptly reversible. 9-AC/DMA is inactive against this tumor type at the dose and schedule employed in this study.

This study evaluated post-treatment performance and quality of life (QOL) outcome in head and neck cancer (HNC) patients treated with organ preservat ion, intens ive chemoradiotherapy (FHX). Participants were 47 Stage II-IV HNC patients with no evidence of disease at least one year post-completion of organ preservation, concomitant FHX treatment. Patients were assessed via a semi-structured in-person interview, standardized measures of QOL (FACT-H, CES-D), performance (PSS-HN) and patients' perception of residual side effects. Disease, treatment and toxicity data were retrieved from medical charts and protocol records. The most salient performance impairment was inability to eat a normal solid food diet, with 50% of patients able to eat soft foods or take liquids only. This specific functional deficit was not related to global QOL, nor to specific quality of life dimensions. Dry mouth, the most frequent and severe residual effect, was not associated with outcome diet, depression or QOL. Residual pain, seen in only 15% of patients, appeared to influence both functional and QOL parameters as well as being a marker for other troublesome symptoms. Twenty-three per cent of patients were depressed; depression was associated with past problems related to alcohol abuse. Decreased QOL and increased depressive symptomatology were related to total number and severity of residual effects. The data highlight the importance of systematic study of QOL dimensions and caution against making assumptions about patients' experience of particular disease and treatment sequelae.

We conducted a double-blind, randomized crossover study to compare the toxicity and antiemetic efficacy of the 5-hydroxytryptamine3 receptor antagonist batanopride with that of metoclopramide in 21 chemotherapy-naive patients receiving at least 70 mg/m2 cisplatin. The study was terminated when hypotension was observed following the infusion of batanopride at other institutions testing similar drug schedules. Although we observed no hypotension following treatment with batanopride in this trial, we did note asymptomatic prolongation of the corrected QT interval (QTc), PR interval, and QRS complex on the EKG in the batanopride arm. Of 15 evaluable patients, 8 experienced less than or equal to 2 episodes of emesis within 24 h of the first batanopride infusion, whereas 9/15 subjects experienced less than or equal to 2 emetic episodes following the administration of metoclopramide. Overall, the evidence suggests that this dosing schedule for batanopride may be too toxic for clinical use.

Eighteen patients entered this study of the efficacy of homoharringtonine (HHT) treatment in advanced squamous cell carcinoma of the head and neck (SCCHN). Seventeen eligible patients received at least one day of the first 5-day cycle of HHT (4.0 mg/m2/day) by continuous IV infusion. Cycles were scheduled to repeat every 28 days. The major severe toxicities encountered were hypotension and myelosuppression. There was one drug-related death. Fourteen patients were evaluable for response, and no patient exhibited an objective response to treatment with HHT.