In vivo resistance towards anthracyclines, etoposide, and cis-diamminedichloroplatinum(II).

From a single wild-type strain of Ehrlich ascites tumor, sublines resistant to daunorubicin, etoposide, and cis-diamminedichloroplatinum(II) have been developed in vivo. Different levels of resistance were achieved after 4 to 8 months for anthracyclines (greater than 32-fold), cis-diamminedichloroplatinum(II) (4-fold), and etoposide (greater than 6-fold). Anthracycline resistance was associated with decreased nuclear steady-state concentration of anthracyclines, increased content of high-molecular-weight membrane glycoproteins, and glucose-dependent drug extrusion after metabolic blockade with sodium azide. A similar "pump" system which was apparently not drug specific was also documented in etoposide resistance. Resistance towards cis-diamminedichloroplatinum(II) was accompanied by decreased cis-diamminedichloroplatinum(II)-induced DNA damage in vitro when proteinase K-resistant interstrand cross-links were measured by alkaline elution. Parallel in vivo studies revealed cross-resistance of various degrees among a number of anthracycline analogs, complete cross-resistance among daunorubicin, doxorubicin, and 4'-(9-acridinylamino)methanesulfon-M-anisidine (amsacrine), and partial cross-resistance between daunorubicin and etoposide. However, cis-diamminedichloroplatinum(II) was curative in anthracycline- and etoposide-resistant cells, as daunorubicin and etoposide were curative in acquired resistance towards cis-diamminedichloroplatinum(II). cis-Diamminedichloroplatinum(II) resistance was also overcome by the derivative 1,2,diaminocyclohexylplatinum malonate. The Vinca alkaloid vindesine, although only marginally active in the control tumor, was highly active in cells selected for cis-diamminedichloroplatinum(II) resistance. These in vivo patterns of cross-resistance and collateral sensitivity may be related to observations in clinical chemotherapy.

Combination chemotherapy with carboplatin, etoposide, and vincristine as first-line treatment in small-cell lung cancer.

PURPOSE: The antineoplastic activity of carboplatin and etoposide may be improved by the addition of vincristine (CEV) because of its low myelosuppressive potential and its activity in small-cell lung cancer (SCLC). A phase II study with CEV was carried out. PATIENTS AND METHODS: One hundred twenty-one untreated patients with SCLC (63 with limited disease [LD], 58 with extensive disease [ED]) were treated with a combination of 300 mg/m2 intravenous (IV) on day 1, etoposide 140 mg/m2 IV daily on days 1 to 3, and vincristine 1.4 mg/m2 IV on days 1, 8, and 15 every 4 weeks. RESULTS: A 90% rate overall response rate including 56% complete responses (CRs) was achieved in LD and an 83% overall response rate including 35% CRs was observed in ED. Median survival time was 13 months in limited disease and 9.5 months in extensive disease. The 24 and 36 months survival rates were 29% in LD and 9% in ED. Myelosuppression was the main form of toxicity. CONCLUSION: The combination of CEV is a new active and well-tolerated regimen in the treatment of SCLC. Prospective randomized studies of CEV with conventional chemotherapy are warranted.

Irinotecan in the treatment of colorectal cancer: clinical overview.

PURPOSE AND METHODS: For more than three decades, the therapeutic options for patients with advanced colorectal cancer have almost exclusively been based on fluoropyrimidines. With the recognition that topoisomerase-I (TOP-I) is an important therapeutic target in cancer therapy, irinotecan, a semisynthetic TOP-I-interactive camptothecin derivative, has been clinically established in the treatment of colorectal cancer. RESULTS: Irinotecan was investigated as second-line chemotherapy after prior treatment with fluorouracil (FU)-based regimens in two large randomized phase III trials comparing irinotecan with either best supportive care or an infusional FU/leucovorin (LV) regimen. The outcomes of these trials established irinotecan as the standard therapy in the second-line treatment of colorectal cancer. The therapeutic value of irinotecan in the first-line treatment of metastatic colorectal cancer was investigated in two large randomized phase III trials comparing the combination of irinotecan and FU/LV with FU/LV alone. Both trials demonstrated significant superior efficacy for the combination of irinotecan and FU/LV in terms of response rate, median time to disease progression, and median survival time. Consequently, the combination of irinotecan and FU/LV has been approved as first-line chemotherapy for patients with metastatic colorectal cancer and constitutes the reference therapy against which other treatment options must be tested in the future. CONCLUSION: In this review, the clinical rationale and update of the present clinical status of irinotecan in the treatment of colorectal cancer and future prospects of irinotecan-based combinations are discussed.

Phase I study of a weekly schedule of irinotecan, high-dose leucovorin, and infusional fluorouracil as first-line chemotherapy in patients with advanced colorectal cancer.

PURPOSE: To determine the maximum-tolerated dose (MTD) of a weekly schedule of irinotecan (CPT-11), leucovorin (LV), and a 24-hour infusion of fluorouracil (5-FU24h) as first-line chemotherapy in advanced colorectal cancer and to assess preliminary data on the antitumor activity. PATIENTS AND METHODS: Twenty-six patients with measurable metastatic colorectal cancer were entered onto this phase I study. In the first six dose levels, fixed doses of CPT-11 (80 mg/m2) and LV (500 mg/m2) in combination with escalated doses of 5-FU24h ranging from 1.8 to 2.6 g/m2 were administered on a weekly-times-four (dose levels 1 to 4) or weekly-times-six (dose levels 5 to 6) schedule. The dose of CPT-11 was then increased to 100 mg/m2 (dose level 7). RESULTS: Seventy-nine cycles of 5-FU24h/LV with CPT-11 were administered in an outpatient setting. No dose-limiting toxicities were observed during the first cycle at dose levels 1 to 6, but diarrhea of grade 4 (National Cancer Institute common toxicity criteria) was observed in three patients after multiple treatment cycles. Other nonhematologic and hematologic side effects, specifically alopecia and neutropenia, did not exceed grade 2. With the escalation of CPT-11 to 100 mg/m2 (dose level 7), diarrhea of grade 3 or higher was observed in four of six patients during the first cycle; thus, the MTD was achieved. Sixteen of 25 response-assessable patients (64%; 95% confidence interval, 45% to 83%) achieved an objective response. CONCLUSION: The recommended doses for further studies are CPT-11 80 mg/m2, LV 500 mg/m2, and 5-FU24h 2.6 g/m2 given on a weekly-times-six schedule followed by a 1-week rest period. The addition of CPT-11 to 5-FU24h/LV seems to improve the therapeutic efficacy in terms of tumor response with manageable toxicity.

Phase II study with the combination etoposide, doxorubicin, and cisplatin in advanced measurable gastric cancer.

In this phase II multicenter trial, 67 evaluable patients with advanced measurable gastric carcinoma were treated with a combination of etoposide, Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH), and cisplatin (EAP). The overall response rate was 64%, including 21% complete responses (CRs). In 55 patients with metastatic disease, 31 responses (51%) including eight CRs (15%) were achieved. Responses were seen in all metastatic sites, but the response rate was lower in patients with peritoneal carcinomatosis. In 12 patients with locoregional disease, six CRs and six partial responses (PRs) were observed. Eight CRs (three and five in patients with metastatic and locoregional disease, respectively) were pathologically confirmed. The overall median response duration was 7 months; it was 16 months for patients achieving CR (22 months for pathologically confirmed CR [pCR]), and 6 months for PR. The median survival time for all patients was 9 months, for the patients who achieved CR 17 months, for pCR 23 months, and for PR 9.5 months. Median survival time for all patients with metastatic disease was 8 months, and for locoregional disease 12.5 months. Six patients (9%) (four local, two metastatic disease) were alive at 2 years, and four patients are alive and disease free at 35+ to 56+ months. Main toxicities were leukopenia and thrombocytopenia, with 64% of patients developing grade 3 to 4 myelosuppression and 12% severe infections. Nonhematologic toxicities of World Health Organization (WHO) grade 4 were not observed.

Preoperative chemotherapy in locally advanced and nonresectable gastric cancer: a phase II study with etoposide, doxorubicin, and cisplatin.

Thirty-four patients with locally advanced, nonresectable gastric cancer (staged by laparotomy) received etoposide, Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH), and cisplatin (EAP). Thirty-three patients were evaluable for response and toxicity. Second-look surgery with removal of residual tumor by gastrectomy and lymphadenectomy was performed in case of complete/partial remission (CR/PR) after EAP. After successful resection (R0- and R1-resection), two cycles of EAP were administered for consolidation therapy. Patients refusing reoperation received up to six cycles of EAP. The response rate (CR/PR) after EAP was 70% (23/33), including a 21% (7/33) rate of clinical CRs (CCRs). Two patients had minor remission (MR)/no change and seven had progressive disease. There was one early death. Nineteen of 23 responders (5 CCRs, 14 clinical PRs [CPRs]) and one patient with MR underwent second-look surgery. Five CCRs were pathologically confirmed; 10 patients with CPR were without evidence of disease (NED) after resection. In three patients (CPR), R1-resections (microscopically tumor-cell positive proximal margin) were performed; two patients are disease-free, 22+ and 33+ months after consolidation chemotherapy. In two patients, the tumor was again considered nonresectable. Twenty patients were disease-free after EAP +/- surgery +/- consolidation chemotherapy. Toxicity was primarily hematologic. Leukopenia and thrombocytopenia of World Health Organization (WHO) grade 3 occurred in 30% and 9%, respectively and grade 4 in 18% and 9% of the patients, respectively. There was no increased peri- or postoperative morbidity. After a median follow-up of 20 months for disease-free patients, the relapse rate is 60% (12/20). The median survival time for all patients is 18 months and for disease-free patients 24 months. EAP is highly effective in locally advanced gastric cancer, and offers a chance for surgery with curative intention in patients with an otherwise fatal prognosis.

Current options in treatment of anthracycline-resistant breast cancer.

Breast cancer is a chemosensitive tumour and anthracyclines are one of the most active cytotoxic agents in chemotherapy treatment. Failure after anthracycline-containing chemotherapy is a poor prognostic factor because of low response rate to salvage chemotherapy. Several factors like P-glycoprotein mediated drug resistance (MDR-1 or MRP), glutathione or amplification of topoisomerase II have been found to be involved in anthracycline resistance. No clear benefit for patients treated with 'resistance-modifier' agents like verapamil, dexverapamil or quinidine has yet been demonstrated. Most clinical studies with non-cross resistant cytotoxic agents are lacking a strict definition of anthracycline resistance. A strict definition of anthracycline resistance implies progressive disease during anthracycline chemotherapy. Among the cytotoxic drugs only 5-Fluorouracil (given as 24 h continuous infusion with folinic acid) and the taxanes produce more than 20% objective remission (RR) in case of anthracycline resistance, whereas the highest response rate was reported for docetaxel (32-57%). Only few randomized studies were performed: docetaxel showed higher anti-tumor activity than methotrexat/5-FU (RR: 42% vs 19%, P<0.001) or mitomycin/vinblastine (RR: 30% vs 12%;P<0.001) and treatment with paclitaxel (175 mg/m(2)) was in favour to mitomycin (RR 17% vs 6%). In combination chemotherapy most activity have been reported for paclitaxel plus high-dose 5-fluorouracil (given as 24 h continuous infusion with folinic acid) (RR: 58%) or for docetaxel plus cisplatinum (RR: 46%). High-dose regimens with growth factor or stem cell support seems to be active in anthracycline-resistant disease but the toxicity is considerable. In conclusion, the taxanes, especially docetaxel as single agent or paclitaxel plus high-dose 5-FU, are the most promising therapeutic options in treatment of anthracycline resistant disease. Further clinical phase II/III studies in breast cancer should include exact definition of anthracycline pretreatment and resistance.

5-Fluorouracil, folinic acid, etoposide and cisplatin chemotherapy for locally advanced or metastatic carcinoma of the oesophagus.

38 patients with advanced oesophageal carcinoma were treated with intravenous (i.v.) folinic acid (300 mg/m2), 5-fluorouracil (500 mg/m2), etoposide (100 mg/m2), and cisplatin (30 mg/m2) (FLEP), on days 1, 2 and 3, every 22-28 days. 26 patients had locally advanced disease (LAD) and 12 had metastatic disease (M1). Oesophagectomy was planned for patients with LAD in case of tumour regression after chemotherapy, while patients with M1 disease received chemotherapy only. The overall remission rate was 45% (17/38) including four clinical and two pathologically confirmed complete remissions. 16 patients underwent oesophagectomy, 12 after response to FLEP, and 4 after FLEP and subsequent irradiation +/- 5-fluorouracil/mitomycin. Toxicity was mainly haematological, with WHO grade 3 and 4 leukocytopenia in 50% and thrombocytopenia in 31% of the patients. Two treatment-related deaths were observed; one due to chemotherapy and one postoperatively. Median survival time of LAD patients was 13 months, and actuarial 2-year survival was 31%. Patients with complete tumour resection after FLEP had a median survival time of 18 months and a 2-year survival rate of 42%. Median survival of M1 patients was 6 months. FLEP is an active combination for oesophageal cancer, especially when used preoperatively in LAD.

Carboplatin plus radiation therapy in head and neck cancer.

To determine toxicity and response, escalating dose levels of carboplatin were given simultaneously with accelerated radiation to 36 previously untreated patients with unresectable squamous cell carcinomas of the head and neck (SCCHN) (2 with stage III and 34 with stage IV disease). Twenty-three patients received a total radiation dose of 58.8 Gy with two daily fractions of 2.1 Gy on days 1 through 4 in weeks 1, 2, and 5 and on two additional days in week 6. Simultaneous carboplatin was given intravenously at escalating dose levels: 20 mg/m2 in 3 patients, 30 mg/m2 in 5 patients, 40 mg/m2 in 5 patients, 50 mg/m2 in 6 patients, and 60 mg/m2 in 4 patients. Another 13 patients were treated with an escalated radiation dose of 67.2 Gy, which resulted in 2 more days of radiochemotherapy in week 6. Six patients in this group received 60 mg/m2/d and 7 received 50 mg/m2/d carboplatin. All patients were evaluable for toxicity according to World Health Organization (WHO) criteria and 35 of 36 patients were evaluable for response. Dose-limiting toxicity was myelosuppression with WHO grades 3 and 4 leukopenia in 5 of 6 patients treated with 60 mg/m2 carboplatin and 67.2 Gy. With radiochemotherapy doses of 67.2 Gy and 50 mg/m2, no grade 4 myelosuppression occurred and toxicity was generally tolerable. Independent of the carboplatin dose, mucositis grade 3 or 4 was seen in 12 patients. No other toxicities above WHO grade 2 occurred, except in 2 patients with grade 3 nausea and vomiting. There were 19 complete responses (53%) and 16 partial responses (44%). Our preliminary data suggest that 50 mg/m2 carboplatin together with a total radiation dose of 67.2 Gy might be the best combination for advanced, unresectable SCCHN.

Phase I/II study of simultaneous carboplatin and radiotherapy in unresectable squamous cell carcinoma of the head and neck.

Escalating dose levels of carboplatin together with simultaneous accelerated radiation were administered to 36 previously untreated patients with unresectable carcinomas of the head and neck (two stage III and 34 stage IV disease). Twenty-three patients received a total radiation dose of 58.8 Gy with two daily fractions of 2.1 Gy on days 1 to 4 in weeks 1, 2, and 5 and on another 2 days in week 6. Simultaneous carboplatin was given intravenously in escalating dose levels: 20 mg/m2 in three patients, 30 mg/m2 in five patients, 40 mg/m2 in five patients, 50 mg/m2 in six patients, and 60 mg/m2 in four patients. Another 13 patients were treated with an escalated radiation dose of 67.2 Gy, which led to 2 additional days of chemoradiotherapy in week 6. Six patients in this group received carboplatin 60 mg/m2/d, and seven received 50 mg/m2/d. All patients were evaluable for toxicity according to World Health Organization (WHO) criteria, and 35 of 36 patients were evaluable for response. Dose-limiting toxicity was myelosuppression, with WHO grades 3 and 4 leukopenia in five of six patients treated with carboplatin 60 mg/m2 and 67.2 Gy radiation. In patients treated with carboplatin 50 mg/m2 and 67.2 Gy radiation, no grade 4 myelosuppression developed and toxicity was generally tolerable. Independent of the carboplatin dose, grade 3 or 4 mucositis was seen in 12 patients. No other toxicities above grade 2 occurred. There were 19 complete responses (53%) and 16 partial responses (44%). Comparing these results with our earlier data with sequential chemoradiotherapy (carboplatin/5-fluorouracil followed by conventional radiotherapy) indicated that the higher tumor-clearing rate of simultaneous chemoradiotherapy produced significantly better rates of survival and disease-free response.

Neoadjuvant therapy for cervical cancer.

The stage-by-stage prognosis for cervical cancer patients has not improved in the past decades. Our research work concerning adjuvant chemotherapy for the early stages induced a pilot study with untreated patients in advanced stages. Patients were treated with carboplatin 300 mg/m2 plus ifosfamide 5 g/m2 on day 1. In cases of remission or no change, the therapy was repeated after 4 weeks. A third course was given only after further remission. After chemotherapy, patients were treated with surgery or radiotherapy according to feasibility. A total of 34 patients were admitted to this study. Thirty-two patients with 88 chemotherapy courses were evaluable for response and toxicity. Nineteen patients achieved remission; three achieved complete remission. The most common toxic effects were myelosuppression with grade four leukopenia (28%) and thrombocytopenia (13%). Alopecia (60%) was the main nonhematologic toxicity. In conclusion, we suggest that this regimen is as effective as other platin-containing regimens for squamous cell carcinoma of the cervix uteri, but its hematologic toxicity precludes its recommendation in an adjuvant setting.

Phase II studies with carboplatin in non-small cell lung cancer.

Since 1987, we have evaluated carboplatin alone or in combination with etoposide in two separate phase II trials of patients with non-small cell lung cancer (NSCLC) who had not received prior chemotherapy. Single-agent carboplatin produced a 20% response rate in 51 patients treated with 390 mg/m2 intravenously every 4 weeks. A 3-day schedule of etoposide 140 mg/m2 on days 2, 3, and 4, and carboplatin 150 mg/m2 on days 1 and 5 also resulted in a 26.7% response rate in 46 patients. Myelosuppressive toxicity associated with carboplatin/etoposide was substantially greater than that seen with carboplatin alone. Carboplatin as a single agent is active in previously untreated patients with advanced NSCLC. The two-drug combination of carboplatin and etoposide also shows activity in NSCLC similar to other combination chemotherapeutic regimens based on comparable prognostic factors in untreated patients. Further evaluation of carboplatin as part of combination chemotherapy in NSCLC is warranted.

Phase II and III studies with carboplatin in small cell lung cancer.

Carboplatin is one of the most active agents in untreated small cell lung cancer (SCLC) (11% complete response [CR], 59% CR plus partial response [PR]). Combination carboplatin/etoposide/vincristine (CEV) (phase II trial) led to an overall remission rate of 84% in patients with limited disease (LD), with 52% CRs. The median survival time with this combination was 14 months in patients with LD and 9.5 months in those with extensive disease (ED). The 30-month survival rates are 30% in LD and 10% in ED, which represents a plateau of the survival curve. This regimen is highly effective and exhibits low toxicity in SCLC. To evaluate the role of carboplatin in combination chemotherapy in patients with extensive SCLC, a phase III trial was performed. In this ongoing trial comparing CEV and etoposide/vincristine in ED patients, CR and overall response rates to date are higher in the CEV arm (CR, 20% versus 15%; CR plus PR, 83% versus 65%), but as yet the differences are not statistically significant. In summary, chemotherapy regimens containing platinum compounds are among the most active in the treatment of SCLC. The use of the new compound carboplatin instead of cisplatin has led to similar or increased remission rates and is preferable because it has fewer side effects. Preliminary results from this ongoing, prospective, randomized phase III trial are presented.

Carboplatin in small cell lung cancer.

Carboplatin is one of the most active agents in untreated small cell lung cancer (SCLC) (14% complete response [CR] and 61% CR + partial response [PR]). The combination carboplatin/etoposide/vincristine (CEV) (phase II trial) led to an overall remission rate of 84% in patients with limited disease, with 52% CR. The median survival time with this combination was 13 months in patients with limited disease and 9.5 months in those with extensive disease. The 30-month survival rates are 30% in limited disease and 10% in extensive disease with a plateau of the survival curve. This regimen is highly effective and exhibits low toxicity in SCLC. To evaluate the role of carboplatin in combination chemotherapy in patients with extensive SCLC, a phase III trial was performed. In this ongoing trial comparing CEV and etoposide/vincristine in SCLC patients with extensive disease, CR and overall response rates to date are higher in the CEV arm (CR 30% v 10%, CR + PR 90% v 75%), but as yet the differences are not statistically significant. In summary, chemotherapy regimens containing platinum compounds are among the most active in the treatment of SCLC. The use of the new compound carboplatin instead of cisplatin has led to similar or increased remission rates and is preferable because it has fewer side effects. Preliminary results from this ongoing, prospective, randomized phase III trial will be presented.

New developments in the treatment of gastric carcinoma.

The recent successes being achieved with combination chemotherapy regimens, such as FAMTX (fluorouracil [5-FU], doxorubicin, methotrexate), EAP (etoposide, doxorubicin, cisplatin), and ELF (etoposide, leucovorin, 5-FU), strongly indicate that gastric cancer is chemosensitive. With these regimens, objective remission rates of more than 50% were recorded, including approximately 10% complete remissions (CRs). Moreover, some of these CRs were histopathologically confirmed. The finding that locally advanced disease (LAD) and technically unresectable disease could be rendered resectable by preoperative chemotherapy (EAP) was important. Thirty-six patients with LAD had been treated in a phase II trial with preoperative EAP, inducing 24 (70%) overall remissions (two clinical CRs, six pathologic CRs, 16 partial remissions [PRs] in 35 evaluable patients. Twenty-one patients were disease-free after chemotherapy with or without second-look surgery. The median survival time was 18 months for all patients and 24 months for disease-free patients. At 30+ months, 21% of all patients are still living disease-free. The expected survival of patients with unresectable LAD is approximately 4 to 6 months without any treatment and 6 to 9 months with standard chemotherapy. Compared with the latter results, the preoperative use of effective regimens (eg, EAP) seems to improve prognosis of patients with LAD. Moreover, such a multimodal approach may increase the number of long-term survivors among patients with resectable gastric cancer, especially those whose stage indicates a high risk of relapse (stages IIIa or IIIb). However, partly because of the severe toxicities (myelosuppression, nausea/vomiting), a considerable number of patients cannot be treated with these new regimens for the following reasons: Two of three patients with gastrointestinal disease are older than 60 years. Nontumorous diseases of the cardiovascular system, kidney, and others are frequent in this age group and may complicate or even prevent treatment with aggressive regimens. Considering the predominantly palliative treatment intentions in far advanced (metastasized) gastric cancer, regimens with low toxicities and acceptable activity should be preferred. For these reasons, we developed and investigated the combination ELF in a phase II trial in elderly patients (greater than 65 years) and in patients with cardiac risks who could not be treated with anthracyclines. The overall response rate in 51 evaluable patients was 53% (27 of 51) including six clinical CRs (12%). The median remission duration was 9.5 months and the median survival time was 11 months. Tolerability was excellent. Only 16% and 4% of patients, respectively, experienced WHO grades 3 and 4 leukopenia. Nausea/vomiting and mucositis/stomatitis were mild.(ABSTRACT TRUNCATED AT 400 WORDS)

Carboplatin and radiotherapy in the treatment of head and neck cancer: six years' experience.

Between 1987 and 1991, 103 patients with advanced head and neck carcinoma were treated with radiochemotherapy plus carboplatin. Tumors were located in the oral cavity in 33 patients, the oropharynx in eight, and the hypopharynx in seven. Four patients had a tumor of the epipharynx and three, tumor of the larynx. In 48 patients tumor involvement included two or more compartments. Radiotherapy was performed with cobalt-60 rays or 8-MeV photons in a fractionation of 5 x 2 Gy/wk to a dose of 50 Gy. Carboplatin 60 to 70 mg/m2/d was administered days 1 through 5 and 29 through 33. For inoperable patients radiotherapy was continued to a dose of 70 to 74 Gy. To date, 103 patients have entered the study and 100 have completed treatment; three patients died during the treatment period. Actuarial 1- and 2-year survival rates are 77% and 53%, respectively, for all patients; comparable figures for patients with interposed surgery are 93% and 69%, and for the patients treated with radiotherapy alone, 71% and 47%. In a pilot study conducted between 1990 and 1991, 15 patients with advanced head and neck carcinomas underwent hyperfractionated accelerated radiotherapy (2 x 1.6 Gy/d 5 days per week; total dose, 64 to 67.2 Gy) and simultaneous intravenous carboplatin (60 mg/m2, days 1 through 5 and 29 through 33). Eleven patients had T4 and four had T3 tumors. At the end of the treatment period, 12 patients had achieved a complete tumor remission and all others attained a partial tumor involution. Although acute side effects were more pronounced compared with conventional irradiation, this treatment regimen is feasible and the initial complete remission rate of 80% is encouraging. As a result of the encouraging results achieved with hyperfractionated accelerated radiotherapy, we initiated a multicenter randomized study in November 1991. Patients with advanced head and neck carcinomas are either randomized for conventional radiotherapy plus carboplatin or hyperfractionated accelerated irradiation plus carboplatin. As of July 1994, 178 patients have been entered in the study. Results will be evaluated after the study is completed.

Biochemical modulation of 5-fluorouracil by folinic acid or alpha-interferon with and without other cytostatic drugs in gastric, esophageal, and pancreatic cancer.

5-Fluorouracil (5-FU) is one of the important antineoplastic agents for the treatment of gastrointestinal cancers. The biochemical modulation of 5-FU by various drugs has brought about the two combinations of 5-FU/folinic acid (FA) and 5-FU/alpha-interferon (IFN), which have shown clinical activity in phase II and III trials, especially in colorectal cancer. The experience with both combinations in upper gastrointestinal cancers, however, is limited. In esophageal cancer, two phase II studies with 5-FU/IFN reported seven (27%) objective remissions in 26 patients, indicating superiority of 5-FU/IFN over 5-FU monotherapy. Trials with 5-FU/FA alone are lacking in esophageal cancer. The modulation of 5-FU by IFN or FA failed to show clinically significant activity in pancreatic cancer. However, in gastric cancer, 5-FU/FA and 5-FU/IFN seem to induce higher complete and overall remission rates in advanced gastric cancer compared with 5-FU alone. With the daily times five schedule of 5-FU/FA, 27% objective remissions were achieved; in combination with other cytotoxic drugs, such as etoposide, anthracyclines, cisplatin, mitomycin, or methotrexate, objective response rates up to 50% and more were reported.

Accelerated split-course radiation and simultaneous chemotherapy in patients with unresectable head and neck-cancer.

Forty-nine patients with unresectable squamous cell carcinomas of the head and neck were treated with accelerated radiotherapy (2 x 2.1 Gy/day, day 1-4 in week 1,2,5 and 6, total dose of 67.2 Gy) and simultaneous carboplatin (50 Mg/M2/ treatment day). Mucositis (21% grade 3 and 4, WHO) and leukopenia (40% grade 3 and 8% grade 4, WHO) were the most important side effects but did not limit the treatment schedule. The response rate was: 46.5% CR (20 pts), 46.5% PR (20 pts), 5% NC (2 pts) and 2% PD (1 pt). After three years overall survival was 35% (median 14 month) and in complete responders disease-free survival was 52%. Our results indicate that combined accelerated radio-chemotherapy might improve the poor results achieved with conventional radiotherapy or sequential chemo-radiotherapy in this difficult patient population. Further studies are neccessary to clarify whether modified radiotherapy or simultaneous chemotherapy or the combination of both are the reason for the improved treatment results.

Carboplatin/etoposide as first-line chemotherapy in advanced ovarian carcinoma: a pilot study.

In a pilot study, 18 patients with advanced ovarian cancer were evaluated for tolerance and response to a combination treatment with a fixed dose of carboplatin (350 mg/m2 given i.v. on day 1) and escalated doses of etoposide (70-130 mg/m2 daily given i.v. on days 1-3) as first-line chemotherapy. The maximum tolerated dose of etoposide was 130 mg/m2 when given i.v. on days 1-3 in combination with 350 mg/m2 carboplatin given i.v. every 4 weeks. At these dose levels, bone marrow toxicity was manageable and did not appear to be cumulative. In all, 12 objective responses, including 9 complete responses (CRs) and 3 partial responses (PRs), were achieved in 18 patients; 6 of the 9 CRs were confirmed as pathological CRs by second-look surgery.

Etoposide in patients with previously untreated non-small-cell lung cancer: a phase I study.

In a phase I study, a range of doses of etoposide (200-370 mg/m2 given i.v. daily on 3 consecutive days) were evaluated for tolerance and response as first-line treatment in 26 patients with non-small-cell lung cancer. The dose-limiting toxicity was myelosuppression, especially leukopenia. At dose levels of 350 and 370 mg/m2 etoposide per day, leukopenia of WHO grade 4 occurred in two and one of seven patients, respectively. No thrombocytopenia of this degree was observed. Myelosuppression was quickly reversible and noncumulative. Apart from alopecia, nonhematologic organ toxicities above WHO grade 2 were not seen. Toxicity analysis suggests that the recommended dose of single-agent etoposide for phase II studies in untreated patients is 330-370 mg/m2 given i.v. daily for 3 days. At the dose levels tested, 6 (23%) major responses could be induced. All responses were seen at a starting dose of greater than 300 mg/m2 per day. The median duration of response was 4 months. The median survival for all patients was 8 months and that for responding patients was 15 months.