Capecitabine and irinotecan as first-line chemotherapy in patients with metastatic colorectal cancer: results of an extended phase I study.

BACKGROUND: To define the maximum-tolerated dose (MTD) and to evaluate the dose-limiting toxicities (DLTs) of the combination of capecitabine and irinotecan in patients with metastatic colorectal cancer. PATIENTS AND METHODS: Thirty-seven patients with measurable metastatic colorectal cancer with no prior chemotherapy for metastatic disease were treated at three dose levels (DLs). For the first two dose levels, irinotecan (70 mg/m(2)) was administered once a week for 6 weeks in combination with 2 weeks of capecitabine at 1000 mg/m(2) (DL1) or 1250 mg/m(2) (DL2) twice daily, starting on days 1 and 22. In the last dose escalation step, the dose of irinotecan was increased to 80 mg/m(2) (DL3). One cycle lasted 7 weeks. RESULTS: In the subsequent phase I trial, 96 cycles of capecitabine and irinotecan were administered. At DL3, three out of six patients experienced DLTs (diarrhea, neutropenia, asthenia). In order to confirm the safety of the recommended dose, DL2 was extended to 15 patients. Five patients (33%) showed DLTs at this dose level, which was considered too high to embark on further clinical studies. Subsequently, the starting dose (DL1) was extended to a total of 16 patients, with diarrhea being the main toxicity. The overall response rate was 38% [95% confidence interval (CI) 21% to 58%], with a median response duration of 8.7 months (95% CI 6.4-11.5 months). CONCLUSIONS: The recommended doses for further studies are irinotecan 70 mg/m(2) and capecitabine 1000 mg/m(2). The combination of capecitabine and irinotecan appears to have significant therapeutic efficacy with manageable toxicity.

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.

Combined radiochemotherapy with docetaxel in patients with unresectable locally advanced head and neck tumors.

BACKGROUND: As the treatment with docetaxel in metastatic head and neck cancer resulted in an encouraging response rate, the following phase-I study examined the effects of a combined radiochemotherapy with weekly docetaxel in patients with inoperable advanced head and neck tumors. PATIENTS AND METHODS: Six patients with Stage IV head and neck cancer were included into the study. Within the treatment regimen the primary tumor and the involved lymph nodes were irradiated up to a total dose of 70 Gy, the non involved cervical and supraclavicular lymph nodes received 50 Gy in conventional fractionation. Simultaneously docetaxel was given 1 hour before radiotherapy. The initial dose was 15 mg/m2. RESULTS: A dose escalation was impossible because of several dose limiting toxicities (NCI-CTC) already in the first dose level. Two patients showed skin reactions Grade 4, 2 patients pulmonary complications Grade 4, 2 patient neurologic side effects Grade 3 and 1 a thrombocytopenia Grade 3. The response rate resulted in 3 complete and 1 partial remission, 1 death, 1 patient was not evaluable. CONCLUSION: Unexpectedly already in the first dose level several dose limiting toxicities were evaluated. For that reason the treatment scheme is not feasible.

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.

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.

Paclitaxel in combination with weekly 24-hour infusional 5-fluorouracil plus leucovorin in the second-line treatment of metastatic breast cancer: results of a phase II study.

PURPOSE: To evaluate the antitumor activity in terms of response rate (RR), time to progression (TTP) and survival of paclitaxel in combination with weekly 24-hour infusional 5-fluorouracil (5-FU)/leucovorin in pretreated metastatic breast cancer (MBC). PATIENTS AND METHODS: Fifty-four patients with bidimensionally measureable disease were included during phase II. Thirty-two had anthracycline resistant disease. Treatment consisted of 5-FU (24-hour i.v. infusion) 2.0 g/m2, leucovorin (two-hour i.v. infusion prior to 5-FU) 500 mg/m2, weekly for six weeks (day 1, 8, 15, 22, 29, 36) and paclitaxel (three-hour i.v. infusion) 175 mg/m2 was administered additionally on days 1 and 22, q 50 days. RESULTS: We observed complete remissions in 4% of patients (2 of 54), partial remissions in 55% (30 of 54), stable disease in 37% (20 of 54) and progressive disease in 4% (2 of 54). The overall RR was 59% (95% CI 48%-72%). The RR in 32 patients with anthracycline resistant disease was 59% (19 of 32). The median duration of response was 12 months (3-22), median TTP eight months (2-22) and median survival time 15 months (2-28). Neutropenia was common, but of CTC grade 2 or 3 in most patients. Nonhematologic toxicities mostly consisted of CTC grade 1 and 2 myalgia, diarrhea, mucositis, nausea and vomiting. CONCLUSIONS: Paclitaxel combined with weekly 24-hour infusional 5-FU/leucovorin is well tolerated in the second line treatment of MBC. High efficacy was documented even in the treatment of anthracycline resistant disease, which warrants further evaluations.

Infusional 5-FU, folinic acid, paclitaxel, and cisplatin for metastatic breast cancer.

Our phase II study results demonstrating high efficacy and low toxicity for a weekly schedule of high-dose, 24-hour infusional 5-fluorouracil(5-FU)/folinic acid (HD5-FU/FA) in intensively pretreated patients with metastatic breast cancer prompted addition of paclitaxel (Taxol) to the regimen, for a phase I/II study of outpatient second-line treatment of metastatic breast cancer. That study further prompted the addition of cisplatin (Platinol) to the regimen for first-line treatment. So far, 28 patients with metastatic breast cancer have been evaluated. Pretreatment comprised adjuvant chemotherapy in 24 of 28 patients, but no prior chemotherapy for metastatic disease. Patients were treated with HD5-FU 2 g/m2 (24-hour infusion) plus FA 500 mg/m2 (2-hour infusion prior to FU) weekly for 6 weeks (days 1, 8, 15, 22, 29, and 36); in addition, paclitaxel 175 mg/m2 (3-hour infusion) was administered on days 0 and 21 and cisplatin 50 mg/m2 (1-hour infusion) on days 1 and 22 prior to HD5-FU/FA, repeated every 50 days. Patients were treated as outpatients using Port-a-Cath systems and portable pumps. Neutropenia was common (67% World Health Organization grade 3) but mild to moderate in most patients and was of short duration. No hospitalizations were required because of febrile neutropenia, and no granulocyte colony-stimulating factor support was used. Aside from common total alopecia, nonhematologic toxicities consisted mainly of moderate myalgia, diarrhea, mucositis, and nausea and vomiting. Hand-foot syndrome and peripheral neuropathy were cumulative and occurred most commonly during the third treatment cycle, with mild-to-moderate expression. In 28 patients with bidimensionally measurable disease, 25% (7/28) attained a complete response, 57% (16/28) achieved partial response, 11% (3/28) had stable disease, and 7% (2/28) had disease progression. Overall response was 82% (95% confidence interval, 66% to 100%). Eight of 28 patients are still receiving treatment. It is concluded that the combination of paclitaxel/cisplatin with weekly HD5-FU/FA appears to be effective in the first-line treatment of metastatic breast cancer. Preliminary results must be confirmed by the final analysis of response duration, time to progression, and survival.

Phase I/II study with a weekly 24-hour infusion of 5-fluorouracil plus high-dose folinic acid (HD-FU/FA) in intensively pretreated patients with metastatic breast cancer.

BACKGROUND: In metastatic breast cancer patients who have had prior exposure to anthracyclines, single agents induce less than 15% and combination chemotherapy less than 20%-30% of objective responses. Therefore more active and tolerable salvage regimens are needed. PATIENTS AND METHODS: Forty-three patients with advanced breast cancer pretreated with 1-5 (median 2) different chemotherapy regimens were entered into this phase I/II trial. Treatment consisted of folinic acid (FA) (500 mg/m2, i.v., 2-hour infusion) followed by a 24-hour infusion of 5-fluorouracil (FU) which was escalated from 1.5 g/m2 (dose level (dl 1)), to 1.8 g/m2 (dl 2) to 2.1 g/m2 (dl 3). Therapy was given as outpatient treatment once weekly times 6 followed by a 2-week rest. RESULTS: HD-FU/FA was well tolerated. No dose-limiting toxicity occurred at dl 1 or 2. Only 3/32 (9%) patients had WHO grade 3/4 toxicities (gastrointestinal toxicities, hand-foot-syndrome) at dl 3. The response rate for all 32 of the patients treated at dl 3 was 41% (13/32). In the 24 patients with anthracycline-refractory disease, a response rate of 41% (10/24) was achieved. The median remission duration was 11 months and the median survival time 19 months. CONCLUSIONS: This schedule of FU/FA is a safe outpatient treatment with substantial activity in intensively pretreated breast cancer patients.

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.

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.

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.

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.

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.

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 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 and simultaneous radiation in the treatment of stage IIIA/B non-small cell lung cancer.

The radiosensitizing properties of carboplatin were investigated in preclinical and clinical studies. In human non-small cell lung cancer (NSCLC) cell lines (EPLC 65 H and LCLC 97 TM1) combined carboplatin and radiation therapy was superior to chemotherapy or radiotherapy alone, indicating the existence of additive effects for both treatment modalities. In a subsequent clinical phase II trial, escalating doses of carboplatin were given concurrently with radiation to patients with stage IIIA/B NSCLC. Radiotherapy was given in daily doses of 2 Gy, 5 days a week, during weeks 1-3 and 6 and 7. Carboplatin was given on day 1 in weeks 1-3 and 6 and 7. The starting dose level was 100 mg/m2, followed by dose escalations to 120, 130, 140, 150, 160, 180, and 200 mg/m2. Five patients were to be treated at each dose level until intolerable toxicity (World Health Organization grade 3 or 4 leukopenia) occurred in 3 of the 5. To date, 34 patients have been entered into the study. Toxicity was mild and, even at the 180-mg/m2 dose level, no severe myelosuppression was observed. Thus, the maximum tolerated dose of carboplatin has not yet been reached. Preliminary analysis of response and survival shows an overall response rate of 53% and a median survival of 10 months. Patients receiving higher carboplatin doses (140-160 mg/m2) survived longer than patients who received lower doses (100-130 mg/m2). These preliminary results indicate that combination carboplatin and radiation therapy is a well-tolerated, active regimen in patients with locally advanced NSCLC. Splitting carboplatin administration may reduce its hematologic toxicity.

Simultaneous radiotherapy and chemotherapy with carboplatin in inoperable squamous cell carcinoma of the head and neck: a phase II study.

Fifty-six untreated patients with inoperable squamous cell carcinoma of the head and neck were treated with carboplatin 70 mg/m2 i.v. daily on days 1-5 and 29-33 in combination with simultaneous conventional radiation up to a target volume dose of 50 Gy. Depending on tumor response and upon recommendation of surgeons, 21 of 56 patients underwent surgery after a radiation dose of 50 Gy and two courses of carboplatin. Patients who showed pCR after surgery received no further radiotherapy. In all other patients radiotherapy was continued using a shrinking field technique up to a target absorbed dose of 70-74 Gy. Combined modality induced 66% complete remission (CR) and an overall response rate of 98%. After completion of the whole treatment program (combined modality +/- surgery) 53 (94%) of the 56 patients were disease free. The median survival for all patients is 25+ months and the percentage of two-year survivors is 53%. Myelosuppression was the most frequent toxicity, but rarely was severe; leukopenia and thrombocytopenia of WHO grade 3 occurred in 21% of the patients. No other toxicities above WHO grade 2 occurred. Nephrotoxicity, neurotoxicity and ototoxicity were not seen. The addition of carboplatin did not increase the rate of surgical complication over that expected for preoperative radiotherapy. Two patients died of pulmonary embolism after surgery. Combined modality with carboplatin and simultaneous radiation is a highly active and well-tolerated regimen for untreated patients with inoperable squamous cell carcinoma of the head and neck.

Determining carboplatin/etoposide dosage in extensive stage small-cell lung cancer (SCLC).

In order to define the maximum tolerance level of combined carboplatin/etoposide dosage, patients with extensive stage small-cell lung cancer (SCLC) were treated with a fixed dose of carboplatin (300 mg/m2 iv on day 1) and escalating doses of etoposide starting with 80 mg/m2 iv on days 1-3. Five patients were given this starting and every following dose level. The daily dose of etoposide was increased in increments of 20 mg/m2 iv until severe myelosuppression occurred in 3 of 5 patients. Leuko- or thrombocytopenia WHO grade 3 or 4 occurred in 0/5 of the patients at the dose levels of 80 and 100 mg/m2, in 1/4 of the patients at the level of 120 mg/m2, in 2/5 of the patients at a level of 140 mg/m2, and 3/5 patients at a level of 160 mg/m2. Thus, increase in dosage was stopped at an etoposide dose of 160 mg/m2. Other side effects were mild and consisted predominantly of nausea and vomiting in 14/25 of the patients. The overall response rate was 40% with a 12% complete remission rate, median survival was 9.3 months and median progression-free survival totalled 4.3 months. These results indicate that combined carboplatin/etoposide is a well tolerated regimen in extensive-stage SCLC, with response rates comparable to those of other standard protocols. Using treatment intervals of 4 weeks the recommended dose of etoposide in combination with 300 mg/m2 carboplatin was identified as 140 mg/m2 iv for 3 consecutive days.

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.