H. Sancho-Garnier

Second malignant neoplasms after a first cancer in childhood: temporal pattern of risk according to type of treatment

SummaryThe variation in the risk of solid second malignant neoplasms (SMN) with time since first cancer during childhood has been previously reported. However, no study has been performed that controls for the distribution of radiation dose and the aggressiveness of past chemotherapy, which could be responsible for the observed temporal variation of the risk. The purpose of this study was to investigate the influence of the treatment on the long-term pattern of the incidence of solid SMN after a first cancer in childhood. We studied a cohort of 4400 patients from eight centres in France and the UK. Patients had to be alive 3 years or more after a first cancer treated before the age of 17 years and before the end of 1985. For each patient in the cohort, the complete clinical, chemotherapy and radiotherapy history was recorded. For each patient who had received external radiotherapy, the dose of radiation received by 151 sites of the body were estimated. After a mean follow-up of 15 years, 113 children developed a solid SMN, compared to 12.3 expected from general population rates. A similar distribution pattern was observed among the 1045 patients treated with radiotherapy alone and the 2064 patients treated with radiotherapy plus chemotherapy; the relative risk, but not the excess absolute risk, of solid SMN decreased with time after first treatment; the excess absolute risk increased during a period of at least 30 years after the first cancer. This pattern remained after controlling for chemotherapy and for the average dose of radiation to the major sites of SMN. It also remained when excluding patients with a first cancer type or an associated syndrome known to predispose to SMN. When compared with radiotherapy alone, the addition of chemotherapy increases the risk of solid SMN after a first cancer in childhood, but does not significantly modify the variation of this risk during the time after the first cancer.

Phase I clinical trial and pharmacokinetic evaluation of doxorubicin carried by polyisohexylcyanoacrylate nanoparticles

SummaryDoxorubicin (DXR) incorporated into biodegradable acrylate nanoparticles such as polyisohexylcyanoacrylate (PIHCA) has been shown to increase DXR cytotoxicity and reduce cardiotoxicity by modifying tissue distribution in preclinical studies. We have conducted a phase I clinical trial of DXR-PIHCA in 21 patients with refractory solid tumors (10 male, 11 female, median age: 53 years, median PS: 1, prior free-DXR therapy: 7 patients). A total of 32 courses at 28 day intervals were administered at 6 dose levels (15, 30, 45, 60, 75 and 90 mg/m2). The drug was given as a 10 minute IV infusion on day 1 to the first 5 patients: 2 of them presented a grade 2 allergic reaction (W.H.O. criteria) during infusion, which was rapidly reversible once drug administration was discontinued. Subsequently, in the other 16 patients, the administration was modified to a 60 minute i.v. perfusion diluted in 250 cc of Dextrose 5%: only 1 patient presented the same allergic reaction. Grade 2 fever and vomiting occurred in 9 patients and 7 patients respectively during the first 24 h after treatment. There was no cardiac toxicity among the 18 evaluable patients. Grade 3 or 4 hematologic toxicity occurred at the 75 and 90 mg/m2 dose level. The dose limiting toxicity was neutropenia. The maximum tolerated dose was 90 mg/m2 and the recommended phase II dose was 75 mg/m2. A pharmacokinetic evaluation of DXR-PIHCA was conducted in 3 patients each at a different dose level (60,60 and 75 mg/m2) and was compared with free DXR given to the same patients in the same conditions.

Leukaemias and cancers following iodine-131 administration for thyroid cancer.

We studied 1771 patients treated for a thyroid cancer in two institutions. None of these patients had been treated with external radiotherapy and 1497 had received (131)I. The average (131)I cumulative activity administered was 7.2 GBq, and the estimated average dose was 0.34 Sv to the bone marrow and 0.80 Sv to the whole body. After a mean follow-up of 10 years, no case of leukaemia was observed, compared with 2.5 expected according to the coefficients derived from Japanese atomic bomb survivors (P = 0.1). A total of 80 patients developed a solid second malignant neoplasm (SMN), among whom 13 developed a colorectal cancer. The risk of colorectal cancer was found to be related to the total activity of (131)I administered 5 years or more before its diagnosis (excess relative risk = 0.5 per GBq, P = 0.02). These findings were probably caused by the accumulation of (131)I in the colon lumen. Hence, in the absence of laxative treatment, the dose to the colon as a result of (131)I administered for the treatment of thyroid cancer could be higher than expected from calculation of the International Commission on Radiological Protection (ICRP). When digestive tract cancers were excluded, the overall excess relative risk of second cancer per estimated effective sievert received to the whole body was -0.2 (P = 0.6).

Alternating radiotherapy and chemotherapy schedules in small cell lung cancer, limited disease

Sixty-three evaluable patients with limited small cell lung carcinoma were entered into two pilot studies alternating 6 cycles of combination chemotherapy (Doxorubicin 40 mg/m2 d 1; VP16213 75 mg/m2 d 1, 2, 3; Cyclophosphamide 300 mg/m2 d 3, 4, 5, 6; and Methotrexate 400 mg/m2 d 2--plus folinic acid rescue--or Cis-Platinum 100 mg/m2 d 2) with 3 courses of mediastinal radiotherapy as induction treatment. The first course of radiotherapy started 10 days after the second cycle of chemotherapy; there was a 7 day rest between chemotherapy and radiotherapy courses. This 6 month induction treatment was followed by a maintenance chemotherapy. The total mediastinal radiation dose was increased from 4500 rad in the first study to 5500 rad in the second. Both protocols obtained a complete response (CR) rate of greater than 85% (with fiberoptic bronchoscopy and histological verification). Local control at 2 years was 61% in the first study and 82% in the second. Relapse-free survival at 2 years was 32 and 37%, respectively. Toxicity was acceptable. We conclude that our results justify further clinical research in alternating radiotherapy and chemotherapy schedules.

Results of a european randomized trial of Etanidazole combined with radiotherapy in head and neck carcinomas

Purpose: The aim of the study was to evaluate the efficacy and toxicity of Etanidazole, a hypoxic cell sensitizer, combined with radiotherapy in the treatment of head and neck squamous cell carcinoma. Methods and Materials: A total of 374 patients from 27 European centers were included in this trial between 1987 and 1990. Treatment was either conventional radiotherapy alone (between 66 Gy in 33 fractions and 74 Gy in 37 fractions, 5 fractions per week), or the same radiotherapy dose plus Etanidazole 2 g/m 2 , three times weekly for 17 doses. A minimization procedure, balancing for center, site, and T stage (T1-T3 vs. T4) was used for randomization. Results: Among the 187 patients in the Etanidazole group, 82% received at least 14 doses of the drug. Compliance to the radiotherapy protocol was 92% in the Etanidazole group and 88% in the control group; the main cause of deviation was acute toxicity, which was observed at an equal rate in the two treatment groups. Fifty-two cases of Grade 1 to 3 peripheral neuropathy were observed in the Etanidazole group vs. 5 cases, all of Grade 1, in the control group (p < 0.001). The 2-year actuarial loco-regional control rates were 53% in the Etanidazole group and 53% in the control group (p = 0.93), and the overall 2-year survival rates were 54% in each group (p = 0.99). Conclusion: Adding Etanidazole to conventional radiotherapy did not afford any benefit for patients with head and neck carcinoma. This study failed to confirm the hypothesis of a benefit for patients with N0-N1 disease, which had been suggested by the results of a previous study (10).

HPV self‐sampling or the Pap‐smear: A randomized study among cervical screening nonattenders from lower socioeconomic groups in France

Today in France, low attendance to cervical screening by Papanicolaou cytology (Pap‐smear) is a major contributor to the 3,000 new cervical cancer cases and 1,000 deaths that occur from this disease every year. Nonattenders are mostly from lower socioeconomic groups and testing of self‐obtained samples for high‐risk Human Papilloma virus (HPV) types has been proposed as a method to increase screening participation in these groups. In 2011, we conducted a randomized study of women aged 35–69 from very low‐income populations around Marseille who had not responded to an initial invitation for a free Pap‐smear. After randomization, one group received a second invitation for a free Pap‐smear and the other group was offered a free self‐sampling kit for HPV testing. Participation rates were significantly different between the two groups with only 2.0% of women attending for a Pap‐smear while 18.3% of women returned a self‐sample for HPV testing (p ≤ 0.001). The detection rate of high‐grade lesions (≥CIN2) was 0.2‰ in the Pap‐smear group and 1.25‰ in the self‐sampling group (p = 0.01). Offering self‐sampling increased participation rates while the use of HPV testing increased the detection of cervical lesions (≥CIN2) in comparison to the group of women receiving a second invitation for a Pap‐smear. However, low compliance to follow‐up in the self‐sampling group reduces the effectiveness of this screening approach in nonattenders women and must be carefully managed.

Epidermal growth factor receptor in human breast cancers: Correlation with estrogen and progesterone receptors

Epidermal growth factor receptor (EGFR), determined by the Scatchard curve method, was found in 22 cases of a random series of 100 patients with breast carcinoma. Two groups of patients were identified, one (n = 16) with a low concentration (0–50 fm/mg protein) of EGFR but with a high affinity (Kd = 3.2 nM), and the other (n = 6) with a high concentration (90–210 fm/mg protein) of EGFR but with a lower affinity (Kd = 6.3 nM).A significant inverse relationship was found between the presence of EGFR and receptors for estrogen (p<0.001) and progesterone (p = 0.001). EGFR was found in no (0/8) tumors with Grade I histoprognostic grade, 17% (10/58) Grade II, and 38% (11/29) Grade III (p<0.05). EGFR is present therefore in poorly differentiated tumors and associated with other factors of poor prognosis. Ourin vivo analyses confirm results found in tissue culture derived from human breast carcinoma cells.

Oestrogen and progesterone cytosolic receptors in clinically inflammatory tumours of the human breast

Oestrogen (RE) and progesterone (RP) cytosolic receptors have been studied in 59 clinically inflammatory tumours of the human breast. The results were compared to those obtained in a series of 496 operable tumours. A single saturating dose of oestradiol for RE and R 5020 for RP was used and the cut-off between negative and positive tumours was 100 fmol/g tissue. A significant difference was seen (P less than 0.02) between the 2 classes of patients: (RE-, RP-) tumours were commoner among clinically inflammatory tumours (48%) than among operable ones (28%), independently of menopause. Concerning the histological type (based on an assessment of differentiation) and the histological grading (Scarff and Bloom) there was a significant difference (P less than 0.001) between the 2 populations of tumours. No significant difference was found in the distribution of RE and RP among the 3 histological types, whereas a significant correlation existed between histological grading and RE (P less than 0.02). Finally, patients with RE+ clinically inflammatory tumours constitute a lower risk group, especially when they are free of metastases at the time of diagnosis. The presence of RE therefore seems to indicate, as in the operable tumour group, a favourable prognosis.

Alternating radiotherapy and chemotherapy in 173 consecutive patients with limited small cell lung carcinoma

One-hundred seventy-three patients with limited small cell lung cancer were included in three consecutive protocols alternating radiotherapy and chemotherapy. The alternating schedule consisted of six courses of chemotherapy (doxorubicin, VP16213, cyclophosphamide, and methotrexate in the first protocol; methotrexate being replaced by cisplatinum in the other two protocols) and three series of thoracic radiotherapy delivering a total dose of 45, 55, and 65 Gy in each consecutive protocol. Radiotherapy was started after the second course of chemotherapy. A 1-week gap was respected between each course of chemotherapy and each series of radiotherapy. Seventy percent of patients were in complete remission at the end of the induction treatment. The actuarial 5-year local control was 60% and the 5-year overall survival was 18%. Sixty percent of patients developed distant metastases. The death rate unrelated to cancer was 10%. These results show that alternating radiotherapy and chemotherapy schedules are reproducible, and provide a consistent long-term local control and a long-term survival rate exceeding 15% in limited disease.

Randomised EORTC Head and Neck Cooperative Group trial of preoperative intra-arterial chemotherapy in oral cavity and oropharynx carcinoma

Between February 1978 and January 1984, 222 eligible patients were randomised in a multicentre trial of preoperative intra-arterial chemotherapy in the treatment of oral cavity and oropharynx carcinoma. Patients were randomised between either surgery or preoperative chemotherapy. This latter group received vincristine and bleomycin for 12 days. Patients were stratified according to the primary site: floor of the mouth (FM) versus posterior oral cavity or oropharynx (POC) and institution. The FM group received postoperative radiotherapy depending upon quality of the margins and lymph-node pathological involvement, when it was systematically applied in the POC group. Tumour regression after chemotherapy either complete (CR) or partial (PR greater than 50%) was observed in 48% in the FM group and 41% in the POC group, and lymph-node regression (CR + PR) was respectively 15% and 23%. Some discrepancies appeared between clinical regression and pathological response, and the number of cases without histological response was clearly higher than the number of cases without clinical response. The overall survival showed a statistically significant difference (P = 0.048) between FM and POC groups. In the FM group, median survival in the chemotherapy arm was estimated at 7 years compared with 3 years in the surgery arm. In the POC group, median survival was estimated at 3 years in both treatment arms. Chemotherapy lowered the uncontrolled disease and local recurrence in the FM group. These differences do not exist in the POC group, which may be due to the systematically postoperative radiotherapy.