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  Volume 95
Numero 6
novembre-dicembre 2009 		I documenti sono in formato PDF, consultabili utilizzando Acrobat Reader
 
Off-label prescription of antineoplastic drugs:
an Italian prospective, observational, multicenter survey

Fausto Roila, Enzo Ballatori, Roberto Labianca, Filippo De Braud, Karen Borgonovo, Olga Martelli, Ciro Gallo, Angelo Tinazzi, Francesco Perrone
1Medical Oncology Division, S. Maria Hospital, Terni; 2Dept of Internal Medicine and Public Health, University of L’Aquila, L’Aquila; 3Dept of Medical Oncology, Bergamo; 4European Institute of Oncology, Milan; 5Dept of Oncology, Fatebenefratelli Hospital, Milan; 6Dept of Oncology,
S. Giovanni Hospital, Rome; 7Dept of Medicine and Public Health, 2nd University of Naples, Naples; 8Medical Informatics and Biometry Unit, Sendo Tech, Milan; 9National Cancer Institute, Naples, Italy. *Investigators and participating centers are reported in the Appendix

Key words: antineoplastic agents, chemotherapy, off-label.

abstract

Aims and background. An appropriate use of drugs should follow the registered indications. Different reasons can induce oncologists to prescribe drugs off-label. The aim of this study was to describe incidence and characteristics of these prescriptions in Italy. 
Methods. Patients submitted to chemotherapy in 15 Italian oncology centers were evaluated for two randomized non-consecutive days of two weeks in May 2006.
Results. The study enrolled 644 patients receiving 1,053 drugs. Overall, 199 of 1053 (18.9%) prescriptions were off-label. In 92 of 199 cases (46.2%), the drugs were used for a neoplasm for which they were not approved, but there was scientific evidence (one or more randomized clinical trials or more phase II studies published in a major oncology journal) justifying the prescription. In 27 cases (13.6%), the drugs were prescribed for a rare neoplasm (cisplatin and gemcitabine in mesothelioma). In 20/21 cases (10.1%/10.5%), drugs were used in association/alone in contrast with the approved use (capecitabine in association in colorectal cancer). In 28/11 cases (14.0%/5.6%), the drugs were used in lines of chemotherapy subsequent/previous to that approved.
Conclusions. Off-label use of antineoplastic drugs, in this observational survey, represents less than 20% of the prescriptions, and most of them are based on scientific evidence of efficacy.

Introduction
An appropriate use of antineoplastic drugs, essential to reproduce in daily clinical practice the results achieved in clinical trials, should follow the registered indications at the approved doses. However, when drugs are used in clinical practice, there is a natural trend to extend their utilization to certain patient categories, for example to the elderly or to children, for which there is no evidence of efficacy or tolerability documented by randomized clinical trials. Especially in oncology, drugs are often prescribed off-label for other reasons 1,2. Among these are lack of precision in the indications of some of the oldest drugs (i.e., cyclophosphamide has been approved as a “cytostatic treatment”) or in the case of rare tumors, for which the documentation of activity, efficacy and tolerability is generally scarce so that often there are no drugs approved for such indications. Pressure from patients, who require in any case treatment for their disease, is another reason for off-label prescriptions. Last but not least, the rapid diffusion of preliminary results of clinical trials and the late approval of new drugs (or extension of indications of drugs already approved) by the European Medicines Agency with respect to the US Food and Drug Administration (FDA) are other potential important reasons for off-label prescriptions 3,4.
It is clear that the off-label utilization of an anticancer drug could determine possible health problems due to the potential toxic effects of the drug and to the frequent lack of efficacy data, legal problems for the physicians prescribing off-label drugs, and economic problems for the National Health Service.
Few data are available on the incidence of off-label prescriptions. A 2001 national survey of USA office-based physicians showed that 150 million prescriptions (21%) were for off-label use. The phenomenon was more common among cardiac medications and anticonvulsants. More important was the fact that 73% of off-label prescriptions had little or no scientific support5.
This could be the consequence of the 1997 FDA Modernization Act, which allowed pharmaceutical companies to disseminate articles from peer-reviewed journals about off-label use6. According to the Act, such changes were to allow physicians to make more informed prescribing decisions and to motivate pharmaceutical companies to do the clinical studies necessary to get these indications added to drug labeling.
A recent estimate by the National Comprehensive Cancer network calculated that 50-75% of all uses of drugs in cancer care in the United States are off-label5. Furthermore, approximately 90% of patients with rare diseases are given at least one drug that is off-label6, and three fourths of the prescriptions on the market do not have labeling indications for children7-9.
A survey carried out in 1991 on 681 members of the American Society of Clinical Oncology showed that almost all drugs were prescribed for off-label use at least once, and that all types of cancer examined were treated with some drugs that were prescribed for off-label use. One third of the over 5,000 drug administrations were given for off-label use, and over half (56%) of the patients received at least one drug of their treatment regimen that was prescribed for off-label use. In general, off-label use was higher in those cases where there was no agreement on the best therapy, higher in patients treated with a palliative intent than with a curative intent, and higher in patients with metastasized cancer than in those with cancer at early stages of development 10.
More recently, an Australian study prospectively evaluated the medication charts of a single day of 130 cancer patients hospitalized in January 200111. Among 1351 prescriptions, 293 (22%) were off-label and 85% of patients received at least one drug off-label.
In 2006 the Italian Association of Medical Oncologist (AIOM) planned and supported a survey to verify the real incidence and characteristics of off-label prescriptions in Italian oncological centers.

Materials and methods
The study was proposed by e-mail to 386 Italian oncology institutions. No recall procedure was made nor was there any check of receipt. Reasons for nonacceptance were not collected.
The protocol planned that all consecutive patients submitted to cancer chemotherapy during two days selected at random were asked to participate in the study. To avoid the same patient being invited twice, randomization was conditioned so that the two days assigned to each participating center had to fall in two different and consecutive weeks and that the two days had to be different. Patients submitted only to supportive/palliative care and patients refusing to participate in the study for any reason were excluded. The study was approved by the local ethics committee. The investigators filled out a form reporting patient data (age, sex, ECOG performance status, type and stage of cancer) and the type of chemotherapy received during the current visit to the center or in a previous visit.
Descriptive analysis was done initially considering each drug as a unit. Before data computerization, it was decided that each single administered drug should be categorized within one of five categories:
1) used appropriately, according to registration;
2) used for a non-rare cancer for which the drug is not registered;
3) used for a rare cancer (defined as a cancer with a prevalence of 50/100,000) for which the drug is not registered;
4) used with inappropriate combination, including two subcategories: a) used in association with other drugs for drugs registered as single agents, b) used as single agents for drugs registered in association;
5) used with inappropriate timing, including two subcategories: a) used before the line of treatment for which the drug is registered, b) used after the line of treatment for which the drug is registered.

A hierarchical criterion of classification was adopted (in the order reported above). Therefore, categories were mutually exclusive except for points 4 and 5, for which a drug could have been used with inappropriate combination and inappropriate timing (Table 1). Registration status of each drug in Italy was considered at the time of the data collection (May 2006).
Finally, an analysis that considered each patient as a unit was performed in order to describe the appropriateness of the use of drug combinations, frequently used in oncology.

Table 1 - Categories of prescription

In-label prescription no. (%)

854/1053 (81.1)

Off-label prescription, no. (%)

199/1053 (18.9)

1.

Different cancer

 92 (46.2%)

2.

Different timing

 

 

Used earlier

 11 (5.6%)

 

Used in subsequent lines

 28 (14.0%)

3.

Rare neoplasia

 27 (13.6%)

4.

Inappropriate combination

 

 

Used in association while registered

 20 (10.1%)

 

  as single agent*

 

 

Used as single agent while registered

 21 (10.5%)

 

  in association§

 

 

 

 

*In 4/20 patients, capecitabine, used in combination while registered as a single agent, was also used after it was indicated.

§In 1/21 patients, cetuximab, used as a single agent while registered in association with irinotecan, was also used before it was indicated.



Results
Fifteen institutions (8 in the north, 3 in the center, and 4 in the south of Italy) agreed to participate in the study, which was conducted during the month of May 2006, enrolling an overall number of 644 patients. As can be observed in Table 2, patients were mostly females, older than 50 years and with a good performance status; cancer was metastatic in about two-thirds of the cases; breast and colorectal cancer accounted for more than 50% of the cases.
Classification of prescriptions according to the proposed scheme are reported in Table 1. Overall, 199/1053 (18.9%) prescriptions were off-label for at least one reason.
In 92 of 199 prescriptions (46.2%), the drugs were used on a neoplasm for which they were not approved (Table 3).

Table 2 - Characteristics of 644 patients

Characteristic

No.

%

 

 

 

 

Sex

 

 

 

Females

358

55.6

 

Males

282

43.8

 

Not specified

  4

 0.6

Age, yr

 

 

 

<50

127

19.7

 

50-64

250

38.8

 

≥65

263

40.8

 

Not specified

  4

 0.6

Performance status (ECOG)

 

 

 

0

430

66.8

 

1

151

23.4

 

2

 23

 3.6

 

3

  6

 0.9

 

Not specified

 34

 5.3

Presence of metastatic disease

 

 

 

No

240

(37.3)

 

Yes

404

(62.7)

Type of cancer

 

 

 

Breast

206

32.0

 

Colorectal

143

22.2

 

Lung

 85

13.2

 

Gastric

 27

 4.2

 

Ovarian

 24

 3.7

 

Head & neck

 20

 3.1

 

Bladder

 19

 3.0

 

Other

120

18.6


Table 3 - Description of off-label prescriptions due to type of cancer

Drug

Type of cancer

No. of prescriptions

 

 

 

5-Fluorouracil

Esophageal

1

Gemcitabine

Small cell lung

2

Cisplatin

Breast

2

 

Melanoma

2

 

Pancreas

1

 

Stomach

6

Oxaliplatin

Esophageal

1

 

Stomach

1

 

Pancreas

4

 

Unknown primary

1

Paclitaxel

Cervix

2

 

Endometrial

3

 

Small cell lung

5

Carboplatin

Endometrial

3

 

Breast

8

 

Non-small cell lung

10

 

Bladder

4

Capecitabine

Pancreas

2

 

Stomach

1

 

Unknown primary

1

Epirubicin

Endometrial

3

Irinotecan

Small cell lung

2

 

Stomach

3

Docetaxel

Stomach

1

 

Head & neck

2

 

Ovarian

1

Cladribrine

Non-Hodgkin lymphoma

4

Fludarabine

Non-Hodgkin lymphoma

2

Ifosfamide

Small cell lung

1

Methotrexate

Bladder

1

Topotecan

Small cell lung

2

Vinblastine

Renal

1

 

Melanoma

1

Vinorelbine

Small cell lung

1

 

Head & neck

2

Etoposide

Ovarian

1

 

Endometrial

3

 

Non-small cell lung

1


In 27 patients (13.6%), the drugs were prescribed for a rare neoplasm (i.e., fluorouracil and mitomycin in anal cancer, and cisplatin and gemcitabine in mesothelioma and biliary tree cancer) (Table 4).
In 21 patients (10.5%), the drugs were used alone despite the fact they were approved only in association (gemcitabine in breast and ovarian cancer, paclitaxel, docetaxel and lyposomal doxorubicin in breast cancer) (Table 5). Finally, 20 colorectal cancer patients (10.1%) were treated with capecitabine in association with other antineoplastic agents while the drug was approved for use as a single agent (Table 5).

Table 4 - Drugs used for rare neoplasms

Drug

Type of cancer

No. of prescriptions

 

 

 

Gemcitabine

Biliary tree

6

 

Pleural

2

 

Sarcoma

1

 

Testicular

1

Cisplatin

Biliary tree

3

 

Pleural

1

Etoposide

Testicular

3

 

Ovarian non-epithelial

1

5-Fluorouracil

Anal

1

Mitomicyn C

Anal

1

Oxaliplatin

Peritoneal carcinomatosis

1

 

Biliary tree

1

Paclitaxel

Testicular

1

 

Thymus

1

Carboplatin

Thymus

1

Epirubicin

Biliary tree

1

Tomudex

Peritoneal carcinomatosis

1

Table 5 - Drugs used alone or in combination but approved differently

Group and drug

Type of cancer

No. of prescriptions

 

 

 

Prescribed alone

 

 

but approved

 

 

in combination

 

 

Docetaxel

Breast

9

Gemcitabine

Breast

5

 

Ovarian

2

Paclitaxel

Breast 

2

Cetuximab

Colorectal

2

Lyposomal doxorubicin

Breast

1

Prescribed in combination

 

 

but approved alone

 

 

Capecitabine

Colorectal

20


Thirty-nine prescriptions were inappropriate because of their timing.
In 11 patients (5.6%), the drugs were used in lines of chemotherapy previous to that approved (i.e., paclitaxel, trastuzumab and capecitabine as first line for breast cancer and cetuximab as first line for colorectal cancer) (Table 6). In 28 patients (14%), the drugs were used in lines of chemotherapy subsequent to that approved (i.e, oxaliplatin and capecitabine as second and subsequent lines in colorectal cancer, paclitaxel in breast cancer, irinotecan combined with folinic acid and fluorouracil in colorectal cancer, bevacizumab as second line in colorectal cancer) (Table 6).

Table 6 - Drugs used for lines of treatment different from that for which they are registered

Group and drug

Type of cancer

No. of prescriptions

 

 

 

Prescribed after the line

 

 

for which it is registered

 

 

Irinotecan

Colorectal

13

Oxaliplatin

Colorectal

4

Trastuzumab

Breast

4

Bevacizumab

Colorectal

4

Paclitaxel

Breast 

2

Capecitabine

Colorectal

1

Prescribed before the line

 

 

for which it is registered

 

 

Paclitaxel

Breast

4

Capecitabine

Breast

3

Trastuzumab

Breast

2

Cetuximab

Colorectal

2


In the study, 246 patients received a single drug and 398 a combination of two or more antineoplastic agents. The prescription of 172 of 398 schemes of chemotherapy (43%) was not consistent with registration; details are reported in Table 7). In 92 combinations (54%), one or more drugs were not registered for the use that was being made of them. In 54 combinations (31%), the drugs were approved singularly but not associated; among these there were 17 combinations of capecitabine plus oxaliplatin for colorectal cancer (while capecitabine was registered as single agent only), 10 combinations of trastuzumab with vinorelbine, gemcitabine or capecitabine for breast cancer (while trastuzumab was registered only with paclitaxel and docetaxel), 8 combinations of capecitabine plus vinorelbine for breast cancer (capecitabine being registered only with docetaxel), 5 combinations of carboplatin plus paclitaxel for ovarian cancer (paclitaxel registered only with cisplatin). In 23 cases (13%), the combination was used after the line of treatment for which it was approved, including trastuzumab plus docetaxel or paclitaxel for breast cancer patients and irinotecan in different combinations with folinic acid and 5-fluorouracil or with bevacizumab for colorectal cancer. Finally, in 3 cases the combination was used before the line of treatment for which it was approved, including 2 patients who received cetuximab plus irinotecan and one who received cetuximab plus oxaliplatin, folinic acid and fluorouracil for colorectal cancer as first-line chemotherapy (while cetuximab was approved only in patients refractory to irinotecan in combination with irinotecan) (Table 7).

Table 7 - Reasons for off-label prescriptions of drugs used in combination (172 patients)

 

No. of patients (%)

 

 

One or more drugs not approved

92 (54)

Approved but not in combination

54 (31)

Not approved after first line

23 (13)

Not approved as first line

 3 (2)



Discussion
The off-label use of antineoplastic agents is an important health, legal and economic problem. To date, few data are available on off-label prescription, and data of prospectively evaluated off-label prescriptions in several oncology centers are lacking. This survey adds important information about the incidence and the characteristics of off-label prescription. First, off-label use of the single antineoplastic drugs represents less than 20% of the prescriptions, and most of them are based on evidence of efficacy (i.e., one or more randomized clinical trials or more phase II trials published in a major oncology journal) justifying their prescription (Table 3) (i.e., fluorouracil in esophageal cancer, cisplatin in breast and gastric cancer, paclitaxel in endometrial and cervical cancer, carboplatin in non-small cell lung, breast and bladder cancer, epirubicin in endometrial cancer, methotrexate in bladder cancer, topotecan in small cell lung cancer, irinotecan in gastric cancer). Based on the results of the present study, the Italian Drug Agency (AIFA) decided to review evidence supporting the use in clinical practice of many of these antineoplastic agents and then to reimburse them 12.
An apparently superior rate is observed when we consider chemotherapeutic schemes (43%), However, in this case, the evidence for non-approved combinations is strong and, therefore, the true off-label incidence not supported by scientific evidence is even lower. Therefore, the most important conclusion is that off-label prescriptions are limited.
Our study presents some important limitations, such as the scarce number of patients evaluated, which contrasts with the large variability induced by the variety of the type of neoplasm, of chemotherapeutic schemes, of antineoplastic drugs used, etc. Precisely, because some of the different categories identified are not mutually exclusive, and the choice of prevalence criteria to classify each one of them has a component of arbitrariness. Finally, the off-label classification proposed has not been tested for reproducibility and validity. All these limitations suggest that the results should be confirmed by other groups with other studies.

Appendix
Investigators and Participating Centers National Cancer Institute, Naples: Alessandro Morabito, MD, Sandro Pignata, MD, Carmen Pisano, MD; Medical Oncology Division, Perugia: Gianni Ciccarese, MD, Stella Porrozzi, MD, Sonia Fatigoni, MD; Dept. of Medical Oncology, Bergamo: Elena Rota Caremoli, MD, Stefania De Grossi, MD, Sara Acerboni, MD; Medical Oncology Division, Sacco Hospital, Milano: Elena Piazza, MD; Medical Oncology Division, Treviglio-Caravaggio Hospital, Treviglio: Sandro Barni, MD, Mary Cabiddu, MD; Medical Oncology Unit, San Bortolo Hospital, ULSS 6 Vicenza: Stefania Schiavon, MD, Marcello Magazu, MD; Medical Oncology Division, Galliera Hospital, Genoa: Cinzia Caroti, MD, Andrea Decensi, MD; Medical Oncology Division, Hospital Cardinal Massaia, Asti: Franco Testore, MD; Medical Oncology Division, Mater Salutis Hospital, Legnano: Andrea Bonetti, MD; Medical Oncology Division, G. Rummo Hospital, Benevento: Bruno Daniele, MD, Giacinto Turitto, MD; Ettore Conti Oncological Center, Hospital, Gaeta-Terracina: Enzo Veltri, MD; Medical Oncology Division, ULSS15 Alta Padovana, Camposampiero - Cittadella: Fernando Gaion, MD; Medical Oncology Division, Belcolle Hospital, Viterbo: Luca Moscetti, MD; Medical Oncology Division, University, Cagliari: Bruno Massidda, MD; Medical Oncology Division; Azienda USL 3, Pistoia: Marco Di Lieto, MD.

References
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 2. Boos J: Off-label use – label off use? Ann Oncol, 14: 1-5, 2003.
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12. Gazzetta Ufficiale n° 129 del 6.6.2007, Supplemento Ordinario n° 132, Agenzia Italiana del Farmaco, Determinazione 29.5.2007: Aggiornamento dell’elenco dei medicinali, istituito con il provvedimento della Commissione Unica del Farmaco (CUF) datato 20 luglio 2000, pubblicato nella GU n° 219 del 19.9.2000 con errata-corrige nella GU n° 232 del 4.10.2000, erogabili a totale carico del Servizio Sanitario nazionale, ai sensi dell’articolo 1 comma 4 del decreto legge 21.10.1996 n° 536 convertito dalla legge 23.12.1996 n° 648.



 
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