Basic Remarks:

(1)

Introduction

In various cancer types the spread of cancer into the sentinel lymph nodes or more or less exten- sively into regional basins is one of the indications for adjuvant or neoadjuvant chemotherapy. Tested and internationally accepted regimens are used as the basis of individual decision making.

However, in many cases the decision on adju- vant cancer treatment has to be tailored to the in- dividual case under scrutin and based on knowl- edge and evaluation of important individual bio- logical and prognostic features.

Therefore, it is only possible to lay down the most important international currently practiced therapy regimens related to the different cancer types discussed in the part of this book devoted to them.

Basic Remarks:

Side Effects and their Clinical Detection (see Table 1) Some substances have known frequent side effects, and prophylactic medication is recommended to deal with these. Examples are ifosfamide or cyclo- phosphamide (mesna is given to prevent cystitis) and cisplatin at doses >60 mg/m

²

, with which ami- fostine is given to prevent nephrotoxicity.

Furthermore, it may have affinity to proteins that regulate magnesium absorption.

Chapter 33

Therapy Regimens Used in Adjuvant and Neoadjuvant Treatment 33 of the Discussed Tumor Types

K. Possinger, A. Schauer, F. Griesinger, A.C. Roever

Table 1.Side effects and their clinical detection Side effect Organ-related methods used in

detection Cardiotoxicity Echocardiography,

measurement of ejection fraction Nephrotoxicity Control of electrolytes, urea, creati-

nine, especially creatinine clearance Neurotoxicity Detailed anamnesis, neurological ex-

amination, superficial (contact) and deep (vibration) sensitivity, reflexes Ototoxicity Audiogram

Hepatotoxicity Transaminases, in chronic states:

Quick, albumins, etc.

Bone marrow

toxicity Blood count

(2)

Adjuvant Chemotherapy Regimens for Breast Cancer

Classification According to Risk Factors

Well-established risk factors for recurrence of breast cancer are:

·

Tumor size

·

Nodal status

·

Grading

·

Endocrine responsiveness

·

Age

According to these risk factors a classification into minimal, average (moderate) and high risk was established and recently modified at the St.

Gallen Consensus Meeting 2003 (Table 2). Ap- proaches to therapy are based on this risk stratifi- cation (Table 3).

Chemotherapy and Endocrine Therapy Regimens The most frequently used regimens are shown in this chapter (Tables 4±12). The efficacy of the ad- juvant treatment depends largely on the dosage ap- plied and on the frequency of therapy courses.

Therefore reduction of the dosage and lengthening of the cycles should be avoided.

The cytostatic regimens are listed first. Note that CMF is still the most frequently used basic regimen (Tables 4, 5); in cases with higher degrees of malignancy (even in N0 stages) and in cases with positive nodes or HER/neu overexpression, however, anthracyclin-containing therapy regimens (Tables 6±9) are definitely preferred. In cases with

Table 2. Classification according to risk factors for patients

with node-negative breast cancer (modified according to Goldhirsch et al. 2003)

Riskcategory Endocrine responsive Endocrine non-responsive Minimal ER and/or PR positive and

all of the following:

pT £2 cm, grade 1, age >35 years

Not applicable

Average ER and/or PR positive and one of the following:

pT >2 cm, grade 2±3, age <35 years

ER and PR negative

Table 3. Adjuvant systemic treatment for patients with operable breast cancer (modified according to Goldhirsch et al.

2003)

Risk category Endocrine responsive Endocrine nonresponsive

Premenopausal Postmenopausal Premenopausal Postmenopausal Node negative,

minimal risk Tamoxifen or none Tamoxifen or none Not applicable Not applicable Node negative,

average risk GnRH analogue + tamoxifen or chemotherapy ? tamoxifen or tamoxifen or GnRH-A

Tamoxifen (or aro- matase-inhibitor) or chemotherapy ? tamoxifen

Chemotherapy Chemotherapy

Node positive Chemotherapy ? tamoxifen (Ô GnRH-A) or GnRH-A + tamoxifen

Chemotherapy ? tamoxifen or tamoxifen

Chemotherapy Chemotherapy

Table 4.Classic CMF regimen (Bonadonna 1995)

Symbol Expansion Dosage Route Mode Days

C Cyclophosphamide 100 mg/m² p.o. Days 1±14

M Methotrexate 40 mg/m² i.v. Bolus Days 1, 8

F 5-Fluorouracil 600 mg/m² i.v. Bolus Days 1, 8

6 cycles, every 4 weeks

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Adjuvant Chemotherapy Regimens for Breast Cancer 505

Table 5.Modified i.v. CMF regimen (Bonadonna 1995)

C Cyclophosphamide 600 mg/m² i.v. Bolus Days 1, 8

M Methotrexate 40 mg/m² i.v. Bolus Days 1, 8

F 5-Fluorouracil 600 mg/m² i.v. Bolus Days 1, 8

6 cycles, every 4 weeks

Table 6.Regimens including anthracycline/anthraquinone: doxorubicin/cyclophosphamide (AC)

A Adriamycin (doxorubicin) 40 mg/m² i.v. Bolus Day 1

C Cyclophosphamide 600 mg/m² i.v. Bolus Day 1

Four cycles, every 3 weeks; caveat: doxorubicin-limiting dosage

Table 7.FEC (Levine 1998)

Expansion Dosage Route Mode Days

5-Fluorouracil 500 mg/m² i.v. Bolus Days 1, 8

Epirubicin 60 mg/m² i.v. Bolus Days 1, 8

Cyclophosphamide 75 mg/m² p.o. Days 1±14

Six cycles, every 4 weeks; caveat: epirubicin-limiting dosage

Table 8.Doxorubicin/cyclophosphamide ? paclitaxel (AC?T) (Henderson et al. 1998)

A=D Doxorubicin 60 mg/m² i.v. 15-min infusion Day 1

C Cyclophosphamide 600 mg/m² i.v. 30-min infusion Day 1

Repeat from day 22 for a total of four cycles; then paclitaxel

T Paclitaxel 175 mg/m² i.v. 90-min infusion Day 1

Four 3-week cycles of cyclophosphamide followed by four 3-week cycles of paclitaxel

Table 9.TAC (Nabholtz 2002, 2003)

Expansion Dosage Route Mode Days

Docetaxel 75 mg/m² i.v. 1-h-infusion Day 1

Doxorubicin 50 mg/m² i.v. bolus Day 1

Cyclophosphamide 500 mg/m² i.v. 15-min-infusion Day 1

Six 3-week cycles; caveat: doxorubicin-limiting dosage

Table 10.Tamoxifen (Fisher et al. 1996)

Agent Dose Route Regimen

Tamoxifen 20 mg (absolute) p.o. Daily, continuous^a

aDuration: 5 years

(4)

c-erb B1 and B2 overexpression, substitution of ta- moxifen (Table 10) by anastrozole or letrozole (Ta- bles 11, 12) is possible.

A few publications documenting current inter- national experience may give some indication in which cases it is better to use the new substances in preference to tamoxifen.

In a joint analysis of two randomized trials in- vestigating three versus six cycles of CMF, Colleoni et al. (2002) showed that three cycles rather than six cycles were adequate in both studies for pa- tients older than 40 years with estrogen-receptor- positive tumors (n=594; risk ratio 0.86; 95% con- fidence interval 0.68±1.08; P=0.19).

The 95% confidence interval excluded an ad- verse effect of more than 2% with respect to abso- lute 5-year survival.

In contrast, three cycles appeared to be inferior to six cycles for women under 40 years old (n=190; risk ratio 1.25; 95% confidence interval 0.87±1.80; P =0.22) and for women with estrogen- receptor-negative tumors (n=302; risk ratio 1.15;

95% confidence interval 0.85±1.57; P=0.37).

Comments on Steroid Receptor Expression Threshold for Tamoxifen Therapy and on Effectiveness of Anastrozole and Letrozole

Responsiveness to endocrine therapy regimens de- pends on the expression of ER and/or PR in the cancer cells (percentage of positive cancer cells and staining intensity).

The exact threshold beyond which steroid hor- mone receptor expression limits the endocrine re- sponsiveness of tumors is unknown. At present, approximately 10% positive staining of cancer cell nuclei might be considered a threshold for definite endocrine response.

With a view to the far-reaching consequences (choice of the optimal therapy regimen, long-term high costs), highly skilled immunohistochemical quantitative receptor analysis with appropriate quality controls is necessary.

Information on the percentage of positive can- cer cells and the staining intensity, summarized in individual cases as grade I±III, must be dealt with by the investigating pathologist.

Pros and Contras of Tamoxifen for Breast Cancer Prevention

(Scientific Discussion see Cykert 2003)

Comments on the International Breast Cancer In- tervention Study (IBIS-1) report (Sept 14, p 187, 2002) criticize the underestimation of tamoxifen's benefit in breast cancer prevention and the lack of important explanations for tamoxifen-related mor- tality rates (Cykert 2003). In addition, Caine et al.

(2003) recommend thrombosis prophylaxis and doubt whether patients at risk should receive ta- moxifen in the first place. In the authors' reply, Cu- zick for IBIS reflects on the overall reduction in breast cancer by one third (N.B. similar results in the IBIS group and in European trials), but em- phasizes that there is a serious need for thrombo- sis prophylaxis.

Alternatives to Tamoxifen

Buzdar et al. stressed the effectiveness of anastro- zole (1mg respectively 10 mg/day) as long ago as 1996. They state that the effects are similar to those of megestrol acetate, which was in trial at the same time. Anastrozole was even effective in postmenopausal women with advanced breast can- cer that had progressed during tamoxifen therapy.

In 2003, Buzdar reported on new findings, com- paring anastrozole (1mg once daily) alone and in combination with tamoxifen (20 mg once daily). In summary, he states that anastrozole is quite effec- tive: (a) in breast cancer prevention; (b) in the early stages of breast cancer as already document- ed; and (c) also in cases of receptor-positive can- cer that has progressed since the menopause.

In the comparative studies of ATAC and tamoxi- fen (2002) an improvement in disease-free survival was demonstrable in hormone-receptor-positive,

Table 11.Anastrozole (Buzdar 1996)

Anastrozole 1mg p.o. Daily

Table 12.Letrozole (Dombernowsky 1998)

Letrozole 2.5 mg p.o. Daily

(5)

but not in hormone-receptor-negative, cases. The incidence of phase-shifted development of contra- lateral breast cancer was significantly lower in the group treated with anastrozole than in subjects treated with tamoxifen (P=0.007).

In addition, tolerance of anastrozole was also superior to that of tamoxifen, anastrozole less fre- quently being followed by:

Endometrial carcinoma development P=0.02 Vaginal bleeding and discharge P=0.0001

Cerebrovascular events P=0.0006

Venous thrombosis P=0.0006

Tamoxifen was better tolerated than anastrozole with respect to musculoskeletal disorders and frac- tures (P=0.0001for each).

In a double blind randomized trial Domber- nowsky et al. (1998) demonstrated that the aroma- tase inhibitor letrozole has a dose-dependent effect and is more effective and better tolerated than me- gestrol acetate (Table 12) in the treatment of post- menopausal women with advanced breast cancer previously treated with antiestrogens. In a phase III randomized clinical trial Ellis et al. (2001) con- firmed the results of Dombernowsky et al. (1998).

They showed that in postmenopausal patients with ER- and/or PR-positive primaries the response to tamoxifen (20 mg daily: response rate 41%) was inferior to the response to letrozole (2.5 mg daily, response rate 60%).

The differences in the response rates ± letrozole versus tamoxifen ± were especially marked in c-erb B1- and/or c-erb B2-positive cancer cases (RR88 versus 21%, P =0.004).

These results led to the conclusion that c-erb B1 and c-erb B2 signaling through the ER is ligand dependent and that the growth-promoting effects of these receptor tyrosine kinases on ER-positive cancer can be inhibited by potent estrogen depri- vation therapy.

Anti-HER2 Therapy

At present, no adjuvant therapy is recommended in N0M0 cases.

In p185 (HER/neu) N-positive and/or M-positive cases the use of anti-HER (herceptin) within study programs must be discussed and should be recom-

mended. There is a positive correlation between overexpression of HER/neu and high proliferation of the cancer, vimentin positivity, BAX positivity, and lymphogenic and hematogenous tumor pro- gression; and a negative correlation between over- expression of HER/neu and ER and PR status and positive BCl2 reaction.

Overall, HER/neu tumors generally have a worse prognosis than HER2-negative disease. Anti-HER2 therapy is a monoclonal antibody treatment. In contrast to chemotherapy it inhibits tumor growth without affecting normal tissues and obviously stimulates the patient's immune response directed against the tumor.

It is worth knowing that Trastuzumab (hercep- tin) induces HER2 receptor down-regulation and this results in inhibition of critical signaling path- ways (ras-RAF-Mark and PI 3K/Akt) and blocks cell cycle progression by inducing the formation of p27/Cdk2 complexes (Albanell et al. 2003).

In a trial involving 222 patients carried out by Cobleigh et al. (2000) the cancer response rate was 16%. Vogel et al. reported at the ASCO meeting in 2000 (see also 2003) on first-line treatment of 114 cases with anti-HER2 monotherapy. The results are summarized in Table 13.

Combined Therapy Modality

In the randomized combination study of Slamon et al. (ECCO 1999, Abstract 1261) one patient group received anti-HER2 therapy (H) plus chemotherapy (CT) and a second group, chemotherapy alone

Adjuvant Chemotherapy Regimens for Breast Cancer 507

Table 13. Results obtained with first-line anti-HER2-monotherapy (Vogel et al. 2000)

Standard dose High dose Anti-HER2

regimen 4-mg/kg loading dose, then 2 mg/

kg weekly

8-mg/kg loading dose, then 4 mg/

kg weekly

No. of patients 59 55

Overall response

rate 25% 27%

Median time to

progression 3.5 months 3.8 months Median overall

survival 22.9 months 25.8 months

(6)

(Table 14). This was the first treatment for 489 pa- tients using this scheme for advanced cancer, but 90% of the patients had adjuvant therapy. The drugs used were anthracycline plus cyclophospha- mide (AC) or paclitaxel (P).

Administration schedule. Anti-HER2 was given weekly; chemotherapy every 3 weeks.

With both regimens (AC, P plus anti-HER), overall response and median time to progression were better with added anti-HER2 therapy than alone.

In the Leyland-Jones (2003) studies Trastuzu- mab was given as a loading dose of 8 mg/kg i.v.

(day 1) after paclitaxel 175 mg/m

²

(day 0). After- wards Trastuzumab was given at a dosage of 6 mg/

kg on the same day as paclitaxel (175 mg/m

²

) every 3 weeks for seven cycles.

Trastuzumab (herceptin) (Genentech Inc., South San Francisco, Calif.) is not recommended or paid for by insurance companies for the adjuvant treat- ment of breast cancer. The HERA studies sup- ported by the Roche company to investigate adju- vant HER2-positive cancer cases are still in pro- gress, so that no end-results are yet available.

In contrast to this inconclusive state, herceptin therapy is routinely applied for the palliative treat- ment of HER2-positive cancer cases, and in these circumstances the costs are paid by insurance companies, in Germany for example.

The current status on payment in other coun- tries is not known to us at present.

Table 14. Results of the pivotal anti-HER2 therapy/chemotherapy combination study (Slamon et al., ECCO 1999, Ab- stract 1261, cited in Cobleigh, MBCC 2000) (CT chemotherapy, H anti-HER2 therapy, P paclitaxel, AC anthracycline + cyclophosphamide)

Regimen No. of

patients Overall response rate (%)

Median time to progression (months)

CT+H 235 49 7.6

CT 234 32 4.6

P+H 92 42 6.9

P 96 1 6 3.0

AC+H 143 52 8.1

H 138 43 6.1

(7)

Therapy Regimens for Thyroid Cancer

Radioiodine Therapy

Adjuvant treatment of thyroid cancers with iodine- 131 (radioiodine therapy, RIT) is indicated in all cases of follicular and papillary cancers in which primaries are larger than 1 cm across (pT1a), which in stage pT1b also means N0M0 cases.

Most papillary cancers are also 131-iodine sen- sitive, because 98% of cancers of this subtype synthesize thyroglobulin. The treatment is advised regardless of whether or not there is lymph node involvement, and the main purpose of a search for SLN is therefore the achievement of precise locore- gional surgical cancer clearance.

RIT is not indicated in anaplastic and medullary thyroid cancers.

Execution of RIT. As a rule, RIT is governed by the guidelines of radiation control laws of the dif- ferent countries. The standard activity used is 1±

3 GBq iodine-131 or the dose is estimated individ- ually according to Marinelli, with the aim of a fo- cal dose of more than 300 mCi (see German Can- cer Society 2000).

Daily controls are needed during the course of this therapy:

·

Measurement of activity for dosimetric control

·

Whole-body scintigraphic evaluation to reach current staging values at the day of release, but not before 72 h after administration of iodine- 131. Early side effects are seen 8±14 days after com- pletion of RIT: painful swelling of the remaining thyroid gland tissue in 10±20% of cases; transitory gastric symptoms in approximately 30%; transitory bone marrow syndrome (thrombopenia and leuko- penia) in approximately 70%; and sialadenitis in about 30%.

Late side effects are sicca syndrome (in 10±20%

of cases), bone marrow depression, leukemia (1%), and azoospermia (this is rare).

Therapy of Locoregional Recurrence

·

Primarily surgical locoregional clearance of nod- al and/or delineated soft tissue relapses.

·

Subsequent radioiodine diagnosis and, in the case of focal iodine storage, iodine-131 therapy (standard activity 5±8 GBq iodine-131).

·

In cases of nonstorage of iodine percutaneous local radiotherapy is used; radiochemotherapy is applied in cases with distant metastases.

Therapy of Distant Metastases

·

In cases with a single metastasis, surgical re- moval, if possible, is the method of choice.

·

In the case of local inoperability RIT can be ad- vised when radioiodine storage is sufficient.

·

In cases with insufficient radioiodine storage percutaneous radiotherapy can be tried.

·

Depending on the localization, 30 Gy (10´3 Gy) can be given in 2 weeks or 45±50 Gy in 5 weeks.

Chemotherapy

·

In cases with diffuse metastasis mono- or com- bined chemotherapy or radiochemotherapy can be applied.

·

Monotherapy with doxorubicin is possible. The effects of other agents (cisplatin, carboplatin, etoposide) are small compared with that of doxorubicin.

In cases with diffuse metastasis of an undiffer- entiated cancer the effect of polychemotherapy is superior to that of monotherapy. The use of doxo- rubicin plus cisplatin or etoposide gives better re- sults than monotherapy with doxorubicin alone.

Multimodal therapy regimens should be selected after consultation within interdisciplinary teams and should be applied exclusively in specialized cancer centers.

Therapy Regimens for Thyroid Cancer 509

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Therapy Regimens for Head and Neck Cancers

Adjuvant therapy regimens can be used with cura- tive intent and for palliation in head and neck cancers.

Radiotherapy can theoretically be used

·

As the sole treatment regimen.

·

As an additional (supplementary) treatment be- fore or after surgery.

·

As interstitial brachytherapy to increase the local dosage (boost) after extensive percutaneous radiotherapy or as the only method in focal radio- therapy for a small primary tumor or a relapse.

·

Postoperatively to allow more precise determi- nation of what further treatment is indicated on the basis of histopathology-supported staging.

·

Resection with curative intent after neoadjuvant therapy (radiotherapy and/or chemotherapy) must take account of pretherapeutic assessment of the cancer's extension. Such strategies are in contrast to the exact surgical locoregional can- cer clearance based on the SLN concept.

·

In the case of inoperable cancer high-dosage radiotherapy or combined radiochemotherapy is indicated.

·

Locoregional recurrences in patients who have not previously undergone radiotherapy can be treated by radiotherapy.

List of Indications for Radiotherapy

·

RT is possible in R1 and R2 resection for surgi- cal cancer clearance.

·

pT4 with cancer infiltration of regional tissue structures (pN2, 3)

·

Perforation of the lymph node capsule to a lim- ited extent

·

Regional lymphangiosis carcinomatosa

·

Depending on the localization of the primary, pT1±3pN0 or pT1±3pN1. In positions 3±5 the strategies of the SLN concept can help to ensure radiotherapy is used more precisely.

Combined Radiochemotherapy. In cases of locore- gional inoperability locoregional high-dosage radiotherapy is also unsatisfactory. Simultaneous administration of radio- and chemotherapy (RCT) seems to be more successful. The following agents have been used in clinical trials: 5-fluorouracil (5- FU), cis- or carboplatin, mitomycin, and taxane.

The use of 5-FU and cisplatin has given the best results.

Radiotherapies have been improved with the in- troduction of hyperfractionated and accelerated radiotherapy. Randomized studies in which RCT is administered according to the preliminary results obtained are in progress.

Cancers of the lip, oral cavity, oropharynx, hy- popharynx, and larynx must be treated with due consideration for patient age, localization of the primary, disease stage and surgical options open.

Especially in advanced stages, radiotherapy or RCT must be considered as the sole treatment or an ad- ditional treatment.

Current treatment strategies available for oro- pharyngeal and laryngeal cancers and the option of SLN-related N staging are presented in Table 15.

Intraoperative Radiotherapy of Head and Neck Cancers

Intraoperative electron beam radiotherapy (IORT), used at the Mayo Clinic for head, neck and skull base cancers in dosages of 6±15 MeV (6 MeV is the dosage most commonly used) at doses of 12.5±

22.5 Gy produces tumor control and survival in patients who are likely to have microscopic resid- ual disease, especially in sites where it is difficult to resect, such as the skull base (Pinheiro et al.

2003).

Combined Radiochemotherapy: New Approaches With chemoradiotherapy ªFARº (=5 Fluorouracil 250 mg/day i.v.), vitamin A (50,000 U/day i.m.) and external radiation (2 Gy/day upto 60±70 Gy) in T2N0 glottic cancer, the cumulative 5-year voice preservation and complete laryngeal preservation rates were 91% and 87%, respectively. The cumula- tive 5-year disease-free survival rate was 97% (Ku- mamoto et al. 2002).

ªHyperradplatº (hyperfractionated radiation and intra-arterial cisplatin) combination therapy in stage III and IV head and neck cancers has been successfully tried by Valentino et al. (2002).

These authors recommend new evaluation tech-

niques, such as metabolic imaging and molecular

analysis, as tools for exploration of interval surgi-

cal resections.

(9)

Therapy Regimens for Head and Neck Cancers 511

Table 15. Current treatment regimens for oropharyngeal and laryngeal cancers (RND radical neck dissection, ERND ex- tended RND, MRND modified RND, SND selective lymph node dissection, RCT radiochemotherapy, RT radiotherapy)

Localization

of primary Lip Oral cavity Pharynx Larynx

Stage-related

indications Oropharynx Nasophar-

ynx Hypopharynx

pT1±2 Surgery or

primary RT Surgery or

primary RT pT1:

transoral or transcervical excision

Standard:

primary RT (PN+N)

pT: transoral or transcervical partial resection of hypopharynx

Supraglottic:

T1±3: partial laryngectomy;

pT1±2: Sur- gery not in sano (R1±2)

Postopera-

tive RT Postopera-

tive RT T2±4: lateral pharyngec- tomy

Occasionally

operation T2: as before plus ipsilateral thyroidectomy

T3: sometimes with partial pha- ryngectomy

pT3±4 Resection

plus plastic reconstruc- tion

Resection plus plastic reconstruc- tion

T3±4: plus laryngectomy

In stages III and IV simultaneous RCT

T3: partial resection of hypopharynx plus laryngectomy plus ipsilateral thyroidectomy

T4: total laryngectomy plus partial pharyn- gectomy

T4: plus mandibulec- tomy

T4: pharyngola- ryngectomy plus ipsilateral thyroidectomy

Glottic: T1:

chordectomy

R1±2: post-

operative RT T2: partial resec-

tion in special cases laryngectomy

pT2±4 (uvu- la, palate, tonsil, root of tongue)

T3 and T4: partial pharyngec- tomy plus laryngectomy (in some cases partial) In early

stages SLN search can be tried

+ + + + + Subglottic: T1±4:

no standard therapy; rare lesion

N stage

N0 In pT1:

ªwait and seeº; SLN labeling

In pT1ªwait and seeº;

SLN labeling

SND or

observation In pT1: ªwait and

seeº or SND, possibly with guidance from search for SLN

Mostly bilateral SND; >T1: bilateral neck dissection; SLN guidance must be evaluated N1SND or

MRND SND or

MRND Node posi-

tivity still existing after RT: neck dissection

SND, possibly with guidance from search for SLN, or MRND

SND or MRND, with guidance from search for SLN

(10)

In a phase I study (Spencer et al. 2003) in unre- sectable head and neck cancers chemotherapy and reirradiation was used. 5-Fluorouracil administered as a bolus was escalated from 300 mg/m

²

to a 10- hour infusion increased by increments of 150 mg/

m

²

per day. Hydroxyurea remained constant at 1.5 g.

Chemotherapy was given in weeks 1and 4. RT was given daily: 2.0 Gy per fraction in weeks 1and 2, followed by a 1-week break, then hyperfractio- nated in weeks 4 and 5, to give a total dose of 50 Gy. The 1-year survival rate was 41%.

A mass reduction of local tumor infiltration in advanced head and neck cancers was achieved at least in some cases by intratumoral cisplatin epi- nephrin gel (CDD-epi-gel) infiltration (Castro et al. 2003; phase III study in North America).

Amdur et al. (2001) reported on radiotherapy and neck dissection for T1±2 sinus piriformis can- cers with 5-year local control rates of 90% for T1 cancers and 80% for T2 lesions. Chemotherapy was found to be unlikely to improve larynx preser- vation, but may have improved local and regional control.

Treatment of Cancer with Specific Oncogene Over- expression and Mutated Suppressor Gene Expression (c-erb B2, p53)

Evaluation of the prognostic significance of c-erb B2 overexpression in patients treated with chemo-

therapy for recurrent head and neck cancers has been carried out by Shiga et al. (2002). Patients re- ceived either cisplatin and 5-fluorouracil or cispla- tin and paclitaxel (Taxol). Response to chemother- apy was significantly correlated with improved sur- vival (progression-free survival P= 0.0005; overall survival P=0.007). Overexpression of c-erb B2 was associated with significantly decreased progres- sion-free survival (P=0.023) and overall survival (P=0.029).

Bradford et al. (2003) reported results demon- strating higher sensitivity of head and neck can- cers expressing mutated p53.

As tested in cell lines, the average ID

50

(drug dose required to inhibit 50% of cell growth) of cis- platin was 6.8 lM for cancer cell lines with mutant p53, whereas the average ID

50

for wild-type cell lines was 13.7 lM. These results support the im- portance of testing cancers for mutated p53 tumor suppressor gene activity as an important marker for response to cisplatin in head and neck squa- mous cell cancers (HNSCC).

Treatment of Cancers with Special Localizations After radiotherapeutic locoregional treatment for esthesioneuroblastoma (elective neck irradiation) at 5 years, the local control rate was 59%; the cause-specific survival rate, 54%; and the absolute survival rate, 48% (Monroe et al. 2003).

Table 15(continued) Localization

of primary Lip Oral cavity Pharynx Larynx

N2 SND or

MRND; in selected cases RND

SND or MRND; in selected cases RND

SND (with guidance from search for SLN) or MRND; in special cases RND

SND or MRND;

in special cases RND

N3 RND or

MRND RND or

MRND RND, MRND

or ERND N3a (squa- mous cell cancers):

operation before RT

RND; possibly

MRND or ERND RND; possibly MRND, ERND

(11)

Chemotherapy Regimens for Lung Cancer

Chemotherapy Regimens Most Commonly Used in Treatment of Small-Cell Lung Cancers

The regimens most frequently used in small-cell lung cancer (SCLC) are cisplatin + etoposide (Ta- ble 16), adriamycin + cyclophosphamide + vin- cristine (Table 17) and epirubicin + cyclophospha- mide + vincristine (Table 18). Another regimen used is carboplatin + etoposide + vincristine (Ta- ble 19).

New Results and Approaches in Treatment of Small Cell Lung Cancer

In a randomized phase III study (Reck et al. 2003), patients in stages I±IV with SCLC disease were treated with paclitaxel, the topoisomerase II inhibi- tor etoposide, and carboplatin. Patients with pre- viously untreated disease showed improved pro- gression-free and overall survival and less frequent hematological toxicities than patients treated with standard therapy.

Triple combination therapy (Greco 2003) using topotecan with paclitaxel and carboplatin yielded impressive complete response rates in SCLC treat-

Chemotherapy Regimens for Lung Cancer 513

Table 16.Cisplatin (P)/etoposide (E) regimen used in small-cell lung cancer (SCLC)

Symbol Expansion Dose Route Mode Regimen

P Cisplatin 90 mg/m² i.v. Bolus Days 1±7

E Etoposide 100 mg/m² i.v. Bolus Days 1±3

Every 3 weeks

Table 17.Adriamycin/cyclophosphamide/vincristine (ACOII) regimen used in SCLC (Niederle 1982)

Symbol Expansion Dose Route Mode Regimen^a

A Adriamycin 60 mg/m² i.v. Short time Day 1

C Cyclophosphamide 750 mg/m² i.v. Short-time Days 1, 2

O Vincristine 1.5 mg^a i.v. Bolus Days 1, 8, 15

Every 3 weels

aPatients <50 years: 2 mg; <60 years: 1.5 mg, >60 years: 1 mg

Table 18.Epirubicin cyclophosphamide vincristine (EPICO)

Symbol Expansion Dose Route Mode Regimen

Epi Epirubicin 70 mg/m² i.v. Short term Day 1

C Cyclophosphamide 1000 mg/m² i.v. Short time Day 1

O Vincristine 2 mg i.v. Bolus Day 1

Every 3 weeks

Table 19.Carboplatin/etoposide/vincristine (CEV) regimen used in SCLC (Eberhardt 1993)

Agent Dose Route Mode Regimen

Carboplatin 300 mg/m² i.v. Short time Day 1

Etoposide 140 mg/m² i.v. 2-h infusion Days 1, 2, 3

Vincristine 1.5 mg i.v. Bolus Days 1, 8, 15, 22

Every 4 weeks

(12)

ment of 37±51% in cases with recurrence in lim- ited stages.

In treatment of SCLC using mitomycin 8 mg/m

²

on day 1, vinblastine 4 mg/m

²

on days 1±8, and cisplatin 100 mg/m

²

on day 1, or the same regimen except with cisplatin substituted by carboplatin 300 mg/m

²

on day 1every 3 weeks the following results were obtained: the carboplatin regimen had a significantly better toxicity profile than the cis- platin-containing regimen (documented by the EORTC questionnaires).

The response rates were 43.1and 38.6%, respec- tively in the MVP and the MVC arm (P=0.59).

The median survival rates of 10.2 and 7.2 months, respectively, for the cisplatin and carboplatin arms (P=0.39) did not differ significantly (Paccagnella et al. 2004).

Chemotherapy Regimens for Non-Small-Cell Lung Cancer

Surgery and radiotherapy remain the best treat- ment options for resectable non-small-cell lung cancer (NSCLC). The role of adjuvant chemother- apy in successfully resected NSCLC is still highly controversial. Whereas the largest trial (IALT, In- ternational Adjuvant Lung Cancer Trial) (see Tona- to 2002) showed a small but significant survival benefit for patients treated with cisplatin-based chemotherapy, the Italian trial (ALPI) (see Alexa- nian and Torri 2000) and the UK trial (Big Lung Trial) (see Evans 2004) did not show any signifi- cant differences.

In patients with unresectable tumors combina- tion chemotherapy is the cornerstone of treatment.

Patients with a good performance status benefit more from the combination therapy than patients with a poor condition. New drugs have been evalu- ated (taxanes, gemcitabine, vinorelbine). Up to now there is no standard therapy regimen, but therapies should be platinum based. Tables 20±23 show combination chemotherapy regimens fre- quently used for the treatment of NSCLC.

Table 20.Cisplatin/gemcitabine (Schiller 2000) Cisplatin 100 mg/m² i.v. Day 1 Gemcitabine 1000 mg/m² i.v. Days 1, 8, 15 Every 4 weeks

Table 21. One example of a new chemotherapy regimen developed for NSCLC and so far applied only under study conditions: carboplatin + paclitaxel

Paclitaxel 225 mg/m² i.v. Day 1

Carboplatin AUC 6 i.v. Day 1

Repetition from day 28

Table 22.Cisplatin/vinorelbine

Cisplatin 80 mg/m² i.v. Day 1 Vinorelbine 30 mg/m² i.v. Days 1, 8, 15 Every 3 weeks

(13)

For elderly patients and for patients with a poorer performance status (³2) monochemother- apy with a newer drug, such as vinorelbine, doce- taxel or gemcitabine, is beneficial (Tables 24±26).

Single-agent docetaxel therapy is also discussed by Laurie and Kris (2000).

New Therapeutic Approaches

One promising new therapeutic approach is tar- geted immune therapy. The epidermal growth fac- tor receptor (EGFR) is such a promising target for anticancer drugs, and with EGFR tyrosine kinase inhibitors (gefitinib=Iressa, erlotinib=Tarceva) and a monoclonal antibody against EGFR (cetuxi- mab=Erbitux), new drugs have been developed.

Gefitinib has recently been approved in various countries; in Europe it is approved only in Switzer- land, and only since April 2004.

Gefitinib is used as a single agent in a dose of 250 mg/day orally. Response rates were 18.4% and

11.8% in the IDEAL trials I and II (Iressa dose evaluation in advanced lung cancer).

New Approaches in Treatment

of Advanced Non-Small-Cell Lung Cancer

A combination therapy using vinorelbine and docetaxel was carried out by Miller (2000), who also suggested phase II and III studies.

Reboul (2004) has recently reviewed past and current strategies for treatment of locally advanced NSCLC. After giving a detailed overview of the phase II and III study results with cis- or carbo- platin, accelerated hyperfractionated radiotherapy, and the radiosensitizing effects of cisplatin, he em- phasizes the significance of `third-generation drugs,' such as taxanes, vinorelbine and gemcita- bine, with favorable toxicity profiles and major radiosensitivity properties. He states that weekly administration of these drugs during a full course of conformational radiotherapy with up to 70 Gy resulted in a median survival excess with a 2-year survival rate of 50% and a 3-year survival rate of 40%. The respective benefits of either induction and consolidation full-dose chemotherapy with these new drugs before or after concurrent che- moradiotherapy are currently being evaluated in phase III studies.

Ongoing studies of topotecan/paclitaxel alternat- ing with etoposide/cisplatin and thoracic irradia- tion in cases with limited SCLCs (Lu et al. 2003) and by Treat (2003) using topotecan and gemcita- bine and vinorelbine are in progress. Ginsberg, at the Sloan Kettering Cancer Center (2000), de- pressed by the results of postoperative chemother- apy, radiotherapy and chemoradiotherapy, has now turned to induction therapeutic regimens (chemo- therapy or chemoradiation). Phase II and III stud- ies were encouraging, especially in stages I B and II. Ginsberg (2000) suggests that multimodality treatment with initial induction therapy improves

Chemotherapy Regimens for Lung Cancer 515

Table 23.Mitomycin C/ifosfamide/cisplatin (MIC) (Rosell et al. 1994)

Agent Dose Route Mode Regimen

Mitomycin C 6 mg/m² i.v. Bolus Day 1

Ifosfamide 3 g/m² i.v. 24-h infusion Day 1

Cisplatin 50 mg/m² i.v. 1-h infusion Day 1

aRepetition from day 29

Table 24. Vinorelbine as a single agent for elderly patients or those with poor performance status

Vinorelbine 30 mg/m² i.v. Days 1, 8 Every 3 weeks

Table 25. Docetaxel as a single agent for elderly patients or those with poor performance status

Docetaxel 100 mg/m² i.v. Day 1 Every 3 weeks

Table 26.Regimen used by Sculier et al. (2000) in a phase II trial of gemcitabine as second-line chemotherapy for NSCLC, with an overall response rate of 72% and a partial response rate of 6%

Gemcitabine 1mg/m² i.v. Days 1, 8, 15, every 4 weeks Partial response 6%

(14)

patient tolerance to chemotherapy, and perhaps also survival. Several phase III trials are under way in attempts to confirm these early encouraging re- ports.

Reduction of Toxicities in the Course of Chemotherapy by Amifostine

In locally advanced NSCLCs amifostine was used to reduce radiochemotherapeutical induced toxici- ties (Antonadou et al. 2003). The grouping was ap- plication of paclitaxel 60 mg/m

²

or carboplatin once weekly during a 5- to 6-week course of con- ventional radiotherapy given as 2-Gy daily frac- tions, 5 days a week upto a total dose of 55±

60 Gy.

Endoscopic controlled grade 2 or more ad- vanced esophagitis was significantly reduced by amifostine protection (P=0.061).

Amifostine was also recommended for protec- tion against radiation-induced pneumonitis by Choi (2003). The drug was well tolerated, with low incidences of toxicities (nausea and vomiting 3±

5%) and of transient hypotension during intrave- nous infusion (7%).

Ongoing Approaches blocking Neoangiogenesis in NSCLC

Bates (2003) reported on ongoing studies within the ZD-6474 project carried out in the Microvascu- lar Research Laboratories at the University of Bris- tol, UK.

ZD-6474 is a series of studies in which inhibi- tors of the vascular endothelial growth factor re- ceptor tyrosine kinase, which also has activity against the epidermal growth factor receptor tyro- sine kinase, are being tested. Phase II trials in NSCLC were ongoing in 2003.

Successful use of antiangiogenic drugs in com- bination with chemotherapeutic agents in the treatment of advanced colon cancer patients has encouraged to try attempts to treat NSCLC patients in a similar way (Kerbel 2004). Unfortunately, the initial pilot studies demonstrated that the forma- tion of proangiogenic and angiogenic factors was more difficult in subtypes of NSCLC. However, there may be promising candidates for acutely act- ing vascular targeting agents.

Further research work is in progress to evaluate

particular drug targets (e.g. bioactive VEGF recep-

tor-2 bound VEGF). It is necessary to work out

how to select the optimal biologic/therapeutic

doses of antiangiogenic drugs and how best to

monitor antiangiogenic drug activity in tumors

and determine the optimal combinations to use

with chemotherapy regimens.

(15)

Therapy Regimens for Esophageal Cancer

New Protocol in Chemotherapeutic and Combined Treatment

In superficial esophageal cancers, analysis by Shi- mizu et al. 2004 resulted in 5-year overall survival rates of 87% in surgically treated cases only (EMR) and approx. 100% in cases treated with cis- platin and fluorouracil plus 40±46 Gy irradiation.

Advanced esophageal cancers can be treated with radiation or chemoradiation using adjuvant or neoadjuvant chemotherapy regimens. In chemo- radiation cisplatin + 5-fluorouracil is a standard regimen (Table 27; for more details see Crossby et al. 2004).

Crossby et al. (2004) obtained a 2-year survival rate of 67% and a 5-year survival rate of 32% in T4 cases who underwent no surgery. A similar treatment protocol was also followed by Nabeya and Ochiai (2003).

In a preliminary phase II study Keresztes et al.

(2003), at Cornell University, New York, used the following scheme:

Paclitaxel 200 mg/m

²

and carboplatin given on days 1and 22, and esophagectomy (in week 6±8).

The resectability rate was 71%, with a complete re- mission rate of 11%.

Urba et al. (2003) used cisplatin combined with paclitaxel and radiotherapy 1.5 Gy twice per day on days 1±5, 8±12 and 15±18. The total dose of radiotherapy amounted to 45 Gy. This cisplatin- based preoperative regimen was well tolerated. The authors emphasize that this is a reasonable approach for patients with esophageal cancer that is still localized. Polee et al. (2003), in Rotterdam, used the following chemotherapy regimens for treatment of advanced esophageal cancers: cispla- tin/etoposide, cisplatin/etoposide/5-fluorouracil, cisplatin/paclitaxel (weekly) and cisplatin/paclitax- el (bi-weekly). The 1-, 2- and 5-year survival rates

of all patients were 33%, 12% and 4%, respectively.

Ajani et al. (2003), at the M.D. Anderson Cancer Center, used Irinotecan (CPT-11, Camptsar) and cisplatin as step 1, followed by concurrent radio- therapy and chemotherapy with continuous-infu- sion 5-fluorouracil (5FU) and paclitaxel as step 2.

The South West Oncology Study Group (Urba et al. 2004) treated patients with metastatic or recur- rent esophageal cancer with gemcitabine, 1000 mg/

m

²

, on days 1, 8, 15 and cisplatin, 100 mg/m

²

, on day 15. The cycles were repeated every 28 days.

The 3-month survival rate was 81% and the 1-year survival rate 20%.

In a further study of neoadjuvant chemotherapy a combination of mitomycin, 6 mg/m

²

, ifosfamide, 3 g/m

²

, and cisplatin, 50 mg/m

²

, was given before esophagectomy.

After chemotherapy in patients with advanced esophageal cancers, esophagectomy was possible in 79% (Darnton et al. 2003). The complete respond- ers and the node-negative patients survived signifi- cantly longer than those in other categories (P=0.001).

In a further neoadjuvant trial preoperative mi- tomycin (6 mg/m

²

), ifosfamide (3 g/m

²

) and cispla- tin (50 mg/m

²

) was administered at the Birming- ham Cancer Research Institute (UK). There was a 61% response rate to this chemotherapy, with 9%

complete responses.

Chemoresistance of Esophageal Cancers

In the case of esophageal cancer too, it is impor- tant to realize that c-erb B2-positive cancers are chemoresistent (Akamatsu et al. 2003). This point must be taken into account in the development of new therapeutic strategies.

Chemoradiotherapy: Assessment of Operability by PET In Munich the Schwaiger-Siewert Group (Wieder et al. 2004) has analyzed the significance of PET in the assessment of operability and surgical strate- gies in the course of preoperative chemoradiother- apy. This is important to find out which patients will not respond, allowing early modifications of the treatment protocol.

Therapy Regimens for Esophageal Cancer 517

Table 27.Radiochemotherapy of esophageal cancer

Cisplatin 6 mg/m² Day 1Every 3

weeks 5-Fluorouracil 300 mg/m² Day (±1)

Reduced to 250 mg/m² Day (±1) RT delivered in 25 fractions over 5 weeks

(16)

Chemotherapy Regimens for Gastric Cancer

The effect of adjuvant chemoradiotherapy has been investigated in a large intergroup study (Macdo- nald et al. 2001). The treatment protocol consisted in one cycle of 5-FU + leucovorin (Table 28), fol- lowed by radiotherapy + 5-FU and then two cycles of 5-FU + leucovorin. The median overall survival in the surgery-only group was 27 months, as against 36 months in the chemoradiotherapy group. However, adjuvant treatment is still subject to some debate and cannot be described as stan-

dard procedure. Frequently used chemotherapy regimens in metastatic disease are shown in Tables 29 to 31.

The Italian Group for the Study of Digestive Tract Cancer (GiSCAD) also used a regimen simi- lar to the Cunningham scheme (Table 32), plus 6S- leucovorin, 250 mg/m

²

, for weekly preoperative, lo- cally advanced and nonresectable gastric cancer (Cascinu et al. 2004).

together with 6S-leucovorin (250 mg/m

²

) for weekly preoperative chemotherapy of locally ad- vanced unresectable gastric cancer (Cascinu et al.

2004).

Kalmar et al. (2003) used the ECF scheme (Ta- ble 29) for neoadjuvant treatment of locally ad- vanced gastric cancer, making R0 resection possi- ble in a group of 24 patients (epirubicin and cis- platin on day 1and continuous infusion of 5- fluorouracil on days 1±21; 12 weeks of treatment, followed by 4 weeks without). The group hopes for cure of patients with cancers that are only locally advanced.

In a phase II study, Schull et al. (2003) tested a combination of cisplatin and docetaxel (Table 33).

DiCosimo et al. (2003) reported on eight phase II and III studies in which docetaxel as a single agent and in combination with cisplatin or epiru- bicin were used. The group looks foreward to pre- senting docetaxel as a key drug that will improve the treatment of gastric cancer.

Park et al. (2004) combined docetaxel and cape- citabine in a preliminary study (42 patients), in the hope that a synergistic interaction of the two drugs mediated by taxane-induced up-regulation of thymidine phosphorylase might increase their efficacy (Table 34).

Table 28. 5-Fluorouracil/folic acid regimen (monthly) used for gastric cancer at the Mayo Clinic (Poon et al. 1991)

Folic acid 20 mg/m² i.v. Bolus Days 1, 2, 3, 4, 5 5-Fluoro-

uracil 425 mg/m² i.v. Bolus Days 1, 2, 3, 4, 5

Table 29.ECF (Cunningham 1991; see also Ross et al. 1998)

Epirubicin 50 mg/m² i.v. Day 1

Cisplatin 60 mg/m² i.v. Day 1

5-FU 200 mg/m² i.v. Continuous

Every 3 weeks

Table 30.MCF (Ross 2002)

Mitomycin 7 mg/m² i.v. Day 1

Cisplatin 60 mg/m² i.v. Day 1

5-FU 300 mg/m² i.v. Continuous

Every 3 weeks

(17)

Chemotherapy Regimens for Gastric Cancer 519

Table 31.Fluorouracil/leucovorin (=folinic acid) regimen in current use for gastric cancer: 1 ´block A?Radiotherapy with 4500 cGy; simultaneously 1´block B?2´block A, monthly (Macdonald 2000, unpublished)^a

Block Agents Dose Route Mode Days given

A Leucovorin 20 mg/m² i.v. Bolus Days 1, 2, 3, 4, 5

5-Fluorouracil 425 mg/m² i.v. Bolus

B Leucovorin 20 mg/m² i.v. Bolus Days 1, 2, 3, 4, and the last

3 days of radiotherapy

5-Fluorouracil 400 mg/m² i.v. Bolus

aIn cases with incipient stomatitis, prophylactic oral ice cooling for 30 min at the beginning of the 5-FU injection. In cases with diarrhea: immediate therapy with standard medication (loperamide). In cases with massive (severe) diarrhea or inef- fectiveness of standard medication: octreotide (Sandostatin) 100 lg twice daily. Caution: doses should be reduced in cases with elevated bilirubin or alkaline phosphatase values, because of the possibility of severe toxicity

Table 32. Regimen used by the Italian Group for the study of digestive tract cancer

Cisplatin 40 mg/m²

5-Fluorouracil 500 mg/m²

Epidoxorubicin 35 mg/m²

Table 33.Regimen tested by Schull et al. (2003) in advanced gastric cancers with primising therapeutic index

Cisplatin 50 mg/m² Days 1, 15

Docetaxel 50 mg/m² Days 1, 15

Table 34.Combination of docetaxel and capecitabine used in a perliminary study (Park et al. 2004)

Protocol: Capecitabine oral Docetaxel

1250 mg/m²twice daily on days 1±14

75 mg/m²i.v. on day 1 Overall response rate 60%

Median progression-free

survival 5.2 months

Median overall survival 10.5 months

(18)

Therapy Regimens for Colorectal Cancers

Adjuvant chemotherapy is the standard of care for patients with stage III disease, as demonstrated in large clinical trials. These studies were carried out with various regimens using 5-FU and folic acid (examples are shown in Tables 35 and 36).

Recently Patel et al. (2004) reported the results obtained at Leeds Cancer Centre (UK) with 5- fluorouracil and leucovorin (Table 37).

New approaches to the treatment of advanced colorectal cancers have been established. New drugs, such as irinotecan and oxaliplatin, on the one hand and new modes of administration for well-known drugs, e.g. continuous infusion of 5- FU and oral administration of the 5-FU prodrug capecitabine, on the other have shown promising benefit for the patients. Frequently used regimens are shown in Tables 38 and 39.

Table 35.5-Fluorouracil/folic acid treatment weekly,^aas given for colorectal cancer at the ªGITSGº (Petrelli et al. 1989)

Agent Dose Route Mode Timing

Folic acid 500 mg/m² i.v. 2-h infusion Days 1, 8, 15

5-Fluorouracil 500 mg/m² i.v. Bolus^b Days 1, 8, 15

aThe regimen should be repeated weekly for at least 6 weeks

bBolus after end of the folic acid infusion

Table 36.5-Fluorouracil/folic acid (5-FU/FA) monthly,^aas given in the Mayo Clinic for colorectal cancers (Poon et al. 1991)

Agent Dose Route Mode Timing

Folic acid 20 mg/m² i.v. Bolus Days 1, 2, 3, 4, 5

5-Fluorouracil 425 mg/m² i.v. Bolus Days 1, 2, 3, 4, 5

aRepetition on days 29±36; if response is achieved six cycles are administered

Table 37.Regimen used^aat Leeds Cancer Centre

425 mg/m²5-FU as bolus (5 min) Once weekly

45 mg/m²dl-leucovorin Once weekly

a24-week treatment planned; disease-free intervals achieved

Table 38.FOLFIRI (Saltz 2000)

Irinotecan 125 mg/m² i.v. Days 1, 8, 15, 22

Leucovorin 20 mg/m² i.v. Bolus Days 1, 8, 15, 22

5-FU 500 mg/m² i.v. Bolus Days 1, 8, 15, 22

Every 6 weeks

Table 39.FOLFOX 6

Oxaliplatin 100 mg/m² i.v. 2 h Days 1, 15

Leucovorin 400 mg/m² i.v. 30 min Days 1, 15

5-FU 400 mg/m² i.v. Bolus Days 1, 15

5-FU 2400 mg/m² Continuous over 48 h Days 1, 15

Every 4 weeks

(19)

Comparison of FOLFOX, IROX, and IFL

In a randomized controlled trial comparing the ef- ficiency of irinotecan and oxaliplatin in a total of 795 patients, Goldberg et al. (2004) obtained the results displayed in Table 40. Based on these re- sults, the authors consider FOLFOX the standard therapy for patients with advanced cancer and re- commend it as such.

The Spanish group (Cassinello et al. 2003) basi- cally combined the Mayo Clinic protocol with parts of the FOLFOX 6 protocol to give the scheme shown in Table 41.

Preliminary results were comparable to other regimens.

Shields et al. (2004) administered oxaliplatin, 130 mg/m

²

, on day 1of each 3-week cycle and ca- pecitabine at a dosage of 1500 mg/m

²

per day in two divided doses on days 1±14 of each cycle. This regimen was effective and convenient. Compari- sons with other first-line regimens were recom- mended.

In a phase II trial (E4296) the Eastern Coopera- tive group (Marsh et al. 2002) gave 5-FU at a dose of 1mg/m

²

p.o. and eniluracil in a dosage of 10 mg/m

²

twice daily for 28 days. The tumor re- sponse rate was 13.2%.

Advantages of irinotecan (CPT-11) and oxalipla- tin have been already demonstrated by the French group (Rougier and Mitry 2001) and the Spanish group (Calvo et al. 2002).

New Radioimmunotherapeutic Approach in Treatment of Advanced Colorectal Cancers

Radioimmunotherapeutic efforts are still in their early stages. In a phase I study using

⁹⁰

Y-anticarci- noembryonic antigen chimeric T 84.66 combined with 5-FU administration in patients with ad- vanced colorectal cancers both feasibility and pos- sible advantages were demonstrated. However, further experience is necessary before any decision on the real stage value of this therapeutic strategy is possible.

Therapy Regimens for Colorectal Cancers 521

Table 40.Comparison of FOLFOX, IROX, and IFL (Goldberg et al. 2004)

Regimen Time to progression Response rate Median survival

FOLFOX (oxaliplatin; 5-FU + leuco-

vorin by infusion) 8.7 months 45% 19.5 months

IROX (irinotecan and oxaliplatin) 6.5 months 35% 17.4 months

IFL (irinotecan and bolus 5-FU +

leucovorin) 6 months 31% 15 months

Table 41.Regimen used by the Spanish group (Cassinello et al. 2003)

Oxaliplatin 85 mg/m² 2 h i.v. Days 1, 7, 14

5-FU 500 mg/m² Bolus Days 1, 7, 14

Leucovorin 20 mg/m² 2 h i.v. Days 1, 7, 14

Every 4 weeks

(20)

Therapy Regimens for Neuroendocrine Tumors

Neuroendocrine tumors make up a wide group of malignant diseases with a wide spectrum of clini- cal syndromes depending on the presence of se- creted hormones. Their symptoms derive mainly from hormone secretion rather than from bulky tumors.

Treatment options are surgery with curative in- tent, medical options aiming at controlling the symptoms of the various hypersecretion syn- dromes, and chemotherapy. With a developing ar- mamentarium of antihormone therapies, chemo- therapy is reserved for aggressively growing tu- mors that are resistant, to other treatments. Fre- quently used chemotherapy regimens are shown in Table 42.

Somatostatin analogs are highly effective in the treatment of somatostatin receptor scintigraphy (SRS scan)-positive neuroendocrine tumors. Stan- dard treatment consists in octreotide or longer act- ing preparations.

Another promising therapy option is a targeted therapy with radiolabeled somatostatin analogues in SRS scan-positive tumors, for example

⁹⁰

Y-dota- d-Phe

¹

-Tyc

³

-octreotide. Preliminary results ob- tained in phase I and II studies were recently pub- lished by Waldherr et al. (2001) and are summa- rized below.

In the phase I study, 29 patients with advanced NETs who had received no previous treatment were each given four single doses of

⁹⁰

Y-DOTATOC with ascending activity at intervals of 6 weeks (cu- mulative dose 6120Ô1347 MBq/m

²

). Stabilization of the disease was achieved in 20 of the 29 pa- tients, partial remission in 2, and minor response in 4; in 3 of the 29 disease progression was ob- served.

In the phase II study 41patients with NET (gas- troenteropancreatic and bronchial tumors), 82% of them with therapy-resistant or progressive disease, were each treated with four i.v. injections of a total of 6000 MBq/m

^{2 90}

Y-DOTATOC, administered at intervals of 6 weeks. The overall response rate ob- tained in the 41patients was 24%. Of the 41pa- tients with endocrine pancreatic cancers, 36 achieved a 24-month survival time (76Ô16% cal- culated by the Kaplan-Meier method).

The latest results of evaluating 80 patients in a phase II study as summarized by Waldherr et al.

(2001) are displayed in Table 43, which gives more details on the results of therapy.

In biotherapy of metastasized cases of NET with the somatostatin analogues octreotide or lanreo- tide, which has been considered the method of choice (Oeberg 1998; Faiss et al. 1996), the follow- ing results were obtained:

Response rate in patients with endo-

crine pancreatic tumors (EPT) 12%

Rate of stabilization according to

Ruszniewski et al. (1996) 25±30%

Biochemical response rates 40±70%

Objective response rates according

to WHO (Krenning et al. 1989) 4±10%

As an alternative to the specific biological treat- ment option, in the last few years the use of li- gands to the somatostatin receptor, i.e., interferon-

a therapy, has also been offered and practiced.

The following data have been published in the literature (see Sporn and Greenberg 1990; Rusz- niewski et al. 1996; Oeberg 1998):

Biochemical response rate 43%

Objective response rate 11%

Table 42.Treatment of patients with neuroendocrine tumors of the gastrointestinal tract (Oeberg 1996)

Tumor type First-line treatment Second-line treatment

Endocrine pancreatic tumors (EPT) Streptozotocin + 5-FU streptozotocin

+ doxorubicin Somatostatin analog Ô interferon-a Anaplastic endocrine pancreatic

tumors (ana-EPT) Streptozotocin + doxorubicin;

alternative cisplatin + etoposide Cisplatin + etoposide; streptozotocin + 5-FU streptozotocin + IFN-a streptozotocin + somatostatin analog Midgut carcinoids Interferon-a + somatostatin Cisplatin + etoposide

Hindgut carcinoids Interferon-a Ô somatostatin Cisplatin + etoposide

(21)

Classic Therapeutic Regimens and Newer Approaches McKinnon (1993) emphasized the efficacy of oc- treotide and omeprazole in improving the hor- monal symptoms of carcinoids, islet cell tumors, and medullary thyroid carcinoma. Even in 1993, he stated already that newer cytotoxic chemother- apy regimens had increased the response rates over those of traditional therapy and reflected on the benefits of more aggressive surgical treatment of metastatic processes.

Because somatostatin analogues and interferons have sometimes failed to control neoplastic growth of neuroendocrine tumors, Bajetta et al. (1998) tried to improve the previously used FDE regimen as summarized in Table 44. Their new regimen was as effective as other comparable schemes used.

The group working at the Swedish Endocrine Oncology Unit (Skogeseid 2001) regards streptozo- tocin and 5-FU or doxorubicin as the first-line treatment regimen for pancreatic endocrine tu- mors with liver metastases; in contrast, midgut

carcinoids are often resistant to such systemic regimens. Treatment attempts including interferon-

a and somatostatin analogues are thought prefer-

able. Somatostatin receptor-targeted radiotherapy is still under investigation.

At the Memorial Sloan Kettering Cancer Center (Brentjens and Saltz 2001), streptozotocin-based combinations are also recommended as standard first-line treatment for metastasizing pancreatic endocrine tumors.

The British London group (Kaltsas et al. 2002) used an alternative nitrosourea compound, instead of streptozotocin, namely lomustine (CCNU), in combination with 5-FU for the treatment of neuro- endocrine gastroenteropancreatic cancers.

Many reports have dealt with the better activity of chemotherapy in pancreatic NETs than in carci- noid tumors, with response rates of 40±60% and 20%, respectively.

The standard chemotherapy for pancreatic NETs is doxorubicin (Adriamycin) and streptozotocin or 5-FU and streptozotocin.

In more highly malignant tumors response rates of 41±69% have been reached with use of VP16 and CDDP in combination (Rougier and Mitry 2000).

Comparative studies by Hatton and Reed (1997) of dacarbazine, vincristine and cyclophosphamide (DOC) and modified schemes (OPEC and DOPEC) revealed comparable, response rates and side ef- fects. The response rates were acceptable at 53%.

Oeberg, working in the Department of Endo- crine Oncology at the University Hospital, Uppsala,

Therapy Regimens for Neuroendocrine Tumors 523

Table 43.Tumor response (WHO standard criteria) in both phase II trials (n=80) in which patients received either 6000 or 7400 MBq/m^{2 90}Y-DOTATOC (EPT endocrine pancreatic tumor, NET neuroendocrine tumor)

Complete remissions (CR)n

Partial remissions (PR)n

Stable disease (SD)n

Progressive disease within or after treatment n

Overall tumor response n

CR, PR, SD

%

EPT (n=27) 2 8 13 4 37 86%

Intestinal NET

(n =20) ± 118 1 5 95%

Bronchial

NET (n=10) 117 120 90%

NET of unknown origin (n =17)

± 5 10 2 29 89%

Other (n=6) ± ± 4 2 0 67%

All (n=80) 3 15 52 10 23 85%

Table 44. New regimen used by Bajetta et al. (1998) in patients with neuroendocrine tumors

5-Fluorouracil (5-FU) 500 mg/m² i.v.

Dacarbazine (DTIC) 200 mg/m² i.v.

Epirubicin 30 mg/m² i.v.

Days 1, 2, 3 of each 3-week cycle

(22)

Sweden, reported in 1998 on attempts to use biotherapeutic agents, including interferon and so- matostatin analogues, in the treatment of slow- growing neuroendocrine tumors, such as midgut carcinoids. When treatments of this kind fail tu- mor-targeted irradiation can be attempted. 131-Io- dine-MIBG (metaiodobenzylguanidine) and

⁹⁹

Y- DOTA (1,4,7,10-tetraazacyclododecane N,N(I),- N(II),N(III)-tetraacetic acid) octreotide can be used. Oeberg (2003) summarized the treatment op- tions as follows:

1. Surgery as the only chance of cure.

2. Cytoreductive procedures, including radiofre- quency ablation, laser treatment, and chemoem- bolization.

3. Biological treatments including that with cyto- toxic agents such as somatostatin analogues and interferon-a (used for slow-growing neoplasms).

4. Combination regimens, including cisplatin, eto- poside, streptozotocin, and 5-FU (reserved for treatment of highly proliferative tumors).

In view of the possibility of early systemic spread, the aggressive neuroendocrine Merkel cell cancer needs

a) Radiation therapy of the nodal chain in special cases

b) Chemotherapy.

Upto now, no chemotherapy protocol has been shown to improve survival (Lavenda et al. 2001).

The best treatment strategy for nonsinonasal neuroendocrine cancers of the head and neck is postoperative sequential chemotherapy (platinum + etoposide) and radiation therapy (66 Gy) (Barker et al. 2003). Sinonasal undifferentiated carcinomas (SNUC) and sinonasal neuroendocrine carcinomas (SNEC) are rare entities (Smith et al. 2000). No statistically evaluated results are available. These aggressive cancers are surgically resected with in- clusion of regional lymph node dissection. Trials of postoperative radiation and/or chemotherapy are in progress.

Neuroendocrine Small-cell Cancers of the Cervix Neuroendocrine small-cell cancers of the cervix (NECC) are rare. The presence or absence of lymph node metastases is the most important vari- able. These tumors have a high mortality rate de- spite aggressive surgery with therapeutic intent.

According to Abulafia and Sherer (1995) and

Boruta et al. (2001), postoperative chemotherapy,

e.g. with a platinum + etoposide scheme (PE) or

vincristine + doxorubicin (Adriamycin) + cyclo-

phosphamide (VAC), seems to be most likely to

improve the survival rate.

(23)

Therapy Regimens for Neuroblastoma

Secondary therapeutic regimens for neuroblastoma after primary surgical treatment are focused on the high chemo- and radiosensitivity of this tumor type, which generally develops in the first few years of life. The treatment protocol has been de- veloped by the German Society of Pediatric Oncol- ogy. Figures 1 and 2 illustrate the strategy.

Therapy Regimens for Neuroblastoma 525 Fig. 1.Protocol for the Neuroblastoma Study Program

(NB97); therapy regimens worked out by the German So- ciety for Pediatric Oncology and Hematology, started on 1 January 1998; Chairman of the study was Prof. Dr. F. Ber- thold, Center for Children's Oncology, University Clinics of Cologne, Joseph Stelzmann Straûe 9, 50924 Cologne, Ger- many (ADR adriamycin, ASCT autologous stem cell support (transplantation), DTIC dacarbazine, ETO etoposide, G-CSF granulocyte colony-stimulating factor, IFO ifosfamide, VCR vincristine, VDS vindesine, Mycn N-myc, not amplified, RT radiotherapy, Sgl. baby, SR standard risk)

(Figure see p. 526)

"

(24)

Fig. 1

Legend see p. 525

(25)

Therapy Regimens for Neuroblastoma 527

Fig. 2.Details of treatment blocks in neuroblastoma treatment protocol elaborated by the German Society for Pedia- tric Oncology

(26)

Fig. 2(continued)

(27)

Therapy Regimens for Malignant Melanoma

The usual therapy regimen for treatment of malig- nant melanomas is shown in Table 45. For more information the reader is also referred to Chapter 25. In recent years, the adjuvant therapy regimen using Interferon (IFN)-a

2 b

has been tested in many investigations, its efficacy has been confirmed in some (Agarwala and Kirkwood 2002; Wheatley et al. 2002; Molife and Hancock 2002; Pawlik and Sondak 2003; Mohr et al. 2003). However, the bio- logical profile of melanoma cases in which the therapy is efficient is still not clear, and controver- sies persist (Sabel and Sondak 2003).

In Kefford's cumulative studies (2003) high-dose IFN-a (HDI) treatment did not prolong overall sur- vival. In the specific investigations of Schachter et al. (2003) patients treated for stage II B disease fared better than those treated for stage III, regard- less of whether the patients had regional microme- tastases or palpable metastases. CNS relapses ob- viously could not be significantly prevented by ad- juvant IFN treatment.

In recent randomized studies performed by Hauschild et al. (2003), adjuvant combination ther- apy using IFN-a

2 b

(3 million IU/m

²

, days 1±7 in week 1; then three times weekly in weeks 3±6, re- peated every 6 weeks) plus IL-2 (IMU/m

²

per day on days 1±4 in week 2 of each cycle) for 48 weeks, did not improve disease-free or overall survival.

In their analysis, Kleeberg et al. (2004) com- bined the data from EORTC studies and from the DKG-80-1trial. No advantage of adjuvant melano- ma treatment with rIFN-a

2

or rIFN-c was found in the treatment of high-risk melanoma patients.

Hancock et al. (2004) treated 674 patients with thick melanomas (>4 mm), some of whom had lo- coregional metastases. Low-dose IFN-a

2 a

(3 mega units) three times per week for 2 years or until re- currence showed no benefit in these high-risk melanoma cases.

Hakansson et al. (2003) used cisplatin (30 mg/

m

²

i.v., days 1±3), dacarbazine (250 mg/m

²

i.v.

days 1±3, IFN-a

2 b

(10 million IU s.c.) on 3 days a week. Their results demonstrated the occurrence of some antitumor reactivity in the majority of cases. Patients with extensive regressive changes in 75±100% of the biopsies analyzed were also found to have a longer overall survival (P=0.019).

In recent years phase I and II studies of treat- ment with dendritic cell vaccines in patients with disseminated melanomas have been started. Her- shey et al.'s (2004) experience has shown that as a source of antigen for DC vaccines autologous ly- sates of melanomas may be more effective than melanoma peptides. The negative results of chemotherapy efforts in the 1980s, when dacarba- zine (DTIC), vincristine, 5-FU, and hydroxyurea were used, have lately been reconfirmed by Kretschmer et al. (2002).

In addition, tamoxifen has been found not to inhibit metastasis of malignant melanoma (Lens et al. 2003); nor has HER/neu evaluation of malignant melanomas with a view to trastuzumab (Hercep- tin) therapy proved successful (Potti et al. 2003).

Medalie and Ackerman (2003) recently de- manded that the search for the sentinel node be abandoned, having found no advantage of it in terms of survival. However, their argumentation is diffuse and in important points inadequate. Be- cause of changes in and deviations from treatment protocols and the wide variation in initial biologi- cal behavior, it is very difficult to establish cumu- lative judgments from a purely statistical point of view.

In locally advanced cancers surgical clearance aimed at R0 resection is essential, because in indi- vidual cases survival is absolutely dependent on the surgical intervention alone and this is opti- mized by the search for the sentinel node(s) and the determination of the local basins that this al- lows.

Therapy Regimens for Malignant Melanoma 529

Table 45.Interferon as single-agent chemotherapy for malignant melanoma

Agent Dose Route Frequency

Interferon-a 5±10 million

IU s.c. 3 ´ weekly

for 1±2 years