Chemotherapy and irradiation in locally advanced squamous cell carcinoma of the uterine cervix: A review

Chemotherapy and Irradiation in Locally Advanced Squamous Cell Carcinoma of the Uterine Cervix: A Review Carlos A. Perez) Perry W Grigsby) and Clifford K.S. Chao This article describes the potential role of chemotherapy combined with irradiation in the management of patients with locally advanced carcinoma of the uterine cervix. A review of a Medline literature search and preliminary data from a nonrandomized study comparing irradiation alone with irradiation plus chemotherapy (S-fluorouracil and cisplatinl in the management of patients with locally advanced carcinoma of the uterine cervix treated at Washington University between 1984 and 1992 are presented. Except for one report, there is currently no conclusive evidence that chemotherapy plus irradiation significantly improves tumor control or

survival in these patients. Nevertheless, chemotherapy may have a potential role in managing carcinoma of the uterine cervix as an adjuvant to irradiation in patients with pelvic or para-aortic lymph nodes or recurrent tumor after surgery or radiation therapy. Treatment morbidity has been acceptable. Based on available data, chemotherapy should not be advocated in the standard management of carcinoma of the uterine cervix, and patients and physicians should be strongly encouraged to participate in properly designed prospective clinical trials. Copyright © 1997 by IN.B. Saunders Company

urgery, radiation therapy (RT), or the combination yields high cure rates in patients with stage I and IIA cervical carcinoma. However, patients with stage III or IV disease have a 5-year survival of 45% to 50% and 10% to 20%, respectively. 1 Pelvic recurrences and distant metastases occur in 50% and 80% of these patients, respectively.2 Chemotherapy has been used increasingly in cervical carcinoma over the past 10 years. Although many patients require effective systemic therapy, significant hurdles exist to obtain satisfactory results: (I) drug delivery to the pelvic tumor can be impaired by altered blood supply, secondary to the lesion or vessel irradiation effects; (2) tumor cells may be resistant to cytotoxic agents; (3) some patients may have limited bone marrow reserve and are less tolerant of high-dose chemotherapy, and thus cytotoxic drug doses may not be optimal; and (4) advanced or recurrent cervical cancer may be associated with ureteral obstruction and resultant renal failure, which eliminates as therapeutic choices certain nephrotoxic drugs and complicates the use of other agents that are renally excreted.:J Malignant tumor management is conditioned by tumor location, stage, and histologic type and by the general condition of the patient (including immunologic response). Analysis of specific patient prognostic factors enhances our ability to select the most appropriate treatment.

Steel and Peckham postulated the biologic basis of cancer therapy as spatial cooperation (in which one agent is active against tumor cells spatially missed by another agent), additive of antitumor effects by two or more agents, and nonoverlapping toxicity and protection of normal tissues. 4,5 The classic modalities used in the management of patients with cervical cancer are surgery and irradiation; chemotherapy may be used for micrometastasis (adjuvant therapy) in patients with extensive tumors (neoadjuvant, definitive), or for disseminated disease (palliative). Figure I illustrates the selective use of a given therapeutic modality to achieve tumor control in each compartment. 6 Large primary tumors or metastatic lymph nodes must be removed surgically or treated with definitive radiation therapy; regional microextensions are eliminated by irradiation without the anatomic and physiologic deficit produced by equivalent surgery. Chemotherapy mainly controls disseminated subclinical metastasis and may also affect some specific primary tumors. Many patients potentially might benefit from integrated multimodality treatment, including those with locally advanced tumors of the uterine cervix.

S

From the Radiation Oncology Center, Mallinckrodt Institute if Radiology, Washington UniverJity School ifMedicine, St Louis, MD. Address re/,nnt requests to Carlos A Pere::" MD, Radiation Oncology Center, 4511 Forest Park, Suite 200, St Louis, MO 63108. COl!ynght © 1997 by WB. Saunden Company 1053-4296/97/0703-0208$5.00/0

Biologic Considerations in Combined Chemotherapy and Irradiation Anticancer drug resistance may have implications for resistance to radiation therapy. For many drugs, resistance mechanisms are multifactorial. For example, resistance to cisplatin may be due to decreased drug uptake, increased DNA repair, increased expression of sulfhydryl compounds such as glutathione and metalothionine, and increased gluta-

SeminaH in Radiation Oncology, Vol 7, No 3, Suppl2 (July), 1.997: pp 45-65

45

46

Perez, Gril"sly, and Chao

TUMOR CELL BURDEN AND EFFECTIVENESS OF THERAPY

9

3

Primary L. Nodes

MicroSubclinical "Circulating" extensions Metastases Cells

thione-S-transferase expression. Combined radiation and drug treatment might result in an improved therapeutic index if resistance mechanisms are independent.7 Microenvironmental factors including oxygen, pH, and nutrient supply play an important role in the combined effects of chemotherapy and irradiation on tumor cells.s Hypoxic cells are less radiosensitive and chemosensitive, and chronic hypoxia can alter cellular age distribution and proliferation rate, both important modifiers of cellular response to ionizing radiation and drugs. In addition, chronic hypoxia can affect cellular ability to repair radiation- and druginduced DNA damage. Bioreductive drugs such as mitomycin C are activated to toxic species and affect solid animal tumors under hypoxic conditionsY DNA repair, cell cycle age distribution, and the activity and stability of some chemotherapeutic drugs also may be pH dependent, which therefore may affect cell sensitivity to irradiation and cytotoxic agents. It is possible that hypoxic conditions, which commonly exist in tumors, may lead to gene amplification. Activation and increased oncogene expression, such as ras, c-myc, and c-rqf I, have been associated with increased radioresistance in some malignant and normal human cell lines in vitro. IO ,11 Although demonstrated in several mouse tumor cell lines, this

Figure 1. Diagrammatic representation of using different treatment modalities to eliminate a given tumor cell burden. 6

effect was not observed in three human cell lines studied by Tannock.7 Investigation of cytotoxic agent mechanisms of action, as well as further studies of factors that modulate the activation and expression of genes encoding these substances, may enhance our understanding of the genetic regulation of cellular sensitivity/resistance to radiation therapy and chemotherapy.12 Some cytokines, including tumor necrosis factoralpha and interleukin,13 and growth factors, such as platelet-derived and fibroblast growth factors, are seen in malignant and normal human cells after irradiation. I} These cytokines and growth factors enhance the radiation and chemotherapy cytotoxic effects in tumor cells 15 or offer radioprotection in normal cells. '6 Possible mechanisms of chemotherapy and irradiation interaction include the following:

1. Modification of the dose response curve slope, as shown with actinomycin D, cisplatin, doxorubicin, mitomycin C, 5-fluorouracil (5-FU), and other agents. 2. Decreased accumulation or inhibition of sublethal damage (as induced by actinomycin D, cisplatin, bleomycin, hydroxyurea, and nitrosoureas) repairY-19 Doxorubicin and other DNA intercalators decrease the shoulder widths but do not

Chemotherapy and Irradiation in Cervix Cancer

3.

4.

5.

6. 7.

decrease the slope or suppress the lethal damage repair in in vitro studies. 2o Inhibition of potentially lethal damage repair, as shown with actinomycin D, doxorubicin, and cisplatin. 21 ,22 Perturbation of cell kinetics; for instance, after hydroxyurea treatment, which acts in the S phase, cells may become partially synchronized and blocked at the G/S cell cycle phase. If irradiation is delivered during the sensitive phase after the cells emerge from the block, an enhanced cytotoxic effect may occur. Selective cytotoxicity and radiosensitization of hypoxic cells, which occurs with mitomycin C and cisplatin.9,23,24 Inhibition of cell repopulation. Decrease in tumor bulk, improved blood supply, reoxygenation, and cell recruitment, resulting in increased radiosensitivity and chemosensitivity.

Factors influencing the combined effects ofchemotherapy and irradiation also include tumor and normal tissue type; cytotoxic drug class, dose, and schedule; drug administration timing in relation to irradiation; irradiation dose, fractionation schedules, and irradiation dose rate; and microenvironmental factorsP The combination of modalities may enhance normal tissue toxicity. In combined treatment, toxicity may decrease tumor control because the added morbidity may require lowering the doses of the effective agents, which in turn decreases the response rate. Initial increased fatal toxicity may affect tumor response and overall survival. A possible drawback in the administration of cytotoxic drugs before radiation therapy is the phenomenon of accelerated cell proliferation or repopulation. 25 As some tumor regression is induced by the cytotoxic agent (drugs or irradiation), the distance between the tumor cells and adjacent functional capillaries decreases, which may induce tumor cell proliferation such that higher irradiation doses are required to control the tumor. This occurs in carcinoma of the head and neck2 6 and uterine cervix. 27 In fact, neoadjuvant chemotherapy induces significant malignant tumor regression in head and neck carcinoma, but without improvement in survival.28 As pointed out by Tannock,7 although the clinical effect of accelerated repopulation is hypothetical, it suggests caution in the use of induction chemotherapy and explains why an initial tumor response may not

47

necessarily translate into a therapeutic advantage with combined modality treatment. Chemotherapy usually is not sufficiently potent to sterilize any tumor field at treatment onset, and use of this modality should not compromise potentially curative modalities such as irradiation or surgery.

Clinical Trial Considerations Chemotherapy plus irradiation may be used as neoadjuvant chemotherapy prior to surgery or irradiation in patients with localized tumors, or as adjuvant therapy in combination with other local modalities as part of the initial curative treatment. The effects of chemoradiotherapy may be independent, additive, or interactive, and the modalities can be administered sequentially or concomitantly. A conclusion often reached when induction chemotherapy is given before radiation therapy is that patients who respond to chemotherapy do better after combined treatment than those who fail to respond. This may occur because chemotherapy is beneficial or because patients who were destined to do well with irradiation are those who initially respond to chemotherapy. Furthermore, it has been shown that patients who do not initially respond to either modality generally will not respond to the second modality. Another consideration when chemotherapy is administered concurrently with fixed-dose irradiation is that local tumor control and survival may be improved in comparison with irradiation alone, but at the expense of increased morbidity.29 It is possible that similar improvements in therapeutic results could be obtained by increasing irradiation dose and accepting corresponding greater normal tissue sequelae. Cytotoxicity mechanisms and possible interactions with irradiation and cytotoxic agents commonly used in cervical carcinoma were defined by Fu. 12 The mode and time of cytotoxic agent administration may significantly influence the effect on tumor or normal tissues. For example, 5-FU is more effective when administered as a continuous infusion rather than a bolus injection.3o In a multivariate analysis, Bonomi et aPl also noted that better performance status, increasing age, longer disease-free interval, and poorly differentiated histology were significant favorable prognostic factors for chemotherapy response in squamous cell cervical carcinoma. It is important to recognize these factors in the stratification design of prospective clinical trials.

48

Perez, Grigsby, and Chao

Chemotherapy in Carcinoma of the Cervix Chemotherapy is being more extensively evaluated in bulky and advanced cervical cancer, primarily because of less than satisfactory results of initial therapy with other modalities; however, cytotoxic agents in patients with advanced and recurrent cervix carcinoma have shown less than optimal efficacy.:J2 Nevertheless, chemotherapy may eventually play an important role in the management of several groups of patients including those with advanced (stage III and IV) tumors, pelvic or para-aortic nodal metastasis with a low potential for cure with current local treatment modalities, and recurrent disease after surgery and radiation therapy.:J3 Significant activity (20% to 25% tumor response) for 5_FU34 and cisplatin35 has been documented in well-designed studies with adequate patient numbers. Efforts continue to identify additional drugs with high activity. Multiple combination chemotherapy studies have been reported 3ti-:J
observed a 31 % overall response with cisplatin 100 mg/m 2 compared with 21% with cisplatin 50 mg/m 2, although there was only a minimal increase in complete response (13% and 10%, respectively) and no improvement in response duration, progressionfree interval, or survival. Some investigators, including Kersch et al,46 Potish et al,47 and Roberts et al,4H documented good tolerance of combined cisplatin plus 5-FU with fulldose external pelvic irradiation including brachytherapy. Friedlander et a1 4'l also observed an 18% complete response and 66% overall response rate with a combination of vinblastine, bleomycin, and cisplatin. Ozols50 noted that, because of a GOG study reported by McGuire et aJ5! in which carboplatin administration resulted in a 15% response rate compared with a 27% response rate previously reported with cisplatin, the latter remains the treatment of choice in advanced or recurrent cervical carcinoma. In contrast, studies performed in Mexico demonstrate similar activity for carboplatin and cisplatin. Irreversible renal damage can occur as a result of tubular necrosis after cisplatin administration; this can be avoided with adequate hydration and mannitol or furosemide diuresis. Other adverse effects include nausea, vomiting, and mild myelosuppression with nadir usually occurring between 18 and 23 days after drug administration and recovery by day 39:'2 Peripheral neuropathy with paresthesias or Lhermitte's sign also has been reported. It appears that toxicity is less severe with continuous infusion of cisplatin.')3 Of 815 patients reported as having been treated with cisplatin as a single agent, 782 were part of GOG trials. 35,4! An objective response was observed in 23% of the patients; a 24-hour infusion produced significantly less nausea and vomiting than bolus administration. 35 5-FU, a pyrimidine analogue that binds thymidilate synthase and inhibits DNA synthesis, also is incorporated into cellular RNA (as a uracil analogue), which leads to defective RNA synthesis. In experimental models, Vietti et al ,4 showed a greater effect when 5-FU was administered concurrently with irradiation or within 8 hours after exposure. They concluded that increased cell killing by combined 5-FU and irradiation was due to inhibition of sublethal damage repair induced by irradiation. Because the biological half-life of 5-FU is 10 minutes, the drug is an effective radiosensitizer only when administered by continuous infusion. Hydroxyurea inhibits ribonucleotide reductase, an enzyme necessary for DNA synthesis and repair,

Chemotherapy and Irradiation in Cervix Cancer

kills cells in S phase of the cell cycle, and inhibits progression from G 1 into S phase, which results in cell accumulation in the G, phase, which is more radiosensitive. 46 ,55 Hydroxyurea toxicity is primarily myelosuppression with a rapid drop in white blood count. 55 In a recent phase I trial,55 14 patients received hydroxyurea continuous intravenous (IV) infusion (escalating doses from 0.5 to 2.5 g/m 2/d) and demonstrated acceptable toxicity (leukopenia and stomatitis). Tolerable infusion duration is a function of the administered hydroxyurea dose. Further clinical trials may be warranted to evaluate the potential radiosensitizing effect of IV hydroxyurea, which theoretically could be superior to that with oral administration of the compound. Mitomycin C is an antibiotic that acts as an alkylating agent and inhibits DNA and RNA synthesis. It causes DNA cross-linking proportional to its guanine and cytosine content and acts as a cell cycle-phase nonspecific agent. 46 When activated via xanthine oxidase and nicotinamide adenine dinucleotide phosphate, cytochrome-c reductase produces lethal interstrand DNA cross links.:lli There is evidence that mitomycin C activation is increased in hypoxic conditions, thus acting as a hypoxic radiosensitizer. Bone marrow depression, which may be cumulative, is the primary dose-related delayed toxicity with the nadir at 4 to 5 weeks. Interstitial pneumonitis and pulmonary fibrosis usually are also related to the drug dose. Dexamethasone IV, given before mitomycin C administration, may prevent pulmonary toxicity. Other less severe side effects include stomatitis, diarrhea, and alopecia. Renal or hepatic toxicity is rare. Ifosfamide, an alkylating agent chemically similar to cyclophosphamide, showed significant activity in 25 to 84 patients (29%).57 GOG demonstrated lower ifosfamide activity (14%) in squamous cell cervical carcinoma. 58 A GOG phase II randomized trial compares cisplatin plus either ifosfamide or dibromodulcitol (a halogenated sugar) to cisplatin alone in an effort to determine whether cisplatin combined with another clearly active drug might yield superior response rate and survivaI,59 In another randomized phase III trial, GOG compares ifosfamide plus cisplatin with or without bleomycin.

Nonrandomized Studies of Chemotherapy and Irradiation In recent years, numerous preliminary reports have been published on ncoadjuvant/concomitant cis-

49

platin and 5-FU, with or without mitomycin C, and combined with irradiation to treat patients with . 1carCInoma. . 6061 locally advanced or recurrent cefVlca '

Trials With Cisplatin, 5-FU, or Both The first studies of cisplatin combined with irradiation in carcinoma of the uterine cervix were conducted by Potish et al 47 and Twiggs et al,62 who administered cisplatin weekly (escalating doses from 10 to 20 mg/m 2) in combination with standard irradiation. Relapse-free survival was 61 % at 30 months for 22 patients with stage IB-IIB tumors in the Potish et al study.47 In the Twiggs et al report, 81 % of prescribed doses were administered. li2 Thomas et alli3 reported one of the largest phase l/II studies in which 200 patients with bulky primary uterine cervical carcinoma received concurrent chemotherapy and pelvic irradiation. Mitomycin C (6 mg/m 2 on day 1) or 5-FU (1 g/m 2 infusion on days 1 and 4) was administered in conjunction with splitcourse pelvic irradiation (50 Gy on daily or partial hyperfractionated schedules to avoid anticipated mitomycin C toxicity) and followed by a single Cesium 137 (l37CS) application (40 Gy to point A). The 3-year pelvic tumor control rates in stage IBIII and III/IV patients were 85% and 50%, and survival rates were 71 % and 42%, respectively; the 3-year pelvic control rate for historical controls receiving irradiation alone was 58% (P = .13). Serious bladder sequelae occurred in six patients (3%), and major bowel toxicity in 25 patients (eight associated with recurrent tumor). Injury involved the rectum and rectosigmoid colon in 20 patients and the ileum in nine patients; 10 patients required colostomy. Treatment-related deaths occurred in three patients. Bowel complications correlated with chemotherapy: 17 of78 patients (22%) who received mitomycin C developed bowel complications compared with only eight of 122 (6.6%) who received 5-FU. John et al 64 published final results of a phase l/II trial in patients with advanced cervical carcinoma that evaluated concurrent radiation therapy (36 Gy to the whole pelvis over 4 weeks, additional 9 Gy to the parametrium with midline block, and 4,000 milligram hours [mgh] intracavitary application, total 74 to 75 Gy to point A) plus 5-FU (1 g/m 2/d continuous IV infusion on days 8 to 11), cisplatin (75 mg/m 2 in a 6-hour IV infusion starting I hour before removal of the radioactive sources), and mitomycin C (10 mg/m 2 IV administered during the second week of radiation). The 5-year survival was 48% for 30 patients with unfavorable stage lIB disease and 39%

50

Perez, Grigsby, and Chao

for 30 patients with stage III-IVA disease. Pelvic tumor recurrence in 60 patients with stage lIB, III, or IVA disease was 34% to 41% at 5 years. Unlike the experience at our institution or the Princess Margaret Hospital, there were no toxic deaths, and grade 3/4 small and large bowel toxicity was 7%, possibly due to lower irradiation doses. The most severe chemotherapy toxicity was leukopenia (7% of patients). Grigsby and Perez li5 reported an analysis of 52 patients with advanced or recurrent gynecologic tumors who received somewhat higher chemotherapy doses (cisplatin 75 mg/m 2 and 5-FU I g/m 2, continuous infusion over 4 days) administered concomitantly with external pelvic irradiation and two 137Cs insertions (85 Gy to point A). The 5-year progression-free survival was 61%. In this review, we update our experience lili in 58 patients with primary locally advanced cervical carcinoma (stages IB, bulky lIA, lIB, III, IVA) who received irradiation plus chemotherapy (minimum follow-up, 3 years; median, 5 years); the results are compared with 257 patients with similar disease stages receiving irradiation alone during the same period. Disease-free and cause-specific survival in both groups are comparable (Fig 2A and 2B). Pelvic tumor control also was equivalent in both groups (84% and 96% in stage IB and bulky lIA tumors and 62% and 59% in stage III and IVA lesions, respectively) (Table I). As reported previously, moderate and severe morbidity were somewhat greater in patients receiving chemoirradiation (Tables 2 and 3, Fig 3). The incidence of rectal or bladder fistula was 7% (four of 58) in the chemoirradiation group compared with 4% (II of 257) in patients treated with irradiation alone (P = .61). There was one death due to pulmonary embolism in a patient receiving chemoirradiation. The overall treatment time was longer in patients receiving combined chemoirradiation, and more pelvic failures were observed in patients for whom treatment lasted 8 weeks or longer (58%) than in those with a shorter overall treatment time (40%) (P = NS). Runowicz et al li7 noted 29 complete responses (91 %) in 32 patients with various stages of cervical carcinoma (primarily stage lIB or higher) who received definitive irradiation and concomitant cisplatin (20 mg/m 2 for 5 days every 21 days). Three patients developed rectovaginal fistulae (two associated with disease progression), and two had radiation proctitis. Of 16 evaluable patients with stage lIB or

IVA tumors, 13 (81 %) had no evidence of disease at the time of the report (median follow-up, 12 months). Monyak et al 6s used a different cisplatin schedule (20 mg/m 2 IV once weekly 2 hours before irradiation) in 49 patients, 38 of whom had clinical stage I to IVA cervical carcinoma who also received definitive irradiation (80 to 85 Gy to point A with external beam irradiation and intracavitary therapy). Survival for the entire group was 52% at 3 years. Acute toxicity was acceptable in all patients. Late toxicity included three cases of bowel obstruction requiring surgery, one rectovaginal fistula, and one vesicovaginal fistula. Park et al 69 described their experience in 113 patients with high-risk invasive cervical carcinoma (bulky tumor, advanced stage, regional lymph node metastasis, or small cell histology) treated with two to three cisplatin cycles (100 mg/m 2 IV), immediately followed by 5-FU (I g/m 2/d, 24-hour IV infusion for 5 days). For adenocarcinoma, doxorubicin (45 mg/m 2 IV) was added on days I, 2, and 3. The patients subsequently received radiation therapy (not described in the publication). These patients were compared with 77 patients treated with radiation therapy alone. Complete response with induction chemotherapy was 27%, and the partial response was 60%. In stage I and II disease with tumors larger than 4 em, the 5-year survival rate with chemoirradiation was 78% versus 48% with radiation therapy alone (P = .0 1); in stages III and IV disease, 5-year survival was 69% and 57%, respectively. Grade 3 hematologic toxicity was observed in 9% and nausea and vomiting in 83% of patients. No chemotherapy-related deaths occurred. The incidence of nephrotoxicity was low (3%); hepatotoxicity was frequent (53%) but rarely symptomatic. Toxicity in the combined chemoirradiation patients was not significantly higher compared with irradiation alone. Sardi et aFo described results in 107 patients with stage lIB disease and 44 patients with stage IIIB disease who received three cycles of vincristine, bleomycin, and cisplatin before irradiation (50 Gy to the pelvis and intracavitary insertion). Surgery was carried out in some patients when technically feasible. The 2-year disease-free survival was 96% in 33 patients undergoing surgery, 78% in 50 patients with complete parametrial tumor regression and partial regression in the cervix, 61 % in 47 patients with part ial response in both areas, and 33% in 21 patients without tumor regression after chemotherapy. Because this was a nonrandomized study with significant patient selection and short follow-up time,

51

Chemotherapy and Irradiation in Cervix Cancer

-+-

A 10~'----{

--0-

RT ALONE Stage IB, IIA Bulky, lIB (n = 210) RT + CT Stage IB, IIA Bulky, lIB (n = 24)

80 ~

Z ~

60

U

~

~ 40

20

- - . - RT ALONE Stage III, IVA (n

......fr

=47)

RT + CT Stage III, IVA (n =34)

01....------J-------'-----~-------I------1

o

1

2

3

5

4

YEARS AFTER THERAPY

80 ~

Z ~

..-~.-_~-------.

p= .37

60

U

~

~

40

-e-

-0----A-......fr

20

RT ALONE Stage IB, IIA Bulky, lIB (n = 210) RT + CT Stage IB, IIA Bulky, lIB (n = 24) RT ALONE Stage III, IVA (n = 47) RT + CT Stage III, IVA (n =34)

01....------1...----....L...------L

o

1

2

3

.....I-

4

---'

5

YEARS AFTER THERAPY Figure 2. Carcinoma of thc uterine cervix (MIR 1984-1992): Survival correlated with treatment modality. (A) Disease-free. (B) Cause-specific.

meaningful conclusions cannot be drawn from these results. In a later report by Sardi et al,71 results with neoadjuvant chemotherapy were improved only in patients with bulky stage IB tumors (more than 60 mL). However, the low pelvic relapse rate (8%) seen in the neoadjuvant arm is comparable to that usually reported with adequate standard radiation therapy alone.7 2-H

Nguyen et aIl5 treated 38 patients with locally advanced cervical carcinoma (26 patients with bulky stage IBIIIB tumors and 12 with stage lIB-IVA tumors) with mitomycin C (10 mg/m 2 IV, days I and 30) plus 5-FU (I g/m 2 IV infusion, days I to 4 and 30 to 33) in conjunction with 45 to 50 Gy administered concurrently to the pelvis and followed by brachytherapy (generally two implants) to complete 80 to

52

Perez, Grigsby, and Chao

Table 1. Carcinoma of the Uterine CelVix (MIR 1984- I 992): Treatment Correlated With Failure Site Failure Site

Treatment

No. of Patients

Pelvis Only

210

15 (7%)

Stage IE, bulky IIA, lIB Irradiation alone Irradiation and chemotherapy Stage III-NA Irradiation alone Irradiation and chemotherapy

24

o

47 34

9 (19%) 6 (18%)

Pelvi.l/Distant Metastases

Pelvis Alone + Pelvis/Distant Metastases

Diftant Metastases Only

19 (9%) 1(4%)

16% 4%*

30 (14%) 2 (8%)

38% 41%

5 (11%) 10 (29%)

9 (19%) 8 (24%)

*p = .021, compared with irradiation alone.

100 Gy to point A. The bladder and rectal dose was limited to 70 Gy. Early in the study, 21 patients underwent staging laparotomy; this procedure was later discontinued because five patients developed wound dihiscence, and therapy was delayed for 27 to 63 days. Of 36 evaluable patients, 29 (8 1%) showed a complete response and seven (19%) a partial response. Pelvic tumor control was 93% in 29 patients who had a complete response compared with only 43% (three of seven) of those with a partial response (P = .02). Disease-free survival was 47% and overall survival was 55% at 48 months. Hematologic toxicity (neutropenia and thrombocytopenia) occurred in four patients. Three patients developed cancerrelated small bowel obstruction requiring surgical correction (each underwent staging laparotomy and two received para-aortic irradiation). One patient developed chronic hematuria.

Souhami et aFIi treated 50 patients with bulky locally advanced cervical carcinoma with weekly cisplatin (30 mg/m 2) plus concurrent radiation therapy (46 Gy whole pelvis plus three high-dose rate intracavitary insertions once weekly to a total dose of 30 Gy to point A). The complete tumor response rate was 88% (44 of 50). At 44 months, the actuarial survival rate was 65%, total pelvic failure rate was 26%, and distant metastases were present in 24% of patients. Late gastrointestinal toxicity was high, with 10 rectal ulcers (four colostomies required for severe bleeding), two rectovaginal fistulae, and two small bowel obstructions. Resbeut et aF7 described results in 40 patients with bulky stage IB, lIB, and III cervical carcinoma treated with concurrent chemotherapy (cisplatin, 60 mg/m 2 on days I and 21, followed by 5-FU, 600

Table 3. Carcinoma of the Uterine CelVix Table 2. Carcinoma of the Uterine CelVix

(MIR 1984-1992): Treatment Correlated With Major Late Sequelae

(MIR 1984-1992): Treatment Correlated With Moderate Late Sequelae

Sequelae Gastrointestinal Small bowel obstruction Proctitis Rectal ulcer Rectal stricture Malabsorption syndrome Genitourinary Cystitis Other Vault necrosis Vaginal stenosis Total* *p= .17.

Irradiation Illone (n = 257)

Irradiation Plus Chemotherapy (n = 58)

2 (0.8%) 3 (I %) 1 (0.4%) 0

0 0 I (2%) 1(2%)

I (0.4%)

0

I (0.4%)

I (2%)

I (0.4%) 0 9 (3.5%)

1(2%) 1(2%) 5 (9%)

Sequelae Gastrointestinal Rectovesical fistula Rectouterine fistula Small bowel obstruction Proctitis Rectal stricture Genitourinary Bladder fistula Other Deep vein thrombosis (leg) Pulmonary embolism Vault flt'crosis Total* *p = .09.

Irradiation Alone (n = 257)

Irradiation Plus Chemotherapy (n = 58)

6 (2%) 1(0.4%) 7 (3%) 0 0

3 (5%) 0 0 1(2%) I (2%)

4 (2%)

1(2%)

0 0 1(0.4%) 19 (7%)

I (2%)

1(2%) 1(2%) 9 (16%)

53

Chemotherapy and Irradiation in Cervix Cancer

-.-

9 - -0-

-A-

8

--l:r-

RT ALONE Grade 2 (n =257) RT + CHEMO Grade 2 (n =58) RT ALONE Grade 3 (n =257) RT + CHEMO Grade 3 (n =58)

7

E-t 6

Z ~

U 5 ~ ~ ~

4

3

2 1 0

o

1

2

3

4

5

YEARS AFTER THERAPY Figure 3. Carcinoma of the uterine cervix (MIR 1984-1992): Sequelae correlated with treatment.

mg/m 2/d, continuous IV infusion for 4 days) and pelvic irradiation (45 Gy, 1.8 Gy per fraction, given twice daily in the last 20 patients, and a low-dose rate intracavitary insertion for 15 Gy to the reference isodose). Subsequently, 35 patients underwent colpohysterectomy with lymphadenectomy or pelvic exenteration. The 2-year disease-free survival rates were 61 % in patients with stage IE, 66% with stage lIB, and 77% with stage III lesions. Pelvic tumor control was achieved in 81 % of patients with stage IE and IIA disease and 74% of those with stage III and IV tumors. Five (15%) patients developed severe complications requiring a second surgery. Of 16 patients who had a negative histopathologic specimen at the time ofsurgery, only one (stage IE disease) developed a pelvic recurrence. Therefore, it seems possible to select patients for whom a surgical procedure would not be required. Park et aIlS treated patients with stage I and II cervical carcinoma larger than 4 cm with irradiation alone (45 Gy to the whole pelvis, 10 to 15 Gy parametrial boost, and 39 Gy to point A with highdose rate brachytherapy delivered in 3-Gy fractions); two or three cycles of cisplatin, 5-FU, and irradiation; or one to six cycles of sequential neoadjuvant chemotherapy (cisplatin or carboplatin and 5-FU) and concurrent irradiation. The 30-month survival rates

were 100% with concurrent chemoirradiation, 90% with sequential treatment, and 80% with irradiation alone (P = .05). The most common hematologic toxicities were leukopenia (55%), anemia (38%), and thrombocytopenia (26%). The incidence of hepatic and renal toxicity was 27% and 24%, respectively. Varia et all'! reported on protocol GOG 125, in which 87 evaluable patients with biopsy-confirmed para-aortic lymph nodes from cervical cancer received extended-field irradiation (45 Gy in 1.5-Gy fractions) and higher doses to the pelvis (about 80 Gy to point A) in combination with 5-FU (1 g/m 2, days 2 through 5 and 30 through 33) and cisplatin (50 mg/m 2, days 1 and 29 of irradiation). The 3-year progression-free and overall survival was 33% and 39%, respectively. Grade 3/4 hematologic toxicity occurred in 13 patients (15%), chronic proctitis occurred in three (3.5%), and four (4.6%) required surgery for rectal complications. Tables 4 and 5 summarize collected series of patients with carcinoma of the uterine cervix treated with concomitant irradiation and chemotherapy in which the reported survival rate was about 60% and the pelvic control rate was 75% to 80%. These results are comparable to those reported with irradiation alone. I ,72,S9

54

Perez, Grigsby, and Chao

Table 4. Results of Radiation Therapy and Concomitant Cisplatin-Based Chemotherapy in Patients With Cervical Cancer

Recurrence Site No.qf Patients

Author Lipsztein 80

2 5 3 9

PiverS l Monyak fi8

II 13

II 3 Haie H2

Wongfil RTonly RT + weekly cisplatin RT + twiceweekly cisplatin Parkfi
Status *

Follow-up (rna)

Stage IB (barrel) IIB IIIB Positive PN IB lIB III IVA

NAlJ 2 4

11-26 12-25 6-48

Pelvis DOD Only

AWD

I

I I

I

I

2

2

5

2

Pelvis +DM

5

52% 3-yT RFS

2

II

IVB

24

III

44% 4-yrOS

56% 4-yr

IVA

28% 4-yr OS

LR±DM 85% 4-yr LR±DM

II

II

IVB

25 22

IIB-IIIB IIB-IIIB

13 10

II

4 4

5 4

17

IIB-IIIB

10

6

3

3

8

5 4

113

12

3 4

I-II 78% 5-yr OS

I-III

77 37 34

DM Only

48% 5-yrOS 40% 5-yr OS 40% 5-yrOS

IIB-IVA

II

7 2

Abbreviations: NED, no e\;dence of disease; AWD, alive with disease; DOD, dead of disease; DM, distant metastases; PN, para-aortic nodes; RFS, relapse-free survival; OS, overall survival; LR, locoregional; RT, radiation therapy. *There were no deaths due to complications. tRandomized study. Data from Grigsby and Perez G5

Table 5. Results of Radiation Therapy and Concomitant 5-FU in Patients With Cervical Cancer Recurrence Site Author

No.qf Patients

Stal-Ie

SmithH4 Thomas H.5 John H'; Evans H7 Ludgate HH Roberts'10 Grigsby and Perezfi5

17 200 32 10 38 18 10 29

Advanced Advanced Advanced Advanced Advanced Advanced IB-IIB III-IVA

Follow-up (rna) 24-60 7-83 3-37 7-38 .1-36 36-72 36-72

Status NED 7

7 26 9

AWD 3 54% 3-yr OS 63% 2-yr OS

I 4 70% 5-yrOS 25% 5-yr OS

DOD

Death Due to Cornplicatiom

7 3 0 3 10 5

Pelvis Only

Pelvis +DM

DM Only

7 50*

20

2 13

I 3

I

0 6

2 3 2 8

2 6

I I 8

Abbreviations: NED, no evidence of disease; AWD, alive with disl'ase; DOD, dead of disease; DM, distant metastases; OS, overall survival. *One patient NED after pelvic exenteration. Data from Grigsby and PerezY5

Chemotherapy and Irradiation in Cervix Cancer

Trials With Mitomycin C al90

Christie et described results III three patient groups with stage lIB and III cervical carcinoma treated with external pelvic irradiation and intracavitary cesium insertion plus chemotherapy. Group A (64 patients) received 5-FU during the first and last weeks of external irradiation plus bolus mitomycin C (10 mg/m 2 IV), group B (29 patients) received 5-FU without mitomycin C, and group C (84 patients) received irradiation alone. With a 7.2-year median follow-up, the 5-year survival rates were 56%, 32%, and 36%, respectively. The corresponding diseasefree survival rates were 54%, 32%, and 32%, respectively. Of the relapses, 48% were in the pelvis alone, and 23% were both within and beyond the pelvis. The percent of patients relapsing in the pelvis was lower in group A (23%) than in the other groups (41 % in B and C). The incidence of distant metastases was comparable in the three groups (13%,14%, and 12%, respectively). The 5-year local tumor control rates were 73%, 53%, and 50%, respectively. The study showed greater efficacy for the mitomycin C-containing combination. However, toxicity was higher in this group (36% grade 3/4) compared with patients receiving 5-FU and irradiation (14%) or irradiation alone (20%). Seven of 64 patients in group A required a colostomy versus only two patients each in groups Band C. The authors concluded that 5-FU plus mitomycin C should be used with caution in cervical carcinoma and further clinical trials were necessary. Denehy et al 91 reported on 40 patients with stage IB to IVA carcinoma of the uterine cervix (tumors larger than 5 em) treated with bolus mitomycin C (10 or 15 mg) on day 1and 5-FU (400 mgon days 1and 5) followed by pelvic irradiation (50 Gy in 2-Gy fractions combined with intracavitary insertion for 3,120 mgh, total dose to point A, 75 to 80 Gy). Pelvic tumor control was achieved in 23 of 40 patients (58%). Control was achieved in 76% of the 25 patients with stage IB and lIB disease and only 27% of the 15 patients with stage III and IVA disease. The pelvic tumor control rates were 100% in three patients with tumors less than 5 em and 54% in 37 patients with larger tumors. Nine patients (23%) developed distant metastases. There were three severe side effects in 24 patients receiving mitomycin C, 15 mg: thrombocytopenia, radiation enteritis, and radiation proctitis. Results are similar to those observed with irradiation alone.

55

Intra-arterial Chemotherapy Intra-arterial chemotherapy infusion in cervical carcinoma has held considerable interest for some years based on the distinct arterial supply to the tumorbearing area. Unfortunately, responses have been uncommon and short, and toxicity and complication rates have been significant.92 Morris et al 93 reported on 16 patients with squamous cervical carcinoma stages lIB, IIIB, or IVA with diameters of 7 em or greater. Patients underwent surgical staging with pelvic and para-aortic lymphadenectomy and bilateral intra-arterial catheter placement in the anterior division of the internal iliac arteries, terminating in separate subcutaneous ports. No patient had metastasis at the high common iliac or para-aortic nodes. Patients received 40- to 50-Gy whole pelvis external irradiation followed by brachytherapy. During the first 2 weeks of whole pelvic irradiation, patients also received a I-hour 5-FU deoxyribonucleoside (FUdR) infusion; during the second 2 weeks, a I-hour cisplatin infusion was administered. Each drug was delivered daily by external pump with the daily whole pelvis irradiation fraction. Additional cisplatin was infused during brachytherapy. Five dose levels were evaluated, ranging from 6.5 to 27 mg/m 2 daily for FUdR and 2 to 8 mg/m 2 daily for cisplatin. Doselimiting toxicity was grade 3/4 nausea in three of four patients at dose level 5. No patient had neurotoxicity or ototoxicity, and there was no grade 4 myelosuppression. Eight patients had a complete response, and six had a partial response. With a mean 22-month follow-up, 10 patients had no evidence of disease, two were alive with disease, and four had died of disease.

Randomized Studies of Chemotherapy and Irradiation Because the intent of chemotherapy administration in these patients is to improve results achieved with radiation therapy, it is essential to evaluate the efficacy of such an approach through randomized phase III trials. Thomas 94 summarized the rationale and potential limitations of neoadjuvant chemotherapy in stage IB cervical carcinoma. She pointed out that four randomized trials of neoadjuvant chemotherapy and irradiation have been reported in patients with stage lIB and III cervical cancer. 83 ,95,96 Although response rates to the chemotherapy were between 30% and 85%, none of the studies demonstrated an advantage for pelvic tumor control or survival.

56

Perez, Grigs0, and Chao

Hydroxyurea The GOG evaluated irradiation plus concomitant hydroxyurea or placebo in patients with stage IIIB or NA disease. 97 The study is tarnished by three criticisms: (I) the patients were not surgically staged before study entry; (2) 50% of the 190 enrolled patients were inevaluable for study parameters; and (3) irradiation doses were low compared with studies at large single institutions. I ,H9 Despite these criticisms, the response rates favor concomitant hydroxyurea (68% v 49% for placebo-treated patients). However, hematologic toxicity was more common and more severe in patients receiving hydroxyurea. In 1974, Piver et al 9H reported a study of 37 women with untreated stage lIB or IIIB cervical cancer, 22 of whom were randomized to irradiation and placebo and 15 to irradiation and hydroxyurea (80 mglkg every third day starting on the first day of radiation therapy and continuing for 12 weeks). In 1977, the same authors published an update with 130 evaluable patients, 75 ofwhom were surgically staged.99 Of 66 evaluable patients who underwent surgical staging, 33 received hydroxyurea and 33 received placebo in combination with irradiation. Of the patients who did not undergo surgical staging, 27 received hydroxyurea and 37 received placebo. Of the 130 patients, 13 had biopsy-proven metastasis to the para-aortic lymph nodes. For stage lIB patients, external irradiation doses were 50 Gy to the pelvis combined with 35 to 40 Gy to point A with intracavitary radium. Patients with stage IIIB disease received 60 Gy in 6 weeks to the pelvis followed by 25 Gy to point A with intracavitary radium. There was a second randomization to external beam irradiation with continuous or splitcourse therapy (23 patients in each group). Of the 27 women who received hydroxyurea for stage lIB disease without biopsy-proven para-aortic node metastasis, 20 (74%) were alive without disease 2 years after treatment compared with 17 of 39 (44%) in the placebo group (P < .01). This includes 12 of 18 (67%) and nine of 24 (38%) patients receiving hydroxyurea or placebo, respectively, who were not surgically staged. Of the women with stage IIIB tumors without biopsy-proven metastasis to para-aortic nodes, 12 of 23 (52%) in the hydroxyurea group and nine of 27 (33%) in the placebo group were alive without disease at 2 years. Seven of 14 patients (50%) receiving hydroxyurea who were surgically staged and had biopsy-negative para-aortic nodes were alive without disease at 2 years compared with eight of 14 (57%) who received placebo. Only two of 13 patients (15%)

with proven metastasis to the para-aortic nodes were alive without disease at 2 years. A later report described 40 patients with stage lIB carcinoma of the uterine cervix undergoing pretherapy staging para-aortic lymphadenectomy. lOG Patients received irradiation and were randomized to either hydroxyurea or placebo. Only one patient (5%) in the hydroxyurea group died of cervical cancer compared with nine (45%) patients in the placebo group. The 5-year life table survival rates were 94% for the hydroxyurea group and 53% for the placebo group. Dembo,101 in a critical analysis of this publication, commented that if a life table survival analysis was performed without censoring causes of death other than cervical carcinoma, the 5-year actuarial rates are 65% and 45% for the hydroxyurea and placebo groups, respectively (P = .3, WilcoxonGehan). In a later report, Piver et al 102 published results in 45 patients with stage IIIB cervical carcinoma, 38 of whom underwent pretherapy surgical staging through a midline intraperitoneal incision and seven through a retroperitoneal incision. Patients were randomized to hydroxyurea plus irradiation or irradiation alone. There were seven recurrences in the 20 patients (35%) receiving combination therapy compared with 14 recurrences in 25 patients (56%) treated with irradiation alone. The overa1l5-year progression-free survival rates were 60% for those receiving chemoirradiation and 52% for those receiving irradiation alone. Toxicity included diarrhea (10%) and leukopenia (80%). Complications requiring surgical correction or leading to death occurred in seven (35%) patients receiving chemoirradiation and eight (32%) patients receiving irradiation alone. In another larger randomized GOG trial reported by Stehman et al,I03 296 surgically staged patients with stage lIB through IVA disease and negative para-aortic nodes were randomized to irradiation plus hydroxyurea (139 patients) or misonidazole (157 patients). The median progression-free survival was 42.9 months for patients receiving hydroxyurea and 40.4 months for those receiving misonidazole. For patients with stage IIIB or N A tumors who received hydroxyurea, the progression-free survival curve was similar to that for the stage lIB patients, but the curve for the misonidazole arm falls below the others (Fig 4). Survival was not statistically different between the regimens, with 34% mortality in the hydroxyurea group and 39% mortality in the misonidazole group (P = .25). Failure limited to the pelvis occurred in 18% of patients in the hydroxyurea group

57

Chemotherapy and Irradiation in Cemix Cancer

1.0

o.t

o..a L

0.7

0o..a

----

W

z

L

--

-l

'E~

--

L-

- ------c.

i~ lU Q..2

---------

0.1

----

Rx·St9

NED

t.IIiIo. . II

411 51

45

toIMl·III/IV 22 HydralL . I II II V 23

41

HydralL ·11

F*d

33

30

TamI

.. a4

113 53

p.O.04O

0..0 0

8

t2

eo

18

Months on Study Figure 4. Progression-free survival correlated with treatment and stage in patients randomized to irradiation plus either hydroxyurea or misonidazole. (Reprinted with permission. 103 ) and 24% of the misonidazole group. Fletcher,s9 Horiot et al,72 and Perez et all have noted similar survival and tumor control with radiation therapy alone compared to those observed with the addition of hydroxyurea (Fig 5). Leibel et al,104 in a randomized Radiation Therapy Oncology Group (RTOG) trial of patients with stage III disease, and Overgaard et al 105 reported lower survival in patients receiving misonidazole than those receiving irradiation alone. Results of trials with hydroxyurea are summarized in Table 6. Cisplatin Wong et al 61 randomized 25 patients to irradiation alone (40 Gy in 2.5-Gy daily fractions, four fractions per week, and two intracavitary applications of 60 to 65 Gy), 22 to irradiation and weekly cisplatin, and seven to twice-weekly cisplatin and irradiation for stage lIB and III carcinoma of the uterine cervix. Cisplatin (25 mg/m 2 IV bolus) was administered within 30 minutes before irradiation on day I and repeated weekly or twice per week (days I and 3 of each treatment week). Complete response after therapy was noted in 20, 14, and 15 patients, respectively. Five-year survival was similar in the three groups (45% to 50%). A few patients developed

radiation proctitis and cystitis, and a vesicovaginal fistula occurred in one patient. A French studt7 randomized 151 patients with stage lIB or III disease to either cisplatinlmethotrexate/chlorambuciVvincristine followed by radiation therapy or radiation therapy alone. Two to four chemotherapy courses yielded an overall response rate of 42%. No overall survival differences were observed. Tattersall et al 107 evaluated 71 patients with stage IB-IIA cervical carcinoma who had metastatic pelvic lymph nodes after radical hysterectomy and were entered into a randomized trial comparing pelvic radiation therapy (45 to 55 Gy administered in 4 to 5 weeks) alone or combined with three cycles of cisplatin (50 mg/m 2), vinblastine (4 mg/m 2), and bleomycin (15 mg), followed by the same pelvic irradiation. There was no difference in survival in the two groups. Later, Tattersall et alIOS reported a randomized trial of 260 patients with stage lIB to IVA cervical cancer: 131 received pelvic irradiation (45 to 55 Gy in 4 to 5 weeks followed by 30 to 35 Gy intracavitary insertion) and 129 received chemotherapy (cisplatin 60 mg/m 2 and epirubicin 110 mg/m 2, administered at 3-week intervals for three cycles) followed by similar pelvic irradiation. Patients who received primary chemother-

58

Perez, Grigsf!y, and Chao

1.0 0.9 0.8 CIJ

0.7

CIJ

0.6

CIJ ....... rIJ

til CIJ

rIJ

0.... l:

0.5

CIJ

0.4

Q.,

0.3

...u CIJ

0.2 0.1

Total 157 137 106

Failed 86 63

Rx NED 71 Misonidazole 74 Hydroxyurea MIR - R.O.C.

p = 0.050

0.0 0

18

12

6

24

42

36

30

54

48

60

Months on Study Figure 5. Progression-free survival correlated with treatment. MIR data are compared with those of the GOG study. NED, no evidence of disease; MIR, Mallinckrodt Institute of Radiology; ROC, Radiation Oncology Center. (Data from Stehman et al. lIJ3 )

apy had a significantly higher pelvic failure rate (29%) than those who received radiation therapy alone (19%) (P = .003). Patients who received chemotherapy had significantly lower survival compared

with those who received radiation therapy alone (P = .02) (Fig 6). Souhami et aF6 randomized 107 patients with stage lIIB cervical carcinoma to irradiation alone or

Table 6. Results of Radiation Therapy and Concomitant Hydroxyurea in Patients With Cervical Cancer

Author

No. of Patients

Hreshchyshyn97 RT RT

+ hydroxyurea

46

mB, IVA

51

mB, IVA

Piver JOo RT 20 RT + hydroxyurea 20 20 Piver J06 Piver 102 RT 25 RT + hydroxyurea 20 Stehman 104 Hydroxyurea 139 Misonidazole

Stage

157

lIB lIB

IE

Follow-up (rna)

NED

DM Only

7.6-mo median PFS l3.6-mo median PFS 72-108 72-108 6-83

8 12 17

mB mB

52% 5-yr PFS 60% 5-YT PFS

lIB, IVA

43-mo median PFS 40-mo median PFS

lIB, IVA

Death Recurrence Site Due to Compli- Pelvis Pelvis AYVD DOD cations Only +DM

Status

9 I I

2 4

18% (pelvis) 23.6% (pelvis)

Abbreviations: NED, no evidence of disease; AWD, alive with disease; DOD, dead of disease; DM, distant metastases; RT, radiation therapy; PFS, progression-free sUf\~val. Data from Grigsby and Perez. 51

59

Chemotherapy and Irradiation in Cervix Cancer

Propclf1iM SUIVlVtng

Group CT·> RT RT only······

I

j

0.6

0.4

02

Figure 6. Time to disease progression according to randomization group. CT, chemotherapy; RT, radiation therapy. (Reprinted with permission. IIIM )

00L-------:---------:2~------_:;_------_;' Time (years)

Numbe< at RISk 127 127

55 72

irradiation plus bleomycin, vincristine, mitomycin, and cisplatin (BOMP). The overall5-year survival for neoadjuvant-treated patients was 23% compared with 39% for those treated with irradiation alone (P = .02). Locoregional and distant failures were similar in both groups. Chiara et al IIllJ described a randomized study of advanced cervical carcinoma patients (stage lIB and III) of which 29 received irradiation alone (40 Gy whole pelvis and one low-dose intracavitary insertion, 40 Gy to point A, and additional 15- to 20-Gy boost to the parametrium) or a combination of cisplatin (60 mg/m 2 N) on days I and 15 before radiation therapy initiation and four cycles concurrent with radiation therapy. The actuarial 3-year progression-free survival rates were 72% in the irradiation-alone arm and 59% in the chemoirradiation arm. Recurrences were observed in four of 22 (18%) and eight of 24 (33%) patients, respectively. Late complications occurred in two patients receiving irradiation alone and one receiving chemoirradiation. Kumar et aJl III reported on 94 patients with stage lIB to N cervical carcinoma randomized to chemotherapy (two cycles of bleomycin, ifosfamide, mesna, and cisplatin) followed by radiation therapy and 90 patients randomized to irradiation alone. Radiation therapy consisted of 40 Gy to the whole pelvis followed by lOGy with midline shielding in 1- to 2-Gy fractions in addition to 30 Gy to point A with low- or medium-dose intracavitary insertion. In the chemoirradiation group, 32-month survival was 64% for lIB disease, 50% for IIIB disease, and 23% for N A tumors. The corresponding survival rates in patients receiving irradiation alone were 59% for lIB disease

24 41

10 18

o

o

and 27% for patients with lIIB tumors. In the chemoirradiation group, 23 patients demonstrated local failure, three had both local failure and distant metastases, and one had distant metastases alone. In the radiation therapy group, 30 patients had local recurrences, three had both local and distant disease, and eight had distant metastases only. There was no difference in radiation-induced toxicity between the two groups. In a Swedish study,11I 47 patients with stage IIB-NA cervical carcinoma were randomized to external irradiation alone (64.8 Gy, 1.8-Gy fractions, box technique) and 47 patients to three cycles of cisplatin (100 mg/m 2 N) and 5-FU (I g/m 2/d, N continuous infusion for 5 days) administered every third week, followed by the same pelvic external irradiation. The 5-year disease-free survival rates were 70% with chemoirradiation and 57% with irradiation alone (P = .07). The incidence of pelvic recurrence was 60% and 47%, respectively, and distant metastases occurred in 19% and 35% of patients, respectively. Two patients in the chemoirradiation and one in the irradiation-alone group died as a consequence of therapy. Published reports on neoadjuvant chemoirradiation in cervix cancer are summarized in Table 7.

Randomized Studies in Progress The GOG evaluated patients with clinical stage lIB, III, and N A cervical carcinoma and negative paraaortic nodes who received external pelvic irradiation (51 Gy) plus 30 Gy to point A with intracavitary brachytherapy and either 5-FU (I g/m 2 N infusion for 4 days) plus cisplatin (50 mg/m 2 N on days 1,29,

60

Perez,

Crigs~,

and Chao

Table 7. Neoadjuvant Chemotherapy in Cervical Cancer: Review of the Literature Author

No.qf Patients

Weiner l12 Kirsten 11:1

20 47

Symonds 114 Kim llJ Sardi 70

51 54 151

FICO Stage

Study Design/ Chemotherapy

IB-IVA CT-RT,MOBP lIIB-IVA CT-RT/Sx, PYE ill-IVA IB-IIB IIB-IIIB

CT-RT,PYB CT-Sx,PYE CT-Sx/RT, BOP BOP

OR (%)

CR ("10)

72 66

II

53 94 1IB-64

0 47

IIIB-31

Lara I 16 Kuhnle l17 Panici llH Volterrani 119 Panici 120

24 32 26 23 75

IIIB IIB-IVB IB-III II-Ill ill-III

CT-RT,IP CT-RT,CI CT-Sx, PB CT-RT,PB CT-Sx,PBMx

63 59 88 52 83

Rabinovich 121 Maranz l22

31 15

lIB-IVA llA-IIIB

23 73

0 27

Gamucci 123 Fontanelli 124

15 27

lA-lIB IE-II

CT-RT, BOP CT-Sx; CT-RT; IP5-FU CT-Sx, BIP CT-Sx, BP

80 78

33 II

Chauvergne 9f; 138: CT-RT = 68; lIB RT= 72

PBMChl

35

Tobias 12:,

llA-IV

ElP

lIB

PECy

IIIB

BOMP

Comments Median survival 88wk 2-yr DFS 94% 2-yr DFS 79% v 47% 2-yr DFS 50% v 26% 3-yr DFS 54%

9 19 15

3-yr DFS: IB-llA, 100%; lIB, 81 %; III,66%

Randomized Studies

Cardenas 95 Souhami 76

Sundf0r lll Kumar llo

66: CT-RT = 32; RT= 34 24: CT-RT = II; RT= 13 107

CT-RT = 47; IIIB-IVA CT-RT, P5FU RT = 47 177: CT-RT = 89; lIB-IVA ElP RT = 88

1.5

2-yr DFS CT-RT 63%v RT60%, NS 6 CR after CT-RT 69 75%, RT 56% 73 9.0 CT-RT CR 6/9 v RTCR 12/13 47 CT-RT; 33 RT 5-yr sut\fival: CT-RT23%v RT39% 80 CT-RT; 82 RT 53 CT-RT; 57 RT CT-RT 5 yr DFS 70%; RT 57% 4.5 DFS at 30 mo: 72 CT-RT69%v RT67%;NS

Abbreviations: FIGO, International Federation of Gynecology and Obstetrics; OR, overall response; CR, complete response; CT, chemotherapy; RT, radiation therapy; M, mitomycin C; 0, vincristine; B, bleomycin; P, cisplatin; V, vinblastine; DFS, disease-free survival; I, ifosfamide; C, carboplatin; Mx, methotrexate; 5-FU, 5-fluorouracil; ChI, chlorambucil; S, not significant; E, epirubicin; Cy, cyclophosphamide.

and 30 to 33) or hydroxyurea (80 mglkg orally twice weekly) (GOG 85).126 Surgical staging was required with extraperitoneal sampling of para-aortic lymph nodes and intraperitoneal exploration and washings. Patient accrual has been completed; follow-up and data analysis are in progress. Mter completion of GOG 85, the GOG opened their current study (GOG 120) to the same patient population; it is a three-arm randomized trial comparing irradiation plus either hydroxyurea, weekly cisplatin, or hydroxyurea, cisplatin, and 5-FU. The GOG also is conducting a study (GOG 123) comparing radiation therapy plus

hysterectomy and the same treatment combined with weekly cisplatin. Finally, an Intergroup study initiated by GOG for patients with positive pelvic lymph nodes at radical hysterectomy is comparing postoperative pelvic irradiation alone or combined with 5-FU and cisplatin. The RTOG is conducting a study in which patients with stage IE (>4 cm) to IVA cervical carcinoma are randomized to either pelvic and para-aortic irradiation (best arm of RTOG protocol 79-20) 127 or pelvic irradiation and three concomitant chemotherapy cycles of cisplatin (75 mg/m 2) and 5-FU (I g/m 2/d

Chemotherapy and Irradiation in Cervix Cancer

for 4 days).128 This ongoing study is expected to be completed in I to 2 years. Other prospective phase III studies being performed in Canada and Europe for patients with stage IE-IVA cervical cancer include neoadjuvant cisplatin and methotrexate versus adjuvant chemotherapy (United Kingdom, Medical Research Council), neoadjuvant bleomycin, ifosfamide, and cisplatin versus irradiation alone (United Kingdom, Cancer Research Campaign Trials Unit), and concurrent cisplatin and irradiation versus irradiation alone (National Cancer Institute of Canada Clinical Trials Group).

6. 7.

S.

9.

10.

Conclusions As stated by McGuire,129 "There are no published data to suggest that in patients with carcinoma of the cervix survival significantly improves after combination chemotherapy, and some patients who have received combination chemotherapy in randomized studies had inferior survival compared with patients who were administered single-agent cisplatin because of treatment-related deaths." Contrary to the opinions of some authors such as Stehman et al 103 and Thigpen et aI,39 we strongly believe that, based on available data, chemotherapy should not be advocated in the standard management of carcinoma of the uterine cervix, and patients should be encouraged to participate in properly designed clinical trials. Nevertheless, chemotherapy does have three potential roles in the management of patients with carcinoma of the cervix: (I) as an adjuvant to irradiation in the treatment of locally advanced tumors; (2) in patients with pelvic or para-aortic nodal metastasis with a low potential for cure with current local treatment modalities; and (3) for recurrent disease after surgery or radiation therapy.130

References 1. Perez CA, Camel HM, Kuske RR, et al: Radiation therapy alone in the treatment of carcinoma of the uterine cervix: A 20-year experience. Gynecol Oncol23: 127-140,1986 2. Fagundes H, Perez CA, Grigsby PW, et al: Distant metastases after irradiation alone in carcinoma of the uterine celVix. IntJ Radiat Oncol Bioi Phys 24:197-204,1992 3. Perez CA, Kurman RJ, Stehman FB, et al: Uterine cervix, in Hoskins WJ, Perez CA, Young RC (eds): Principles and Practice of Gynecologic Oncology. Philadelphia, PA, Lippincott, 1992, pp 591-662 4. Steel GG: The search for therapeutic gain in the combination of radiotherapy and chcmotherapy. Radiother Oncol 11:31-53,1988 5. Steel GG, Peckham MJ: Exploitable mechanisms in com-

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lH.

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20.

21.

61

bined radiotherapy-chemotherapy: The concept of additivity. IntJ Radiat Oncol BioI Phys 5:85-91, 1979 Perez CA, MarksJ, Powers WE: Preoperative irradiation in head and neck cancer. Semin OncoI4:387-397, 1977 Tannock IF: Potential for therapeutic gain from combinedmodality treatment, in Meyer JL, VaethJM (eds): Frontiers of Radiation Therapy and Oncology: Radiotherapy/Chemotherapy Interactions in Cancer Therapy, vol 26. Basel, Switzerland, Karger, 1992, pp 1-15 Durand RE: Keynote address: The influence of microenvironmental factors on the activity of radiation and drugs. Int J Radiat Oncol BioI Phys 20:253-258, 1991 Rauth AM, MohindraJK, Tannock IF: Activity of mitomycin C for aerobic and hypoxic cells in vitro and in vivo. Cancer Res 43:4154-4158, 1983 Chang EH, Pirollo KF, Zou ZQ, et al: Oncogenes in radioresistant, noncancerous skin fibroblasts from a cancer-prone family. Science 237:1036-1039,1987 Sklar MD: The ras oncogenes increase the intrinsic resistance of NIH 3T3 cells to ionizing radiation. Science 239:645647, 1988 Fu KK: Interactions of chemotherapeutic agents and radiation, in Meyer JL, Vaeth JM (eds): Frontiers of Radiation Therapy and Oncology: Radiotherapy/Chemotherapy Interactions in Cancer Therapy, vol 26. Basel, Switzerland, Karger, 1992, pp 16-30 Woloschak GE, Chang-Liu CM,Jones PS, et al: Modulation of gene expression in Syrian hamster embryo cells following ionizing radiation. Cancer Res 50:339-344,1990 Witte L, Fuks Z, Haimovitz-Friedman A, et al: Effects of irradiation on the release of growth factors from cultured bovine, porcine, and human endothelial cells. Cancer Res 49:5066-5072, 1989 Kwok Tf, Sutherland RM: Enhancement of sensitivity of human squamous carcinoma cells to radiation by epidermal growth factor.J Natl Cancer Inst 8 I: 1020-1024, 1989 Neta R, OppenheimJJ, Douches SD: Interdependence of the radioprotective effects of human recombinant interleukin I alpha, tumor necrosis factor alpha, granulocyte colonystimulating factor, and murine recombinant granulocytemacrophage colony-stimulating factor. J Immunol 140: 108111,198H Carde P, Lavel F: Effects of cis-dichlorodiammine platinum II and x-rays on mammalian cell survival. IntJ Radiat Oncol BioI Phys 7:929-933, 1981 Kelland LR, Steel GG: Inhibition of recovery from damage induced by ionizing radiation in mammalian cells. Radiother OncoI13:2H5-299,1988 Siemann DW: Interactions between nitrosoureas and xirradiation, in Hill BT, Bellamy AS (eds): Antitumor DrugRadiation Interactions. Boca Raton, FL, CRC Press, 1990, pp 141-151 Donaldson SS, Moskowitz PS, Canty EL, et al: Combination radiation-Adriamycin therapy: Renoprival growth, functional and structural effects in the immature mouse. Int J Radiat Oncol Bioi Phys 6:851-859, 19HO Dritschilo A, Piro AJ, Kelman AD: The effect of cisplatinum on the repair of radiation damage in plateau phase Chinese hamster (V-79) cells. Int J Radiat Oncol Bioi Phys 5: 13451349,1979

22. Wallner KE, Li GC: Effect of cisplatin resistance on cellular

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