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Time to add chemotherapy to radiotherapy for cervical cancer
Time to add chemotherapy to radiotherapy for cervical cancer Although screening for cervical cancer has greatly reduced both the incidence of and death rates from invasive cervical cancer in the western world, the disease remains the commonest cancer among women in Africa, Asia, and South America. A high proportion of these cancers present at an advanced stage, for which the main treatment option has been radiotherapy. However, the US National Cancer Institute has sent out a clinical alert stating that strong consideration should be given to adding chemotherapy to radiotherapy for the treatment of invasive cervical cancer. It draws attention to five phase III studies that have each shown statistically significant improvements in survival rates when chemotherapy was added to standard radiotherapy regimens. Three of the studies are reported this week in the New England Journal of Medicine,1-3 and the other two were presented at the meeting of the Society of Gynecologic Oncologists last month in San Francisco. As the clinical alert puts it, “Overall, across the five studies, concurrent cisplatinbased chemoradiation reduced the risk of death by 30 percent to 50 percent”. In the South West Oncology (SWOG) Protocol 8797 (a collaborative study including Intergroup Protocol 0107, GOG Protocol 109, RTOG Protocol 9112) (principal investigator William Peters III, Seattle), the patients eligible were women with cervical cancer at FIGO stages IA2, IB, and 2A and who had metastatic disease in the pelvic lymph-nodes, parametrial invasion, or positive surgical margins at the time of primary radical hysterectomy with total pelvic lymphadenectomy. Their para-aortic lymph-nodes had to be negative, as confirmed histologically. If these nodes had not been sampled, the women’s common iliac lymph-nodes had to be confirmed as negative. 243 patients were accrued between 1992 and 1996. Two regimens were used:
• •
Regimen I was a combination of external beam radiation to the pelvis with a single dose of cisplatin 70 mg/m2 and a 4-day infusion of 5-FU (4000 mg/m2) given every 3 weeks for four courses (127 patients) Regimen II consisted of external beam radiation to the pelvis (116 patients).
Radiotherapy was identical in both arms, with 4930 cGy being delivered to the pelvis via a four-field box technique. Patients with invasion of high common-iliac nodes had 4500 cGy to a para-aortic field. The 3-year survival was 87% with combination therapy and 77% with radiotherapy alone. The women eligible for the Gynecologic Oncology Group (GOG) Protocol 1201 were those with disease in FIGO stages IIB, III, and IVA. They had undergone extraperitoneal surgical sampling of the para-aortic lymph nodes. Women with intraperitoneal disease or metastases to the para-aortic lymph-nodes were not eligible. 526 patients were accrued .
• •
•
Regimen I consisted of external beam radiation to the pelvis, intracavitary radiation, and 40 mg/m 2 of cisplatin weekly for 6 weeks (177 patients). Regimen II consisted of external beam radiation to the pelvis, intracavitary radiation, and cisplatin (50 mg/m2), 96 h continuous infusion of 5FU (4000 mg/m2) twice 3 weeks apart, and oral hydroxyurea 2 mg/m2 twice a week for 6 weeks (173 patients). Regimen III consisted of external beam radiation to the pelvis, intracavitary radiation, and hydroxyurea 3 mg/m2 twice a week for 6 weeks (176 patients).
1288
Radiation, identical for all three groups, was delivered with either anteroposterior or posteroanterior parallel ports or a four-field box technique. The median follow-up for survivors was 34·7 months. The 3-year survival rate for women in both the weekly cisplatin plus radiation group and the 5-FU, cisplatin, plus hydroxyurea group was 65%, compared with 47% for women receiving hydroxyurea plus radiation. Weekly cisplatin was associated with less leucopenia and less gastrointestinal toxicity than the three-drug cisplatin combination.These findings from the GOG study show that radiation given concurrently with cisplatin or cisplatin plus 5-FU improves survival for women with stages IIB, III and IVA disease. For the Radiation Therapy Oncology Group (RTOG) Protocol 9001 the patients eligible were women with FIGO stages IIB-IVA, or stage IB or IIA with biopsyproven invasion of pelvic lymph-nodes or with tumour 5 cm or greater in diameter.2 389 patients were recruited between 1990 and 1997. Two regimens were used:
• •
Regimen I consisted of external beam radiation to the pelvis, intracavitary radiation, and cisplatin 75 mg/m2, followed by 96 h intravenous infusion of 5-FU (4000 mg/m 2 on days 1 and 22 of the external beam radiation (195 patients). Regimen II consisted of extended field external beam radiation (ie, to pelvis and para-aortic region) and intracavitary radiation therapy (193 patients).
The total pelvic irradiation dose was 4500 cGy with reference point a receiving 8500 cGy. The median followup for survivors was 43 months. The 3-year survival rate for the chemotherapy group was 75%, compared with 63% for the radiation-only group. For GOG Protocol 85 (principal investigator Charles W Whitney, Newark) and SWOG protocol 8695 eligible patients were women with carcinoma of the cervix (FIGO stages IIB, III and IVA) who had undergone extraperitoneal lymph-node sampling of the para-aortic lymph nodes as well as intraperitoneal exploration and intraperitoneal washings. Women with invasion of the intraperitoneal or para-aortic nodes were excluded from the trial. 386 patients were recruited between 1986 and 1990. The two regimens were:
• •
Regimen I, which consisted of external beam radiation to the pelvis, intracavitary radiation, and cisplatin 50 mg/m 2 on days 1 and 29 and 5-FU 1000 mg/m2 per day on days 2–5 and 30–33 during the external beam radiotherapy (177 patients). Regimen II, which consisted of external beam radiation to the pelvis, intracavitary radiation, and hydroxyurea 80 mg/kg twice a week (191 patients).
Radiotherapy was modified according to the stage of disease. After a median follow-up of 8·4 years, the 3-year survival rate for women on the chemotherapy was 67%, compared with 57% for women on hydroxyurea. The GOG protocol 1233 included patients with bulky (greater than 4 cm) stage IB carcinoma of the cervix with negative pelvic and para-aortic lymph-nodes as determined radiographically, surgico-pathologically, or by both methods. 368 patients were recruited between 1992 and 1997. The regimens were:
• •
Regimen I, which consisted of external beam radiation to the pelvis, intracavitary radiation, and cisplatin 40 mg/m2 weekly for 6 weeks, followed by extrafascial hysterectomy (183 patients). Regimen II consisted of external beam radiation to the pelvis and intracavitary radiation, followed by extrafascial hysterectomy (186 patients).
Radiotherapy was standard. After a median follow-up of 35·7 months, the survival rate for women treated with
THE LANCET • Vol 353 • April 17, 1999
cisplatin was 83%, compared with 74% treated with radiotherapy alone. The findings of the five studies are clearly of great benefit to the large number of patients who continue to present with advanced cancer of the cervix. There is also demonstrable benefit for those patients who, despite small tumours, have metastases, especially to the pelvic nodes. Discussion at the San Francisco meeting also suggested that there may be advantages for patients with adenocarcinoma of the cervix. How cisplatin interacts with radiation is uncertain, but one suggestion is that the two act synergistically, perhaps with cisplatin preventing DNA repair during radiotherapy and damaging the reproductive ability of the cancer cells. What is unclear from the papers is whether the advantage of chemotherapy plus radiation was due solely to the combination or whether the maintenance of a high haemoglobin concentration contributed to the treatment. Grogan and colleagues4 have shown the beneficial effect of a high haemoglobin concentrations (>120 g/L) before and during radiation treatment. There is no information on correction of anaemia in any of the five studies. Haematological adverse effects were commoner in the combination-therapy than in the radiation-alone groups. Correction of these adverse effects may have resulted in higher overall haemoglobin concentrations in the combination-therapy groups. It is clearly important to extend the period of review beyond the 3 years taken by these studies. However, since cancer of the cervix tends to recur in the first 2 years of review, the longer-term recurrence pattern is unlikely to be significantly different from that with traditional treatments. There are two important practical implications of the findings. Those responsible for the provision and delivery of cancer services will have to find the extra resources for costs of the chemotherapeutic agents and for hospital stay. In three of the five papers, 12-16 days’ stay was required for the infusions of 5 FU, although this can be mitigated using ambulatory delivery systems. The other important implication is whether there is justification for continuing with existing trials, such as those run by the UK Medical Research Council and the European Organisation on Research and Treatment of Cancer, in which one of the comparison groups is receiving radiation alone. A final point is that all these five large studies have come from North America, which raises questions about the pace at which similar European studies are implemented and completed. John Monaghan Depar tment of Gynaecological Oncology, Queen Elizabeth Hospital, Gateshead, Tyne and Wear, NE9 6SX, UK 1
Rose PG, Bundy BN, Watkins EB, et al. Concurrent cisplatin-based radiotherapy and chemotherapy for locally advanced cervical cancer. N Engl J Med 1999; 3 4 0 : 1144–53. 2 Morris M Eifel PJ, Lu J, et al. Pelvic radiation with concurrent chemotherapy compared with pelvic and para-aortic radiation for high-risk cervical cancer. N Engl J Med 1999; 3 4 0 : 1137–43. 3 Keys HM Bundy BN, Stehman FB, et al. C i s p l at i n ,r a d i at i o n ,a n d adjuvant hsyterectomy compared with radiation and adjuvant hysterectomy for bulky stage 1b cervical carcinoma. N Engl J Med 1999; 3 4 0 : 1154–61. 4 Grogan M, Thomas GM, Melamed I, et al. The importance of maintaining high hemoglobin levels during radiation treatment of carcinoma of the cervix. Presented at the 30th Annual meeting of the Society for Gynecological Oncology in San Francisco, M a r c h ,1 9 9 9 .
THE LANCET • Vol 353 • April 17, 1999
Lessons from the Di Bella affair See page 1310 Most Italian oncologists will probably remember 1998 as their annus horribilis. Although now and then unsubstantiated claims of a treatment for cancer are made world wide, to the best of our knowledge, never before, anywhere, has so much turmoil been wrought by one therapeutic claim as the Di Bella affair did in Italy.1,2 It even caused the medical profession to abandon the principle of evidence-based medicine. What exactly happened and why it could have happened are not easy questions to answer. Di Bella was an 85-year-old retired professor of physiology who had for years been treating cancer patients with a mixture that included somatostatin, melatonin, vitamins, and small amounts of cyclophosphamide. This mixture purportedly induced remission of advanced cancer without the serious sideeffects of conventional antineoplastic drug regimens. Di Bella claimed that he had cured thousands of patients with this therapy, which, however, had not been tested in animals or in clinical studies. Not even anecdotal reports of success had been published in medical journals. At the end of 1997, Di Bella was catapulted, probably unwillingly, into the limelight. His patients, who had formed an association, tried to obtain reimbursement for this form of therapy, which could cost up to US$5000 per patient per month, from the national health system. The health authorities did not approve the reimbursement, and were astonished when the courts ruled that the government should pay for this treatment, on the grounds of “freedom of cure”. The most determined of these outspoken judges was depicted by the press as a modern hero fighting against the interests of the medical establishment and pharmaceutical industry. The media gave the issue unprecedented coverage. Supporters held rallies in Rome. Politicians promptly jumped onto the bandwagon, with the right-wing opposition in favour of Di Bella, and the centre-left government supporting Health Minister Rosy Bindi.3 During this time the medical community was set aside: those members who tried to foster scientific reasoning were ridiculed as patients’ enemies.4 Others sheepishly agreed to collaborate with Di Bella and his entourage in launching the first clinical trials of this regimen. The trials had been ordered by parliamentary decree and funded by a government usually deaf to the needs of researchers. What is left, 1 year later? Ten hastily conceived clinical studies whose design has been criticised by several experts have shown that the treatment does not block progression of cancer and is not as free of side-effects as had been claimed.5 The bill for the trials and for the somatostatin that judges had ruled should be prescribed for some patients has reached $20 million. But worse, the hopes of patients have been shattered. And perhaps some patients might have abandoned traditional therapy for Di Bella’s even before they entered the terminal phase of their disease. Why did all this happen? The results of a survey of patients conducted by Italian oncologists that are reported in this issue of The Lancet offer some insights. There is overwhelming evidence that the media contributed most to the affair. This finding is not surprising since the matter had all the ingredients of a perfect cover story: a life-threatening disease; an old 1289
• •
Regimen I was a combination of external beam radiation to the pelvis with a single dose of cisplatin 70 mg/m2 and a 4-day infusion of 5-FU (4000 mg/m2) given every 3 weeks for four courses (127 patients) Regimen II consisted of external beam radiation to the pelvis (116 patients).
Radiotherapy was identical in both arms, with 4930 cGy being delivered to the pelvis via a four-field box technique. Patients with invasion of high common-iliac nodes had 4500 cGy to a para-aortic field. The 3-year survival was 87% with combination therapy and 77% with radiotherapy alone. The women eligible for the Gynecologic Oncology Group (GOG) Protocol 1201 were those with disease in FIGO stages IIB, III, and IVA. They had undergone extraperitoneal surgical sampling of the para-aortic lymph nodes. Women with intraperitoneal disease or metastases to the para-aortic lymph-nodes were not eligible. 526 patients were accrued .
• •
•
Regimen I consisted of external beam radiation to the pelvis, intracavitary radiation, and 40 mg/m 2 of cisplatin weekly for 6 weeks (177 patients). Regimen II consisted of external beam radiation to the pelvis, intracavitary radiation, and cisplatin (50 mg/m2), 96 h continuous infusion of 5FU (4000 mg/m2) twice 3 weeks apart, and oral hydroxyurea 2 mg/m2 twice a week for 6 weeks (173 patients). Regimen III consisted of external beam radiation to the pelvis, intracavitary radiation, and hydroxyurea 3 mg/m2 twice a week for 6 weeks (176 patients).
1288
Radiation, identical for all three groups, was delivered with either anteroposterior or posteroanterior parallel ports or a four-field box technique. The median follow-up for survivors was 34·7 months. The 3-year survival rate for women in both the weekly cisplatin plus radiation group and the 5-FU, cisplatin, plus hydroxyurea group was 65%, compared with 47% for women receiving hydroxyurea plus radiation. Weekly cisplatin was associated with less leucopenia and less gastrointestinal toxicity than the three-drug cisplatin combination.These findings from the GOG study show that radiation given concurrently with cisplatin or cisplatin plus 5-FU improves survival for women with stages IIB, III and IVA disease. For the Radiation Therapy Oncology Group (RTOG) Protocol 9001 the patients eligible were women with FIGO stages IIB-IVA, or stage IB or IIA with biopsyproven invasion of pelvic lymph-nodes or with tumour 5 cm or greater in diameter.2 389 patients were recruited between 1990 and 1997. Two regimens were used:
• •
Regimen I consisted of external beam radiation to the pelvis, intracavitary radiation, and cisplatin 75 mg/m2, followed by 96 h intravenous infusion of 5-FU (4000 mg/m 2 on days 1 and 22 of the external beam radiation (195 patients). Regimen II consisted of extended field external beam radiation (ie, to pelvis and para-aortic region) and intracavitary radiation therapy (193 patients).
The total pelvic irradiation dose was 4500 cGy with reference point a receiving 8500 cGy. The median followup for survivors was 43 months. The 3-year survival rate for the chemotherapy group was 75%, compared with 63% for the radiation-only group. For GOG Protocol 85 (principal investigator Charles W Whitney, Newark) and SWOG protocol 8695 eligible patients were women with carcinoma of the cervix (FIGO stages IIB, III and IVA) who had undergone extraperitoneal lymph-node sampling of the para-aortic lymph nodes as well as intraperitoneal exploration and intraperitoneal washings. Women with invasion of the intraperitoneal or para-aortic nodes were excluded from the trial. 386 patients were recruited between 1986 and 1990. The two regimens were:
• •
Regimen I, which consisted of external beam radiation to the pelvis, intracavitary radiation, and cisplatin 50 mg/m 2 on days 1 and 29 and 5-FU 1000 mg/m2 per day on days 2–5 and 30–33 during the external beam radiotherapy (177 patients). Regimen II, which consisted of external beam radiation to the pelvis, intracavitary radiation, and hydroxyurea 80 mg/kg twice a week (191 patients).
Radiotherapy was modified according to the stage of disease. After a median follow-up of 8·4 years, the 3-year survival rate for women on the chemotherapy was 67%, compared with 57% for women on hydroxyurea. The GOG protocol 1233 included patients with bulky (greater than 4 cm) stage IB carcinoma of the cervix with negative pelvic and para-aortic lymph-nodes as determined radiographically, surgico-pathologically, or by both methods. 368 patients were recruited between 1992 and 1997. The regimens were:
• •
Regimen I, which consisted of external beam radiation to the pelvis, intracavitary radiation, and cisplatin 40 mg/m2 weekly for 6 weeks, followed by extrafascial hysterectomy (183 patients). Regimen II consisted of external beam radiation to the pelvis and intracavitary radiation, followed by extrafascial hysterectomy (186 patients).
Radiotherapy was standard. After a median follow-up of 35·7 months, the survival rate for women treated with
THE LANCET • Vol 353 • April 17, 1999
cisplatin was 83%, compared with 74% treated with radiotherapy alone. The findings of the five studies are clearly of great benefit to the large number of patients who continue to present with advanced cancer of the cervix. There is also demonstrable benefit for those patients who, despite small tumours, have metastases, especially to the pelvic nodes. Discussion at the San Francisco meeting also suggested that there may be advantages for patients with adenocarcinoma of the cervix. How cisplatin interacts with radiation is uncertain, but one suggestion is that the two act synergistically, perhaps with cisplatin preventing DNA repair during radiotherapy and damaging the reproductive ability of the cancer cells. What is unclear from the papers is whether the advantage of chemotherapy plus radiation was due solely to the combination or whether the maintenance of a high haemoglobin concentration contributed to the treatment. Grogan and colleagues4 have shown the beneficial effect of a high haemoglobin concentrations (>120 g/L) before and during radiation treatment. There is no information on correction of anaemia in any of the five studies. Haematological adverse effects were commoner in the combination-therapy than in the radiation-alone groups. Correction of these adverse effects may have resulted in higher overall haemoglobin concentrations in the combination-therapy groups. It is clearly important to extend the period of review beyond the 3 years taken by these studies. However, since cancer of the cervix tends to recur in the first 2 years of review, the longer-term recurrence pattern is unlikely to be significantly different from that with traditional treatments. There are two important practical implications of the findings. Those responsible for the provision and delivery of cancer services will have to find the extra resources for costs of the chemotherapeutic agents and for hospital stay. In three of the five papers, 12-16 days’ stay was required for the infusions of 5 FU, although this can be mitigated using ambulatory delivery systems. The other important implication is whether there is justification for continuing with existing trials, such as those run by the UK Medical Research Council and the European Organisation on Research and Treatment of Cancer, in which one of the comparison groups is receiving radiation alone. A final point is that all these five large studies have come from North America, which raises questions about the pace at which similar European studies are implemented and completed. John Monaghan Depar tment of Gynaecological Oncology, Queen Elizabeth Hospital, Gateshead, Tyne and Wear, NE9 6SX, UK 1
Rose PG, Bundy BN, Watkins EB, et al. Concurrent cisplatin-based radiotherapy and chemotherapy for locally advanced cervical cancer. N Engl J Med 1999; 3 4 0 : 1144–53. 2 Morris M Eifel PJ, Lu J, et al. Pelvic radiation with concurrent chemotherapy compared with pelvic and para-aortic radiation for high-risk cervical cancer. N Engl J Med 1999; 3 4 0 : 1137–43. 3 Keys HM Bundy BN, Stehman FB, et al. C i s p l at i n ,r a d i at i o n ,a n d adjuvant hsyterectomy compared with radiation and adjuvant hysterectomy for bulky stage 1b cervical carcinoma. N Engl J Med 1999; 3 4 0 : 1154–61. 4 Grogan M, Thomas GM, Melamed I, et al. The importance of maintaining high hemoglobin levels during radiation treatment of carcinoma of the cervix. Presented at the 30th Annual meeting of the Society for Gynecological Oncology in San Francisco, M a r c h ,1 9 9 9 .
THE LANCET • Vol 353 • April 17, 1999
Lessons from the Di Bella affair See page 1310 Most Italian oncologists will probably remember 1998 as their annus horribilis. Although now and then unsubstantiated claims of a treatment for cancer are made world wide, to the best of our knowledge, never before, anywhere, has so much turmoil been wrought by one therapeutic claim as the Di Bella affair did in Italy.1,2 It even caused the medical profession to abandon the principle of evidence-based medicine. What exactly happened and why it could have happened are not easy questions to answer. Di Bella was an 85-year-old retired professor of physiology who had for years been treating cancer patients with a mixture that included somatostatin, melatonin, vitamins, and small amounts of cyclophosphamide. This mixture purportedly induced remission of advanced cancer without the serious sideeffects of conventional antineoplastic drug regimens. Di Bella claimed that he had cured thousands of patients with this therapy, which, however, had not been tested in animals or in clinical studies. Not even anecdotal reports of success had been published in medical journals. At the end of 1997, Di Bella was catapulted, probably unwillingly, into the limelight. His patients, who had formed an association, tried to obtain reimbursement for this form of therapy, which could cost up to US$5000 per patient per month, from the national health system. The health authorities did not approve the reimbursement, and were astonished when the courts ruled that the government should pay for this treatment, on the grounds of “freedom of cure”. The most determined of these outspoken judges was depicted by the press as a modern hero fighting against the interests of the medical establishment and pharmaceutical industry. The media gave the issue unprecedented coverage. Supporters held rallies in Rome. Politicians promptly jumped onto the bandwagon, with the right-wing opposition in favour of Di Bella, and the centre-left government supporting Health Minister Rosy Bindi.3 During this time the medical community was set aside: those members who tried to foster scientific reasoning were ridiculed as patients’ enemies.4 Others sheepishly agreed to collaborate with Di Bella and his entourage in launching the first clinical trials of this regimen. The trials had been ordered by parliamentary decree and funded by a government usually deaf to the needs of researchers. What is left, 1 year later? Ten hastily conceived clinical studies whose design has been criticised by several experts have shown that the treatment does not block progression of cancer and is not as free of side-effects as had been claimed.5 The bill for the trials and for the somatostatin that judges had ruled should be prescribed for some patients has reached $20 million. But worse, the hopes of patients have been shattered. And perhaps some patients might have abandoned traditional therapy for Di Bella’s even before they entered the terminal phase of their disease. Why did all this happen? The results of a survey of patients conducted by Italian oncologists that are reported in this issue of The Lancet offer some insights. There is overwhelming evidence that the media contributed most to the affair. This finding is not surprising since the matter had all the ingredients of a perfect cover story: a life-threatening disease; an old 1289