KOLKATA, India - They lie in long rows of beds in a hospital women's ward - weak and forlorn as they battle cervical cancer.
Theplight of such women inspired a team of doctors from Louisville, Ky.,and Kolkata in 2007 to explore a new treatment for the potentiallydeadly disease.
But that team is now reaching a disappointingconclusion: An experimental radiation and immunotherapy regimen appearsless effective against advanced cancer than the traditional Westerntreatment, which remains out of reach for many poor, Indian women.
"Thedata show that chemo and radiation, which is the consensus way to treatadvanced cervical cancer in the States," seems to work better than theexperimental treatment among the Indian patients, said University ofLouisville researcher Dr. A. Bennett Jenson.
"I was (initially) under the notion it was as effective as chemo. And I don't think it is," said Jenson, of the James Graham Brown Cancer Center."I'm disappointed. It wasn't the answer we wanted. ... (But)seventy-five percent of clinical trials don't yield the results you wantthem to yield."
Initial results from the five-year study at India's Chittaranjan National Cancer Institutelooked promising, with the experimental regimen accounting for slightlymore recoveries than the conventional treatment two years into thestudy.
Hopes were high that the experimental regimen might helpimpoverished women around the world, including in rural, low-incomeareas.
But now, nearly a year after the last woman enrolled, the results have become discouraging.
Of103 women in the experimental arm of the trial, 42 are free of disease,six are alive with recurrent disease, and 55 have died. Of the 106women in the control arm - those treated with conventional treatment -61 are free of disease, 10 are alive with a recurrence, and 35 havedied.
Cervical cancer at late stages is uniformly fatal if leftuntreated, and even with chemo-radiation treatment, the five-yearsurvival rate is 50 percent or less.
As of now, "the study showsthe immunotherapy does not have any advantage over the conventionalchemo-radiation," said Dr. Partha Basu, head of the department ofgynecological oncology at Chittaranjan and principal investigator in thestudy.
"I wish the immunotherapy arm would have done a littlebetter. I really wanted it to work better for the patients," saidDebapriya Banerjee, clinical trials manager for gynecological oncologyat Chittaranjan.
Basustressed that they are still following up with patients, and questionsremain - including some that raise doubt about whether the difference indeaths is statistically significant and will hold up over the longterm.
For example, he said, more women who joined the study earlywere placed into the experimental arm, meaning they've had more time forrelapses and death to occur than those in the control arm. Also, hesaid, it's been difficult to determine what has happened to everyparticipant, since some women never returned from remote villages forfollow-up.
No matter what they find, Basu and Jenson said there'san undeniable upside to the study: a commitment to providing morepatients with chemotherapy.
Before 2007, Basu said mostChittaranjan patients with advanced cervical cancer received onlyradiation because there weren't enough hospital beds for chemotherapy.
"Aswe started providing chemotherapy through the trial, more patientsstarted demanding chemotherapy," Basu said, resulting in a daychemotherapy center opening at the hospital.
Deadly in India
Basu and Jenson said the study also underscores the need for cervical cancer prevention.
Jenson, one of the inventors of the Gardasilshots that protect against the human papillomavirus that causes mostcervical cancer, is now working on an inexpensive version for thedeveloping world that would cost as little as $3.
Basu, meanwhile, has become more involved in improving cervicalcancer detection and awareness, partly through "screening camps" inremote areas. He recently operated on 50-year-old Neburjan Bibi, wholives in a village seven hours from Kolkata and whose early-stage cancerwas discovered at a screening camp.
"The chance of recurrence is very low," Basu said, touching Bibi's arm as she lay in a hospital bed. "She'll be OK."
Cervicalcancer is both preventable and curable at early stages. Yet it remainsthe biggest cancer killer of Indian women, striking 130,000 each yearand killing 75,000.
Poverty, combined with a lack of cervicalcancer screening and access to health care, means the vast majority ofcases are diagnosed late.
In the United States, women areroutinely screened for cervical cancer with Pap smears and often haveprecancerous lesions removed before they turn into cancer. About 12,000American women are diagnosed with cervical cancer each year, and about4,000 die.
A study released in 2009 by the World HealthOrganization found that Indian women have a lower rate of infection fromhuman papillomavirus, or HPV, than Americans.
But Indians facerisk factors Americans don't. For example, village women often marry intheir teens and get pregnant soon afterward, which suppresses immunesystems weakened by malnutrition and increases the likelihood that anHPV infection will progress to cancer.
And once cancer strikes,getting care can be difficult for the poor, rural women who are hardesthit. There are fewer than a third as many hospital beds per person inIndia as in the United States, and many rural villages are hours fromhospitals.
A new approach
The Louisville-Kolkatatrial, which began enrolling women in the fall of 2007, randomlyassigned participants with advanced cancer to the chemotherapy-radiationcontrol group or the study group.
Those in the study group gotradiation plus immunotherapy consisting of pills of retinoic acid, aderivative of Vitamin A; and shots of the protein interferon-alpha. Whenrecruiting subjects, doctors said they emphasized the experimentalnature of the regimen.
This wasn't the first trial to test thetreatment; it had shown promise in three of four pilot studieselsewhere. But researchers said it is the first time it was tested inuntreated women with cancer as advanced as the majority of cases inIndia.
Doctors said both treatments cost about the same. Treatmentmedications and hospital care are free to participants, and Jensonpersonally donated $5,000 for other medicines that patients in the trialmight need.
Basu said there were fewer side effects among womenin the experimental arm of the trial. And two years into the trial, 69of the 114 who had enrolled were disease-free, with the experimental armaccounting for a greater number of disease-free patients than thecontrol arm.
But over the next few years, cancer returned amongmore patients taking the immunotherapy treatment than in those receivingtraditional chemotherapy.
As chiefcoordinator of the Cervical Cancer Prevention & Control Initiative,a partnership among Chittaranjan, the medical testing company Qiagen ofGermany, and the ministry of health in West Bengal, the state whereKolkata is located, Basu said he is focused now on trying to head offcervical cancer before it starts.
His efforts include working withseveral nongovernmental organizations, training field workers to raiseawareness in their communities and using a Qiagen HPV test to screen forpre-cancers among women in remote areas.
Meanwhile, research on a new HPV vaccine continues in Louisville.
Jensonand colleagues are looking at using Kentucky tobacco to develop theinexpensive vaccine and hope to have a federally approvable versionwithin two years.
"What we want more than anything is to deliveran economically viable vaccine that can be used in places like India,"Jenson said. "If we are successful with this, Partha would be the firstperson to vaccinate women. And I would hope to go there to see the firstperson be vaccinated."